3 National Guidelines On DRTB 2019 PDF

2019
NATIONAL GUIDELINES ON
Drug Resistant Tuberculosis

Management
END
TB
Government of Nepal
Ministry of Health and Population
Department of Health Services
National Tuberculosis Centre
Thimi, Bhakatapur
TABLE OF CONTENTS
PREFACE 3
1. INTRODUCTION 1
1.1 Background 1
1.2 Key definitions 4
1.3 Organisation of DR-TB control in Nepal 7
1.4 Roles and responsibility 7
2. DIAGNOSIS OF DR-TB 11
2.1 Identification of presumptive DR-TB 11
2.2 Management of presumptive DR-TB 11
2.3 Diagnostic tests 12
2.4 Diagnosis of extrapulmonary DR-TB in the absence of DST 20
2.5 Diagnostic pathway 20
2.6 Diagnosis of DR-TB in special groups 22
3. REGISTRATION CATEGORY OF DR-TB 24
4. TREATMENT OF DR-TB 25
4.1 Patient Education 25
4.2. Drugs used to treat DR TB and Principles of Treatment 27
4.3. RR/MDR-TB treatment regimens 32
4.4 Shorter Standardized Treatment Regimen (SSTR) 36
4.5 Treatment of INHr TB 42
4.6 Treatment of MDR-TB in special situations 44
4.7 Adjuvant therapies and interventions 57
4.8 Surgery 57
5. MANAGEMENT AND MONITORING ASPECTS OF DR-TB 58

5.1 Preparation prior to starting second-line treatment 59
5.2 Treatment administration 60
5.3 Organization of the treatment 61
5.4 Drug Intake 62
5.5 Follow-up monitoring investigations during and after completion of treatment 63
5.6 Monitoring of treatment progress 66
5.7 Follow-up after the end of treatment 67
5.8 Palliative care 67
5.9 Management of contacts of MDR-TB patients 68
6. ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (ADSM) 69

6.1 Management of AEs or ADRs 72
6.2 Causality Assessment of the Serious Adverse Event (SAEs) 90
7. INFECTION CONTROL 91
7.1 General principles of infection control 91
7.2 Infection control at TB consultation room 94
7.3 DR-TB Patient isolation room 94
7.4 Infection control at home 95
7.5 Health worker and Infection Control 95
8. MONITORING AND EVALUATION FOR TB CONTROL PROGRAM 96

8.1 Recording and reporting of DR-TB programme 96
8.2 Monitoring of DR-TB Case Detection and Treatment Activities 100
ANNEXES 103-173
N AT I O N A L G U I D E L I N E S O N D R U G R E S I S TA N T T U B E R C U LO S I S M A N A G E M E N T vii
ACKNOWLEDGEMENT
The National TB Centre director (Dr. Sagar Rajbhandari) expresses my sincere gratitude to all the
authors and reviewers of this guideline particularly to the World Health Organization and all
the others who contributed in coming up with this comprehensive National Tuberculosis (TB)
Management Guideline 2019
1. Dr. Bhim Singh Tinkari, (Previous NTC Director)

2. Dr. Ashesh Dhungana, Chief Consultant Chest Physician, NTC
3. Dr. Sharad Kumar Sharma, Chief - SMEAR section, NTC
4. Mr. Anil Thapa, (Previous Chief - SMEAR section, NTC)
5. Dr. Naveen Prakash Shah, Consultant Chest Physician, NTC
6. Mr. Gokarna Raj Ghimire, Laboratory In-charge, NTC
7. Mr. Pushpa Raj Joshi, Statistical officer, NTC
8. Ms. Basundhara Sharma, Senior Public Health Officer, NTC
9. Ms. Meera Hada, Medical Technologist, NTC
10. Prof. Dr. Brajendra Srivastav, NAINS College of Medicine
11. Dr. Suvesh Kumar Shrestha, Technical Specialist-TB, SCI
12. Dr. Ashish Shrestha, National Consultant-TB, WHO
13. Dr. Pramod Raj Bhattarai, Damien Foundation
14. Dr. Bhawana Shrestha, Project Manager, NATA/GENETUP
15. Dr. Praveen Sanker, Laboratory Consultant, SCI-FIND
16. Mr. Rajendra Basnet, SCI/NTC
17. Mr. Ratna Bahadur Bhattarai, Monitoring and Evaluation Specialist- SCI/NTC
18. Mr. Gokul Mishra, Liaison Officer, NTC/LSTM
19. Mr. Bhagawan Maharjan, Microbiologist, GENETUP
20. Mr. Nilaramba Adhikari, SCI/NTC
21. Mr. Lok Raj Joshi, SCI/NTC
22. Mr. Naval Kishor Shrestha, SCI/NTC
23. Mr. Chitra Jung Shahi, DTLO, NTC
24. Mr. Krishna Adhikari, Lab Technician Officer, NTC
25. Ms. Kamala Devi Wagle, Public Health Nurse Officer, NTC
26. Ms. Tara Sharma, NTC
27. Ms. Anju Basnet, NTC
28. Mr. Saroj Roy, NTC
29. Mr. Brij Ranjan Yadav, NTC
30. Mr. Gopi Prasad Rupakheti, Kharidar/Supervisor, NTC
31. Dr. Mohammed Asif, Consultant, rGLC Member
32. Dr. Medea Gegia, Technical Officer Programme, WHO-HQ
33. Dr. Lungten Z. Wangchuk, Scientist- Team -Lead, CDS, WHO, Nepal
N AT I O N A L G U I D E L I N E S O N D R U G R E S I S TA N T T U B E R C U LO S I S M A N A G E M E N T ix
THE MAIN CHANGES IN THE WHO 2019

RECOMMENDATIONS
• It is recommended that any patient – child or adult – with RR-TB in whom isoniazid resistance
is absent or unknown be treated with a recommended MDR-TB regimen, either a longer MDR-
TB regimen to which isoniazid may be added or a standardized shorter MDR-TB regimen
• Shared based decision making between doctor and patient for choice of treatment either
longer or shorter regimens
• A package of treatment adherence interventions may be offered to patients on TB treatment
in conjunction with the selection of a suitable treatment administration option
• In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, ,
treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for
a duration of 6 months. it is not recommended to add injactables.
• Regrouping of medicine (A, B & C) based on most recent available evidence and all oral
longer (Inj free) regimen is recommended
• All three Group A agents and at least one Group B agent should be included to ensure that
treatment should start with at least four TB agents likely to be effective and that at least
three effective agents are included for the rest of treatment period after the Bdq is stopped
by month 6
• There is strong recommendation to use all Group A drugs(Mfx/Lfx, Bdq,Lzd) in longer
regimen, until and unless there is contraindication to include in regimen.
• Most patients can be treated with 18 months duration by using Longer Regimen
• Kanamycin and capreomycin are no longer to be the part of treatment of RR/MDR-TB
regimens. Only Amikacin or Streptomycin is to be used under certain conditions
• Bedaquiline should be included in longer MDR-TB regimens for patients aged 18 years or
more
• Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6-17 years
• Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on
longer regimens
• It is strongly recommended that Clavulanic acid should not be included in the treatment of
MDR/RR-TB patients on longer regimen, only in combination use with Imipenem
• Intensive phase of 6-7 months will only be considered if Injectables (Am, S) are part of
regimen
• In MDR/RR-TB patients on longer regimens, a total treatment duration of 18-20 months is
suggested for most patients
• Regimens without an injectable agent are considered not to have an intensive phase
• On longer regimens, a treatment duration of 15 to 17 months after culture conversion is
suggested for most patients
• Any modifications on standard shorter regimen should be conducted under operational
research conditions
• aDSM is applicable to all RR TB patients
• It is desirable for sputum culture to be repeated at monthly intervals.
CHAPTER 1
INTRODUCTION
1.1 BACKGROUND
National TB programme is moving forward with the vision of TB Free Nepal by 2050 in accordance
with the National Health Policy 2014 and under the strategic direction of the worldwide initiative
to end TB – the End TB Strategy.
The goal of National Strategic Plan 2016-21 is to decrease the TB Incidence rate by 20%, from
2015 to 2021 i.e. to identify additional 20,000 new TB cases by next 5 years.
The overall objectives of NSP 2016-21 are as follows:

Objective 1: To increase case notification through improved health facility-based diagnosis;
increase diagnosis among children (from 6% at baseline, to 10% of total cases by 2021);
examination of household contacts and expanded diagnosis among vulnerable groups within
the health service, such as PLHIV (from 179 cases at baseline to over 1,100 cases in 2020/21), and
those with diabetes mellitus (DM).
Objective 2: To maintain the treatment success rate of 90% for all forms of TB (except drug
resistant TB) by 2021
Objective 3: To provide DR TB diagnose services to 50% of the presumptive MDR TB patients

by 2018 and 100% by 2021 and to successfully treat at least 75% of those diagnosed.
Objective 4: To expand case finding by engaging providers for TB care from the public sector
(beyond MoH), medical colleges, NGO sector, and private sector through results based financing
(PPM) schemes, with formal engagements (signed MoUs) to notify TB cases
Objective 5: To gradually scale up Community System Strengthening Programme (CSS) at 60% of

the local administrative units by 2018 and to 100% of the administrative units by 2021. It will help
in creating a patient friendly ambience in the health facilities, advocacy for TB patients regarding
their rights which will, in turn, contribute to the diagnosis and management of TB cases
Objective 6: To contribute to health system strengthening through HR management and

capacity development, financial management, infrastructure, procurement and supply
management in TB
Objective 7: To develop comprehensive Monitoring and Evalutaion system
Objective 8: To develop plans so that NTP can function even at times of crises like natural
disasters or public health emergencies.
2 N AT I O N A L G U I D E L I N E S O N D R U G R E S I S TA N T T U B E R C U LO S I S M A N A G E M E N T
1.1.1 Multi Drug Resistant Tuberculosis (MDRTB) in the world

According to the most recent WHO Global Tuberculosis Report (2018) the total number of new
(incident) TB cases worldwide in 2017 was estimated at 10.0 million. Among these, 9% were HIV+.
Worldwide in 2017, 6.4 million new cases of TB were officially notified to national authorities and
then reported to the WHO. The number of incident RR/MDR-TB cases in 2017 was estimated at
558 000. Globally, 160,684 cases of MDR/RR-TB were detected and notified in 2017 (a small increase
from 153 119 in 2016). Of these, a total of 139,114 people (87%) were enrolled on treatment with a
second-line regimen, up from 129,689 in 2016 but still only 25% of the estimated 558,000 people
who developed MDR/RR-TB in 2017. China and India alone accounted for 40% of the global gap;
these and eight other countries 10 accounted for 75%. Treatment success remains low, at 55%
globally. Examples of high burden countries in which better treatment success rates are being
achieved include Bangladesh, Ethiopia, Kazakhstan, Myanmar and Viet Nam (all of which have
rates above 70%). Closing gaps in detection and treatment requires much higher coverage of
drug susceptibility testing among people diagnosed with TB, reducing under diagnosis of TB,
models of care that make it easier to access and continue treatment, new diagnostics, and new
medicines and treatment regimens with higher efficacy and better safety.
FIGURE 1.1: DR-TB burden
1.1.2 MDR in SEAR countries

Besides the high rate of relapse, the emergence of drug-resistant tuberculosis poses a major
challenge to ending TB with traditional therapeutics. In SEAR, less than half the MDR-TB cases
(49%) were cured. In SEAR, the estimated incidence of MDR/RR-TB was 200 000, with India alone
accounting for 130 000.
N AT I O N A L G U I D E L I N E S O N D R U G R E S I S TA N T T U B E R C U LO S I S M A N A G E M E N T 3
FIGURE 1.2: Ranking of SEAR countries by MDR-TB incidence, 2015
1.1.3 MDR-TB in Nepal

In Nepal, the burden of DR TB is not as high as the regional or global burden. There are estimated
around 1500 cases of DR TB annually. However, 350 to 450 MDR TB cases are notified annually.
Four hundred twenty cases were notified in 2017/18. The lack of availability of and access to an
early screening of presumptive TB cases with Rapid DST may still be the main reasons for this
stagnation of DR TB cases in the country. The proportion of new cases with multidrug-resistant TB
(MDR-TB) was 2.2% among new cases and 15.4% among retreatment cases based on DRS survey
carried out in 2011/12. In 2016/17, a total of 257 RR/MDR TB, 91 Pre-XDR TB and 18 XDR TB were
enrolled for treatment. Treatment Success Rate (TSR) of RR/MDR patients was 71%. However, the
TSR of Pre-XDR TB is 58% and XDR TB is 61%, which were marginally lower than the RR/MDR
TB cases. The routine surveillance showed a much higher proportion of drug-resistant pattern
among second-line drugs used for the treatment of MDR patients in Nepal. The resistance to
fluoroquinolones (FQ), SLI and both FQ and SLI were 39.3%, 3%, and 4% respectively, altogether
there was 46.3% resistant to SLD among MDR patients. In other words, among all initially
diagnosed as RR-MTB/MDR TB 42.3% of MDR patients may require Pre-XDR treatment similarly
4% may require XDR treatment (Source: NTP Annual Report-2018)
Five drug resistance surveys were conducted between 1996/1997 and 2011/2012:
TABLE 1.1 Findings of the drug resistance surveys conducted in Nepal between 1996 and 2011
Year MDR-TB in new TB patients MDR-TB in retreatment TB patients
1996/1997 1.1% Not available
1998/1999 3.7% 12.5%
2001/2002 1.3% 20.5%
2006/2007 2.9% 11.7%
2010/2011 2.2% 15.4%
An XDR TB survey conducted by GENETUP in 2012 showed that among MDR-TB patients, 28%
had Pre-XDR TB and 8% had XDR TB.
Based on the findings of the last survey, the burden of MDR-TB for 2016 was calculated:
TABLE 1.2: Estimates of MDR-TB disease burden in Nepal for 2016

% of MDR-TB cases among new TB cases 2.2 (1.3–3.8)
% of MDR-TB cases among retreatment TB cases 15.4 (10–23)
Number of MDR-TB cases among notified new TB cases 540 (320–930)
Number of MDR-TB cases among notified retreatment TB cases 620 (410–920)
This means that there are still a huge number of patients that the programme needs to find and
cure. Although Nepal can be considered a low burden drug resistance country, the cases of MDR-
TB are increasing every year.
1.2 KEY DEFINITIONS

• Drug-susceptibility testing (DST): refers to in-vitro testing using either phenotypic methods to
determine susceptibility or molecular techniques to detect resistance-conferring mutations
to a medicine
• Poly-resistance: resistance to more than one first-line drug (other than both isoniazid and
rifampicin).
• Multidrug resistance (MDR TB): resistance to at least both isoniazid and rifampicin .
• Extensive drug resistance (XDR): resistance to the fluoroquinolones (at least one) and
the second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to
multidrug resistance.
• Isoniazid-resistant TB (Hr-TB): resistance to isoniazid only and susceptibility to rifampicin has
been confirmed.
• Rifampicin resistance (RR-TB): resistance to rifampicin detected using phenotypic or genotypic
methods, with or without resistance to other anti-TB drugs. It includes any resistance to
rifampicin, in the form of mono-resistance, poly-resistance, MDR or XDR.
• Pre-XDR: Resistance to either Fluroquinolone or SLD but not to both in addition to MDR
• Extent or severity of disease: in patients older than 14 years, adolescents and adults usually
the severity of diseases is defined by the presence of cavities or bilateral disease on chest
radiography or smear-positivity and grading. While, in children <15 years, severe disease
is usually defined by the presence of cavities or bilateral disease on chest radiography or
extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated
mediastinal mass without compression). In children the occurrence of advanced malnutrition
(defined by syndrome or by metrics) or advanced immunosuppression or positive TB
bacteriology (smear, Xpert MTB/RIF, culture) may also be considered when determining
disease severity (WHO 2018)
• Individualized treatment: Each regimen is designed based on the patient’s past history of TB
treatment and individual DST results. NTP, Nepal has adopted combination of standardized
and individualized approaches.
• Longer MDR-TB regimens: are treatments for MDR/RR-TB which last minimum 18 months or
more and which may be standardized or individualized. These regimens are usually designed
to include a minimum number of second-line TB medicines considered to be effective based
on patient history or drug-resistance patterns. The term “conventional” was previously
used to refer to such regimens but was discontinued in 2016 when WHO first issued a
recommendation for the use of a shorter MDR-TB regimen (WHO 2018)
• Shorter MDR-TB regimen: refers to a course of treatment for MDR/RR-TB lasting 9–12 months,
which is largely standardized, and whose composition and duration follows closely the one
for which there is documented evidence from different settings (WHO 2018)
• Serious adverse events (SAEs): are those adverse events (AE) classified as Grade 3 (severe),
Grade 4 (life-threatening or disabling) or Grade 5 (death related to AE), or which led to the
medicine being stopped permanently (WHO 2018)
• Definitions of Conversion & Reversion: The terms “conversion” and “reversion” of culture as
used here are defined as follows:
• Conversion (to negative): culture is considered to have converted to negative when two
consecutive cultures, taken at least 30 days apart, are found to be negative. In such a case,
the specimen collection date of the first negative culture is used as the date of conversion.
• Reversion (to positive): culture is considered to have reverted to positive when, after an initial
conversion, two consecutive cultures, taken at least 30 days apart, are found to be positive.
• For the purpose of defining Treatment failed, reversion is considered only when it occurs in
the continuation phase.
• The intensive (or injectable) phase: initial part of a shorter regimen for treating multidrug- or
rifampicin-resistant tuberculosis (MDR/RR-TB). During this phase, an injectable agent is used.
Regimens without an injectable agent are considered not to have an intensive phase.
Drug resistance is the result of inadequate therapy

M. tuberculosis resistance to anti-tuberculosis drugs is caused by spontaneous chromosomal
mutations. The proportion of wild-type resistant mutants in an untreated M. tuberculosis
population is usually very small. Treatment with anti-tuberculosis drugs imposes selection
pressure on M. tuberculosis populations, resulting in a reduction in drug-susceptible bacilli, the
advantageous reproduction of drug-resistant mutants and the emergence of drug resistance:
this is acquired resistance, implying that resistance emerges during anti-tuberculosis treatment.
Primary resistance refers to patients infected with M. tuberculosis that is resistant to anti-
tuberculosis drugs before treatment. With a few exceptions, a mutation causes resistance to only
one drug or group of drugs. Resistance to two or more drugs is caused by sequential mutations
in different genes. (The UNION 2018)
A very small portion (around 1 in a million or 1/106) of the tuberculosis bacilli are spontaneously
resistant to INH (these bacilli are called: drug resistant mutants). A TB patient with smear positive
pulmonary TB will be infected with 108 to 109 bacilli. If a TB patient is treated with only INH, most
bacilli will be killed, and the patient may improve clinically and bacteriologically, but 1 out of
every million bacilli will not be killed. These resistant bacilli will continue to multiply, and soon
the patient will again be infected with 108 bacilli, but this time all bacilli will be resistant to H. This
phenomenon is called: selection of drug-resistant mutants.
Additionally, even smaller, portion (around 1 in 100 million or 1/108) of the bacilli are
spontaneously resistant to R. If a patient is treated with only R, almost all bacilli will be killed, but
those few that are resistant to R will not be killed and will multiply. The result is a patient with TB
that is resistant to R.
The main reason why drug resistance develops is monotherapy, giving only 1 drug a time. MDR
develops as a result of sequential monotherapy: first, the bacilli become resistant to 1 drug,
usually INH (this is called mono-resistance). Next, the bacilli develop additional resistance to R.
This process can continue for one drug after the other. If the bacilli become resistant not only to R
and H, but also to the fluoroquinolones and the injectable second-line drugs (such as kanamycin),
this is called extensive drug-resistant TB or XDR-TB
TABLE 1.3: Causes of Resistance
Health care providers: Drugs: inadequate supply/ Patients: inadequate drug intake or
Inappropriate treatment quality treatment response
Inappropriate guidelines Poor quality Lack of information
Non-adherence to Unavailability of some drugs Lack of means to adhere to treatment
guidelines (stock outs) (transportation, food, etc.)
Absence of guidelines Poor storage conditions Social barriers
Poor training Inappropriate dosage or Adverse events (AEs)
combination
Lack of treatment Poor regulation of medicines Inadequate directly observed
monitoring treatment (DOT)
Poor management of Poor absorption of drugs
adverse drug reactions
Poorly organized or funded Substance abuse/dependence
TB control programs
Source (Companion Handbook to the WHO Guidelines for the programmatic management of drug-resistant
tuberculosis. WHO/HTM/TB/2014.11. Geneva, Switzerland: World Health Organization, 2014)
How to prevent drug resistance?

Resistance to tuberculosis (TB) drugs is a formidable obstacle to effective TB care and prevention
globally. Multidrug-resistant TB (MDR-TB) is multifactorial and fueled by improper treatment of
patients, poor management of supply and quality of drugs, and airborne transmission of bacteria
in public places. Case management becomes difficult and the challenge is compounded by
catastrophic economic and social costs that patients incur while seeking care and on treatment.
There are five principal ways to prevent drug-resistant TB:

1. Early detection and high-quality treatment of drug-susceptible TB.
2. Early detection and high-quality treatment of drug-resistant TB.
3. Effective implementation of infection control measures.
4. Strengthening and regulation of health systems.
5. Addressing underlying risk factors and social determinants.
Source: Companion Handbook to the WHO Guidelines for the Programmematic Management of Drug Resistant
Tuberculosis-2014
1.3 ORGANISATION OF DR-TB CONTROL IN NEPAL

The DRTB programmeme is managed in following ways in Nepal:
• Ministry of Health and Population approves the policies, strategies and allocates the budgets
t0the programme
• National TB Centre (NTC) approves, recommends, strategies and guidelines and manage
necessary central budget for the programme
• Technical Working Groups (TWG) at National TB Programmeme (NTP) provides inputs and
technical advice on policies, strategies and guidelines, plans for DRTB management and
provides technical inputs to the partners and stakeholders.
• DR TB Treatment section at NTC, manages, monitors and evaluates of the DRTB activities and
provide inputs to the DRTB programmeme
• Dedicated human resources for DR TB Treatment Section will manage under NTC and support
to manage the Procurement and Supplies of logistics.
• Provincial Health Directorate supports to implement the DRTB activities; manage to supplies
anti-TB drugs and other logistics, reporting, monitoring, supervision and evaluation of the
DRTB.
• Treatment and Sub-centre will provide treatment, care and support, refer for management of
adverse drug reaction to the DRTB patients, record and report, manage sputum transport for
culture and DST and screening of presumptive DRTB cases.
1.4 ROLES AND RESPONSIBILITY

A. National Level (NTP)
• Develop the policies, strategies and guideline for DRTB
• Support planning, coordination, monitoring and evaluation of TB control activities with
concerned stakeholders.
• Support monitoring and supervision of all personnel involved in tuberculosis work.
• Manage and advise on procurement and distribution of TB drugs and supplies.
• Prepare forms, registers, health education and teaching materials for DRTB
• Compile reports on case-finding and treatment with feedback to lower levels
• Monitor and provide supportive supervision to the provincial level
• Advise and carry out capacity enhancement activities at all levels on DRTB management
• Coordinate with partner agencies.
• Manage budget for implementation of the programme.
• Promote TB/HIV Collaboration and MDR TB management.
• Promote research and development in DRTB
B. Provincial Health Directorate (PHD) Office

• Develop plans and strategies for DRTB programme in line with NTP
• Carry out capacity enhancement activities at provincial and local levels health care workers
on DRTB management
• Implement, coordinate and supervise tuberculosis control activities.
• Review, validate, compile and send quarterly reports on case-finding and treatment to NTP
on time (end of the month following the quarter that just ended)
• Coordinate with partner agencies at the province level
• Request, receive, distribute and manage TB drugs, diagnostics and other supplies for the
diagnosis and management of TB
• Monitor and provide supportive supervision to the provincial level
• Establish provincial TB, TB /HIV and PMDT committees and coordinate implementation of
their respective activities in their provinces
• Provide feedback to the Heatlh facilities on the quality of the reports
• Conduct and ensure quality assurance for sputum microscopy services (EQA) for the facilities
• Coordinate with partners and mobilise community based organisations to support
implementation of DR-TB activities
• Monitor, evaluate and review DR-TB activities in their respective provinces
District Level
• Develop the plan at the district level
• Manage, organise and facilitating TB training to health workers
• Monitoring, supervision and evaluation of the programmeme
• Implement the programmeme following the national policies and guideline
• Manage drugs, reagents and required logistics for the programmeme
• Coordinate with different stakeholders at district level
• Organise awareness and education programmeme to increase knowledge on TB in the
community
• Update recording and reporting forms and registers and submit timely
C. Local Level (Palikas)

• Manage, organise and facilitating DRTB training to health workers
• Organise supportive supervision at the treatment and sub-centre to enhance the performance
of the programmeme
• Organise quarterly (4 monthly) workshop to review the performance of treatment and
diagnostic centre
• Coordinate with different stakeholders at palikas
• Support to implement the programmeme following the national policies and guidelines
• Manage drugs, reagents and required logistics for the programmeme

• Organise awareness and education programmeme to increase knowledge on DRTB in the
community
• Enhance capacity of health workers on DRTB management
D. Treatment/Sub Centre Levels

• Provide directly observed Treatment (DOT) to all DRTB patients
• Monitor TB treatment through follow up sputum examinations and reviews.
• Trace and retrieve lost to follow up and or patients missing treatment or poor compliant
patients.
• Complete and update all recording and reporting forms including TB treatment cards and
registers and submit quarterly reports on time
• Provide health education and counseling to the patients and to the community.
• Educate community on DR-TB.
• Cooperate with the microscopy/diagnostic services, for examination of sputum.
• Coordinate referral of DR-TB patients from hospitals to peripheral centres.
• Promote and implement TB/HIV activities and referral of presumptive MDR TB
• Organise contact tracing activities in the community
• Manage necessary drugs, reagent and necessary logistics for the programmeme
• Update patients’ records and ensure submission on time
E. DOT Providers
• Provide daily DOT to the patient and maintain dublicate treatment card
• Discuss the condition and the treatment being given to the patient with patients and health
staff;
• Recognize and managing adverse effects of medications, and make referrals when necessary
• Assess the patient’s adherence to the regimen and address poor adherence when it occurs.
• Complete appropriate documentations;
• Collaborate with the local public health services;
• Ensure that the patient accepts the proposed cared and support.
• Report patient treatment status to the Treatment centre
• Maintain confidentiality of the patients
• If DOT provider will be absent for providing DOT due to their personal reasons, manage
alternate DOT provider for that durtion.
• Provide referrals for psychological, social and legal support and other services including
substance abuse treatment; Priovide joint (integrated) support for DR TB patients with
addictive behaviours;
F. Patient and Community Level

• DRTB patients to faithfully take drugs under supervision and complete treatment
• The community to supervise and support DRTB patients to ensure treatment completion
• Attend regular follow ups with the health facility staff for monitoring of treatment, submit
sputum, follow up on results and report side effects.
• Refer DRTB presumptive persons to the health institution to check their health.
• Directly observe all DR-TB patients in their communities
• Mobilise patient and peer support groups, which may help also reduce stigma
CHAPTER 2
DIAGNOSIS OF DR-TB
2.1 IDENTIFICATION OF PRESUMPTIVE DR-TB
2.1.1 When to think of presumptive DR-TB?
All staff who are managing TB patients must be able to identify presumptive DR-TB.
The following categories of TB patients are at risk of having DR-TB and need to be screened for
drug resistance:
1. Close contact of DR-TB case

2. Previously treated patients who either:
- failed
- relapsed
- returned after loss to follow-up
3. Smear positive at 2 months or subsequent follow up during first-line treatment
4. Not getting better / getting worse during continuation phase of the first-line treatment and
patients with frequent interruptions and irregular first line drugs.
5. Health care workers with presumptive TB.
6. PLHIV, DM and other immunocompromised
7. Belonging to vulnerable groups such as migrants and refugees
Most patients with presumptive DR-TB will be bacteriologically positive pulmonary cases, but
clinically confirmed pulmonary or extrapulmonary TB cases may also present with presumptive
DR-TB if they show a clinically unfavorable evolution.
2.2 MANAGEMENT OF PRESUMPTIVE DR-TB

2.2.1. Perform a Xpert MTB/RIF test
Carry out the Xpert MTB/RIF testing for all presumptive DR TB cases as per the diagnostic
algorithm. Testing can be done directly via patient going to Genexpert centers themselves or
through the courier up the Genexpert sites from peripheral health facility.
2.2.2. What to do if the Xpert MTB/RIF test shows rifampicin resistance (RR)?
If the result shows RR, the patient must be sent immediately to the nearest DR-TB Centre for
registration and further management as per diagnostic algorithm and treatment mentioned in
this guidelines.
Attention! Patients with Low risk of DR TB: It is also possible that a person with presumptive
TB, whose sputum is examined with Xpert MTB/RIF to confirm the diagnosis of TB, presents
with an RR result. Since the test was done because of a presumption of TB and not because of
a presumption of DR-TB, it is necessary to repeat the test. If the repeat Xpert MTB/RIF test also
shows an RR result, the patient must be sent to the nearest DR-TB Centre without delay.
2.2.3. What needs to be done at the DR-TB Centre?

• The patient must be registered in the DR-TB register (see Form DRTB 01 )
• All the baseline examinations should be done before DR-TB treatment
• 2 morning sputum samples or other specimens should be collected before starting the
treatment and sent to the designated laboratory without delay. Designated Laboratories
perform microscopy, culture and direct line probe assay (LPA) to identify fluoroquinolones
and the second-line injectables resistance
• If the result of LPA from direct sample shows no result or invalid, then repeat LPA from another
sample and/or second LPA will be tested from culture positive. The result of the LPA should
be available at the DR-TB Centre within 2 weeks on an average, after sending the specimens.
• Before LPA result is available, a shorter treatment regimen is started if no contraindication
and based on LPA result, a decision is made for appropriate LR regimen.
2.3 DIAGNOSTIC TESTS

2.3.1 Direct microscopy
Direct examination following proper staining of a sputum smear or other specimen by light
microscopy or fluorescence microscopy is useful to detect TB but does not allow to diagnose DR-
TB. Smear microscopy will be needed, however, to monitor treatment progress.
2.3.2 Xpert MTB/RIF test

Xpert MTB/RIF® is a molecular test recommended by the WHO that identifies, with a very high
sensitivity and specificity:
• the presence of DNA from the tubercle bacillus;

• the occurrence of mutations in the DNA that cause rifampicin resistance.
The test makes use of the Xpert MTB/RIF technology, a small machine that is linked to a computer.
A sputum sample is transferred into a special cartridge that is inserted into the machine.
The machine will analyze the sputum sample through a fully automated, closed-circuit PCR
(polymerase chain reaction) and the computer will print out the findings. The whole test takes
only about 2 hours.
If the presence of Mycobacterium tuberculosis (MTB) is detected, Xpert MTB/RIF will also look for
evidence of rifampicin resistance. If it is present, a result of RR (rifampicin resistance) is shown.
RR is not the same as MDR, because MDR requires resistance to both rifampicin and isoniazid.
But from an operational point of view, RR should be treated as MDR, because 95% of rifampicin
resistance is associated with concurrent resistance to isoniazid, however, monoresistance to
rifampicin is found in approximately 5% of rifampicin resistant strains. Thus, detecting resistance
to rifampicin can be used as a surrogate marker for MDR-TB with a high level of accuracy.
Xpert MTB/RIF ultra can also be used as an alternative to Xpert MTB/RIF assay in all settings and
the interpretation of results of the Xpert MTB/RIF assay for MTB detection are same as for the
Xpert MTB/RIF assay, with the expection of “MTB detected trace” result. Country will transition to
Xpert MTB/RIF ultra, when resource allows.
2.3.2.1 How to collect a sputum sample for Xpert MTB/RIF testing

A single sputum specimen must be collected. It must be of the high quality to ensure a correct
reading by Xpert MTB/RIF:
- Collect one sample (early morning sample or quality spot sample also acceptable).
- Before coughing up the sputum, the patient should rinse the mouth carefully;
- Expectoration from deep inside the chest;
- Minimum quantity 2-3 ml.
* For re-treatment cases, collect two sputum specimen one for Xpert MTB/RIF and othe for LPA
Sputum samples for Xpert MTB/RIF are collected in Falcon tubes (see illustration D1). There is
no need to add any reagent to the specimen. The tubes must be properly identified with a self-
adhesive sticker (see illustration D2). On the sticker, the name of the patient, the registration
number of the patient, the lab number and the date of specimen collection must be written with
an indelible marker. The tubes must be tightly closed. They can be kept at ambient temperature,
but heat and direct sunlight should be avoided.
Since the samples are collected from persons who are potentially contagious, the staff must pay
extra attention to observe proper safety precautions.
D1. Falcon tube D2. Proper identification of Falcon tube
Whenever sputum is collected for Xpert MTB/RIF, it must be entered into the laboratory register
and a Xpert MTB/RIF request form must be filled.
2.3.2.2 Other specimens for Xpert MTB/RIF testing in case of presumptive extrapulmonary
(EP) DR-TB
Xpert MTB/RIF testing on blood, urine or stool is not recommended, but testing of an appropriate
specimen can be very helpful in certain types of presumptive EP DR-TB: see table 2.1. The test will
not perform as well as on sputum, but it can be particularly useful when testing cerebrospinal
fluid or lymph node tissue or aspirate. Xpert MTB/RIF also performs well on gastric lavage. The
test is not very sensitive on pleural fluid or other specimens such as intra-articular fluid, for which
few data are available at present. Nevertheless, always do the test because some cases might be
positive.
It must be borne in mind that a negative Xpert MTB/RIF result on an EP specimen is not the final
answer. For every case of presumptive EP DR-TB, send a specimen for culture and DST.
TABLE 2.1: Specimens collected for Xpert MTB/RIF testing in presumptive EP DR-TB
Quantity* to be Type of
Type of EP TB Specimen
collected container
Tuberculous pleuritis Pleural Fluid 10-15 ml
Tuberculous meningitis cerebrospinal fluid (CSF) Minimum 2 ml
TB of the peripheral lymph adenitis Pus and/or excision biopsy Minimum 2 ml
Intra-articular Fluid
Musculoskeletal TB, Osteo-articular TB Minimum 2 ml Sterile
Biopsy samples
containers
TB pericarditis Pericardial Fluid Minimum 2 ml
TB peritonitis Ascitic Fluid 10-15 ml
Other tissue samples e.g.
TB of other organs
Endometrial Biopsy
2.3.2.3 How to send the sputum (or other) sample to the Genexpert Centre
In health facilities where
the Xpert MTB/RIF testing is
Primary receptacle
present (Genexpert centers), (leakproof or siftproof )
Waterproof
the specimen, together with Cap
the request form, will be taken Rack-type holder
directly to the Genexpert (styrofoam, sponge)
Absorbent
centers. At health facilities packing
Xpert MTB/RIF testing is not material Itemized list of
contents
available, samples will be (specimen record)
transported to the nearest
Genexpert Centers. Tripple
layer packaging must be Secondary Rigid outer
packaging
made for transportation packaging )
leakproof or
of the samples. The tightly siftproof )
Proper shipping
closed Falcon tube is sealed name
with paraffin tape, wrapped
Package marking
in absorbent paper and
placed in a proper packaging To/From labels
as shown in diagram and

must be properly sealed. The
package together with the D3. Sputum sample package
Xpert MTB/RIF request form are
sent to the Genxpert centre. The health facility must make sure that the specimen arrives at the
Genexpert Centre within 24 -48 hours. If available, a courier service may be called upon, but any
other appropriate means of transportation may be used.
2.3.2.4 Xpert MTB/RIF testing results

TABLE 2.2: Results of the Xpert MTB/RIF test
Label Result and Action to be taken

Interpretation
MTB detected, Diagnosis of TB confirmed. Treat with first-line TB regimen.

T rifampicin resistance not
detected
MTB detected, If presumptive MDR- TB case: send to DR-TB Centre.

RR rifampicin resistance If new TB case: consider repeat Xpert MTB/RIF test. If RR result
detected is confirmed, send to DR-TB Centre.
MTB detected, Diagnosis of TB is confirmed. Start treatment with first-line TB

rifampicin resistance regimen and send new sputum specimen to repeat the test.
TI indeterminate Pay special attention to quality of sputum sample, conditions
of storage and transportation and speed of shipment. If the
result of the repeat test is RR, send to DR-TB Centre.
N MTB not detected Additional investigations required to exclude TB.
Invalid/no result/error Send new sputum specimen to repeat the test. Pay special
I attention to quality of sputum sample, conditions of storage
and transportation and speed of shipment
The result is written on the Xpert MTB/RIF request form and sent back to the requesting health facility.
2.3.3 Line Probe Assay (LPA)

When the specimens (2 samples) arrives for LPA at designated Labs, one sample is used for culture
and the other specimen for rapid molecular testing by line probe assay (LPA). This is a nucleic acid
amplification test (NAAT) using the PCR (Polymerase Chain Reaction) technology. It detects the
presence of mutations in certain genes of M. tuberculosis that occur in case of resistance to
specific drugs:
The first-line LPA detects mutations in the rpoB gene (resistance to R) and the katG and inhA
genes (resistance to H). A katG mutation signifies high level H resistance, a inhA mutation without
accompanying katG mutation indicates low level H resistance. It is not necessary to perform
this test if the Xpert MTB/RIF test has already detected rifampicin resistance. Whether or not
additional isoniazid resistance is present in these conditions, it will not have any influence on the
therapeutic decision making. In case of Xpert MBT/Rif test not detecting Rif Resistance, the result
of 1st line LPA is important to make therapeutic decision.
The second-line LPA detects mutations in the gyrA and gyrB genes (resistance to the
fluoroquinolones [FQ]) and the rrs and eis genes (resistance to the second-line injectable drugs
[SLID] Amikacin and capreomycin). The results of the LPA should arrive at the DR-TB Centre as
soon as possible (preferably within 2 week). The result of 2nd line LPA will be used to guide the
therapeutic decision. If no resistance to FQ orSLID is found, the patient can continue the initially
prescribed treatment regimen, either SSTR or a long-course regimen (LR1). If resistance to FQ is
detected irrespective of the SLID, the patient will be put on LR2 regimen.
However, LPA needs higher bacterial load in samples than Xpert for a positive result and hence
smear positive samples and cultures are preferred.
Interpretation of Second-Line (SL) LPA result:

Genotypic mutation on MTBDRsl test Level of Phenotypic result Clinical Implication
resistance to
FQ.
gyrA Mut 1 +/- gyrA WT 2 Low/ • Levofloxacin: Mfx could be used
probe Moderate/ Resistance detected. at higher dose. The
High • Moxifloxacin: Low regimen should be
gyrA Mut 2 +/- gyrA WT 2 Moderate/ level resistance re-evaluated based
probe High detected. on phenotypic DST
High level Mfx results at CB.
gyrA Mut 3A +/- gyrA WT 3 Low susceptibility results
probe to be reported
gyrB Mut 1 +/- gyrB WT probe Moderate within 2 months.
gyrB Mut 2 +/- gyrB WT probe Moderate
gyrA Mut 3B +/- gyrA WT 3 Moderate/ • Levofloxacin: Mfx even at a high
probe High Resistance detected dose cannot be
gyrA Mut 3C +/- gyrA WT 3 sHigh Moxifloxacin: High considered as an
probe level resistance effective medicine.
detected.
gyrA Mut 3D +/- gyrA WT 3 High
probe
gyrA gyrA WT 1 probe Moderate/ • Levofloxacin: Levofloxacin is not
missing High Resistance detected. effective.
gyrA gyrA WT 2 probe Moderate/ • Moxifloxacin: Low Mfx could be used
missing High level resistance at higher dose. The
detected. regimen should be
gyrA gyrA WT 1 and WT Low to High High level Mfx re-evaluated based
2 probe missing susceptibility results on phenotypic DST
gyrA gyrA WT 3 probe Moderate/ to be reported results at CB.
missing High within 2 months.
Based on “Line probe assays for drug resistant tuberculosis detection Interpretation and reporting
guide for laboratory staff and clinicians”, GLI
Interpretation of Second Line (SL) LPA result for SLDs:

Mutation on MTBDRsl test Level of resistance
rrs Mut 1 rrs WT 1 probe missing High to Km, Am and Cm
rrs Mut 2 rss WT 2 probe missing High to Km, Am and Cm
rrs rss WT 1 probe missing High to Km and Cm; Sensitive to Am
rrs rss WT 2 probe missing High to Km, Am and Cm
eis Mut 1 eis WT 2 probe missing
Low to Km; Susceptible or Low resistance
eis eisWT 1 probe missing
to Am and Cm
eis eis WT 2 probe missing
eis eis WT 3 probe missing Susceptible to Km, Am, Cm
2.3.4 Culture and drug susceptibility testing (DST)

When a sample is sent for 2nd line LPA, in parallel culture is also performed for:
• Identifying viability of Mycobacterium.
• Carrying out phenotypic DST
• Confirming the results, where direct LPA testing is not possible.
Culture tests are also used to monitor the treatment response. The frequency of follow up tests
(culture and DST) is described in Table 5.3 and 5.4.
2.3.4.1 How to collect a sputum specimen for culture and DST?

Two samples (good quality) are absolutely necessary in order to provide the best possible
conditions for the culture to grow. If possible, both specimens should be early morning samples,
collected before the patient has eaten. If morning samples are not possible to collect, then good
quality sample taken at spot can also be considered.
To ensure the quality of sputum samples:

• The patient should rinse the mouth carefully before coughing out the sputum
• Expectoration should be from deep inside the chest;
• Minimum quantity of expectorant must be 3-5 ml.
• The expectorants should be mucopurulent.
Sputum samples for culture should not be collected in the usual sputum tubes, but should be
collected in the sterile Falcon tubes. The tubes must be properly labelled indicating the patient’s
name, TB registration no. and dates of collection. See illustrations Figure D1 to D4. Once the
sputum is collected, the tubes are closed tightly and stored in the refrigerator while awaiting
transportation.
In case of EP DR-TB, other specimens can be collected
TABLE 2.3 Specimens collected for culture and DST in presumptive EP DR-TB
Quantity* to be Type of
Type of EP TB Specimen
collected container
Tuberculous pleuritis Pleural Fluid 10-15 ml
Tuberculous meningitis cerebrospinal fluid (CSF) Minimum 2 ml
TB of the peripheral lymph adenitis Pus and/or excision biopsy Minimum 2 ml
Musculoskeletal TB, Osteo-articular Intra-articular Fluid Sterile

Minimum 2 ml containers
TB Biopsy samples
TB pericarditis Pericardial Fluid Minimum 2 ml
TB peritonitis Ascitic Fluid 10-15 ml
Genito-urinary TB Urine 100-200 ml
Endometrial Biopsy
If it was not possible to collect the recommended minimum quantity, the available sample
should still be sent to the laboratory. Avoid sending tissue sample/biopsy in formaldehyde.
Tissue sample should be sent in normal saline.
2.3.4.2 How to send the specimens for culture DST.

A Culture and DST request form must be filled in. The two tubes and the
form must be sent to the designated labs without delay maintaining the
cold chain. The time between sputum collection and initiation of culture
should not exceed 72 hours.
Transportation of the sputum samples, which is likely to contain drug

resistant TB bacilli, must be done in a safe manner. The tightly closed Falcon
tubes are sealed with paraffin, wrapped in absorbent paper and placed in the
container, which must be properly sealed. The container will be put inside a
cold box with ice packs (see illustration D4), which must be closed tightly. D3. Sputum sample in
cold box
Timing and cold chain are critical because the bacilli in the sputum need to
be alive when the specimen is inoculated on the culture medium.
2.3.4.3 Culture result

At the culture labs, culture will be performed on both samples, which will be inoculated onto
a solid culture medium (Löwenstein-Jensen) and/or MGIT. If no growth appeared till 8 weeks,
the culture is considered negative. If bacilli are present in the sample, colonies start to grow on
the medium after 4 to 6 weeks in Solid Culture, and nearly 2 weeks in MGIT. The colonies have a
typical shape: brownish, granular and with a rough surface (see illustration D5).
For solid culture, the colony growth will be graded according to the number of colonies observed:
No colonies after 8
Number of colonies Exact number 10-100 101-200 >200
weeks
Result NEGATIVE 1-9 1+ 2+ 3+
If the culture is contaminated, performing culture with another sample may be considered.
Liquid Culture:
Mycobacteria multiply in a nutrient-rich medium,
while contaminating bacteria are inhibited by
the addition of a cocktail of antibiotics. Growth
of bacteria, including mycobacteria, is indicated
by fluorescence, which increases proportionally
as oxygen decreases in the tube. The instrument
detects this fluorescence in the medium using a UV
light and complex computer algorithms.
Interpretation of Liquid Culture

• Positive for Mycobacterium tuberculosis
complex
D4.MGIT culture result
• Negative for Mycobacterium tuberculosis complex
Drug Susceptibility Testing (DST):

When DST is performed as per the diagnostic algorithm, the following drugs listed below are
tested for susceptibility.
DST in Solid Media DST in Liquid Media
Turn over time: 4 weeks Turn over time: 2 weeks
1st line drugs: 1st line drugs:
- Rifampicin - Isoniazid
- Isoniazid - Rifampicin
- Ethambutol - Ethambutol
- Pyrazinamide
2nd line Drugs: 2nd line drugs:
- Levofloxacin - Levofloxacin
- Moxifloxacin - Moxifloxacin
- Amikacin - Bedaquiline
- Streptomycin - Linezolid
- Clofazimine
- Amikacin
- Delamanid
- Streptomycin
DST for other second line drugs not listed above are not carried out because of limited reliability.
Despite the phenotypic DST results precedes over the LPA results, the patient will be managed
as per the LPA results (given the prolong turnover time required for phenotypic DST). The results
of phenotypic DST will be taken into consideration, if the clinical condition of the patient isn’t
improving.
Xpert MTB/RIF Ultra assay

Despite substantial increased sensitivity for MTB detection compared with smear microscopy,
Xpert MTB/RIF sensitivity is nevertheless suboptimal, in specimens with low numbers of bacill.
The Xpert® MTB/RIF Ultra assay (Ultra) has been developed as the next-generation assay to
overcome this limitation.
The Ultra assay is non-inferior to the Xpert MTB/RIF assay for the detection of MTB and for the
detection of rifampicin resistance. This means that the new Ultra cartridge is at least as good
for the detection of MTB and rifampicin resistance as Xpert MTB/RIF. In certain populations, the
Ultra assay may perform better for MTB detection, especially for individuals whose specimens
are frequently paucibacillary. The Ultra cartridge showed better performance for the detection of
MTB (increased sensitivity) compared to the current Xpert® MTB/RIF cartridge for the detection
of Mycobacterium tuberculosis in specimens with low numbers of bacilli, especially in smear-
negative, culture-positive specimens (such as those from persons with HIV co-infection), in
paediatric specimens and in extra-pulmonary specimens (notably cerebrospinal fluid). The
accuracy in detection of rifampicin resistance is also better. The increased sensitivity of Ultra has
enabled to detect 16 bacilli per ml sputum compared to 131 per ml for Xpert® MTB/RIF.
Next Generation Sequencing (NGS):

NGS is a “high-throughput, massively parallel” sequencing method used to determine the
nucleotide sequence of a whole genome (i.e. whole genome sequencing (WGS)) or part of a
genome (i.e. targeted NGS) in a single biochemical reaction volume. NGS is performed by
non-Sanger-based sequencing technologies that are capable of sequencing multiple DNA
fragments in parallel, which are then pieced together and mapped to a reference genome
using bioinformatics analyses. WGS can provide the near complete genome of Mycobacterium
tuberculosis (MTB) in a sample, while targeted NGS can generate MTB sequence data at specific
genetic loci of interest.
Since drug resistance in MTB is mainly conferred through point mutations in specific gene
targets, targeted NGS offers great promise for rapid diagnosis of DR-TB. However, WGS offers
higher genome coverage as required to combine genomic and epidemiological information
to define transmission clusters during an outbreak, and the generated data contributes to
our understanding of resistance mechanisms for both current and newer drugs as well as
the identification of compensatory mutations. In this context, WGS remains invaluable for TB
research and surveillance, though its clinical utility as a DR-TB diagnostic tool will require further
investigation before routine WGS is more widely implemented for TB diagnosis.
2.4 DIAGNOSIS OF EXTRAPULMONARY DR-TB IN THE

ABSENCE OF DST
Most DR-TB will be pulmonary, but EP DR-TB is possible as well. It must be borne in mind, however,
that the diagnosis of EP TB is not easy. Often, the diagnosis will be based solely on clinical criteria
(see National Guidelines on DR-TB Management 2019).
While it will be difficult to obtain bacteriological confirmation of the EP TB diagnosis, it will be

even more difficult to obtain bacteriological proof of drug resistance. Whenever a presumption
of EP DR-TB is made, all possible efforts should be made to obtain a suitable specimen for Xpert
MTB/RIF testing, culture and DST. Unfortunately, suitable specimens will not always be available.
Even if a specimen is obtained, it may not be possible to arrive at a reliable test result because
tests performed on other specimens are often not as sensitive as tests performed on sputum.
In the absence of culture and DST results, only a presumptive diagnosis of EP DR-TB can be made.
The most likely instances when EP DR-TB will come to mind are:
- an EP TB patient who is a contact of a known TB case with drug resistance
- a correctly treated EP TB patient who presents a clinically unfavorable evolution
Patients with presumptive EP DR-TB should be sent to the DR-TB Centre. The diagnosis of EP DR-
TB must be made in consultation with the expert team constituted under the Technical Working
Group (TWG) of the NTC.
2.5 DIAGNOSTIC PATHWAY

The diagnostic pathway to arrive at a proper diagnosis of DR-TB (and the subsequent prescription
of the appropriate treatment) based on the procedures explained in the algorithm figure 2.1.
FIGURE 2.1: Decision tree for the diagnosis and treatment of DR TB
Box A. Presumptive DR TB cases Box B: Special groups for Xpert MTB/Rif testing
1. DR TB close contacts 1. All New Pulmonary TB patients registered BUT who didn’t prior
2. All Retreatment patients (including failure, have Xpert MTB/Rif testing done
loss to follow up and relapse) 2. Extra pulmonary TB patients (EP samples)
3. Non-converters by month 2 or subsequent
follow-up Presumptive TB cases:
4. Not getting better/getting worse during the Xpert MTB Rif 3. Children < 14 years
continuation phase of the first line Tests 4. PLHIV, DM and other immunocompromised
treatment 5. X-ray suggestive of TB, but smear negative
6. Health care workers
7. Contacts of Index TB cases and people living in congregate setting
8. All presumptive TB cases with access to Xpert MTB/Rif Testing.
MTB Detected Rif No result, error or MTB not Detected ( N ) MTB Detected, Rif MTB Detected Rif
Resistance Detected Invalid test ( I ) Perform additional Resistance Not Detected Indeterminate (TI)
(RR) # Repeat Xpert MTB/Rif investigations and (T) - Initiate first line treatment Tx
test and manage clinical judgement - Repeat Xpert MTB/Rif Test
accordingly followed by Culture DST and manage accordingly
Shorter MDR regimen (perform culture if required)
for eligible patients,
and LR1 for those not
SL LPA Culture followed by DST Initiate First Line Treatment
eligible for SSTR
(For Retreatment cases, consider clinical judgement and if required
other additional tests: smear, culture, etc.)
FQ sensitive & FQ sensitive & FQ resistant & SLI Indeterminate result LPA first line only for points 2, 3, 4 of Box A
SLI Sensitive SLI Resistant Sensitive or Resistant
Repeat direct SL LPA and

- Continue SSTR - Initiate LR1 for evaluate culture report H-Resistance H-Sensitive
- Continue LR1 those who were Initiate LR2
(for those not initially on SSTR
eligible for SSTR Initiate HrTB regimen and Continue First line
- Continue LR1 for 1. Continue SSTR or LR1 and monitor the treatment
in the send for SL LPA and treatment
those who are response unless FQ resistance is reported
beginning) manage accordingly
already on LR1 2. If FQ resistance reported, switch to LR2
N AT I O N A L G U I D E L I N E S O N D R U G R E S I S TA N T T U B E R C U LO S I S M A N A G E M E N T
NOTE:
21
1. # For new cases with low risk of RR-TB clinician can decide to repeat in case required
2. As per interpretation of results, please follow Treatment algorithms both for DS TB and DR TB
3. All Presumptive TB cases with access to Xpert MTB/RIF Testing, Xpert TB/RIF should be first diagnotic tools.
2.6 DIAGNOSIS OF DR-TB IN SPECIAL GROUPS

2.6.1 Diagnosis of DR-TB in children
The term “children” incorporates a broad range as, 2-year-old child requires a different approach
to a 12-year-old, and the treatment of children with MDR-TB will never be a “one size fits all”
approach.
The diagnosis of TB in children is difficult, and the diagnosis of DR-TB is even more challenging.
Children, particularly young ones, do not cough up sputum. Gastric aspiration using a nasogastric
feeding tube should be considered. Sputum induction could be a safe and effective alternative
in children of all ages. However, training and specialized equipment are required to perform this
procedure properly.
Collect the specimen at optimal times (e.g. early morning fasting gastric aspirate; induced
sputum after fasting 2-4 hours; expectorated sputum early morning) Always try to collect an
optimal quantity of sample, which varies by specimen type; larger volumes generally provide
higher bacteriological yields; neutralize stomach acid if gastric aspirate is collected.
Children often have a paucibacillary form of the disease. Direct microscopy of sputum or other
specimens (such as gastric aspirates) often will be negative, and even cultures will not always
show growth. Nevertheless, every effort should be made to obtain a bacteriological confirmation
of diagnosis in order to avoid exposing children to toxic drugs. If a specimen can be obtained,
GeneXpert testing must always be done (the test also performs well on gastric aspirates) and
culture (with subsequent DST) must be attempted.
NBP: GeneXpert MTB/RIF/Ultra and culture in liquid media should be prioritized in children.
Following should always be considered for DR TB in Children to move forward with diagnosis
and decision for treatment;
• A high level of clinical suspicion is needed for timely diagnosis of DR-TB in children.
• Confirmed DR-TB: MDR-TB is identified from the child as per the given sample
• Probable MDR-TB: a. If the child under assessment has symptoms/signs/radiology of
consistent with TB and has been exposed to an infectious DR-TB case In case of probable
MDR TB diagnosis treatment should be based on source case.
• Probable MDR TB. If a child under assessment is not improving after 2-3 months of first-line
treatment and the DOT confirms appropriate drug intake and there is no other likely diagnosis
OR
A close contact of child who died from TB or failed TB treatment or is a TB retreatment case with
unknown DST results, in all these cases, early treatment initiation is imperative.
2.6.2 Diagnosis of DR-TB in PLHIV

The association of TB and HIV/AIDS is well known. and MDR-TB outbreaks among PLHIV have
been reported in situations where MDR-TB is common. MDR-TB in PLHIV is more difficult to treat
and will have a higher mortality than in HIV-negative people. Therefore, all TB/HIV co-infected
patients and all PLHIV with presumptive TB should be tested by GeneXpert.
The diagnosis of TB in PLHIV is often difficult to establish with certainty, particularly in patients
in the advanced stages of HIV infection (with a very low CD4 cell count, below 200). The disease
is likely to present as EP or smear negative TB. Diagnosing MDR-TB will be even more difficult
because many TB/HIV co-infected patients will be paucibacillary, resulting in negative sputum
smears and cultures that may not show any growth, which makes it impossible to perform DST.
Even the GeneXpert test will often be negative. Nevertheless, every effort should be made to
systematically perform culture and DST whenever a PLHIV is diagnosed with TB.
If the presumption of MDR-TB is present in the absence of clear clinical or bacteriological evidence
and both GeneXpert and culture are negative, it is recommended that the diagnosis of MDR-TB
in PLHIV be made by a team of experts at the DR-TB Centre. The team of experts can make a
tentative diagnosis of MDR-TB and decide to start empirical MDR-TB treatment based on contact
history or unfavorable evolution under proper first-line anti-TB treatment.
Note: G.Xpert MTB/RIF Ultra is preferred for HIV patients to diagnose TB/RR -TB but until Xpert
MTB/RIF Ultra is available in Nepal, above mentioned diagnostics procedure should be followed.
CHAPTER 3
REGISTRATION CATEGORY
OF DR-TB
Classification based on history of previous TB treatment (patient registration group): (Reference:
WHO Companion handbook for programmatic management of DR-TB- 2014)
Registration group: Patients are assigned to a registration group based on the most recent
treatment history at the time of initiating DR-TB treatment
1. New. A patient who has received NO or LESS than one month of anti-TB treatment
2. Relapse. A patient who was previously treated for TB and whose most recent treatment
outcome was Cured or Treatment completed, and who is subsequently diagnosed with a
recurrent episode of TB (either a true relapse or a new episode of TB caused by reinfection).
3. Failure. A previously treated TB patient who has received an anti-tubercular treatment whom
the treatment has failed.
3.1 After failure of first line Treatment with FLD
3.2 After failure of Re-Treatment with FLD
3.3 After failure of Treatment with Hr TB Regimen
3.4 After failure of Treatment with SLD
4. Treatment after loss to follow-up: A patient who had previously been treated for TB and was
declared Lost to follow-up at the end of the most recent course of treatment.
5. Other previously treated patients. A previously treated TB patient whose outcome after the
most recent course of treatment is unknown or undocumented.
6. Patients with unknown previous TB treatment history who do not fit into any of the
categories listed above.
CHAPTER 4
TREATMENT OF
DR-TB
4.1 PATIENT EDUCATION

• Patient education is an essential component of any DR-TB control program and is possible
when there is trusting interpersonal communication between patients and medical
personnel.
• Provision of emotional & social support to DR-TB patients may increase the likelihood of
adherence.
• The organization of patient education should be considered equally with the other
components of the DR-TB program (such as detection and diagnostics, drug supply, etc.)
• The patient’s knowledge and understanding of his/her role in achieving a successful treatment
outcome is an essential component for treatment selection.
The following should be covered for patient and Treatment supporter education and support:
TABLE 4.1 Components of Health education and deliverable messages

S.N COMPONENT DELIVERABLE MESSAGES FOR EDUCATION OF PATIENT AND
TREATMENT SUPPORTER
1 Patient knowledge What is TB and DR TB, difference between TB & DR TB, treatment for
and understanding of DR TB,duration of injectables (if applicable) and treatment, monthly
Disease follow ups and routine investigations, benefits of regular treatment
and harms of interruption of treatment.
2 Prevention of Spread of What measures are to be taken to prevent spread of DR TB at household
DR TB and community level, close contact screening, importance of regular
intake of medicine
3 Information about What most common side effects patient may experience and how
possible side effects to report side effects for management, appropriate ways of drug
intake, like FQs should not be taken with milk or calcium, aluminum,
magnesium and iron containing products. PAS should be swallowed
with acidic liquid. The constituted Injecatble (if applicable) dosages
should be used within 24 hrs and kept refrigerated.
4 Patients’ Rights and Explain patients’ role in treatment completion, what are patient rights
Responsibilities and responsibilities during whole period of treatment.
5 Role& Responsibilities Clearly explain the role and responsibility of TS, daily supervised DOT
of Treatment Supporter provision, identifying side effects, emotional support to patient and
family, accompanying patient on monthly follow ups to PMDT site and
on weekly basis to nearest DOTS center, support in contact tracing
benefits of supervised treatment and benefits of successful treatment
completion, and incentives where feasible such as communication
cost for treatment supporter )
6 Psycho-Social support Patients should be supported by the counsellors and to provide
throughout Treatment counseling, support and refer where necessary to psychologists,
explain that all drugs and investigations related to DR TB treatment are
free of cost and delivery of social support in terms of travel allowances
and food baskets where possible.
7 Maintaining The PMDT health team should explore the need of the patient to
confidentiality maintain strict confidentiality regarding their disease and all aspects of
ethical consideration should be applied.
Following are strongly recommended before the treatment initiation is considered:

• Ahead of enrolment on DR-TB treatment, all patients should receive appropriate
counseling to enable informed and participatory decision-making.
• Ensure that patients are appropriately informed about their treatment options.
• Ensure patient-centered approach to the delivery of care including social and
psychological support.
• Active TB drug safety monitoring and management (aDSM) is essential for all patients
enrolled on DR-TB treatment.
• Baseline and follow-up investigations are mandatory as per guideline.
Key Points for RR/MDR TB Treatment

It is challenging to treat and manage DR TB. Since the bacilli are resistant to the most effective
first-line drugs, the treatment must include second-line drugs. These drugs are limited in number,
less effective than the first-line drugs, poorly tolerated, some side effects can be very severe and
difficult to recognize, and drugs are very expensive. Complicated cases with extensive drug
resistance patterns are even more difficult to treat.
In Nepal, 2 types of treatment regimen are used for management of RR/MDR-TB. Both are largely
standardized.
F Standardized Shorter Treatment Regimen (SSTR) of 9-12 months’ duration, prescribed for
uncomplicated RR/MDR-TB provided that eligibility criteria are met refer to SSTR regimen
chapter)
F All oral Longer Treatment Regimen (LTR) of 18-20 months’ duration for those not eligible
for SSTR. There are mainly two standardized LR treatment regimens recommended by the
National TB Programme (LR1, LR2) for most of the RR/MDR-TB patients. For special conditions
in rare cases, there are also provision of other treatment regimen such as LR3 and LR4
4.2. DRUGS USED TO TREAT DR TB AND PRINCIPLES OF

TREATMENT
The probability of treatment success in RR/MDR-TB patients depends upon patients’will and strong
adherence to treatment, including severity of disease, resistance patterns and co-morbidities
as well as access to health care (e.g. regimens with sufficient effective agents, medications of
good quality, attention to adverse events and patient support). Longer MDR-TB regimens with
sufficient effective agents are known to increase the likelihood of cure and lower the risk of death
in adults and children (Ahmed et al 2018, and Harausz at al 2018)
WHO in 2018 convened the GDG (guideline development Group) meeting and assessed the
individual contribution of patient outcomes of medicines used in longer MDR TB regimens using
primarily the estimates of effects from 2018 individual patient data meta-analysis. Following
a thorough assessment of relative benefits to harms, recommendations were made for each
medicine and classified in to three groups:
Group A: Fluoroquinolones (Levofloxacin and Moxifloxacin), Bedaquiline and Linezolid were

considered highly effective and strongly recommended to be included in all regimens unless
contraindicated;
Group B: Clofazimine and Cycloserine or Terizidone were conditionally recommended as agents

of second choice;
Group C: included all other medicines that can be used when a regimen cannot be composed
with Group A and B agents.
The composition of longer regimens is guided by the selection of individual medicines

considered to be effective and also by a need to combine sufficient medicines to maximize the
likelihood of relapse-free cure without increasing toxicity. Regimens may be of standardized
(fixed) composition or may be individualized to the patient needs. Apart from the ranking by
balance of effectiveness and harms, choice is also determined by: a preference for composition
of agents; the results of drug-susceptibility testing (DST); the reliability of existing DST methods;
population drug resistance levels; history of previous use of the medicine in a patient; drug
tolerability; and potential drug-drug interactions.
Table below indicates the overall approaches to designing longer MDR TB regimen as oppose
to the SSTR which is standardized. Based on the WHO 2019 consolidated guideline in DR TB
treatment, drug grouping recommendations, the regimen is designed by adding medicines
sequentially going down from group A to group C.
Grouping of Medicines recommended for the treatment of RR-TB and MDR-TB(adopted from
WHO 2019, guidelines)
GROUPS STEPS MEDICINES ABBREVIATIONS
A Include all three medicines in the Levofloxacin OR Lfx /Mfx

regimen, if no contraindication Moxifloxacin
Bedaquiline Bdq
Linezolid Lzd
B Clofazimine Cfz
Add one or both Medicine
Cycloserine OR Cs, Trd
Terizidone
C Add to Complete regimen and Ethambutol E

when medicines from Group A
and Group B cannot be used Delamanid Dlm
Pyrazinamide Z
Imipenem-cilastatin OR Imp,Cln, Mpm

Meropenem
Amikacin (OR Streptomycin) Am(S)
Ethionamide OR Eto , Pto

prothionamide
P-aminosalicylic acid PAS
Important notes:
1. The recommended duration of use of Bdq is 6 months and its use beyond this duration
is “off label”
2. Bdq can be used in children from 6 years and above
3. Dlm can be used in children 3 years and above
4. Bdq and Dlm can be used together to complete the regimen
5. Lzd preferably to be used for whole duration of treatment or less if not tolerated
6. If DST to Z, E shows susceptibility, can be part of regimen
7. Imipenem should be used with Amox-Clv
8. Use Am and S; if only susceptible and under close monitoring, preferably in patients who are
18 years or above
Principles of MDR TB Treatment and Regimen Construction

The following general principles of DR TB should be followed for regimen designing and the
objective should be with “no harm practice” keeping in view the effectiveness and safety of the
regimen designed;
• At the time of enrollment, patients should be informed about available option of treatment
(longer or shorter) and shared based decision should be made between Doctor and patient
for choices.
• RR / MDR TB diagnosed patients to be treated with a recommended MDR-TB regimen, either
a longer MDR-TB regimen to which isoniazid can be added where required (if susceptible), or
else a shorter MDR-TB regimen in eligible patients.
• It is essential that patient’s MDR/RR-TB strain needs to be tested for susceptibility to medicines
planned for inclusion in the regimen at the time of start of treatment initiation, preferably by
using rapid diagnosis (LPA SL- GenoType MTBDRsl) can be used in both children and adults
and as a direct and indirect test
• Review patient full history of previous treatment, DST results, co-morbid conditions and
concomitant drugs in use
• Empirical treatment with a regimen(SSTR/LTR) likely to be effective should be started as early
as possible and adjusted based on DST results once they become available and potentially
life-saving treatment(SSTR/LTR) should not be withheld.
• Assessment for underline cardiac disease/IHD, peripheral neuropathy, anemia should be
done. Please remember that baseline anemia of some degree will be present in chronic TB/
MDR TB patients due to TB disease, mostly iron deficiency anemia, Lzd should be used with
caution keeping in view anemia severity grading
• For some medicine, DST results would present uncertainties (e.g. cycloserine, streptomycin,
ethambutol). “Likelihood of effectiveness” is generally assessed in the programmatic setting
on the basis of one or more of the following:
(i) confirmed susceptibility in the individual patient;
(ii) confirmed susceptibility in the presumed source case;
(iii) no known resistance to another drug which has cross-resistance to the medicine;
(iv) rare use of the medicine in an area (possibly supported by low drug-resistance levels from
surveillance activities);
(v) no previous use of the medicine in a regimen that failed to cure that same patient.
• The design of the regimen has to take into account the relative benefits to harms to the
individual patient, including drug-drug interactions
• It is recommended by WHO that treatment should start with at least four medicines likely
to be effective and that at least three agents are continued for the rest of treatment after
bedaquiline is stopped.
• Possibly all three Group A agents(Lfx/Mfx, Bdq,Lzd) and at least one Group B agent(Cfz or Cs)
should be part of regimen and if only one or two Group A agents are used, then both Group
B agents are to be included in regimen.
• If the regimen cannot be composed with agents from Groups A and B alone, Group C agents
are added to complete it.
• Starting treatment with five effective agents rather than four may also be a practice and this
provision is expected to apply to those with additional resistance or suspected resistance to
fluoroquinolones or other medicines.
• Bdq use beyond the currently recommended duration ( 6 months) and age group is
considered as “off label” should be case by case keeping in view treatment response and
number of effective drugs on board after Bdq is stopped
• The use of three cardiotoxic drugs (Bdq, Dlm and Cfz) in combination should be with caution
and with close monitoring. However, recent data shows that combined use of Bdq and Dlm is
safe and QTcF interval with co administration of both drugs is clinically modest (Dooley et al,
2019)
• The use of Lzd for whole duration is associated with better treatment outcomes and
lower mortality, but is expected to cause toxic effects in significant number of patients.
The neurological toxicity is associated with duration, while hematological toxicity/
myelosuppression is dose related.
• For Lzd use in the regimen, baseline assessment by Blood picture and neuropathy screening
should be done and if contraindicated, should not be part of regimen or if possible with
lower dose of 300 mg daily or 600 mg alternative days
• The addition of Pyrazinamide(Z) in the regimen is useful as it has synergistic effects when used
in combination with strong bactericidal (FQs, Bdq, Am)and strong sterilizing drugs(Bdq,Cfz).
However, if reliable DST source is confirming resistance then should not be counted effective.
• Injectable, Am should only be used in regimen if there is documented susceptibility to it and
appropriate monitoring for hearing loss is available. WHO also recommends to use Am in 18
years of age or above.
• In cases when there is doubt about the effectiveness of a certain medicine, it may still be
included in the regimen but it should not be considered clean/likely effective to the number
of medicines needed in the regimen and clinical judgment is advised to decide if the benefit
from its inclusion outweighs any added toxicity or pill burden, for example Mfx/Lfx, Cfz.
The basic principle of MDR TB Treatment should always be applied that never add a single drug
to a failing regimen.
If the long-course regimen fails, treatment options will be very limited. The patient must be
referred to the DR-TB Referral Centre.
Contraindications and Drug-Drug Interactions

In line with WHO 2019 guidelines and regrouping of medicine, Bdq and Lzd will be part of
standard MDR TB regimen, while Dlm from group C is an important add on drug and a good
choice to replace in cases with toxicities. Therefore, it is important to thoroughly learn about
these medicines and their use while constructing the regimen. However, in the best judgement of
treating physician and in line with specialist advise these medicines can be used with precautions.
TABLE 4.2 Contraindications and Precautions with Bdq, Dlm and Lzd ( Source: End TB 2018 DR-TB
guideline) Drug Name
RELATIVE CONTRAINDICATION PRECAUTIONS

Bdq, Dlm History of syncopal episodes, Use with caution if QTcF >
ventricular arrhythmias or severe 450/470 ms in male/female
coronary artery disease patients.
Baseline ECG with QTcF > 500 ms Weekly ECG monitoring and
(repeated) serum electrolyte screening
should be performed if Bdq
or Dlm is being used despite a
cardiac contraindication. Dlm is
less cardiotoxic than Bdq(new
data has shown that QTC-F
prolongation with combined
use of Ddq and Dlm is clinically
modest and safe)
Bdq,Lzd,Dlm Severe renal Failure Usually no dose adjustment is
required in mild to moderate
renal failure
With precaution in severe renal
failure/impairment
Bdq Severe hepatic failure Try not to use if patient has severe
liver function impairment
ART should be adjusted if used
in HIV cases particularly efavirenz
containing regimen should be
avoided
Lzd Pre-existing mild to moderate Special precautions when used in
peripheral neuropathy (based combination with Cs, high dose
on Basic Peripheral Neuropathy INH and diabetics.
Screening (BPNS), subjective sensory In mild to moderate
neuropathy scoring ) Myelosuppression and Anemia
Severe Myelosuppression and Lzd can be used with lower
Anemia, moderate neutropenia doses, 300 mg daily or 600
mg alternative days with close
monitoring
Drug-Drug Interactions and Overlapping Toxicities with Bdq, Dlm and Lzd
It is essential to consider the drug-drug interactions with Bdq, Dlm and Lzd as using in concomitant
use of many routinely prescribed drugs may have various level impact having either decreased
or increased absorption, toxicity and adverse events. It may be needed that patients should be
given a card mentioning the name of drugs that should not prescribed by any GP/doctor while
patient is on ambulatory care in community. Therefore, treating physicians should review all the
medicines patients are taking while enrolling on MDR TB Treatment.
Drug-Drug Interactions with Bedaquiline

Following drugs should be avoided to be used with Bdq;
Strong/moderate inducers of cytochrome P450: These may decrease blood levels of Bdq:
Efavirenz, Rifamycins, Phenytoin, Carbamazepine, Phenobarbital.
Drug that may increase blood levels of Bdq: Ritonavir-boosted PIs, Oral azole antifungals (can be
used up to two weeks): Itraconazole,Fluconazole, Macrolide antibiotics other than azithromycin
Drug-Drug Interactions with Delaminid

Fist line Anti TB Therapy (HRZE), as these drugs appear to reduce level of Dlm Overlapping Toxicity
with Bedaquiline and Delaminid
Moreover, many other drugs also have overlapping toxicity when used with Bdq and Dlm:
Antipsychotic drugs (Haloperidone, Risperidone) Many anti-nausea drugs (Ondansetrone,

Granisetron, Domperidone, Chlorpromazine), Methadone, Cardiac drugs that may affect the
heart rhythm(Amiodarone, Beta-blockers,Digoxin,Quinidine)
Linezolid and concomitant medicines that Increase Serotonin Levels: Serotonin re-uptake
inhibitors (SSRIs): fluoxetine, paroxetine Tricyclic antidepressants: amitriptyline, nortriptyline
Serotonin 5-HT1 receptor agonists MAO inhibitors: phenelzine, isocarboxazid Other serotoninergic
agents: meperidine, bupropion, or buspirone, quetiapine
For more information on drug safety and QT interval prolongation can be obtained at https://
crediblemeds.org/
4.3. RR/MDR-TB TREATMENT REGIMENS

Based on the 2019 WHO consolidated guideline, the National TB programme updated the RR/
MDR TB regimens for Nepal. Step wise approach was used in constructing the standard regimens
applicable for the country as Principles of MDR TB Treatment and Regimen Construction. Longer
RR/MDR TB treatment regimen (LR1) should be given only in case where SSTR cannot be initiated.
TABLE 4.3 RR/MDR TB regimen construction in Line with WHO 2019 Regrouping
RESISTANCE PATTERN AND REGIMEN COMMENTS
BACKGROUND HISTORY
LR1 Standard longer RR/MDR 1. In case of toxicity or need
TB Regimen for adults and Bdq(6), 18 Lfx,Lzd,Cfz,Z to decrease or substitute Lzd
children 6 yrs and above with Cs refer to aDSM relevant
section
2. If Lzd is well tolerated, should
Non-eligible for SSTR and be continued throughout the
for those whose FQ results treatment duration
unknown/ awaited/sensitive
Treatment of RR/MDR TB with additional resistance (Pre-XDR and XDR)

1. It is imperative that all diagnosed RR/MDR TB should be placed on DST regardless of choice
of SSTR or Longer regimen and currently availability of rapid molecular DST(LPAs) make the
results availability quicker.
2. The DST result to FQ should be known as soon as possible and regimen to be adjusted
accordingly.
3. However, as implementation consideration there might be delays in result availability and
treatment initiation with best empirical regimen should not be delayed.
4. Principle for designing longer regimen for DR TB patients remains same with or without
additional resistance.
5. The basic principle of having at least 4 effective drugs on board in the beginning and at least
3 drugs to be continued after 6 months (or when Bdq/Dlm is stopped). It is impotant that at
least one strong bactericidal drug should be on board through out.
6. The duration of treatment also applies same as minimum 18 months and can be extended
based on patients response to treatment.
TABLE 4.4 Pre-XDR and XDR regimen construction in Line with WHO 2019 Regrouping
LR2 RR TB with risk Bdq (12),18Lzd, 1. High dose Lfx or Mfx can be added once
of FQ resistance/ Cfz, Cs,Z resistance level to FQs are known
FQ resistance at 2. In cases with intolerance/toxicity to Lzd,
baseline (Pre-XDR) stopping Lzd, replacing with Dlm can may be a
and XDR TB suitable option. If Dlm cannot be added, then
Eto. can be used instead
3. Close and careful monitoring with combination
of three cardiotoxic drugs (Bdq, Cfz, Dlm)
LR3 Failed by MDR TB 6 Am, Dlm, Eto, 1. DST to FLD and SLDs should guide further
standard treatment PAS (Cs), Cfz modification where necessary
(LR1) /Relapse or (Mfx/Lfx) – 12 2. Use Am if documented susceptibility to it, design
recurrence of MDR Dlm (6), Eto, PAS regimen based on previous exposure to SLDs
TB (Cs), Cfz, (Mfx/ and likely effective drugs.
Lfx) 3. If susceptible to FQ, high dose Lfx or Mfx can be
used, if resistance to FQ then FQ can be used in
line with level of resistance reported
4. Extending use of Dlm for whole duration could
be an option
5. If Cs was used as a part of LR1 then use PAS
instead
6. Imp/Clv can be used when injection (Am) cannot
be used, or after Am stopped by 6-8 months
LR4 1.Secondary LR4.1 18 1. DST to FLD and SLDs should guide further
XDR (FQ and SL Dlm(12),Cs, Imp/ modification where necessary
Inj. Resistance) Clv (10), Eto,PAS, 2. Design regimen based on previous exposure to
and Exposure to Cfz,Z SLDs
standard MDR 3. Dlm extension through out treatment may be a
regimen such as good option
failure/relapse/LTFU LR 4.2 18 4. Clinical case discussion with DR experts before
to LR1 Dlm(12), Imp/ initiation of LR4 (Case discussion panel)
2. Failure of LR2 Clv (10), Eto,PAS,
Cfz, Z
34
TABLE 4.5 Adult drug dosages in the long regimen (LR)

Drug Formulation Daily dose 30–35kg 36–45kg 46–55kg 56–70kg >70kg
Moxifloxacin standard dose 400mg tab 7.5-10mg/kg 1 tab 1 tab 1 tab 1 tab 1 tab
Moxifloxacin high dose 400mg tab 1-1.5 tab 1.5 tab 1.5-2 tab 2 tab 2 tab
Levofloxacin (high dose upto 1500mg 250mg tab 15-25mg/kg/day 3 tabs 3 tabs 4 tabs 4 tabs 4 tabs
daily) 500mg tab 1.5 tabs 1.5 tabs 2 tabs 2 tabs 2 tabs
750mg tab 1 tab 1 tab 1.5 tabs 1.5 tabs 1.5 tabs
Amikacin1 <60 years 500mg/2ml 15mg/kg 1x/day 2.5 ml 3 ml 3-4 ml 4 ml 4 ml
per vial (max 1gr)
≥60 years 10mg/kg 1x/day 2 ml 2.5 ml 2.5 ml 2.5-3 ml 3 ml
(max 750mg)
Ethionamide 250mg tab 15-20mg/kg/day 2 tab 2 tab 3 tab 3 tab 4 tab
Clofazimine 100mg cap 100mg/day 1 cap 1 cap 1 cap 1 cap 1 cap
Cycloserine 250mg cap 10-15mg/kg/day 2 cap 2 cap 2 cap 3 cap 3 cap
Pyrazinamide 400mg tab 20–30mg/kg/day 3 tab 4 tab 4 tab 4 tab 5 tab
Ethambutol 400mg tab 15–25mg/kg/day 2 tab 2 tab 3 tab 3 tab 3 tab
Isoniazid high-dose 300mg tab 10mg/kg/day 1.5 tab 1.5 tab 2 tab 2 tab 2 tab
PAS 4gm sachet 150-200mg/kg/day 1 sachet 1 sachet 1 sachet 1 sachet 1-1.5
bd bd bd bd sachet bd
Linezolid 600mg tab 600mg /day 1 tab 1 tab 1 tab 1 tab 1 tab
Delamanid 50mg tab 200mg/day 2 tab bd 2 tab bd 2 tab bd 2 tab bd 2 tab bd
Clavulanic Acid 125mg with Amoxicillin 250mg/day 125mg bd 125mg bd 125mg bd 125mg 125mg bd
& Meropenem bd
Imipenem-cilastatin 500mg vial 4gm/day 1gm bd 1gm bd 1gm bd 1gm bd 1gm bd
Bedaquiline 100mg tab 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks
Meropenem to be used with clavulanic acid 1000mg vial 20 ml 1 vial 3 times or 2 vials 2 times daily IV
Intensive Phase and Treatment Duration:

Intensive (or injectable) phase: WHO has recently in 2019 guidelines, recommended that
regimens without an injectable agent are considered not to have an intensive phase. However,
in Longer MDR TB treatment if Injectable (Amikacin or Streptomycin) has to be used, WHO
recommends an intensive phase of 6 months for most patients and IP duration may be increased
as per response to treatment.
“The recommended duration of an injectable drug during the intensive phase is guided by the
culture conversion. An injectable agent should be used for a minimum of six months with at least
four negative cultures and given that patient remains converted”.
— Missing or contaminated results would not be counted.
— Once patient is converted and if there is one positive culture followed by at least two
consecutive negative cultures and patient is clinically doing well, stable and improving, this
positive culture may be ignored.
— If there are two positive cultures after conversion, then it should be followed by at least 4
negative cultures.
For SSTR, recommendation of Intensive phase remains same as the Injectable(Am) is used for 4
months and may be extended to 6 months case by case depending upon smear results by month 4.
Treatment Duration:
As per new WHO guideines, 2019 for of longer MDR TB regimens duration following is
recommended;
• A total minimum duration of 18 months
• A treatment duration of 16 months is recommended after culture conversion
• The treatment duration may be modified as per patients response to treatment
• Prolonging the treatment longer than 20 months may be considered in patients with
additional resistance or late converters, extensive disease and other risk factors for failure or
relapse of treatment.
Treatment Outcomes for RR-TB/MDR-TB/XDR-TB patients treated using second-line treatment
Cured:
• Treatment completed as recommended by the national policy (minimum 18-months with
16 months past culture conversion) without evidence of failure AND 3(three) or more
consecutive cultures taken at least 30 days apart are negative.
• For the purpose of declaring cure, the patient should have three consecutive negative
cultures reported by the end of treatment, ensuring that cultures are done as per national
policy.
• If there is one positive culture by the end of treatments, this positive culture should be
followed by 3 negative cultures
Treatment completed: Treatment completed as recommended by the national policy

(minimum18 months) without evidence of failure BUT no record that three consecutive cultures
taken at least 30 days apart are negative.
Treatment failed Treatment terminated or need for permanent regimen change of at least two
anti-TB drugs because of:
• lack of conversion by the end of 6 months of treatment or in case of injectable by the end of
intensive phase, OR
• bacteriological reversion in the continuation phase after conversion to negative, OR
• evidence of additional acquired resistance to fluoroquinolones or second-line injectable

drugs, OR
• adverse drug reactions (ADRs) leading to permanent treatment termination
NOTE:
• If an MDR TB patient has 4 positive cultures and is on month 6 of treatment, it is suggested to
repeat LPA/DST to SLDs and act accordingly as per result. Please note that there may be a delayed
response to treatment in XDR-TB patients.
• In case of reversion after six months of treatment or after intensive phase in cases if injectable;
repeat LPA/DST to SLDs, continue with treatment and decide as per result of LPA/DST.
Died: A patient who dies for any reason during the course of treatment
Lost to follow-up: A patient whose treatment was interrupted for 2 consecutive months or more.
Not evaluated: A patient for whom no treatment outcome is assigned. (This includes cases
“transferred out” to another treatment unit and whose treatment outcome is unknown)
Treatment success: The sum of cured and treatment completed
The sum of Cured and Treatment completed is commonly used as an indicator of favorable
outcome, or Treatment success. The outcome Cured is restricted to pulmonary bacteriologically
confirmed TB cases only.
4.4 SHORTER STANDARDIZED TREATMENT REGIMEN (SSTR)

4.4.1 Drugs, dosages, frequency and duration of administration
The SSTR consists of an intensive phase of 4 months with 7 drugs, followed by a continuation
phase of 5 months with 4 drugs. The intensive phase will be extended if smear conversion is not
achieved within 4 months, with a maximum of 6 months (see algorithm in figure 3):
Intensive phase
4 (+1 or 2) months
Continuation phase
Amikacin
5 months (fixed)
Ethionamide
Isoniazid high-dose
Moxifloxacin high-dose
Clofazimine
D
Pyrazinamide FIXE
Ethambutol
4-6 Am Mfxh Eto Hh Cfz E Z / 5 Mfxh Cfz E Z

Drugs are given daily according to the dosages in table A and B below and all drugs are to be
given in a single dose.
TABLE 4.6 (A) Adult dosages of the drugs used in the SSTR
Drug Dosage Weight group (Kg)
30-35
36-45 46-55 56-70 >70
Amikacin1 <60 15mg/kg 500mg 625 mg 750 mg 875mg 1000
(vial 500 mg- years (maximum 1 (2ml) (2.5ml) (3) (3.5) mg
2ml) gram) (4ml)
≥60 10mg/kg 350mg 450mg 500mg 500mg 750mg
years (maximum 750 (1.5ml) (2ml) (2ml) (2ml) (3ml)
mg)
Ethionamide2 15-20mg/kg/d 500mg 500mg 750mg 750mg 1gm
(tablet 250mg) (2 tab) (2 tab) (3 tab) (3 tab) (4 tab)
Isoniazid high-dose 10mg/kg/d 300mg 450mg 600mg 600mg 600mg
(tablet 300mg) (1 tab) (1.5 tab) (2 tab) (2 tab) (2 tab)
Moxifloxacin high-dose 10-15mg/kg/d 600mg 600mg 600- 800mg
(tablet 400mg) (1.5 Tab) (1.5 Tab) 800mg (2 Tab) 800mg
(1.5-2 (2 Tab)
Tab)
Clofazimine 2-3mg/kg/d 100mg 100mg 100mg 100mg 100mg
(capsule 100mg) (1 tab) (1 tab) (1 tab) (1 tab) (1 tab)
Pyrazinamide 20-30mg/kg/d 1000mg 1200mg 1600mg 2000mg 2000mg
(tablet 400mg) (2.5 tab) (3 tab) (4 tab) (5 tab) (5 tab)
Ethambutol 15-25mg/kg/d 800mg 800mg 800mg 1200mg 1200mg
(tablet 400mg) (2 tab) (3 tab) (3 tab) (4 tab) (4 tab)
1
Frequency of administration: 6x/week during months 1 to 4; from month 5 onwards: 3x/week.
2
250mg once daily on days 2 to 4; 2 x 250mg/day on days 5 to 7; 250mg in the morning, 500mg in the evening from
day 8 onwards if patient >50kg.
TABLE 4.6 (B) Pediatric dosages of the drugs used in the SSTR
Drug Dosage Weight group
10-14kg 15-19kg 20-24kg 25-29kg
Amikacin (vial 500 mg – 2ml)
1
15-20mg/kg 200mg 300mg 400mg 500mg
Ethionamide (tablet 250mg) 15-20mg/kg ½ tab ½ tab ½ tab 1 tab
2x/d 2x/d morning 1 2x/d
tab evening
Isoniazid high-dose (tablet 100mg) 10-15mg/kg 1 tab 2 tab 3 tab 4 tab
Moxifloxacin high-dose (tablet 400mg) 10-15mg/kg ½ tab ½ tab 1 tab 1 tab
Clofazimine (capsule 50mg) 2-3mg/kg 2
1 cap 1 cap 1 cap/d 1 cap/d
4x/w 6x/w
Pyrazinamide (tablet 400mg) 30-40mg/kg 1 tab 1½ tab 2 tab 2tab
Ethambutol (tablet 400mg) 15-25mg/kg 3
½ tab ½ tab 1 tab 1 tab
1
Frequency of administration: 6x/week during months 1 to 4; from month 5 onwards: 3x/week. Monitor regularly
through audiometry: see M5.
2
Capsules cannot be divided, as they contain a gel. Give intermittently to arrive at a correct average weekly dose.
Example: child of 13 kg should receive 20-30mg/day corresponding to 182-273mg/week; give Cfz 50mg 4x/week
corresponding to 200mg/week.
3
Doses closer to 15 mg/kg/day are used if the drug is used for more than 2 months
The algorithm in figure 3 shows how the drugs of the SSTR are introduced. On day 1, treatment
will start with all drugs except Eto. The drugs are given together in a single daily administration.
If there is no major adverse event on day 1, Eto 250 mg will be added on day 2. The dosage of
Eto will be escalated to 500mg on day 5 if patient can tolerate Eto 250 mg, and further escalated
to 750mg (250mg in the morning, 500mg in the evening) on day 8 if necessary depending on
patients’ body weight. An antiemetic drug may be used if there is gastrointestinal disturbance.
FIGURE 3. Schematic overview of drug introduction and duration of administration in the SSTR
4.4.2. Criteria to decide when the shorter MDR-TB regimen may be offered
Since 2016, the regimen has been recommended by the WHO for treatment of the MDR- TB
patients who do not present resistance to the FQ or the SLID. Patients with an RR/MDR GeneXpert
result are not eligible to receive the STR if all of the following conditions are fulfilled.
Is any of the following present?

• Preference by the clinician and patient for a longer MDR-TB regimen
• Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB
regimen (except isoniazid resistance)
• Exposure to one or more 2nd line medicines in the shorter MDR-TB regimen for >1 month
(unless susceptibility to these 2nd line medicines is confirmed)
• Intolerance to medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug
interactions)
• Pregnancy
• Disseminated, meningeal or central nervous system TB
• Any extrapulmonary disease in PLHIV
• One or more medicines in the shorter MDR-TB regimen not available
FAILING SHORTER REGIMEN or NON-RESPONSE,

YES DRUG INTOLERANCE, EMERGENCE OF ANY OTHER NO
EXCLUSION CRITERION
Individualized, Standardized, shorter
longer MDR-TB MDR-TB regimen
may be offered
regimens (conditional recommendation)
Beside above mentioned criteria if patient has severe bilateral lung damage or severe disease at
baseline Longer RR/MDR regimen should be initiated.
4.4.3. When to discontinue the administration of the SSTR

The SSTR will have to be discontinued in the following situations:
• Severe toxicity due to Mfx: FQ is the most important drug in the regimen. If the Q-T interval
is seen to increase and risks exceeding >500msec. If this has no effect and the Q-T interval
continues to be elevated, the regimen must be discontinued.
• In case of occurrence of ADR discontinue the SSTR in line with aDSM protocol.
• Pregnancy during treatment
• Sputum smears remain positive up to month 6 (dead bacilli needs to be ruled out)
• Culture remains positive at end of intensive phase or reverts to positive during continuation
phase: see figure 4. In practice, this amounts to:
- Culture is positive at month 4 or 5 or 6, depending on the duration of the intensive phase
- After negative culture at end of intensive phase, 2 consecutive cultures are positive during
the continuation phase
When the SSTR has to be permanently discontinued due to AE, the patient must be sent to the
DR-TB Centre, where an appropriate long-course regimen will be initiated.
Treatment regimen of SSTR and Failure to SSTR (Modified LR2)

SSTR Standard Shorter 4-6 Amk,Mfxh, Cfz, Eto, INHh, E, 1.As per standard protocol (Km
Treatment Z/5 Mfxh,Cfz, Z,E replaced with Am)
Regimen(SSTR) 2. In case of toxicity and SSTR
cannot be continued, then
switch to LR1
Modified Failed by SSTR 18 Bdq(12), Dlm(6), Lzd,Cs,Cfz, DST to FLD and SLDs should
LR2 PAS guide further modification
where necessary
Bdq can be extended to whole
duration case by case as per
likely effective drugs remaining
in regimen after Bdq is stopped.
FIGURE 4. Monitoring treatment progress of SSTR through culture
Sputum smear result

4 months ‒ + + +
5 months ‒ + +
6 months ‒ +
â â â
Stop intensive phase after 4 months after 5 months after 6 months
o o o
culture at 4 culture at 5 culture at 6
months months months
Definition of outcome in SSTR

Generally the outcome definition are similar as of Longer RR/MDR TB Regimens. However, there
is slight change in failure definition.
Cured: Treatment completed without evidence of failure AND three or more consecutive cultures
taken at least 30 days apart are negative after the intensive phase.
Treatment completed: Treatment completed without evidence of failure BUT no record that
three or more consecutive cultures taken at least 30 days apart are negative after the intensive
phase.
Failure: The patient may be declared failure if meets one of the following criteria;
• Acquired resistance to FQ and or injectable
• Sputum smear positive at month 6 along with poor clinical and radiological response or
worsening by the end of intensive phase
• There are two positive Cultures taken at least 30 days apart in continuation phase of SSTR
treatment OR
• One culture positive in the last three months of treatment and recent follow up month smears
are also positive
Clinical decision in consultation with TWG has been made to permanently terminate treatment
early because of poor clinical or radiological response or adverse events
NOTE: Changing or switching treatment to longer regimen due to SAEs is not failure.
Died: A patient who dies for any reason during the course of treatment.
Lost to follow-up: A patient whose treatment was interrupted for 2 consecutive months or more.
Not evaluated: A patient for whom no treatment outcome is assigned. (This includes cases
“transferred out” to another treatment unit and whose treatment outcome is unknown).
Treatment success: The sum of cured and treatment completed

4.5 TREATMENT OF INH RESISTANT TB

Among most potent and effective treatment of TB drugs , Isoniazid (H) plays vital role and
because of its strong bactericidal activity, it is one of the most important first-line medicines for
the treatment of active tuberculosis (TB) and latent TB infection (LTBI). Globally about about 8%
of TB patients are estimated to have rifampicin-susceptible, isoniazid-resistant TB (Hr-TB) ranging
from 5 to 11% between the WHO regions(WHO 2017), Thus emergence of TB strains resistant to
isoniazid threaten to reduce the effectiveness of TB treatment (WHO 2016, 2018). While in Nepal
5.6% are with Hr monoresistance TB(DR Survey 2011, Nepal).
Treatment of mono- and poly-resistance with WHO standardized first-line anti-TB drug regimens
has been shown to increase the risk of treatment failure and even worse, amplification (acquisition
of additional resistance) to multidrug resistance (Jacobson KR et al 2011). Moreoevr, Diagnosis in
such cases may not be known for weeks or months.
TB control programs generally focus on MDR-TB because these highly resistant strains are difficult
to treat, and cause much morbidity and mortality. However, at the same time, the significant
number of Hr TB who remain undiagnosed and inappropriately treated can not be ignored.
4.5.1 Following are the operational ways to treat patients;

• Patients with a history of previous treatment who have pan-susceptible disease to be treated
with first-line drugs
• Patients with mono- or poly-resistance (other than RRTB) should be treated with appropriate
regimens
• Patients with RR/MDR-TB should be treated with second-line therapy
Diagnosis of Hr TB
The Hr TB can be diagnosed using 1st Line LPA and phenotypic conventional DST to 1st line
drugs. This has been observed that such cases are now being increasingly reported and early
detection of such cases is crucial.
Following is suggested to diagnose the Hr TB:

1. Close contacts of patients who are being treated with mono/poly DR TB should be tested
both by Xpert MTB/RIF and by 1st Line LPA if Xpert MTB/RIF shows no RR TB
2. DS TB retreatment patients when tested with Xpert MTB/RIF and result is T, such patient
should be tested by LPA 1st Line
3. Xpert MTB/RIF with result T in DS TB non converters
4. Clinicians should request testing 1st line drugs by liquid/solid DST, where LPA not available or
non-interpretable and patient response in poor to treatment
Once the mono and poly DR TB(other than RR TB) is reported, it is also imperative to request SL
LPA to exclude resistance to FQs, particularly in Nepal as Pre XDR/XDR TB prevalence in high.
WHO in 2017 guidelines for treatment of Hr TB has following recommendation;

In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, treatment
with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration
of 6 months. However, if no REZ FDC is available then the suitable option is to use HREZ FDC.
Intermittent or divided dosing of the 6(H)REZ-Lfx regimen is to be avoided and weight band
dosing scheme for Lfx is recemmended.
The implementation to this recommendations requires that the (H)REZ-Lfx regimen is administered
only in patients in whom resistance to isoniazid is confirmed and resistance to rifampicin has
been excluded. Preferably, testing for resistance to fluoroquinolones possibly prior to treatment
initiation . It is also important to test for resistance to pyrazinamide and later treatment adjusted,
while E and S has no practical implication on treatment as DST is not usually reliable.
In line with WHO recommendations, practically following situations apply at filed level;
1. Hr-TB is confirmed before TB treatment is started: Treatment with the (H)REZ-Lfx is started
immediately. If the diagnosis is strongly presumed (e.g. close contacts of a confirmed Hr-TB
source case) but results of drug susceptibility testing are still pending the regimen may be
introduced. Should drug susceptibility test results taken at start eventually show susceptibility
to isoniazid, then levofloxacin is stopped and the patient continues treatment in order to
complete a 2HREZ/4HR regimen.
2. Hr-TB is confirmed after the start of treatment with 2HREZ/4HR regimen: This includes patients
who had undiagnosed isoniazid resistance at the start or who developed isoniazid resistance
later while on first-line regimen treatment. In such cases, rapid molecular testing for rifampicin
resistance must be done (or repeated). Once rifampicin resistance is excluded, a full 6-month
course of (H)REZ-Lfx is given. The duration is driven by the need to give levofloxacin for 6 months,
which usually implies that the companion first-line medicines are taken for longer than this.
3. If rifampicin resistance is detected, the patient needs to be started on a recommended MDR-
TB treatment regimen.
Moreover, in cases where Lfx can not be used becuase it is hypersensitve or resistance, then WHO
recommends treatment with 6(H)REZ. However, in such situations and in patients with ressitance to
H+Z+E or H+Z+Lfx, the use of 6(H)RZE may not contain enough agents on board to ensure effective
and relapse free treatment. Therefore, the treating physicain in line with pannel discussion has to
decide best treatmnet options and drugs from Linezolid, Ethionomide and Cyclocerine may be
used. However, use of Bedaquiline and delaminid other than RR TB is not recommended so far. The
use of Mfx is also not recommended with rifampicin as the concentration of Mfx is decreased.
Treatment prolongation beyond 6 months: may be considered for patients with extensive
cavitary disease or in patients slow to convert to negative smear/culture.
It is imperative to perform Xpert MTB/RIF in all mono and poly DR cases, before enrolling them
on treatment, this excludes cases with R,RZ,RZE as such cases require full MDR TB treatment.
Likewise, It is essential that always use Xpert MTB/RIF at month 0, 2, and 3 and if rifampicin
resistance is found switch to full MDR-TB treatment. For monitoring purposes, it should be
followed as in DS TB regimen.
* Principle of never adding single drug to failing regimen is the mainstay of treatment
4.5.2. Drug dosage for Hr-TB regimen

Dosage with 4-drug FDC (RHZE) - Adults
Weight bands in adults 4-drug adult FDC Levofloxacin 250mg (15-20 mg/kg)
RHZE-150/75/400/275*
30-39 kg 2 tablets 2 tablets
More than 70 5 tablets 5 tablets
*The dose of levofloxacin should not exceed 1.5 gm per day
Dosage with 3-drug FDC (RHZ) - Children

Weight bands in 3-drug paediatric FDC Ethambutol 100mg Levofloxacin 100mg
children* RHZ-75/50/150
4-7 .9 kg 1 tablet 1 tablet 1 tablet
8-11.9 kg 2 tablets 2 tablets 2 tablets
25 kg + Use adult doses and preparation
* In children weighing 25 kg or more, the adult schedule shown in the previous section is followed.
If levofloxacin 100mg dispersible tablet is not available, the 250mg tablet can be used with 6(H)
REZ in children aged 0-14 years, based on a slightly different weight band from the above:
Weight Levofloxacin 250mg
5 - 6 kg ½ tablet / day
7 - 9 kg ¾ tablet / day
10 – 15 kg 1-1.5 tablet / day
16 – 23 kg 1.5.2 tablets / day
24 – 30 kg 2-2.5 tablets / day
31 kg + Follow adult schedule (up to 1.5g / day)
4.6 TREATMENT OF MDR-TB IN SPECIAL SITUATIONS

4.6.1 MDR-TB in women of child bearing age
4.6.1.1 Pregnancy testing and contraception
Most second-line drugs are toxic for the foetus. Before starting any second-line treatment, all
women of child bearing age should have a pregnancy test. If the test is negative, contraception
must be recommended. The use of oral contraceptives is not contraindicated during MDR-TB
treatment, but several second-line drugs may cause vomiting. Patients who vomit directly after
taking an oral contraceptive can be at risk of decreased absorption of the drug and therefore
of decreased efficacy. The contraceptive should be taken at a time when vomiting as a result of
the anti-TB medications is least likely to occur. Patients who vomit at any time directly after, or
within the first two hours after taking the contraceptive tablet, should use a barrier method of
contraception until they have been able to take the contraceptive tablets without vomiting for
a full month.
4.6.2 Pregnancy and MDR-TB treatment

• Pregnancy is not a contraindication for treatment of active drug-resistant TB, but poses great
risk to the lives of both the mother & fetus.
• All female patients of childbearing age should be tested for pregnancy upon initial evaluation.
• The risks and benefits of treatment should be carefully considered, with the primary goal to
protect the health of the mother and child, both before and after birth.
• Most pregnant patients should be started on treatment as soon as the diagnosis is made
• Treatment may be delayed until the second trimester when the patient is very stable with
minimum disease as majority of taratogenic effects occur during 1st trimester. Risks and
benefits should be carefully evaluated. However, it is better to start treatment with safer
options
• Other family members, especially the father may need to be consulted depending on the
relevant family, religious, cultural and social dynamics
• Treat with three or four oral second-line anti-TB drugs which are likely to be highly effective
plus pyrazinamide and regimen should be reinforced with other drugs as needed immediately
postpartum (WHO 2014)
• Despite limited data on safety and long-term use of fluoroquinolones, cycloserine,
paraaminosalicylic acid (PAS) in pregnancy, they are considered the drug of choice for MDR-
TB treatment during pregnancy. Clofazimine has been used extensively in leprotic pregnant
patients and also now NTPs have developing experience of using Cfz in pregnancy, therefore
Clofazimine is found safer in pregnancy (thugh FDA safety class C) and can be used. Now US
FDA has placed Bedaquiline in safety class B and South Africa has been using safely Bdq in
pregnancy.
• Therefore, the most suitable option of regimen will be Lfx, Cfz, Cs, PAS, Z or if needed Bdq
may be used as best practice option
• Ethionamide should be avoided as can increase the risk of nausea and vomiting associated
with pregnancy, and teratogenic effects have been observed in animal studies.
• The termination of pregnancy may be considered if would carry a significant risk to her life
• If some of the effective drugs were withheld because of the pregnancy, they can be added
back postpartum to make a more complete regimen(WHO 2014)
• Please be informed of the principle of never adding single drug to failing regimen
• Total duration is same as for MDR TB
• The child should receive Bacillus Calmette–Guérin (BCG) vaccination at birth as per WHO
policy.
FDA Safety call of SLD in pregnancy
Drugs US FDA Summary

safety
class
Animal studies have not revealed any evidence of harm to the fetus or
any effects on fertility in females, some males treated with high doses
failed to procuce offspring. There are no controlled data in human
Bdq B pregnancy.22
Pharmacokinetic data in rats treated with doses 1-2 times the
human clinical doese have shown 6 to 12 fold higher bedaquiline
concentrations in milk than the maximum concentrations observed
Not yet in maternal plasma.
assigned In rabbits reproductive studies, embryo-fetal toxicity was observed at
Dlm an FDA maternally toxic dosages. Avoid in pregnancy; however the benefits
safety in patients with no other options may outweigh the risks.
class.
Pharmacokinetic data in animals have shown excretion of delamanid/
metabolites into breast milk. In lactating rats, the Cmax for delamanid
in breast milk was 4 fold higher than that of the blood.
Lzd C
Animal studies have failed to reveal evidence of teratogenicity, but
embryofetal toxicity was observed at maternotoxic doses. Placental
transfer of this drug and/or its metabolites was observed in rats. There
are no controlled data in human pregnancy.
There are no studies of clofazimine use in pregnant women. Few
cases of clofazimine use during pregnancy have been reported in the
Cfz C literature.
Embryofetal toxicity studies were conducted in rats, rabbits and mice.
In mice, clofazimine-induced embryotoxicity and fetotoxicity was
evident.
Ipm/Cln C Developmental toxicity studies with imipenem and cilastatin sodium
(alone or in combination) administered to monkeys, rabbits, rats, and
mice revealed no evidence of teratogenicity. However, an imipenem-
cilastatin dose of 40 mg/kg given to pregnant monkeys by bolus
intravenous injection caused significant teratogenicity/toxicity
Treatment regimen for RR/MDR TB in pregnancy

PLR1 RR/MDR TB 18Lfx, Cfz, Cs, PAS, Z 1. Cfz is relatively safe in pregnancy based on
treatment in experience in human use in Leprosy patients and
Pregnancy now developing experience in MDR TB.
2. FDA classifies BDQ in safety class B in pregnancy,
in south Africa Bdq in pregnancy has shown safety
3. After delivery switch the back to the original
applicable LR regimen
4.6.3 Breastfeeding
Breastfeeding is no contra-indication for MDR-TB treatment as anti TB drugs excretion through
breast milk is in very low concentration that is not harmful for neonate, but the benefit of
breastfeeding has to be weighed against the risk of exposure to MDR-TB infection of the infant, as
well as against the possible risks for the baby associated with the ingestion of second-line drugs
with the mother milk. Infant formula can only be considered a valid alternative to breastfeeding
if all required resources are available and appropriate training has been provided. If the infection
prevention can be maintained through personal protection like mask to the mother and good
environmental control can be achieved then breast feeding is preferred. If not option is to keep
the baby away from the mother as long as she is contagious, and to collect the mother’s milk
using a breast pump and bottle-feed the baby until it is safe to reunite mother and child.
4.6.4 MDR-TB in children

Diagnosis of MDR-TB among children can be challenging and requires a high level of suspicion.
Under field conditions, it may take several weeks from the time a child first presents with signs and
symptoms of TB and the receipt of test results, during which time a child can rapidly deteriorate.
Thus, it is important to consider initiating MDRTB therapy in the absence of bacteriologic
confirmation in line with consultation with pediatrician expert in TB/MDR TB.
GeneXpert Ultra and culture in liquid media should be prioritized in children. All relevant and
available tests should be considered; performing multiple tests on one or more samples of a
variety of specimen types significantly increases the diagnostic yield. Collecting the respiratory
specimen at optimal times is important to enhance the yield e.g. early morning fasting gastric
aspirate, before mobilization; induced sputum after fasting 2-4 hours; expectorated sputum early
morning. Of note, sputum(induced or expectorated) should be minimum 3 ml, Gastric aspirate 5
ml, gastric lavage 10 ml, or 3 ml , nasopharyngeal aspirate 2 ml.
In addition to that there are extra pulmonary samples useful to test by Xpert MTB/RIF to get
diagnosis in children and can be obtained any time, e.g. CSF, and Lymph node aspirate, Urine
(use of the urinary lipoarabinomannan (LAM) may be a useful test to diagnose TB in children
or individuals living with HIV with low CD4 counts). Serosal fluids include pleura, pericardium,
peritoneum, and synovium may also be helpful in diagnostics, but baceriolgical yield is higher in
tissues than fluids.
It is important that TB should be included in the differential diagnosis list of any child with a
persistent non- settling cough or fever, weight loss/failure to thrive, or focal findings that are
suggestive of TB, such as lymphadenitis, spinal deformities, ascites, and joint effusions. Danger
signs of possible meningitis include lethargy/sleepiness, loss of consciousness, and seizures
MDR-TB in children can either be confirmed (they have clinical TB disease and a sample taken
from the child shows MDR-TB) or clinically diagnosed (the child has clinical TB disease and has
risk factors for drug resistance).
Clinically diagnosed TB includes probable and possible MDR-TB.

Sometimes treating MDR TB in children becomes challenging as either some drugs in certain
age can not be used or difficult to monitor side effects as many second-line drug formulations
are not child-friendly, and preparation can be labor intensive. However, there are now child-
friendly, quality assured formulations are available from the Global Drug Facility: pyrazinamide,
ethambutol, levofloxacin, moxifloxacin, ethionamide, isoniazid, and cycloserine and hopefully
delaminid will also be available soon.
• The principles of regimen design for adults also apply for children based on the WHO
recommended regimen design as per grouping of SLDs.
• As per WHO 2019 recommendation,always attempt to treat children with injectable-free
regimens, especially in very young children and those with mild disease and if there is no
other option and Injectable has to be added then close monitoring by audiometry is crucial.
• Treatment of MDR-TB meningitis should be guided by the medicines with good penetration
to CNS
• Regimens should consist of at least 4 drugs to which the organism is likely to be effective and
susceptible and unnecessary/additional drugs should be avoided to avoid toxicity
• WHO in 2019 guidelines recommends bedaquiline for the treatment of children aged 6 years
and above and the use of delamanid for the treatment of children aged 3 years and above.
Moreover both the drugs are recommended for 6 months and beyond 6 months duration is
off label use
• In children with fluoroquinolone resistance or in whom there are limited treatment options,
extension and combination of bedaquiline and/or delamanid could be considered on a
patient-by-patient basis with careful monitoring
• Regimens will need to be designed for each individual patient—taking into account unique
resistance patterns and toxicity risks
• Linezolid being group A drug with good efficacy but its use has been associated with frequent
toxicity and related toxicities are duration dependent. Therefore, its use for throughout
duration cannot be warranted
• In children with HIV and MDR TB co morbidity, Bedaquiline and Efavirenz should be avoided
in combination use as efavirenz lowers the concentrations of Bedaquiline.
• Ethionamide(if no Inh A gene mutation) and PZA are also options to use if documented
susceptibility, PAS can also be used if no other effective option is left.
• The duration of therapy in children should depend upon the site and severity of disease;
children with non-severe disease can be treated for 9 to 12 months while children with severe
disease will require 12-18 months of therapy depending on their clinical progress . Of note,
the 2018 WHO recommendations define severe disease as follows:
“In children <15 years, severe disease is usually defined by the presence of cavities or
bilateral disease on chest radiography or extrapulmonary forms of disease other than
lymphadenopathy”. While Non-severe disease can be defined as TB disease that is isolated
to the lymph nodes or only affects one of the lungs without cavities. However, severity of
disease can also be determined by bacillary load if available.
Following are the regimens for children:
0-5 yo, pediatric 18 Lfx, Lzd,Cfz,Cs,Z 1. With Lzd based regimen

Standard RR/MDR TB monitor closely for related
CLR1 Regimen for FQ sensitive toxicities, especially with
Non-eligible for STR Cs together.
and for those whose 6 Years and above
FQ results unknown/ pediatric Regimen (FQ
awaited/sensitive sensitive and FQ res)
0-3yo, pediatric 18 Lzd,Cfz,Cs,INHh, Z Eto follow adult LRs as
Standard RR/MDR TB applicable
Regimen (FQ-resistant)
Treatment should be done
in close consultation with
pediatrician
CLR2.1
1. In case of toxicity or
need to decrease refer to
aDSM relevant section
2. If Lzd is well tolerated,

should be continued
throughout the treatment
duration
3-5 years pediatric 18 Lzd,Cfz,Cs,Dlm(6),Z
regimen FQ resistant
3. INH high dose showed
CLR2.2 good results in children
as per WHO 2016 IPD
analysis.
The treatment regimens for children are indicted as above. The dosages are indicated in tables
4.6. Daily dosing will be approximate: tablets may be cut into fragments and crushed, capsules
may be opened and the content fractioned. Small discrepancies will even out over time. The
drugs may be mixed with small amounts of liquid or soft food, particularly sweet jam.
50
TABLE 4.6 Pediatric dose of RR/MDT-TB longer regimen:

Weight bands among patients under 15 years old
Medicines Daily dose Formulation
5-6 kg 7-9 kg 10-15 kg 16-23 kg 24-30 kg 31-34 kg >34 kg
100mg dt 1 1.5 2-3 3-4 5 (>14 yrs) (>14 yrs)
Lfx 15-20 mg/kg
250mg tab 0.5 0.5 1-1.5 1.5-2 2 3 (>14 yrs)
Mfx 10-15 mg/kg 100mg dt 0.8 1.5 2 3 4 (>14 yrs) (>14 yrs)
Bdq - 100mg tab - - - 2 tabs OD for 2 weeks then 1 4 tabs OD for 2 weeks then 2
tab OD for 22 weeks tab OD for 22 weeks
15mg/kg in <16 20mg/ml 4 ml 6 ml 8 ml 11 ml 14 ml 15 ml 20 ml
kg suspension
Lzd
10-12mg/kg in 600mg tab 0.25 0.25 0.25 0.5 0.5 0.5 0.75
>15 kg
50mg cap or tab 1 alt. days 1 alt. days 1 alt. days 1 2 2 (>14 yrs)
Cfz 2-5mg/kg 100mg cap or 1 tab 3 times per week 1 alt. days 1 alt. days 1 (>14 yrs) (>14 yrs)
tab
125mg mini cap 1 1 2 3 4 (>14 yrs) (>14 yrs)
Cs 15-20mg/kg
250mg cap - - - 2 2 2 (>14 yrs)
100mg dt 1 2 3 4 - - (>14 yrs)
E 15-25mg/kg
400mg tab - - - 1 1-1.5 2 (>14 yrs)
Dlm* - 50mg tab - - - - 1 bd 1 bd 2 bd
150mg dt 1 2 3 4-5 - - (>14 yrs)
Z 30-40mg/kg 400mg tab 0.5 0.75 1 1.5-2 2.5 3 (>14 yrs)
500mg tab 0.5 0.5 0.75 or 1 1.5 2 2.5 (>14 yrs)
Imipenem- - 0.5gm vial - - - - - - -
cilastatin**
Meropenem to 20-40mg/kg IV 1gm vial/20ml 2 ml 4 ml 6 ml 8-9 ml 11 ml (>14 yrs) (>14 yrs)
be used with every 8 hours
clavulanic acid
Am 15-20mg/kg 500mg/2 ml vial 0.4 ml 0.6 ml 0.8-1 ml 1.2-1.5 ml 2 ml (>14 yrs) (>14 yrs)
Weight bands among patients under 15 years old
Medicines Daily dose Formulation
5-6 kg 7-9 kg 10-15 kg 16-23 kg 24-30 kg 31-34 kg >34 kg
Eto 15-20mg/kg 125mg dt 1 1 2 3 4 4 (>14 yrs)
PAS 200-300mg/kg in PAS sodium salt 1.5gm bd 2-3gm bd 3-4gm bd 4gm bd 6gm bd 8gm bd 8gm
2 divided doses 60% (9.2gm)
sachet
50mg/5ml 8-10 ml 15 ml 20 ml - - - -
Hhigh-dose 15-20mg/kg solution
100mg tab 1 1.5 2 3 4 4 (>14 yrs)
Clavulanic - 62.5mg/5 ml 2 ml bd 3 ml bd 5 ml bd 8 ml bd 10 ml bd (>14 yrs) (>14 yrs)
acid (only tto suspension along
be used with with Amoxicillin
Meropenem
* Only in patients >2 years old (25 mg bd in 3-5 years; 50 mg bd I 6-11 years; 100 mg bd in 12-17 years)
** Not used in patients <15 years (use Meropenem
51
4.6.5 DR-TB and HIV co-infection

The treatment of DR-TB in PLHIV is not different from the treatment in HIV-negative people. They
can receive either SSTR or a long-course regimen, based on eligable criteria. If the TB/HIV patient
is already on ART, it is to be continued. If not yet on ART, it must be prescribed according to
the recommendations of the National Centre for AIDS and Sexually transmitted disease Control
(NCASC) and started rapidly regardless of CD4 count, as soon as the patient is seen to tolerate
the MDR-TB treatment, possibly within 8 weeks. All TB/HIV patients must receive cotrimoxazole
preventive therapy (CPT). All patients co-infected with HIV and MDR-TB must be managed at the
DR-TB Centre.
The DR-TB therapy in PLHIV is complicated by:

• cumulated drug toxicities
• Drug-drug interaction
• other co-infections exacerbating drug toxicity
• malabsorption of drugs leading to treatment failure
• paradoxical worsening of TB symptoms when ART is started (Immune Reconstitution
Inflammatory Syndrome or IRIS: see national HIV/AIDS Guidelines).
The risk of adverse drug reactions in PLHIV treated with second-line TB drugs increases with the
degree of immunosuppression. ART and anti-TB drugs have potential overlapping or additive
toxicities and the identification of the source of adverse effects is difficult. It is often impossible
to link side effects to a single drug. Using agents with shared adverse effect profiles is not the
preferred option but often, the benefit of the drugs outweighs the risk. Increased monitoring of
adverse effects is recommended rather than disallowing a certain combination.
The main overlapping toxicities between the second-line drugs and the anti-retroviral drugs
commonly used when treating TB/HIV co-infected patients (TDF, 3TC and EFV) are shown in table
11. A full listing can be found in table 8.1 in the WHO MDR Guidelines 2014.
TABLE 4.7 Potentially overlapping adverse effects between ART drugs and second-line drugs used
to treat PLHIV with MDR-TB
ART drug Second-line drug Adverse effect

CNS toxicity
EFV Cs (Eto, FQ, H)
Depression
EFV, AZT Cs, Bdq Headache
Many ART drugs Z, H, Bdq (Eto, PAS, FQ) Hepatotoxicity
AZT Lzd (H) Bone marrow suppression
AZT, 3TC Ldz Lactic acidosis
All ART drugs Eto, PAS Abdominal pain
Most ART drugs Eto, PAS, Bdq, Dlm, H, E, Z Nausea, vomiting
Most ART drugs Most Second-line drugs Skin rash
Most ART drugs Bdq, Dlm, Mfx, Cfz Prolongation of Q-T interval
Concomitant use of bedaquiline with efavirenz (EFV) is not recommended due to possible
decrease of Bdq concentration. EFV should be replaced by Dorutegravir. PIs can be used with
bedaquiline but should be administered with extreme caution and close clinical monitoring.
Please see more information in below table.
TABLE 4.8 Possible drug-drug interactions between antiretrovirals and the new TB drugs
Drugs Instructions
ARVs to avoid Efavirenz (EFV) Substitute nevirapine (NVP) or integrase
with Bdq (Using EFV with Bdq inhibitor instead of EFV. Allow a 5 day
will result in low levels washout of EFV if possible (substitute
of Bdq NVP on day 1 and then start MDR
regimen5
days later). If patient is critically ill with
MDR-TB, no washout period is necessary.
• When switching back to EFV after
ending treatment with Bdq, this can
be done immediately after Bdq is
stopped
Ritonavir containing If possible, use an ARV regimen with no
protease inhibitors (PIs) PI. One possible solution is to substitute
(Using ritonavir with the PI with an integrase inhibitors
Bdq will result in high (INSTIs), e.g. dolutegravir (DTG) or
levels of Bdq) raltegravir
(RAL).
• If a ritonavir-containing PI must be
used, check ECG every two weeks.
ARVs to avoid None Dlm has very little drug-drug
with Dlm interactions with ARVs and no extra
drug monitoring or regimen adjustment
is needed.6
Patients receiving ART and MDR-TB treatment must be closely monitored. Daily DOT is obligatory,
because the large pill burden and the many side effects may compromise treatment adherence.
Whenever adverse effects occur, they must be treated without delay. At the same time, it is
important to be alert for signs and symptoms of mal-absorption: diarrhoea, abnormal stools,
poor nutritional status, evidence of vitamin deficiencies, weight loss, etc. Diarrhoea should be
treated aggressively as it may lead to decreased drug absorption and impair correct treatment.
4.6.6 Patients with Extra pulmonary DR TB and DR-TB meningitis

Patient with DR TB with EP TB can be initiated in SSTR except those with severe form of EP TB (TB
meningitis, Bone TB, Miliary TB, Disseminated TB, TB pericarditis) and EPTB with HIV.
Patient with DR-TB meningitis should not be treated with the SSTR nor with the standard MDR
long-course regimen because several of the drugs in those regimens penetrate poorly into bone
and soft tissues and the CSF. Therefore, it is imperative to design appropriate regimen having
sufficient drugs on board with appropriate penetration in to soft tissues and bones and who
cross the blood brain barrier.
Following table should be followed while designing an effective regimen to treat DR TB

meningitis.
TABLE 4.9 Penetration of anti-TB drugs into the central nervous system (CNS)
Medication CNS Penetration
Amikacin Poor penetration except in the presence of meningeal inflammation
Bedaquiline No data available; studies ongoing
Clofazimine Limited data available
Cycloserine CSF levels similar to serum levels
Delamanid Limited human data but good CSF penetration in mice: studies ongoing
Ethambutol Poor penetration
Ethionamide CSF levels similar to serum levels, but higher end dosing (20mg/kg)
(prothionamide) recommended in children
Isoniazid 20% of serum concentrations except in the presence of meningeal inflam-
mation
Levofloxacin 65% of serum concentrations
Linezolid Animal studies show CSF levels at 30% of serum levels: widely used in
humans with excellent results
Meropenem Excellent
Meropenem Excellent
Moxifloxacin Good penetration in animals
PAS Poor penetration except in the presence of meningeal inflammation
Pyrazinamide CSF levels similar to serum levels
4.6.7 Osteomyelitis and soft tissues EP MDR TB

Bedaquiline and Delamind: are with limited experience about penetration in soft tissues and
bones
Linezolid: Excellent bone and soft-tissue penetration; commonly used for osteomyelitis due to
gram positive bacteria.
Clofazamie: Cfz has been used extensively to treat leprosy lesions in soft tissue, though it is
unclear if this means that bone and soft tissue penetration is adequate
Imepeninm/Meropenim: Both drugs have been used to treat osteomyletis caused by other
bacteria
Some forms of EP, when treated, may show a paradoxical worsening. This is quite common in
patients co-infected with TB and HIV (Immune Reconstitution Inflammatory Syndrome or IRIS:
see national HIV/AIDS Guidelines). In certain types of EP, and also if IRIS occurs, adjuvant steroid
therapy may be helpful (see T5.2).
4.6.8 Patients with hepatitis

Many anti-TB medications have the potential to cause hepatotoxicity, and their use must be
carefully contemplated in the setting of severe liver dysfunction. Possible anti-TB drug that
causes hepatotoxicity; Z, H, Cfz, PAS, Eto/Pto, Bdq, FQ, Amx/Clv. Fortunately, the most important
second-line anti-tuberculosis drugs used for treatment of drug-resistant disease do not affect the
liver. Among the first-line drugs, Z is the most hepatotoxic, followed by H. Among the second-
line drugs, Eto and PAS can also be hepatotoxic, although less so than any of the first-line drugs.
Hepatitis occurs rarely with fluoroquinolones. Lfx is less hepatotoxic than Mfx.
Hepatitis itself is not contraindication to start DR TB treatment unless liver enzymes are raised to
unacceptable level i.e 5 fold increase in liver enzyme or active jaundice. Patients with history of
liver disease can receive the usual anti-TB drug regimens provided there is no clinical evidence
of severe chronic liver disease, hepatitis virus carriage, recent history of acute hepatitis or
excessive alcohol consumption. In general, patients with chronic liver disease should not receive
pyrazinamide. All other drugs can be used, but close monitoring of liver enzymes is advised.
If significant aggravation of liver inflammation occurs, the drugs responsible may have to be
stopped.
Treatment of drug-resistant TB in the setting of liver failure is complicated and depends on the
degree of liver damage. A long-course regimen with at least 4 non-hepatotoxic drugs is required.
However, as per newly WHO recomended regimen, the drugs from group A and B are safer to
use and ony in severe hapetic and renal failure Bdq and Lzd may be avoided.
If a patient with acute hepatitis requires MDR-TB treatment, it may not be possible to defer the
treatment until the acute episode has resolved. A similar treatment to the one outlined above
may have to be given. Viral hepatitis should be treated if medically indicated and treatment can
occur during drug-resistant TB treatment.
4.6.9 DR Patients with renal failure

In DR-TB patients with renal insufficiency, the dosing of the second-line drugs that are cleared
by the kidneys will have to be adapted if the creatinine clearance is <30ml/minute. To calculate
the creatinine clearance, see Annex 4. The general strategy is to increase the interval between
dosing rather than to decrease. Standard doses are given unless there is intolerance. There
should be careful monitoring for evidence of neurotoxicity.
TABLE 4.10 Dosing recommendations of anti-TB drugs in adult patients with creatinine clearance
<30 ml/min
Drug Change in frequency? Recommended dose and frequency
Isoniazid (H) No change 300 mg once daily, or 900 mg 3 times/week
Rifampicin (R) No change 600 mg once daily, or 600 mg 3 times/week
Pyrazinamide (Z) Yes 25– 35 mg/kg/dose 3 times/week (not daily)
Ethambutol (E) Yes 15–25 mg/kg/dose 3 times/week (not daily)
Levofloxacin (Lfx) Yes 750 –1000 mg/dose 3 times/week (not daily)
Moxifloxacin (Mfx) No change 400 mg daily
Cycloserine (Cs) Yes 500 mg/dose 3 times/week
Ethionamide (Eto) No change 15–20 mg/kg/day (can be in divided doses)

Para-aminosalicylate (PAS) No change 4 gm/dose twice daily
Linezolid (Lzd) No change 600 mg daily
Clofazimine (Cfz) No change 100mg daily
Capreomycin (Cm) Yes 12–15 mg/kg/dose 2–3 times/week (not
daily)
Kanamycin (Km) Yes 12–15 mg/kg/dose 2–3 times/week (not
daily)
Bedaquiline (Bdq) no change with mild to moderate renal dysfunction but use with cau-
tion in severe renal disease
4.6.10 Patients with diabetes

Persons with latent TB infection and diabetes have an increased risk of progression to active
TB. Also, outcomes for patients who have both TB and diabetes are poorer than for TB patients
without diabetes. The role of diabetes in furthering drug resistance has remained controversial,
but new evidence is accumulating that diabetes does increase the risk of drug-resistant TB. One
possible mechanism for poorer outcomes and acquired drug resistance could be that blood
levels of anti-TB medications may be lower and sub-therapeutic in patients with diabetes.
Diabetes must be managed closely throughout the treatment of drug-resistant TB. If the patient
is on oral hypoglycaemic agents, it is recommended to switch to insulin for the duration of the
MDR-TB treatment. None of the anti-TB drugs are contraindicated.
Patients with diabetes and MDR-TB may be at increased risk of adverse events since many of the
anti-TB drugs have side effects that place diabetic patients at special risk. Patients with long-
standing diabetes may have underlying renal impairment that can be worsened by the second-
line injectable drugs. Neuropathy is a common complication of diabetes and also can be
worsened by several drugs used to treat MDR-TB such as high-dose INH, cycloserine, linezolid and
the fluoroquinolones. Patients with diabetes may have decreased gastric motility (gastroparesis)
and may be at increased risk of nausea and vomiting with medications like ethionamide or other
MDR-TB drugs.
The box summarizes the recommendations when treating patients who have MDR-TB and diabetes
(from Curry MDR Guide 2016).
Recommendations when treating patients who have MDR-TB and diabetes

• Follow renal function carefully and use intermittent dosing for injectable drugs if there is pre-
existing or newly developing renal impairment.
• Monitor creatinine and potassium levels more frequently: weekly for the first month and at
least monthly thereafter in view of the renal effects of the second-line injectables if use.
• Treat symptoms of gastroparesis aggressively with gastric motility agents such as metoclo-
pramide.
• If neuropathy develops, change the offending drug, if possible. If that cannot be done safely,
consider use of agents such as tricyclic anti-depressants, gabapentin, and/or adding or in-
creasing the dosage of Vitamin B-6.
4.7 ADJUVANT THERAPIES AND INTERVENTIONS

4.7.1 Pyridoxine
Several side effects related to the nervous system can be prevented by the daily administration
of pyridoxine. Pyridoxine (vitamin B6) should be given to all TB patients who receive second-line
therapy. The usual dosage is 50mg per day in children and 100mg per day in adults. If Cycloserin is
part of the treatment regimen, the recommended dose is 50 mg for every 250 mg of Cs prescibed:
see table 4.11.
TABLE 4.11 Daily dosing of pyridoxine according to daily administration of cycloserin

Daily dose of cycloserin Daily dose of pyridoxine
250mg 50mg
500mg 100mg
750mg 150mg
1000mg 200mg
4.7.2 Steroids
Steroids are useful in cases of TB meningitis and TB pericarditis, and also for children with miliary
TB or obstruction of the bronchi as a result of mediastinal TB adenitis. Their use may also be
considered in cases with severe respiratory insufficiency. The usual dosage is prednisone 1mg/
kg/day, to be tapered off gradually to arrive at a maintenance dose of 5mg/day. Steroids will
also be given if a severe paradoxical reaction (IRIS) occurs, especially in patients with TB/HIV co-
infection (see Chapter 8.4.5 in the WHO MDR Guidelines 2014).
4.8 SURGERY
Surgery is an adjunct to chemotherapy. If the lung lesions are not extensive, elective partial
lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB
regimen. The role of pulmonary surgery is beneficial to reduce the amount of lung tissue with
intractable pathology and to reduce bacterial load and thus improve prognosis.
• The surgery should be performed under infection control measures

• The benefit of the surgery is when patients has no other associated factors for poor prognosis
• It is considered an adjunct to chemotherapy and appears to be beneficial for improved
outcome.
• It is not indicated in patients with extensive bilateral disease.
• Minimum two months of therapy should be given prior to resection surgery to decrease the
bacterial infection in the surrounding lung tissue.
• Surgery should be performed by a trained thoracic surgeon in patients with localized disease
and result may reduce morbidity and mortality. Prognosis could be better when partial lung
resection is performed after culture conversion and full course of treatment is given with
effective regimen.
CHAPTER 5
MANAGEMENT AND MONITORING

ASPECTS OF DR-TB
Classification based on history of previous TB treatment (patient registration group): (Reference:
WHO Companion handbook for programmatic management of DR-TB- 2014)
Registration group: Patients are assigned to a registration group based on the most recent
treatment history at the time of initiating DR-TB treatment
1. New. A patient who has received NO or LESS than one month of anti-TB treatment
2. Relapse. A patient who was previously treated for TB and whose most recent treatment
outcome was Cured or Treatment completed, and who is subsequently diagnosed with a
recurrent episode of TB (either a true relapse or a new episode of TB caused by reinfection).
3. Failure. A previously treated TB patient who has received an anti-tubercular treatment whom
the treatment has failed.
3.1 After failure of first line Treatment with FLD
3.2 After failure of Re-Treatment with FLD
3.3 After failure of Treatment with Hr TB Regimen
3.4 After failure of Treatment with SLD
4. Treatment after loss to follow-up: A patient who had previously been treated for TB and was
declared Lost to follow-up at the end of the most recent course of treatment.
5. Other previously treated patients. A previously treated TB patient whose outcome after the
most recent course of treatment is unknown or undocumented.
6. Patients with unknown previous TB treatment history who do not fit into any of the
categories listed above.
5.1 PREPARATION PRIOR TO STARTING SECOND-LINE

TREATMENT
Before second-line treatment can be prescribed, the patient must be thoroughly evaluated
clinically, radiologically and biomedically, according to the list in table 5.1. These examinations
are performed at the DR-TB Centre. The initial evaluation serves to establish a baseline (for
comparison when investigations are done during treatment) and may identify patients who are
at risk for adverse side effects or poor outcomes.
Prior to initiating treatment, all patients must receive albendazole.

TABLE 5.1 Baseline clinical, instrumental and laboratory examination*
Medical history including mental illness, drug or alcohol dependence, seizures
Clinical examination including body weight and height, blood pressure, temperature
Chest X-ray
Calculate the Q-T interval with Fridericia’s correction (QTcF):
ECG
see Annex 3
needed as baseline for follow-up examinations during
Sputum smear examination
treatment
Complete Blood Count RBC count, haemoglobin, hematocrit, WBC count, WBC
differential count, platelet count
Liver function tests (LFT) bilirubin, AST, ALT, albumin
Thyroid function tests TSH, T3, T4
(TFT)
Hepatitis B and C Determine viral load if positive for hepatitis B or C
Laboratory Uric acid
examinations
Renal function tests serum creatinine (calculate the estimated creatinine
(RFT) clearance based on the Cockcroft-Gault equation: see
Annex 4), serum potassium (also magnesium and calcium if
potassium is low) and sodium
Serum glucose If hyperglycemia: refer
Serum amylase If Lzd is used
HIV test following PICT
Pregnancy test (for women of child bearing age)
Visual acuity
Audiometry
Peripheral neuropathy assessment
* Diagnostic tests (Xpert MTB/RIF, culture and DST, LPA) are not included here.
5.2 TREATMENT ADMINISTRATION

5.2.1 The need for strict adherence to treatment
Full adherence to DR-TB treatment is essential to prevent the amplification of resistance and
increase the chances of cure. Adherence to DR-TB therapy is particularly difficult because of the
lengthy treatment regimens, the high daily pill burden, the frequent and serious drug adverse
reactions, and the indirect social and economic costs to patients associated with access to care.
Inadequate second- line therapy would also have serious public health consequences. Therefore,
all patients receiving DR-TB therapy should be on 100% DOT, preferably during the whole course
of treatment. Patient centric care including community DOTS where fesibe will be prioritized,
and service will be decentralized as program expands.
DOT, early and effective management of adverse effects of drugs and monitoring and follow-up
of the non-adherent patients are very important to ensure maximum adherence to treatment.
In addition, patient-centred care will further increase the chances of successful treatment
outcome by providing:
• Counselling: health education and counselling must be provided to all patients and their
family members at all levels of the health care system, from the peripheral health centre to
the district hospital to the DR-TB Centre. It is started at the initial point of contact and must
be continued at every visit by the patient to a health facility.
The patients should receive counselling on DR-TB, the duration of treatment, the organization
of the treatment (hospital/ambulatory), requirements for regular monitoring, infection
control, the need for regular treatment (DOT) and the consequences of irregular treatment
or pre-mature cessation of treatment. It is advisable to involve close family members during
the counselling, since family support is an essential component in the management. Patients
should be informed regarding the possible side effects of the drugs and advised to report if
they experience any unusual problem. Female patients of child bearing age should receive
special counselling on family planning because pregnancy should be avoided during second-
line treatment.
• Psychosocial and emotional support to strengthen self-esteem through empathy, trust,
encouragement and care. Having DR-TB can result in severe emotional stress for patients
and their families. The long duration of DR-TB therapy combined with the side-effects of the
drugs may contribute to depression, anxiety and further difficulty with treatment adherence.
A multidisciplinary approach by a support team (doctor, social worker, nurse and treatment
supporter) is recommended.
• Socioeconomic support can enable patients and their families to adhere to DR-TB treatment
and reduce the impact that the disease and treatment have on their quality of life. Patients
must have access to any socioeconomic services they may qualify for. Maximal support
should be given to patients with the highest needs. There is a provision of NPR 3,000 or NPR
1000 per month for each patient (Hostel based Patient = NPR 1000/m, Clinic based Patient
NPR 3000/m) to support the nutrition needs.
5.3 ORGANIZATION OF THE TREATMENT

5.3.1 Hospitalization
Admission for treatment is not mandatory but is may be require in some patients who are really
sick. This will allow assess if the drugs are well tolerated and to gradually increase the dosage of
certain drugs (Eto). Admission of DR-TB patients requires appropriate structures where proper
infection control measures can be observed in order to prevent transmission to staff and other
patients (see chapter 7). Patients who are not seriously ill can be accommodated in hostel-like
structures where they can get proper care and monitoring until they are ready for ambulatory
care. Severely ill patients need to be hospitalized in a specialized DR-TB ward.
5.3.2 Ambulatory treatment under strict DOT

Ambulatory care must be practice under strict DOT. During the initial stage of treatment, while
awaiting the results of the LPA, the patients must remain close to the DR-TB Centre where they
will have to present themselves every day to receive their drugs. Once the LPA results have been
received and the treatment regimen is finalized, treatment may be continued at the DR-TB Centre
or in a DR-TB Treatment Sub-centre. All structures providing treatment to DR-TB patients should
observe proper infection control measures.
If it is not possible for the patient to visit the treatment centre/subcentre on a regular daily basis,
community based DOT (CBD) may be an alternative option. Community based DOT requires very
close daily monitoring. The patient’s family must be well informed and motivated to collaborate,
a reliable DOT provider must be appointed, and regular supervision by the (Health Co-ordinater
appointed for TB Leprosy) is essential. If the patient needs to receive injections, this must be
arranged either at a nearby health facility.
The DOT provider should be a person whom the patient is comfortable with. This may be a
health worker trained to deliver second-line anti-TB medicines. The DOT provider should have
the appropriate training, skills require to provide proper DOT and support.
Every month, patients treated in an ambulatory setting must go to the nearest DR-TB Centre
or Subcentre where the monthly follow-up investigations can be performed. The DOT provider
and the treatment supporter must make sure that the patient does not miss the monthly
appointments.
A DR-TB patient on ambulatory treatment may be contagious, particularly during the early
weeks or months of treatment. It is therefore extremely important that proper infection control
measures are observed, not only in the treatment centres/subcentres but also at the patient’s
home and by the patients themselves. This will require a lot of discipline by the patients, but they
need to understand their responsibility and social duty to protect the community from exposure
to drug resistant germs.
The following instructions should be given to the patient:

• Avoid meeting other people. Do not go to markets, festivals or group meetings. Only take
public transportation when absolutely necessary. If you have to go out, wear a mask at all
times.
• If it is possible, stay at home in a separate room. If you can have a room that is well ventilated
and has windows that let in sunlight, it is even better. Family members must stay out of the
room.
• Eat separately, either in the room or outside.
• Whenever you meet family members or other people, wear a mask. Family members are
provided with N95 masks that they must wear whenever they are together with you.
• If other people come to the house, only meet them outside for a short time and stay at a safe
distance.
Avoid contact with children because they are extremely vulnerable. If this is difficult, consider
letting the children stay with friends or family.
5.4 DRUG INTAKE

Many of the second-line drugs cause gastro-intestinal upset, which is an important cause of
non-adherence to treatment, many patients refuse to take certain medications or even the full
treatment. In order to improve adherence, not all drugs have to be taken together, some may
be administered in split doses and some may be given together with food. The only drugs that
should never be given with food are H and Cs, while other drugs (Cfz, Bdq and Dlm) have to be
taken with food to improve absorption. The other drugs can be taken with or without food, but
some (Eto, PAS) are better given with food to reduce gastro-intestinal upset. Table 5.2 shows a
summary of how the second-line drugs are preferentially ingested.
If split doses are given, DOT is required for every intake.
The daily dose of Eto can be built up

gradually: 250mg once daily on days 2 to
4; 2 x 250mg/day on days 5 to 7; 250mg in
the morning, 500mg in the evening from
day 8 onwards if patient >50kg.
Amikacin is given by deep intramuscular

injection. The injection site must be
changed every day to avoid painful
reactions in the injected area: see diagram.
For every injection, a sterile syringe, a

sterile needle for preparing and pulling up
the solution and another sterile needle for
the injection must be used. These can only be used once and must be disposed of in a safe way
(contaminated waste).
Imipenum and cilastatin injection comes as powder to be mixed with liquid to be injected
intravenously. When it is injected intravenously, it is usually infused over a period of 20 minutes
or 1hour every 6 or 8 hours. Imipenum may cause side effects some of which can be serious
(severer diarrhea, itching rash, difficulty breathing or swallowing, seizures).
TABLE 5.2 Mode of administration of the second-line drugs
With or without food Drug Number of daily doses

Never with food H 1
Cs 2 or 3
Can be with or without food E 1
Z 1
Lzd 1
Possible with food but avoid drug intake within at least Lfx 1 (children <5 years: 2/
2 hours of dairy products, coffee, antacids (especially day)
aluminum-containing), vitamin supplements or mineral
Mfx 1
supplements (such as iron, magnesium, calcium or zinc) or
medication containing divalent cations (such as didanosine
or sucralfate)
Best taken with food to reduce G.I. upset Eto 2 (highest dose in the
evening: e.g. 250mg in the
morning, 500mg in the
evening)
PAS 2-3 (children: 2-4)
To be taken with food to improve absorption Cfz 1
Bdq 1
Dlm 2
Amx-clv 2
5.5 FOLLOW-UP MONITORING INVESTIGATIONS DURING

AND AFTER COMPLETION OF TREATMENT
5.5.1 General considerations
Follow-up monitoring examinations are essential to monitor the response of the patient to
the treatment and to detect side effects of the drugs early. The frequency of the examinations
depends on the treatment regimen (SSTR or LR), the drugs that are administered and the
treatment duration.
For patients treated in an ambulatory setting, the follow-up examinations can take place at the
nearest DR-TB Centre with the required laboratory facilities. If a specialized test (e.g. TFT) cannot
be performed, a sample may be sent to the nearest laboratory that can do the test. When sending
a sputum specimen to the NRL for culture, the timing (within 72 hours) and the cold chain must
be respected.
5.5.2 Follow-up examination during the SSTR
TABLE 5.3 Frequency of follow-up examinations during SSTR

Intensive phase Continuation phase
Examinations Month Month Remarks
1 2 3 4 (5) (6) 1 2 3 4 5
Clinical evaluation
          
including weight
Single specimen,
Sputum smear
           preferable early
examination
morning sample
Single specimen,
Sputum culture            preferable early
morning sample
Chest X-ray(1)  
           Also on days 2, 7 and
ECG(2)
14
Complete Blood
If required
Count(3)
Liver function       In continuation phase:
tests (LFT)(4) as required
Thyroid function
  TSH (T3, T4)
tests (TFT)
Uric acid     
Renal function      
tests (RFT)(5)
Serum glucose If required
      More frequent if
Audiometry
hearing complaints
Only if eye complaints
Visual acuity (For
during administration
optical Neuritis)
of E
On any cultures that
are positive four
SL-LPA and DST
months or beyond af-
ter treatment initiation
(1)
To serve as a reference if later images need to be taken.
(2)
Calculate the Q-T interval with Fridericia’s correction (QTcF): see Annex 3
(3)
RBC count, haemoglobin, haematocrit, WBC count, WBC differential count, platelet count
(4)
Bilirubin, AST, ALT, albumin
(5)
Serum creatinine (calculate the estimated creatinine clearance based on the Cockcroft-Gault equation: see Annex 4),
serum potassium (also magnesium and calcium if potassium is low) and sodium
Ü Frequency of examinations may be increased as needed according to the clinical evolution

of the patient and the decision of the clinicians.
5.5.3 Follow-up examination during the longer treatment regimens
TABLE 5.4 Frequency of follow-up examinations during longer regimen

Treatment duration
Remarks
Examinations Month
1 2 3 4 5 6 7 8 10 12 14 16 18
Clinical evaluation
            
including weight
Sputum smear Single specimen, preferable
            
examination early morning sample
Single specimen, preferable
Sputum culture          
early morning sample
Chest X-ray   
If pre-XDR or XDR regimen:
on days 2, 7 and 14 and
ECG(1)             
monthly thereafter
If MDR regimen: as required
Complete Blood Monthly if Lzd.
            
Count(2) If no Lzd: as required
For PLHIV monthly, otherwise
Liver function as required
       
tests (LFT)(3) (mostly if ETO and/or Z is
used)
Thyroid function TSH, T3, T4

  
tests (TFT) Only if Eto, Pto, or PAS is used
Uric acid     Only if Z is used

Renal function
      Only if Am is used
tests (RFT)(4)
Serum glucose If required
Serum Amylase If required
Peripheral
Neuropathy              (see annex 5)
Assessment
Audiometry       only if Am is used
Monthly if Lzd (see M5).
Visual acuity (for If no Lzd: Only if eye
            
optic neuritis) complaints during
administration of E
On any cultures that are posi-

SL-LPA and DST tive four months or beyond
after treatment initiation
(1)
Calculate the Q-T interval with Fridericia’s correction (QTcF): see Annex 3
(2)
RBC count, haemoglobin, haematocrit, WBC count, WBC differential count, platelet count
(3)
Bilirubin, AST, ALT, albumin
(4)
Serum creatinine (calculate the estimated creatinine clearance based on the Cockcroft-Gault equation: see Annex 4),
serum potassium (also magnesium and calcium if potassium is low) and sodium
Ü Frequency of examinations may be increased as needed according to the clinical evolution of

the patient and the decision of the clinicians.
5.5.4 Follow up after completion of the SSTR and LR

After completion of the SSTR and LR it is required to follow up patients for next two years. Follow
up examination should be done every 6 months which includes:
• A clinical assessment
• Sputum smear examination
• Any additional lab or instrumental analysis as requested by the clinicians
5.6 MONITORING OF TREATMENT PROGRESS

The symptoms should improve within the first few months of treatment. If this is not the case,
look for other possible causes and be alert for treatment failure.
Treatment progress of DR-TB is monitored through sputum smear examinations and culture.
In children, bacteriological follow-up of the treatment is not possible most of the time. Progress
will have to be monitored clinically. The evolution of the weight of the child is of particular
importance.
Bacteriological follow-up of EP DR-TB is difficult. Even if a specimen was obtained for the initial
LPA, culture and DST, obtaining follow-up specimens will usually not be feasible. Progress of EP
DR-TB needs to be monitored clinically.
Laboratory investigations, while useful to monitor side effects, contribute little to monitor
response to treatment.
Chest X-rays are not a sensitive indicator to monitor progress. Often, the radiological image
remains unchanged.
Sputum may become negative well before culture. Negative sputa are a very encouraging sign,
but it is the result of the monthly cultures that will decide whether treatment is progressing well.
The sputum result at 4 and 5 months is useful to determine whether the intensive phase of the
SSTR needs to be extended by an additional month. If the sputum is still positive after 6 months,
the SSTR is considered to have failed and a suitable long course regimen must be initiated.
Sometimes, the sputum examination remains positive while the culture becomes negative. This
is caused by the presence of dead bacilli and does not indicate treatment failure.
Monitoring of progress of the SSTR through culture is shown in table 5.3
Monitoring of progress of the long-course regimens through culture is shown in table 5.4
If the culture is positive at 4 months or reverts to positive after having been negative at 4 months,
LPA and second-line DST have to be performed. Once treatment is stopped, treatment outcome
must be determined (see chapter 8)
5.7 FOLLOW-UP AFTER THE END OF TREATMENT

Follow-up procedures
If the patient has been fully treated and the treatment outcome has been “cured” or “treatment
completed”, the patient must go to the DR-TB Centre every 6 months for 2 years, where a careful
clinical control examination and a sputum examination will be performed. A chest X-ray should
not be requested routinely but only if there is a clinical indication.
If the patient has not become culture negative, but a clinical decision was made to stop the
treatment because of drug intolerance, the DR-TB Centre has to perform a regular clinical,
radiological and bacteriological (sputum and culture) check-up every 3 months for 3 years.
All patients should receive appropriate information and education about the symptoms of a
possible relapse and the need to immediately present themselves to the TB treatment centre.
5.8 PALLIATIVE CARE

If a patient presents a treatment failure and an alternative treatment regimen is not possible,
treatment will have to be suspended. Suspension of therapy should be carefully planned. It
should start with discussions among the clinical team, including all physicians, nurses and DOT
workers involved in the patient’s care. Once the clinical team decides that treatment should be
suspended, a clear plan should be prepared for approaching the patient and the family. This
process usually requires a number of visits and takes place over several weeks. Home visits during
the process offer an excellent opportunity to talk with family members and the patient in a
familiar environment. It is not recommended to suspend therapy before the patient understands
and accepts the reasons to do so and agrees with the supportive care offered.
A number of supportive measures can be used once the therapy has been suspended. It is very
important that medical visits continue and that the patient is not abandoned. Supportive care for
MDR-TB treatment failure includes:
• Pain control and symptom relief: Codeine with paracetamol gives relief from moderate pain
but also helps control cough. Other cough suppressants can be added. If possible, stronger
analgesics, including morphine, should be used to keep the patient adequately comfortable.
• Relief of respiratory insufficiency: Oxygen can be used to alleviate shortness of breath.
Morphine also provides significant relief from respiratory insufficiency and should be offered
if available.
• Nutritional support: Small and frequent meals are often best for a person at the end of life.
• Regular medical visits: When therapy stops, regular visits by the treating physician and
support team should not be discontinued.
• Continuation of ancillary medicines: All necessary ancillary medications should be
continued as needed to treat symptoms such as nausea, vomiting, depression, anxiety.
• Psychological support to the patient and family caregivers to assist in the planning of
decisions related with the end of life and provide emotional support.
• Respect for patient’s beliefs and values: The patient and family caregivers may seek and
find comfort in spiritual and religious practices. The health-care providers should respect this.
• Inpatient-care or home-care: Home-based care should be offered to patients and families
who want to keep the patient at home, whenever appropriate infection control practices
must be followed. Institutional based end-of-life care should be available to those for whom
home care is not feasible or desirable.
• Preventive measures: Oral care, prevention of bedsores, bathing and prevention of muscle
contractures are indicated in all patients. Regular scheduled movement of the bedridden
patient is very important.
• Infection control measures should be continued as the patient often remains infectious for
long period of time.
5.9 MANAGEMENT OF CONTACTS OF MDR-TB PATIENTS

A close contact of an MDR-TB patient is someone who has been exposed to infection with
drug resistant M. tuberculosis by sharing air space with a patient who has confirmed MDR-TB.
Close contacts are defined as people living in the same household or spending multiple hours
a day together with the patient in the same indoor living space. They can be family members,
colleagues, friends, roommates and neighbours.
All close contacts of MDR-TB cases should be identified through contact tracing and those who
are symptomatic will be evaluated for active TB. Special attention needs to be paid to children.
The TB screening will include a complete clinical examination, an Xpert MTB/RIF test of a sputum
sample or other relevant specimen and a chest X-ray. If the Xpert MTB/RIF result is RR, the patient
must be sent to the nearest MDR Unit for futher management.
Screening of contacts of MDR-TB patients should be an ongoing process. Asymptomatic contacts

need to be screened at diagnosis, at the end of the intensive phase and at the end of treatment.
Contacts should also receive appropriate health information and education regarding TB and
MDR-TB.
Preventive therapy is not recommended for contacts of MDR-TB patients. Isoniazid or rifampicin
would be useless, and there is no evidence showing that other drugs would contribute to the
prevention of MDR-TB. Careful clinical follow-up of the contacts of MDR-TB patients is the strategy
of choice.
CHAPTER 6
ACTIVE DRUG SAFETY MONITORING

AND MANAGEMENT (ADSM)
OBJECTIVES OF ADSM
Overall, aDSM aims to detect, manage, and report suspected or confirmed drug toxicities in a
timely fashion. The overall objectives of aDSM are to reduce risks from drug-related harms in
patients on second-line (SL) treatment for DR-TB and to generate standardized aDSM data to
inform future policy updates on the use of such medicines.
Definitions
1. Active drug-safety monitoring and management (aDSM): active and systematic clinical
and laboratory assessment of patients while on treatment. As per recent WHO 2019
recommendation, aDSM applies to all patients on RR/MDR TB treatment with (a) new anti-TB
drugs, such as Bdq and Dlm; (b) new DR-TB regimens, such as the shorter (or 9-month) MDR-
TB regimen; or (c) XDR-TB regimens on new/repurposed drugs, in order to detect, manage
and report suspected or confirmed drug toxicities.
2. Adverse event (AE): any untoward medical occurrence that may present in a TB patient
during treatment with a pharmaceutical product, but which does not necessarily have a
causal relationship with this treatment.
3. Adverse drug reaction (ADR): a response to a TB medicine that is noxious and unintended,
and which occurs at doses normally used in humans.
4. Causality assessment: the evaluation of the likelihood that a TB medicine was the causative
agent of an observed adverse reaction.
5. Serious adverse event (SAE): an AE which either leads to death or a life-threatening
experience; to hospitalization or prolongation of hospitalization; to persistent or significant
disability; or to a congenital anomaly. SAEs that do not immediately result in one of these
outcomes, but which require an intervention to prevent it from happening are included.
SAEs may require a drastic intervention, such as termination of the drug suspected of having
caused the event.
6. AE of special interest: AE documented to have occurred during clinical trials and for which
the monitoring program is specifically sensitized to report regardless of its seriousness,
severity or causal relationship to the TB treatment
7. AE of clinical significance: AE that is either a) serious (SAE), b) of special interest, c) leads to a
discontinuation or change in the treatment, or, d) is judged as otherwise clinically significant
by the clinician
8. Signal: reported information on a possible causal relationship between an adverse event
and a TB medicine, the relationship being unknown or incompletely documented previously
or representing a new aspect of a known association. Signal detection may not be part of
practice in Nepal so far but may be a good future practice.
The second line drugs have lot of side effects. Adverse events (AEs) and Adverse drug reactions
(ADRs) may occur during treatment of DR-TB with various severity grading. With the release of
new WHO guidelines 2019, as new and repurposed drugs are now part of standard regimen,
therefore, aDSM is applicable across the board to all RR TB patients.
Often, AEs or ADRs are the reason for treatment irregularities or inadequate therapy. Timely
recognition and proper management of AEs or ADRs will help avoid these. The adverse events
associated with the drugs used to treat DR-TB are described for each individual drug in the drug
sheets in Annex 1. All health workers dealing with DR-TB must be able to recognize AEs and ADRs
and know how to manage or refer according to their level of the health care system and record
and report in a timely manner.
For Nepal, Core Package of aDSM is adopted which means only serious AEs/ADRs are reported
and all DR TB/MDR-TB /Pre-XDR and XDR patients on treatment will be monitored under aDSM
mechanism. When AEs and ADRs are identified, they are to be graded for seriousness and severity
and SAEs reported as per national guideline.
Important Elements of aDSM

There are three fundamental elements of aDSM to achieve the above objectives:
1. Active and systematic clinical and laboratory assessment during treatment to detect drug
toxicity and AEs. There are ways to help health providers do this step.
a. Observe and listen to patients. The detection of AEs is primarily dependent upon reporting
from patients, nurses, doctors, counsellors, etc. At every DOT encounter, health workers should
ask the patient and family members about clinical symptoms of common AEs including nausea,
vomiting, peripheral neuropathy, skin rash, psychiatric disturbance (headache, anxiety,
depression, irritability, behavior change), hearing loss, jaundice, vestibular toxicity (vertigo,
ataxia, hearing loss), and symptoms of electrolyte wasting (muscle cramping, palpitations).
All healthcare professionals involved must be trained on adverse event screening.
b. Perform routine clinical assessments, e.g., for treatment adherence and tolerance,
psychosocial support and consults with the psychiatrist, ophthalmologist, HIV specialist,
etc. Clinical follow-up with the MDR-TB physician for all patients is at a minimum as per set
protocols.
c. Schedule regular laboratory screening, even if the patient has no specific complaints,
e.g., creatinine, ECG, liver function tests, etc. Regular laboratory monitoring detects occult
adverse effects. Laboratory tests and procedures related to treatment should be available
and accessible to patients, free of charge.
Table 5.3 & 5.4, shows the schedule of clinical and laboratory tests for patients on new and
repurposed drugs and the shorter treatment regimen (SSTR) and LR. As Bdq and Dlm, Mfx,
and Cfz may induce QT prolongation and ECG monitoring is essential.
2. Management of AEs in a timely manner. Early detection of signs and symptoms is key
to proper management of AEs that significantly impacts patient well-being, overall
treatment acceptance, and adherence. Management includes measures taken to alleviate
the signs and symptoms of adverse reactions with careful individual case review, such as:
a) reassurance, if AE is minor b) lowering the dose of the offending drug, c) stopping the
drug, d) drug replacement; e) providing ancillary medications and f ) other interventions

(surgery, transfusion, psychological support, etc.). Ancillary medicines should be available
and accessible to patients, free of charge.
3. Recording and reporting: All AEs must be recorded and reported using DRTB 05 form Annex
11 to NTC either by email or through the online eTB Register (where functional). The reporting
must be done in 24 to 48 hours of occurrence any serious AEs/ADRs. Management of AEs/
ADRs are equally important as monitoring and reporting of the AEs/ADRs.
Following is the pathway for aDSM reporting is followed in Nepal:
Seriousness is defined by the outcome of an adverse event. A serious adverse event

(SAE) is one that leads to any of the below:
1. Death
2. Life-threatening
3. Hospitalization or prolonged hospital admission
4. Permanent disability
5. Other medically serious
6. Congenital anomaly.
Severity is defined by the impact on the patient’s ability to function. It is graded on a scale
of 1 to 5, as shown below in table 6.1
TABLE 6.1 Grading of adverse events

Small or transient inconvenience that does not limit normal daily activity.
Grade 1 Mild
No need for medical intervention or corrective treatment.
Partial limitation of normal daily activity. In some, but not all cases, medical
Grade 2 Moderate intervention or corrective treatment is necessary. No need to discontinue
the treatment.
Limitation of normal daily activity. Medical intervention and corrective
treatment, often requiring hospitalization, are necessary. The responsible
Grade 3 Severe
drug may have to be stopped temporarily, until the symptoms have
disappeared.
Very severe limitation of normal daily activity. Medical intervention
Life
Grade 4 and corrective treatment, requiring hospitalization, are necessary. The
threatening
responsible drug may have to be stopped indefinitely.
Grade 5 Death Death related to adverse event
6.1 MANAGEMENT OF AES OR ADRS:

Management of AEs and ADRs are equally crucial as monitoring and reporting. For a number
of drugs, the toxicity is dose dependent. Reducing the dosage may be an effective method of
managing these adverse effects. But attention! The reduced dose must still be effective! If the
serum level of the drug is too low, it will compromise the treatment regimen. This is particularly
the case for Eto and Cs. Lowering the dose by more than one weight class should be avoided.
In some instances, very serious adverse events will be unavoidable in order to save a life. For
example, hearing loss as a result of the administration of Amikacin may have to be accepted in
order to ensure the patient does not die of TB.
Particular attention needs to be paid to the side effects of linezolid, a potent but toxic drug used
as a part of standard regimen. Monitoring the adverse drug reactions of Lzd requires specific
investigations:
For Peripheral neuropathy, assessment, kindly refer to Annex 5

TABLE 6.2.1 Severity grading scales and suggested action for common AEs (adopted from End TB Guidelines 2019)
Severity grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Mild Moderate Severe Life- threatening Death
1. Peripheral neuropathy
Possible anti-TB drug causes: Lzd,Cs,H,S,Km,Cm,H,FQ,Pto/Eto,E. Possible other causes: d4T, ddI
Paresthesia (Burning, Mild discomfort; no Moderate discomfort; Severe discomfort; Incapacitating; or not
tingling, etc.) treatment required; and/ non-narcotic analgesia or narcotic analgesia responsive to narcotic
or BPNS (Brief Peripheral required; and/or BPNS required with analgesia
Neuropathy Screen) subjective sensory symptomatic
subjective sensory neuropathy score 4-6 on improvement; and/ or
neuropathy score 1-3 on any side. BPNS subjective sensory
any side. neuropathy score 7-10 on
any side.
Action Stop Cs and Lzd. If Stop Cs and Lzd. If Same as Grade 2. Same as Grade 2.
symptoms improve, symptoms improve,
consider restarting these consider restarting Cs. Do
drugs. Consider restarting not reintroduce Lzd.
Lzd at a lower dose
(300mg daily or 600 mg Provide symptomatic relief
thrice weekly).
If Cs is not essential to
the regimen consider
suspending the drug.
2. Myelosuppression (anemia, thrombocytopenia, or neutropenia)
Possible anti-TB drug causes: Lzd. Possible other causes: AZT, cotrimoxazole
Anemia 10.5 - 9.5 g/dL 9.4 - 8.0 g/dL 7.9 - 6.5 g/dL < 6.5 g/dL
Platelets decreased 75,000 – 99,999/mm³ 50,000 – 74,999 /mm³ 20,000 – 49,999/mm³ < 20,000 /mm³
Absolute neutrophil 1500 - 1000/mm3 999 - 750/mm3 749 - 500/mm3 <500/mm3
count low
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74

Action Monitor carefully, and Monitor carefully, and Stop Lzd immediately. In Stop Lzd immediately.
consider reduction of consider reduction of case of Grade 3 anemia, Consider
dose of Lzd (300mg dose of Lzd (300mg consider EPO. Restart hemotransfusion or
daily or 600 mg thrice daily or 600 mg thrice at reduced dose once EPO. Restart at reduced
weekly). weekly); in case of toxicity has decreased to dose once toxicity has
Grade 2 neutropenia, Grade 1. decreased to Grade 1.
stop Lzd immediately. In
case of Grade 2 anemia,
consider erythropoietin
(EPO). Restart at
reduced dose once
toxicity has decreased
to Grade 1.
3. Prolonged QT interval
Possible anti-TB drug causes: Cfz, Bdq, Mfx, Dlm, and Lfx (a mild QT prolonging drug)
Possible other causes: Other drugs, e.g., erythromycin, clarithromycin, quinidine, ketoconazole, fluconazole, antipsychotics (all
have some risk, including haloperidol, chlorpromazine and risperidone), many anti-nausea drugs (ondansetron/granisetron,
domperidone), methadone, and some anti-retrovirals); genetic causes such as long QT syndrome; hypothyroidism
Prolonged QTcF QTcF 450 – 480 QTcF interval 481 QTcF>= 501 ms QTcF>= 501 or
ms. – 500 ms. without signs/ >60 ms change from

symptoms of serious baseline and one of the
arrhythmia. following: Torsade de
pointes or polymorphic
ventricular tachycardia
or signs/symptoms of
serious arrhythmia.
Action Monitor more closely; Monitor more closely; Stop the suspected Stop the suspected
at least weekly ECG at least weekly ECG causative drug(s). causative drug(s).
until QTcF has returned until QTcF has returned Hospitalize and Hospitalize and
to less than grade1. to less than grade 1. replete electrolytes as replete electrolytes as
Replete electrolytes as Replete electrolytes as necessary. necessary.
necessary. necessary.
4. Optic nerve disorder (optic neuritis)
Possible anti-TB drug causes: Lzd,E,Eto/Pto,Cfz,rifabutin,H,S. Possible other causes: ddI
Optic nerve disorder Asymptomatic; clinical Limiting vision of the af- Limiting vision in the af- Blindness (20/200[6/60]
or diagnostic observa- fected eye (20/40[6/12] fected eye (worse than or worse) in the affected
tions only or 20/40[6/12] but better eye
better) than 20/200[6/60])
Action Stop Lzd immediately Stop Lzd immediately Stop Lzd immediately Stop Lzd immediately
if there are any suspi- if there are any suspi- if there are any suspi- if there are any suspi-
cions of optic neuritis. cions of optic neuritis. cions of optic neuritis. cions of optic neuritis.
Do not restart it. Do not restart it. Do not restart it. Do not restart it.
5. Hepatitis
Possible anti-TB drug causes: Z,Lzd,Cfz,Bdq. Possible other causes: unknown
ALT (SGPT) 1.1 – 3.0 x upper limit of >3.0 – 5.0 x ULN >5.0 – 20.0 x ULN >20.0 x ULN
normal (ULN)
AST (SGOT) 1.1 – 3.0 x ULN >3.0 – 5.0 x ULN >5.0 – 20.0 x ULN >20.0 x ULN
Action Continue treatment Continue treatment Stop all drugs, including Stop all drugs, including
regimen. Patients regimen. Patients anti- TB drugs; measure anti-TB drugs; measure
should be followed should be followed LFTs weekly. LFTs weekly.
until resolution (return until resolution (return Treatment may be rein- Treatment may be rein-
to baseline) or stabiliza- to baseline) or stabiliza- troduced after toxicity is troduced after toxicity is
tion of AST/ALT eleva- tion of AST/ALT eleva- resolved. resolved.
tion. tion.
6. Acute kidney injury
Possible anti-TB drug causes: S,Km,Am,Cm. Possible ART causes: Tenofovir (TDF)- rare
Acute kidney Injury Creatinine level increase Creatinine 2 - 3 x above Creatinine >3 x Life-threatening con-
of >0.3 mg/dL; creatinine baseline baseline or >4.0mg/dL; sequences; dialysis
1.5 - 2.0 x above baseline hospitalization indicated indicated
75
76

Action Consider stopping inject- Stop injectable until Stop injectable until Stop injectable until
able until creatinine has creatinine has returned creatinine has returned creatinine has returned
returned to baseline. to baseline. Consider to baseline. Consider to baseline. Consider
Consider restarting the restarting the injectable restarting the injectable restarting the injectable
injectable at lower fre- at lower frequency (e.g., at lower frequency (e.g. at lower frequency (e.g.
quency (e.g., MWF). MWF) or substitute with MWF) or substitute with a MWF) or substitute with
a non-nephro-toxic non- nephrotoxic drug. a non- nephrotoxic
drug. drug.
7. Hypokalemia and hypomagnesemia
Possible anti-TB drug causes: Cm,Km,Am,S. Possible ART causes: TDF(rare)
Hypokalemia 3.4 - 3.0 mEq/L 2.9 - 2.5 mEq/L 2.4 - 2.0 mEq/L or < 2.0 mEq/L or abnor-
intensive replacement mal potassium with
therapy or hospitaliza- paresis, ileus or life-
tion required threatening arrhythmia
Action Continue injectable. Continue injectable. Continue injectable. Stop injectable tempo-
Start oral potassium Start aggressive oral Start IV potassium rarily. Start IV potassium
replacement therapy. potassium replacement replacement therapy in replacement therapy in
Check serum magne- therapy. Replace magne- addition to oral. Replace addition to oral. Replace
sium and replace if sium as necessary. magnesium and other magnesium and other
necessary. electrolytes as necessary. electrolytes as necessary.
Hypomagnesemia 0.60-0.70 mmol/L 0.45-0.59 mmol/L 0.30-0.44 mmol/L <0.30 mmol/L
8. Hypothyroidism
Possible anti-TB drug causes: Eto/Pto, PAS. Possible ART causes: d4T
Hypothyroidism Asymptomatic; clinical Symptomatic; thyroid Severe symptoms; limit- Life-threatening conse-
or diagnostic observa- replacement indicated; ing self-care ADL* hospi- quences; urgent inter-
tions only; intervention limiting iADL (instru- talization indicated vention indicated
not indicated mental activities of daily
living) *
Action Continue anti-TB drugs. Continue anti-TB drugs. Continue anti-TB drugs. Stop all anti-TB drugs.
Start thyroxine. Start thyroxine. Start thyroxine.

*https://www.payingforseniorcare.com/longtermcare/activities-of-daily-living.html#title2
8. Hearing loss
Possible anti-TB drug causes: S,Km,Am,Cm,Clr. Possible other causes: none.
Hearing loss Adults Enrolled on a Adult enrolled in Adult enrolled in moni- Adults: profound bilateral
Monitoring Program monitoring program toring program (on a 1, hearing loss (Threshold>
(ona1,2,4,3,6and8 kHz (ona1,2,3,4,6and8 kHz 2, 3, 4, 6 and8kHzaudio- 80dBHLat2kHz and
audiogram): threshold audiogram): threshold gram): threshold shift above); non-service able
shift of 15 - 25 dB aver- shift of >25 dB averaged of >25 dB averaged at 3 hearing Pediatric: au-
aged at 2 contiguous test at 2 contiguous test contiguous test frequen- diologic indication for
frequencies in at least frequencies in at least cies in at least one ear; cochlear implant and ad-
one ear or subjective one ear. therapeutic intervention ditional speech-language
change in the absence indicated. related services indicated.
of a Grade 1 Threshold Adult not enrolled in Adult Not enrolled in
shift. monitoring program: monitoring program:
hearing loss but hear- hearing loss with hearing
Pediatric (on a 1, 2, 4,3, 6 ing aid or intervention aid or intervention indi-
and 8 kHz audiogram): not indicated; limiting cated; limiting self-care
threshold shift >20 dBat- instrumental ADL. ADL.
8kHzinatleast one ear. Pediatric (on a 1, 2, 3, 4,
Pediatric
6 and 8kHz audiogram):
(ona1,2,3,4,6and8 kHz
hearing loss sufficient
audiogram): threshold
to indicate therapeutic
shift>20 dB at 4 kHz and
intervention, including
above in at least one ear.
hearing aids): Threshold
shift
>20dB at 3kHz and
above in at least one ear;
additional speech-lan-
guage related services
indicated.
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78
TABLE 6.2.2 WHO Classification grading scale for hearing loss
40dB 41-60 dB 61-80 dB Over 81 dB

Slight/Mild Moderate Severe Profound
Difficulty hearing and understanding Difficulty hearing regular speech, May only hear very loud speech or May perceive loud sounds as
soft speech, speech from a distance, even at close distance. loud sounds in the environment, vibrations
or speech against a background of such as a fire truck siren or a door
noise slamming. Most conversation speech
is not heard.
In the case of moderate hearing loss, the range for children is 31-60 dB.
TABLE 6.3 Adverse Events and Management

ADVERSE EFFECT SUSPECTED AGENT SUGGESTED MANAGEMENT COMMENTS
Rash, allergic Any drug 1. For serious allergic reactions, stop all therapy 1. History of previous drug allergies should be
reaction pending resolution of reaction. In the case of carefully reviewed. Any known drug allergies
and anaphylaxis anaphylaxis manage with standard emergency should be noted on the treatment card.
protocols. 2. Flushing reaction to rifampicin or pyrazinamide
2. Eliminate other potential causes of allergic skin is usually mild and resolves with time.
reaction (like scabies or other environmental Antihistamines can be used. Hot flashes, itching,
agents). palpitations can be caused with isoniazid .If
3. For minor dermatologic reactions, various agents this occurs advise patients to avoid foods that
may be helpful and allow continuation of the precipitate the reaction.
medication. They include: 3. Hives (urticaria) can be caused by any drug.
• Antihistamines To identify the drug, introduce the drugs one
• Hydrocortisone cream for localized rash at a time. In the case of hives a desensitization
• Prednisone in a low dose of 10 to 20 mg per day attempt can be made; methods are described
for several weeks can be tried if other measures elsewhere.
are not helpful. 4. Any drug that resulted in anaphylaxis or Steven-
• Phototoxicity may respond to sunscreens, but Johnson syndrome should never be reintroduced
these can also cause rash to the patient, not even as a challenge
• Dry skin may cause itching (especially in
diabetics); liberal use of moisturizing lotion

is recommended. Dry skin is a common and
significant problem with clofazimine.
4. Once rash resolves, reintroduce remaining drugs
one at a time, with the most likely culprit last.
Consider not re-introducing in the challenge any
drug that is highly likely to be the culprit.
5. Suspend permanently any drug identified to be
the cause of a serious reaction.
Nausea and Eto, Pto, 1. Assess for danger signs including dehydration, 1. Nausea and vomiting is universal in early weeks of
vomiting PAS,H, E, Z, Amx/ electrolyte disturbances and hepatitis; initiate therapy and usually abate with time on treatment
Clv,Cfz rehydration therapy if indicated and correct any and adjunctive therapy. Some nausea and even
electrolyte disturbances. If blood in the vomit, vomiting may need to be tolerated at least in the
check haemoglobin and treat possible bleeding initial period and patient should be advised about
ulcers. this side effect.
2. Initiate stepwise approach to nausea and 2. Creatinine and electrolytes should be checked
vomiting. if vomiting is severe. Give IV fluids and replace
• Phase 1: Adjust medications and conditions electrolytes as needed.
without lowering overall dose: 3. Another strategy is to stop a responsible
• Give the Eto/Pto at night medicine for two or three days and then add it
• Give Eto or PAS twice or thrice daily. back, gradually increasing the dose (advise the
• Give a light snack (biscuits, bread, rice, tea) before patient the medicine will be increased back to a
the medications. therapeutic dose in a manner that will be better
• Give PAS 2 hours after other anti-TB drugs tolerated).
• Phase 2: Start antiemetic(s): 4. Odansetron(not recommended with QT Interval
• Metoclopramide 10 mg 30 minutes before anti-TB prolonging drugs) is serotonin 5-HT3 receptor
medications. antagonist and considered to have strong anti-
• Ondansetron 8 mg 30 minutes before the antiemetic properties. It is on the WHO essential
TB drugs and again 8 hours after. Ondansetron drug list. A number of other anti-emetics from
can either be used on its own or with this class of serotonin 5-HT3 receptor antagonists
metoclopramide. (If ondansetron is not available, exist. Trying different antiemetics, even if from the
promethazine can be used) For refractory nausea same class, may be helpful for some patients.
24 mg 30 minutes before the dose can be tried. 5. For patients particularly anxious about the
• Phase 3: Decrease dose of the suspected drug nausea (and who have “anticipatory nausea
by one weight class if this can be done without and vomiting”), a small dose of an anti-anxiety
compromising regimen. Rarely is it necessary to medicine (5 mg of diazepam) 30 minutes prior to

suspend the drug completely. the anti-TB drugs can help.
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80

Diarrhoea PAS, Eto/Pto 1. Encourage patients to tolerate some degree of 1. Consider other causes of diarrhoea:
and/or flatulence loose stools and flatulence. • Pseudo-membranous colitis related to broad-
2. Encourage fluid intake. spectrum antibiotics such as the FQs is a serious
3. Treat uncomplicated diarrhoea (no blood in stool and even life-threatening condition. Fever, bloody
and no fever) with loperamide 4 mg by mouth diarrhoea, intense abdominal pain and increased
initially followed by 2 mg after each loose stool to white blood cells are danger signs of possible p s
a maximum of 10 mg per 24 hours. e u d o -memb r a n o u s colitis.
4. Check serum electrolytes (especially potassium) • Parasites and common water-borne pathogens in
and dehydration status if diarrhea is severe. the area should be looked for in the patient and
5. Fever and diarrhoea and/or blood in the stools treated if present.
indicate the diarrhoea may be secondary to • Lactose intolerance, especially if patient has been
something other than a simple adverse effect of exposed to new foods in a hospital not normally
the anti-TB drugs. part of their diet.
2. Loperamide can be used in children over 2 years
old.
Hepatitis Z, H, R, 1. If enzymes are more than three times the upper 1. History of previous drug hepatitis should be
Pto/Eto, and limit of normal, stop all hepatotoxic drugs and carefully analyzed to determine most likely
PAS, Bdq, FQs continue with at least three nonhepatotoxic causative agent(s); these drugs should be avoided
Alcohol, Hep, A,B,C medications (an example of three non- in future regimens.
viral hepatotoxic drugs are the injectable agent, 2. Viral serology should be done to rule out other
fluoroquinolone and cycloserine). etiologies of the hepatitis if available, especially
2. Eliminate other potential causes of hepatitis (viral to A, B, and C.
hepatitis and alcohol-induced hepatitis being 3. Alcohol use should be investigated and
the two most common causes) and treat any alcoholism addressed if found.
identified. 4. Generally, hepatitis due to medications resolves
3. Consider suspending most likely agent upon discontinuation of suspected drug.
ermanently. Reintroduce remaining drugs one
at a time, with the least hepatotoxic agents
first, while monitoring liver function by testing
the enzymes every three days, and if the most
likely culprit is not essential, consider not re-
introducing it.
Hypothyroidism Eto/Pto, PAS 1. Most adults will require 100 to 150 mcg of 1. Symptoms of hypothyroidism include fatigue,
Thyroxine/levothyroxine daily. Start in the somnolence, cold intolerance, dry skin, coarse
following manner: hair, and constipation, as well as occasional
• Young healthy adults can be started on 75 to 100 depression and inability to concentrate.
mcg daily 2. Do not start treatment unless TSH is above 1.5 to
• Older patients should begin treatment with 50 2.0 times upper normal limit.
mcg daily 3. Completely reversible upon discontinuation of
• Patients with significant cardiovascular disease PAS and/or ethionamide/protionamide.
should start at 25 mcg daily. 4. The combination of ethionamide/ protionamide
Thyroxine should be taken early in the morning with PAS is more frequently associated with
30 minutes before breakfast. hypothyroidism than is the individual use of each
2. Monitor TSH every 1 to 2 months and increase drug.
dose by 12.5–25 mcg until TSH normalizes. Adjust
dose more slowly in the elderly and patients with
cardiac conditions.
Arthralgias Z, Fluoroquinolones 1. Initiate therapy with non-steroidal anti- 1. Symptoms of arthralgia generally diminish over
inflammatory drugs twice daily or ibuprofen time, even without intervention.
400–800 mg three times a day). 2. Uric acid levels may be elevated in patients on
2. Lower dose of suspected agent (most commonly pyrazinamide.
pyrazinamide), if this can be done without There is little evidence to support the addition
compromising regimen. of allopurinol for arthralgias, although if gout is
3. Discontinue suspected agent, if this can be done present it should be used.
without compromising regimen. 3. If acute swelling, redness, and warmth are present
in a joint, consider aspiration for diagnosis (gout,
infection, autoimmune disease, etc).
Electrolyte Cm, Km, 1. Check potassium. 1. If severe hypokalaemia is present, consider
disturbances Am, S 2. If potassium is low, also check magnesium and hospitalization.
(hypokalaemia and calcium (if unable to check for magnesium, 2. Amiloride 5–10 mg per day or spironolactone
hypomagnesaemia) consider empiric treatment with magnesium in all 25 mg per day may decrease potassium and
cases of hypokalemia). magnesium wasting and is useful in refractory
3. Replace electrolytes as needed. Dose oral cases.
electrolytes apart from FQ as they can interfere 3. Oral potassium replacements can cause
with FQ absorption. significant nausea and vomiting. Oral magnesium

may cause diarrhea
81
82

Nephrotoxicity(Renal S, Km, Am, 1. Discontinue suspected agent. 1. History of diabetes or renal disease is not a
toxicity) Cm 2. Consider using capreomycin if an aminoglycoside contraindication to the use of the agents listed
Possible ART: TDF had been the prior injectable in regimen. here, although patients with these co-morbidities
3. Consider other contributing etiologies (NSAIDs, may be at increased risk for developing renal
diabetes, other medications, dehydration, failure.
congestive heart failure, urinary obstruction, etc.) 2. An example of how to calculate a creatine
and address as indicated. clearance based on the serum creatinine
4. Follow creatinine (and electrolytes) closely, every 3. Renal impairment may be permanent.
1 to 2 weeks.
5. Consider changing injectable agent to a safer and
effective drug i.e Bdq, Dlm, Lzd
6. Adjust all TB medications according to the
creatinine clearance
Vestibular S, Km, Am, 1. If early symptoms of vestibular toxicity appear, 1. Ask the patient monthly about tinnitus and
Toxicity Cm, Cs, change the Inj with other safer drug unsteadiness.
(tinnitus and FQs, H Eto, 3. If tinnitus and unsteadiness worsen with the 2. Fullness in the ears and intermittent ringing are
dizziness) Lzd above adjustment, stop the injectable agent. This early symptoms of vestibular toxicity.
is one of the few adverse reactions that cause 3. A degree of disequilibrium can be caused by Cs,
permanent intolerable toxicity and necessitate FQs, Eto/Pto, INH or Linezolid.
discontinuation of a class of agents. Some clinicians will stop all drugs for several days
to see if symptoms are attributed to these drugs.
Symptoms of vestibular toxicity generally do not
improve with withholding medications.
Hearing S, Km, Am, 1. Document hearing loss and compare with 1. Patients with previous exposure to
loss (also Cm, Clr baseline audiometry if available. (Some degree of aminoglycosides may have baseline hearing loss.
see vestibular hearing loss occurs with most patients, starting In such patients, audiometry may be helpful at
toxicity with high-frequency loss). the start of MDRTB therapy.
above) 2. If early symptoms of hearing loss are then 2. Hearing loss may be reversible or permanent
Discontinue the injectable agent and replace with (often permanent).
other suitable drug(Bdq, Dlm) if this can be done 3. Some patients may choose to tolerate significant
without compromising the regimen. hearing loss to achieve a higher chance of cure.
This should be discussed between a physician

trained in MDR-TB and the patient. Continuing
the injectable agent despite hearing loss almost
always results in deafness.
4. While the benefit of hearing aids is minimal to
moderate in auditory toxicity, consider a trial use
to determine if a patient with hearing loss can
benefit from their use.
Myelosuppression (anemia, Lzd, Possible Lzd associated Myelosuppression is very common, Lzd associated Myelosupression is dose related and
thrombocytopenia, or other causes: AZT, approximately 18-21% of patients taking linezolid may occur in few days after start of treatment
neutropenia) cotrimoxazole. TB itself, may experience anemia/ Myelosuppression. Many chronic TB/DR TB patients may have iron
iron deficiency , GI If the patient has thrombocytopenia or neutropenia, deficiency anemia at baseline due to inflammatory
bleeding also causes of this is more likely to be due to linezolid. process and production of hepcidin and influencing
anemia , iron hemostasis
In mild to moderate Anemai/Myelosuppression,
continue close monitoring and consider dose Monitor full blood count regularly
reduction of Lzd to 300 mg daily or 600 mg
alternative day
In severe and life threatening situation(grade 3-4)
stop Lzd immediately
Transfue/hemotrnasfusion, consider Ertyhropyotein
with specialist advise
Restart Lzd at reduced doses, once severity has
become to grade mild(grade 1)
If necessary stop, Lzd and consider other safer drug.
Peripheral Cs, Lzd, H, 1. Increase pyridoxine to maximum daily dose (200 1. Nutritional status is important to see as low BMI
neuropathy S, Km, Cm, mg per day). puts at high risk of PN with use of Lzd,Cs
H, FQs, 2. The neuropathy associated with linezolid 2. Lzd associated May be a result of disrupted
rarely Pto/Eto, E is common after prolonged use and often mitochondrial function in neurons.
extremely painful and irreversible. For this 3. Patients with co-morbid disease (e.g. diabetes,
reason if nerves are permanently damaged, HIV, alcohol dependence) may be more likely
linezolid should be immediately stopped and to develop peripheral neuropathy, but these
not reintroduced when symptomatic neuropathy conditions are not contraindications to the use of
develops (grade 2 or above). Consider additional the agents listed here.
anti-TB drugs to reinforce the regimen.
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84

3. Consider whether the dose of cycloserine can 4. Neuropathy may be irreversible but many
be reduced without compromising the regimen. patients experience improvement when
(Lowering the dose of likely culprits can also be offending agents are suspended.
done – linezolid, isoniazid, ethionamide). However, the neuropathy associated with
4. Initiate medical therapy: linezolid is common after prolonged use and
• NSAIDs or acetaminophen may help alleviate often permanent (for this reason suspension
symptoms. of this agent should be considered when
• Therapy with tricyclic antidepressants such as neuropathy develops).
amitriptyline (start with 25 mg at bedtime; the
dose may be increased to a maximum of 150 mg).
Do not use with QT prolonging drugs. tricyclic
antidepressants with selective serotonin reuptake
inhibitors (SSRIs) antidepressant drugs. Avoid,
Lzd and Amitriptyline together because of risk
serotonergic syndrome.
• Carbamazepine, an anticonvulsant, at 100–400
mg twice daily can be tried. Carbamazepine is a
strong inducer of CYP3A4 and should not be used
with bedaquiline or delamanid
5. Gabapentine: 100-300 mg daily at night or 100
mg TID, is a good therapy to treat PN and many
clinical Trials support its use
6. Rarely, medication may be discontinued, but only
if an alternative drug is available and the regimen
is not compromised.
Depression Socioeconomic 1. Assess and address underlying socioeconomic 1. Socioeconomic conditions and chronic illness
circumstances, issues. should not be underestimated as contributing
chronic 2. Assess patients for co-existing substance abuse factors to depression.
disease, and refer to treatment if appropriate. 2. Depressive symptoms may fluctuate during
Cs, fluoroquinolones, 3. Initiate individual counselling (or group therapy and may improve as illness is successfully
H, Eto/Pto counselling if the patient is smear- and culture- treated.
negative). 3. History of previous depression is not a
4. When depression is more significant, initiate contraindication to the use of the agents listed
antidepressant therapy (amitryptiline, fluoxetine but may increase the likelihood of depression
or similar). Tricyclic antidepressants and SSRIs developing during treatment. If significant
should not be given together and should not be depression is present at the start of treatment,
given to patients on linezolid. Also avoid with QT avoid a regimen with cycloserine if possible.
prolonging drugs. 4. Question the patient regarding suicidal ideation
5. Lower dose of suspected agent if this can be done any time the depression is judged to be more
without compromising the regimen. (Reducing than mild.
the dose of cycloserine and ethionamide to 500
mg daily to see if the depression is lessened is a
common strategy).
6. Discontinue suspected agent if this can be done
without compromising regimen.
Suicidal CS, H, Eto/ 1. Hospitalize the patient and put under 24- hour 1. Keep the patient in the hospital until risk of
ideation Pto surveillance. suicide has passed.
2. Discontinue cycloserine. 2. If no improvement occurs after holding
3. Request psychiatric consultation. cycloserine, hold H and/or Eto/Pto.
4. Initiate antidepressant therapy.
5. Lower the dose of Eto/Pto to 500 mg daily until
the patient is stable.
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Psychotic Cs, H, FQs 1. Stop suspected agent for a short period of time 1. Some patients will need to continue antipsychotic
symptoms (1–4 weeks) while psychotic symptoms are treatment throughout MDRTB therapy (and
brought under control. The most likely drug is iscontinue upon completion of MDR-TB therapy).
cycloserine followed by high-dose isoniazid. 2. Previous history of psychiatric disease is not a
2. If moderate to severe, initiate antipsychotic contraindication to the use of cycloserine, but
therapy (haloperidol). its use may increase the likelihood of psychotic
3. Hospitalize in a ward with psychiatric expertise if symptoms developing during treatment.
patient is at risk to himself/herself or others. 3. Some patients will tolerate cycloserine with an
4. Increase pyridoxine to maximum daily dose (200 antipsychotic drug, but this should be done in
mg per day). consultation with a psychiatrist as these patients
5. Lower dose of suspected agent (most commonly will need special observation and this should only
cycloserine to 500 mg a day) if this can be done be done when there is no other alternative.
without compromising regimen. 4. Psychotic symptoms are generally reversible
6. Discontinue suspected agent if this can be done upon completion of MDR-TB treatment or
without compromising regimen. cessation of the offending agent.
7. Once all symptoms resolve and patient is off 5. Always check creatinine in patients with new-
cycloserine, anti-psychotic therapy can be onset psychosis. A decrease in renal function can
tapered. If cycloserine is continued at a lower result in high blood levels of cycloserine, which
dose, anti-psychotic therapy may need to be can cause psychosis.
continued and any attempts at tapering should
be done with a psychiatrist trained in the adverse
effects of second-line anti-TB drugs.
Seizures Cs, H, 1. Hold cycloserine, FQs and isoniazid pending 1. Anticonvulsant is generally continued until MDR-
fluoroquinolones resolution of seizures. TB treatment is completed or suspected agent
2. Initiate anticonvulsant therapy (carbamazepine, discontinued.
phenytoin, or valproic acid are most commonly 2. History of previous seizure disorder is not a
used). contraindication to the use of agents listed here if
3. Increase pyridoxine to maximum daily dose (200 a patient’s seizures are well controlled and/or the
mg per day). patient is receiving anticonvulsant therapy. (Do
4. Check serum electrolytes including potassium not include cycloserine if an alternative drug is
(K+), sodium (Na+), bicarbonate (HCO3−), calcium available).
(Ca2+), magnesium (Mg2+), chloride (Cl−). 3. Patients with history of previous seizures may
be at increased risk for development of seizures
during MDR-TB therapy.
Adverse Effect Suspected Agent Suggested Management Comments
5. When seizures have resolved, restart medications 5. Always check creatinine in patients with new-
one at a time. Cycloserine should not be restarted onset seizures. A decrease in renal function
unless it is absolutely essential to the regimen. If can result in high blood levels of cycloserine,
cycloserine is reinitiated, start a dose one weight which can cause seizures. Adjusting the dose of
band lower. cycloserine in the presence of low creatinine may
be all that is needed to control the seizures.
Optic neuritis E, Eto/Pto, 1. Stop ethambutol. Do not restart. 1. The most common drug responsible is
Lzd, Cfz, 2. Refer patient to an ophthalmologist. ethambutol. Lzd may also cause ON and
H, S combination of E and Lzd enhances the risk.
2. Usually reverses with cessation of ethambutol,
LZD
3. Improve diabetic control in diabetic patients
Metallic Eto/Pto, Clr, 1. Encourage the patient to tolerate this side effect. 1. Normal taste returns when treatment is stopped.
Taste FQs 2. Sucking hard candy or chewing gum can be
helpful.
Gynecomastia Eto/Pto 1. Breast enlargement can be a troublesome side- 1. Resolution occurs after treatment is stopped
effect of Eto/Pto therapy, especially for male
patients. Galactorrhoea has also been reported.
2. Encourage patients to tolerate this side effect
87
6.2.1 Adverse Event Causality Assessment Flowchart:
For all SAEs, the first level Causality Assessment can be done at the DR-TB treatments centers by the
treating doctor using the below Adverse Event Causality Assessment definitions and Flowchart:
Unknown 1. Did AE start after medicine was started? No Not drug-related
YES
UNASSESSED
or 2. Is timing of AE consistent with drug related effect? No UNLIKELY
UNASSESSABLE*
YES
Unknown 3. Have other possible causes of the AE been excluded? No

YES
4. Were any of the medicines stopped? No POSSIBLE

YES
5. Did patient recover from AE after stopping the medicine? No

YES
6. Was the medicine restarted? No

YES PROBABLE
7. Did the AE occur again after restarting the medicine? No

YES
8. Is the AE a well-defined, objective event? YES CERTAIN
Causality Assessment Flow Chart based on WHO-UMC system standardized case causality assessment available
at: http://www.who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf
Notes:
1. Check the start date of each of the medicines and the onset date of the AE. If the AE started
before the medicines was started, there is no causal relationship between the medicines and
the AE. (Note: is a pre-existing condition got worse after starting medicine it may be a drug-
related effect, in which case select ‘yes’ and go to step 2)
* Select UNASSESSED if unknown but awaiting further information. Select UNASSESSABLE

if unknown and no further information can be obtained (eg, information not recorded at
health facility)
2. Is the time-to-onset of the adverse event consistent with a drug-related effect? Consider
known actions and pharmacokinetics (absorption, distribution, metabolism and elimination)

of the medicines and the pathology of the adverse event (how long would it take for condition
to develop?)
3. Are there other factors that could account for AE, such as:
• Condition for which medicines were prescribed?
• Other illnesses?
• Other medicines (including traditional/herbal medicines)?
** If other factors provide a more likely explanation for the AE, the casual association between
the medicine and the AE is assesses as UNLIKELY
4. DECHALLENGE
5. Did the patient recover from the AE or show objective signs of improvement after the
medicine was stopped? Is it biologically plausible that the response observed after stopping
the medicine was due to the medicine being stopped?
6. RECHALLENGE
7. Was the re-challenge at the same dose or a lower dose? If the re-challenge was negative at a
lower dose, consider whether the AE may have been a dose-related effect
8. The causal association can only be assessed as CEARTAIN if the AE is a well-defined, objective
event. (Vague, non-specific symptoms do not meet the criteria for CEARTAIN)
When required, second level of Causality Assessment will be done by the national level by a
Causality Assessment team from the National Tuberculosis Centre (NTC) using the same Adverse
Event Causality Assessment Flowchart. This will enable the findings from the first level causality
assessment to be verified.
6.2 CAUSALITY ASSESSMENT OF THE SERIOUS ADVERSE

EVENT (SAES):
TABLE 6.4 The WHO-UMC Classification System for causality assessment
Causality term Definition Assessment criteria*
1. Certain Clearly caused by the exposure • Event or laboratory test abnormality, with
There is clear evidence to plausible time relationship to drug intake
suggest a causal relationship • Cannot be explained by disease or other
and other possible contributing drugs
factors can be ruled out. • Response to withdrawal plausible
(pharmacologically, pathologically)
• Event definitive pharmacologically or
phenomenologically (i.e., an objective and
specific medical disorder or a recognized
pharmacological phenomenon)
• Re-challenge satisfactory, if necessary
2. Probable/ Likely to be related to the • Event or laboratory test abnormality, with
Likely exposure reasonable time relationship to drug intake
There is evidence to suggest a • Unlikely to be attributed to disease or other
likely causal relationship and drugs
the influence of other factors is • Response to withdrawal clinically reasonable
unlikely. • Re-challenge not required
3. Possible May be related to the exposure • Event or laboratory test abnormality, with
There is some evidence to reasonable time relationship to drug intake
suggest a causal relationship • Could also be explained by disease or other
(e.g. because the event occurs drugs
within a reasonable time • Information on drug withdrawal may be
after administration of the lacking or unclear
trial medication). However,
the influence of other factors
may have contributed to the
event (e.g. the patient’s clinical
condition, other concomitant
treatments).
4. Unlikely Doubtfully related to the • Event or laboratory test abnormality, with a
exposure time to drug intake that makes a relationship
There is little evidence to improbable (but not impossible)
suggest there is a causal • Disease or other drugs provide plausible
relationship (e.g. the event did explanations
not occur within a reasonable
time after administration of the
study regimen). There is another
reasonable explanation for the
event (e.g. the patient’s clinical
condition, other concomitant
treatment).
5. Conditional There is insufficient information • Event or laboratory test abnormality
or Unclassified about the ADRs to allow for an • More data for proper assessment needed, or
assessment of causality. • Additional data under examination
6. Unassessable There is insufficient information • Report suggesting an adverse reaction
or about the ADRs to allow for an • Cannot be judged because information is
Unclassifiable assessment of causality and NO insufficient or contradictory
MORE is expected. • Data cannot be supplemented or verified
*All points should be reasonably complied for assessment

CHAPTER 7
INFECTION CONTROL
TB infection control is a combination of measures aimed at minimizing the risk of TB transmission

within populations. The foundation of infection control is early and rapid diagnosis, and proper
treatment of TB patients.
7.1 GENERAL PRINCIPLES OF INFECTION CONTROL

There are three levels of infection control measures, operating at different points in the
transmission process, and all are interdependent:
7.1.1 Administrative (managerial) controls

Administrative controls should be implemented as a first priority because they have been shown
to reduce transmission of TB in health-care facilities. Such controls are a vital part of sound
infection control practices, which require people with TB symptoms to be promptly identified,
separated and treated. Administrative control includes:
• Develop and implement written policies and protocols to ensure:

o Rapid identification of TB cases (e.g., improving the turn-around time for obtaining
sputum results)
o Isolation of patients with PTB
o Rapid diagnostic evaluation
o Rapid initiation treatment
• Educate, train, and counsel HCWs about TB
• To the extent possible, avoid mixing TB patients and HIV patients in the hospital or clinic
setting
• Find cases Actively, Separate temporarily and Treat effectively (FAST) is intensified, refocused
administrative approach to TB transmission control in healthcare facilities. Active case finding
with cough screening followed by rapid molecular diagnostics, which enables prompt
treatment of unsuspected drug-sensitive and drug-resistant TB, thereby decreasing TB
transmission. The basis principle for FAST are as follows:
o TB is spread in institutions predominantly by coughing patients with unsuspected TB or
unsuspected drug resistance
o Most potentially infectious patients can be identified by cough surveillance
o Coughing TB patients most likely to be infectious can be diagnosed using rapid molecular
sputum tests
o By dramatically reducing the duration of institutional exposure through effective
treatment, transmission among patients and to health care workers will be reduced
proportionately
Note: For detail please consult FAST Guideline
7.1.2 Environmental controls include methods to reduce the concentration of infectious

respiratory aerosols (i.e. droplet nuclei) in the air, and methods to control the direction of
infectious air.
Such measures include:

• Use of ventilation systems.
• Use upper-room germicidal ultraviolet irradiation (GUV) fixtures, at least when adequate
ventilation cannot be achieved
7.1.2.1 Use of ventilation systems

Adequate ventilation in health-care facilities is essential for preventing transmission of airborne
infections, and is strongly recommended for controlling spread of TB. The choice of ventilation
system will be based on assessment of the facility and informed by local programmatic, climatic
and socioeconomic conditions. Any ventilation system must be monitored and maintained on a
regular schedule.
Kind of ventilation systems:

• Natural
• Mechanical
Natural Ventilation
Created by the use of external airflows generated by natural forces such as:
• Wind
• Differences in temperature
Naturally ventilated rooms can achieve very high ventilation rates (ACH) under ideal conditions
but natural ventilation is unpredictable.
Maximize Natural Ventilation

• Openings on opposite walls (cross ventilation)
• Openings are unrestricted (stay open)
• 10% of floor space should be openable- window-area on each wall
• Upper levels of the building
• Building and openings are oriented to use the prevailing wind, without obstruction by other
nearby buildings
Mechanical ventilation
Well-designed, maintained and operated fans (mixed-mode ventilation) can help to obtain
adequate dilution when natural ventilation alone cannot provide sufficient ventilation rates.
In some settings, mechanical ventilation (with or without climate control) will be needed.
This may be the case, for example, where natural or mixed-mode ventilation systems cannot
be implemented effectively, or where such systems are inadequate given local conditions (e.g.
building structure, climate, regulations, culture, cost and outdoor air quality).
7.1.2.2 Use of upper room or shielded germicidal ultraviolet irradiation fixtures

Priority should be given to achieving adequate ACH using
ventilation systems. However, in some settings it is not
possible to achieve adequate ventilation; for example,
because of climatic changes (e.g. in winter or during the
night) or building structure, or because transmission of TB
would pose a high risk of morbidity and mortality (e.g. in
MDR-TB wards). In such cases, a complementary option
is to use upper room or shielded germicidal ultraviolet
irradiation (GUV) devices. This environmental control does
not provide fresh air or directional airflow.
7.1.3 Personal respiratory protection aims to protect the health workers in areas where
the concentration of droplet nuclei cannot be adequately reduced by administrative and
environmental controls. Health workers should use high filtration masks (N95) or “respirators” to
protect them against the inhalation of airborne infectious droplets. The patients should wear a
surgical mask to reduce the spread of droplets.
Respirator Vs Surgical Mask

RESPIRATORS SURGICAL MASKS
• Designed to filter out droplet nuclei from • Designed to stop droplet nuclei from being
being inhaled by the health-care worker and spread (exhaled) by the patient.
other individuals. • Should NOT be worn by the health-care
• Should properly fit different face sizes and worker
features.
• Should NOT be worn by the patient
Personal respiratory protection by themselves are insufficient to prevent

TB transmission. They will not be worn continuously and are likely not to
be in use when unsuspected TB cases are encountered. Administrative and
environmental controls are more important.
7.2 INFECTION CONTROL AT TB CONSULTATION ROOM

The rooms for TB consultation, counselling and health education should be arranged according
to sound infection control principles:
v Both windows and door should be open all the time.

v Direct sunlight gets into the room easily
v A stand fan ensures an airflow direction toward the opened window
v Patient and health staff sit in front of each other across the airflow
v Exhaust fan to extract the air
v One patient at a time should be received in the room
v The patient should wear a surgical mask
v Staff and family should wear N95 mask
v Appropriate cough hygiene must be observed by the patient
1. The ventilation flow:
Wind Wind Wind Wind

Patient HCW Patient HCW
Good!!! Bad!!!
HCW
Wind Wind
Patient
Good compromise
7.3 DR-TB PATIENT ISOLATION ROOM

The DR-TB isolation room should have large open windows allowing direct sunlight into the
room, a closing door, a stand fan to establish an air flow direction toward the window, and
preferably a UV light installation with a shield to protect the eyes from direct exposure to it. The
UV light should be turned on for 15 to 20 minutes every 12 hours (in the morning and evening),
preferably with the patients not being in the room. An exhaust fan may help to extract the air
from the room. The DR-TB room should be isolated from the other departments, especially the
out-patient clinic, the HIV ward, the pediatric ward and other high risk group departments.
DR-TB infectious patients in the isolation room must wear a surgical mask at all times. If no masks
are available, the patients should use a handkerchief or a piece of cloth to cover their mouth
when talking, coughing, sneezing or speaking. The patients should refrain from spitting on the
floor, but should spit in a sputum cup that will be later burned.
Health workers must wear high filtration (N95) masks, fitted correctly, every time they meet DR-
TB patients or enter the DR-TB ward.
Instructions on how to wear masks should be posted at all entries of the DR-TB area for staff,
patients and visitors
DR-TB patients should not receive many visitors and avoid contact with small children until sputum
smear or culture conversion. Good infection control measures for visitors and small children include:
- Meeting in a room with good ventilation or outside
- Patient wearing surgical mask and visitor wearing high filtration (N95) mask
Room disinfected by appropriate use of UV light
7.4 INFECTION CONTROL AT HOME

Contagious or potentially contagious patient may have to be isolated at home. The following
infection control measures can be taken:
• If feasible, the patient should stay and sleep in a specific room separated from the other
family members.
• If possible, the isolation room should have good ventilation with a large opened window,
direct exposure to sunlight, and preferably with good air flow direction (natural or with fan).
• Other people should not enter the room unless necessary. If they do so, patient must a
surgical mask.
• At all stages the patient should be encouraged to stay outside.
• The patient should eat separately, outside or in the room.
• The patient should wear a surgical mask all the time when in contact with other people.
• Strict coughing hygiene must be observed by the patient, inside as well as outside the house.
• If other people come to see the patient, they should meet outside. They need to keep a safe
distance and duration of contact should be kept as short as possible.
• The patient should avoid contact with children or other high-risk groups and restrict close
contacts with other people during the contagious period.
Role of TB patient in infection control:

• Patient should maintain a well-balanced diet to keep the immune system strong
• Patient should TB patient to stop smoking and minimize intake of alcohol
• Patient should wear mask and hold a cloth or handkerchief over mouth when coughing
• Patient should not spit on the floor but in a container (preferably disposable) and dispose of
properly
7.5 HEALTH WORKER AND INFECTION CONTROL

Always follow recommended infection control procedures in your work in the health facility. Be
aware of possible signs and symptoms of TB in yourself. If one or more of these develop, report
promptly for assessment and care. If you are diagnosed with TB, start treatment promptly and
adhere to treatment until it is completed.
Health workers should decrease their risk factors for TB disease to the extent possible eg. Living
healthy live-styles, stress free, stop smoking, or following treatment for diabetes, knowing their
HIV status or getting retested periodically etc. If a health worker is HIV-infected, he/she may
decrease his/her risk of developing TB by taking CPT, ART and IPT as appropriate. Health workers
who have positive HIV status should be given alternate choice of work area by the employers.
CHAPTER 8
MONITORING AND EVALUATION

FOR TB CONTROL PROGRAM
8.1 RECORDING AND REPORTING OF DR-TB PROGRAMME
In Nepal, The National DRTB program has endorsed 16 DRTB Recording and Reporting tools. Out
of the 20 forms (and the subset of forms) are common for DS and there are 8 forms are specific to
DR-TB (Highlighted in Bold) below.
Forms, Records and Registers

The following recording and reporting are used for DR-TB:
S.N TB NUMBER TOOLS

1 TB 01 Presumptive TB register
2 TB 02a Laboratory Request Form
3 TB 02b Laboratory Report Form (LPA and Culture DST)
4 TB 03a Laboratory Register (Microscopy)
5 TB 03b Laboratory Register (GeneXpert)
6 TB 03c Laboratory Register (Culture DST)
7 TB 03d Laboratory Register (LPA)
8 TB 03e Culture / DST Reporting Forms
9 DRTB 01 DR-TB Register
10 DRTB 02 DR-TB Treatment Card
11 DRTB 03 DR-TB Patient Identity Card
12 TB 07 Contact Investigation form
13 TB 08 Contact and TBPT Register
14 TB 10 Referral / Transfer Slip
15 TB 11 Referral Form (Community, Private, Contact)
16 DRTB 04 Commitment Form
17 DRTB 05 aDSM Recording and Reporting Form
18 DRTB 06 DR-TB Drug Order Form
19 DRTB 07 DR-TB Reporting Form (for cohort reporting)
20 DRTB 08 Six-monthly Report on Detection and Enrolment of DR-TB
1. Presumptive TB register (TB 01).

Once a patient is suspected of having TB in the OPDs/Clinics, then they are registered in
the Presumptive TB Register at the OPDs by the treating physicians/health care workers.
Presumptive TB Register contains sociodemographic information of TB patients, history of
TB, where the patient is referred to for diagnosis, diagnosis result details, TB management
suggested and details where the patient is referred for management (DOT centers). The new
serial number will be assigned at the beginning of each month while using this register. The
register is the same for both DS and DR-TB.
2. Laboratory Request Form (TB 02a)

These forms are filled by OPDs / clinics for diagnosis of TB/DRTB and or from DR TB Treatment
Centers for follow up purpose. There is only one Laboratory Request Form that will be used
for both DS and DR TB diagnosis as well as follow up. Once the tests are done, the lab reports
back the test results of Smear Microscopy and Xpert MTB/RIF testing using the same Form.
Results of LPA and Culture DST are given in separate form using Laboratory Report Form(LPA
and Culture DST) (TB 02b).
The Form is divided broadly into 2 parts.
Part 1 is for Laboratory Test request, which has sub-sections for different requesting different
types of tests (for diagnosis of TB with smear and Xpert MTB/RIF testing Part A, For LPA for
HrTB diagnosis part B, for retreatment cases requiring further confirmation with culture DST
part C, for DRTB baseline and followup test part D, and HIV testing part E).
Part 2 is for reporting the results of smear and Xpert MTB/RIF testing.
3. Laboratory Report Form(LPA and Culture DST) (TB 02b)

The results of LPA and Culture DST are reported by Lab using this form. This is also the same
for DS and DR-TB for initial diagnosis or follow up purpose.
4. Laboratory Register and Form (TB 03)

These registers are present in the Laboratories where the bacteriological test for TB are
carried out. The registers are separate for different types for laboratory process even within
the same Laboratory.
a. Sputum Smear Microscopy Register (TB 03a)
b. GeneXpert Register (TB 03b)
c. LPA Register (TB 03c)
d. Culture DST Register (TB 03d)
Once the results are obtained, it is then sent back to the treatment center requesting for the
tests (via patient or their accompany, courier or other means as available)
e. Culture/DST Reporting Form (TB 03e)

There is also a separate Culture/DST Reporting Form (TB 03e), which is filled by the Culture
Laboratories which contains compiled information of all Culture/DST tests performed by
the respective laboratory in that given time frame. This is submitted to NTP on a monthly/
quarterly basis. Compiled information of other tests; smear, GeneXpert, and LPA are captured
through HMIS 9.3 reporting template, but as detail information regarding culture is required
to NTP, the information is captured and reported separately using this format.
5. DRTB Register (DRTB 01)

This register is present at DRTB Treatment centers where the patients are registered for
treatment. This register also contains the details of patients’ particulars, diagnosis details,
registration category details and treatment details, sputum conversion and outcome details
with other additional details on contact investigation, smoking habits. This register will be
the basis for filling out the DRTB 07 Reporting Format will be used for cohort reporting of
DRTB on monthly basis and analyzed 4 monthly by the NTP.
6. DRTB Treatment Card (DRTB 02)

Once on the DR TB register, a DRTB Treatment card is also issued to the patient. This card
contains all the information of patients that is in the DR TB register including the section for
monitoring daily drug adherence. Three duplicate copies are made of the card. One copy is
kept in the DRTB Treatment center; one is sent to the DR TB treatment Sub-centers and one
copy is given to the treatment supporter if the patient is managed under CBDOT program.
The details of the patient’s smoking habit along with ABC provided are recorded at the
attached Smoking Cessatithe on the card at 0 months and for 3 more visits (in equal
intervals).
7. DRTB Patient Identity Card (DRTB 03)

Once the treatment card is issued, the Patient’s identity card is also issued to be kept by the
patient, which basically has all the information from the treatment card and is also updated
every day.
8. Contact Investigation Form (TB 07)

Though the patient is registered in the DR TB center, the DOT center which referred the
patient to the DR TB Treatment center is responsible for carrying out the contact investigation
and also inform the DRTB treatment center of the finding. Volunteers are given out these
Contact Investigation Forms with details of DR TB index cases, which they use while carrying
out contact investigation in the community. If there are presumptive DRTB among contacts
identified during screening, a separate Referral Form (TB 11) is filled out and issued by the
volunteers and referred for further diagnosis. All the information are then recorded for all
contacts screened in this form and are submitted back to the DOT centers. The same form
will be used to access contacts of drug-sensitive and/or drug-resistant TB.
9. Contact and TBPT Register (TB 08)

Once Household contacts are referred from the community, then they are then registered
in the Contacts and TB Preventive Therapy (TBPT) Register at the DOT center. This register
contains details of the contact, their TB/DRTB status.
10. Referral / Transfer Form (TB 10)

These forms are filled when a patient needs to be referred or transferred out from one center
to the next. This contains the information of the patient’s particular, diagnostic details,
treatment category and regimen details along with details from where and the reason for
referral/transfer out. It also has acknowledgement slip which need to be filled and sent back
by the receiving centre.
11. Community Referral Form (TB 11)

These forms are present in the treatment centers and are provided to the community health
volunteers (esp. FCHVs). These are used while referring presumptive TB cases from the
community (during contact tracing) to the health facilities for further diagnosis or can also
be used for referring a TB patient if they have side effects or requiring other tests and follow
up, which they identify in the community.
12. Commitment Form (DRTB 04)

These forms are maintained in the DR TB treatment centers. These forms are filled taking
consent from the patient regarding their willingness and commitment to be enrolled into
daily DOT DR TB management as well as commitment from service provider to provide the
treatment as required to the DR TB patients.
13. aDSM Recording and Reporting Form (DRTB 05)

These forms are maintained in the DR TB treatment center level where the adverse events
are recorded, managed, and reported. The reporting forms are sent to NTC aDSM unit every
monthly/quarterly basis for minor adverse event but immidiately for severe adverse events.
14. DRTB Drug Order form (DR TB 06)

Drug order forms are present in the treatment centers where DOT is provided. They are filled
in a regular basis and used for ordering drugs for TB program.
15. DRTB Cohort reporting Form (DRTB 07)

DRTB Cohort reporting format is present at the DR-TB treatment centers, where the DRTB
register is being maintained. The cohort reporting is done on a monthly/quarterly basis.
16. Six-monthly Report on Detection and Enrolment of DR-TB (DRTB 08)

These forms are filled and reported by treament centre and sent to the National TB
program for analysis and feedback from the NTC will be given to the treatment centre.
8.2 MONITORING OF DR-TB CASE DETECTION AND

TREATMENT ACTIVITIES
Monitoring DR-TB control activities are important to assess progress and identify areas that need
improvement. The National TB Program monitors the following indicators
1. TB case detection indicators

A. Monitoring is done by NTP level
i. The proportion of DR-TB cases detected ( all forms) among presumptive TB cases and
enrolled under treatment at different levels (national, provincial and local level). The
monitoring is done for all forms of TB.
ii. The proportion of detected DR-TB cases enrolled under treatment.
iii. The Cohort analysis (sputum conversion and Treatment outcome) of the registered DR-TB
cases.
B. Monitoring is done at the DR TB treatment center level

i. Daily treatment adherence of DR -TB cases registered in their center.
ii. Carrying out regular follow up activities of each DR TB cases.
iii. The proportion of adverse events of DR-TB cases and management of adverse events.
iv. Regular (monthly) follow up of DR-TB cases (for daily adherence and follow up tests)
managed by Treatment Sub-centres.
v. Regular (monthly) follow up of DR-TB cases (for daily adherence and follow up tests)
managed under CBDOT program.
iv. The cohort analysis (sputum conversion and Treatment outcome) of each registered DR-
TB cases.
vi. Contact investigation of index DR-TB cases and the proportion of contacts tested for TB,
diagnosed with TB, managed with TB and for <5 year or PLHIV who do not have TB are put
on TBPT.
C. Monitoring is done at the DR TB treatment sub-center level

i. Daily treatment adherence of DR TB cases managed from their center.
ii. Assurance of follow up test is done by the registered DR-TB cases.
iii. Supervision of DR TB cases being managed under CBDOT assigned under their center.
2. TB Treatment Outcome indicators

i. Sputum Conversion Rate
This indicator refers to the conversion of sputum during follow up, which was initially
bacteriologically positive (sputum or culture) at the time of diagnosis. Conversion is seen
usually at each month with smear and culture.
For programmatic analysis:

• For a patient under an SSTR - the sputum smear conversion is checked at 4 months, for which
the cohort analysis is done at 8 months of the start of treatment.
• For Longer Regimen, the conversion of culture is checked at 6 months, for which the cohort
analysis is done at 12 months of the start of treatment.
ii. TB Treatment Outcome

This indicator refers to treatment outcomes for all registered DR TB cases. Treatment Outcome
indicators are measured with the following treatment outcomes. Conversion of sputum and
cohort analysis is done at:
For SSTR - after 16 months of initiation of treatment.
For LR 1,2,3,4 - after 24 months of initiation of treatment.
1. Cured
2. Treatment Completed
3. Treatment Failed
4. Died
5. Lost to follow up
6. Not evaluated
*Treatment Success Rate (proportion of cured plus completed)
The most important treatment outcome is the cure rate for bacteriologically confirmed patients.
The desired cure rate for DR-TB in Nepal is more than 70%.
ANNEXURES
1. Drug information sheets
2. Grading of the severity of Adverse Drug Events
3. Calculating the QT interval
4. Calculating the creatinine clearance
5. Peripheral Neuropathy Diagnostics
6. Forms, records and registers
7. Gastric aspirate Job aid
8. Monitoring and Evaluation Checklist (Programmatic & Clinical) for DR-TB Treatment Site
9. Modified Shorter Regimen and Future SSTR Options
10. Forms, Records and Registers

Annex 1. Drug information sheets

The drug information are a summary of the most relevant information in the medication fact
sheets in Companion handbook to the WHO guidelines for the PMDT, 2014, part 3, p 252-296 and
Curry MDR Guide 2016, part 5, p 99-148. For the complete details as well as the drugs not included
in Annex 1, please consult the reference.
The drugs are described in alphabetical order:
A1.1. Bedaquiline
A1.2. Capreomycin
A1.3. Clofazimine
A1.4. Cycloserine
A1.5. Delamanid
A1.6. Ethambutol
A1.7. Ethionamide
A1.8. Isoniazid
A1.9. Kanamycin
A1.10. Levofloxacin
A1.11. Linezolid
A1.12.a Meropenem
A1.12.b Amoxicillin-clavulanic acid
A1.13. Moxifloxacin
A1.14. Para-aminosalicylic acid
A1.15. Pyrazinamide
A1.1. BEDAQUILINE (BDQ)

Activity against Bactericidal; has strong anti-TB activity with in vitro activity against both
TB replicating and nonreplicating bacilli.
Cross-resistance Cross-resistance with clofazimine has been demonstrated
Dose Adults: 400 mg daily for 14 days, followed by 200 mg 3 times weekly for 22
weeks. Has not been studied past 24 weeks of administration.
Missed doses: After the first 2 weeks of treatment, the dose changes to the
200 mg three times per week, even if doses were missed during the first
2 weeks. Patients should not make up for missed doses during the first 2
weeks of treatment.
Concomitant medications: coadministration of rifamycins (e.g., rifampin,
rifapentine and rifabutin) or other strong CYP3A4 inducers may require dose
adjustment.
Children: Has not been studied in children. Based strictly on weight,
converting from the adult doses in a 70 kg patient, estimated pediatric doses
would be 6 mg/kg daily for 14 days, followed by 3 mg/kg 3times weekly for
22 weeks. However, these doses are not supported by clinical experience.
Renal failure/dialysis: No dose adjustment needed for mild to moderate
renal insufficiency, but should be used with caution in patients requiring
renal dialysis.
Route of Oral.
administration
Preparation 100 mg tablets.
Storage Store at room temperature. Tablets removed from the original packaging
should be stored in a tight, light-resistant container and labeled with an
expiration date not to exceed 3 months.
Oral absorption Good oral absorption. Should be given with a meal to increase
bioavailability.
CSF penetration No data available. Also, there are no data on the treatment of extra-
pulmonary TB (e.g., central nervous system) with bedaquiline.
Special Use in pregnancy/breastfeeding: Pregnancy category B. No fetal harm
circumstances found in animal studies. The drug is concentrated in breast milk and
avoiding nursing should be considered.
Use in renal disease: No dose adjustment needed for mild to moderate
renal insufficiency.
Use in hepatic disease: No dose adjustment is necessary for bedaquiline
in patients with mild or moderate hepatic impairment. Use with caution
in patients with severe hepatic impairment, and only when the benefits
outweigh the risks.
Adverse QTc prolongation, hepatitis, nausea, joint pain, headache, elevated amylase,
reactions coughing up blood, chest pain, loss of appetite, and/or rash.
Contra- None, but use with caution if other QTc prolonging agents, such as
indications clofazimine or fluoroquinolones, are being given.
Monitoring EKG at baseline, 2, 12 and 24 weeks of treatment. Stop bedaquiline if QTc

> 500 and monitor EKGs frequently until QTc returns to normal. Baseline
potassium, calcium and magnesium, repeat if QTc prolongation occurs, and
monthly if on injectable drug.
Baseline and monthly liver function tests.
Warning Only use bedaquiline when an effective treatment regimen cannot
otherwise be provided.
QTc prolongation can occur with bedaquiline. Use with drugs that prolong
the QTc interval may cause additive QTc prolongation.
Patient Avoid alcohol. Take medication with food
instructions Call your doctor and stop the medicine right away if you have:
• serious heart rhythm changes (QTc prolongation). Tell your healthcare
provider right away if you have a change in your heartbeat (a fast or
irregular heartbeat), or if you faint.
• liver problems (hepatotoxicity). Call your healthcare provider right away
if you have unexplained symptoms such as nausea or vomiting, stomach
pain, fever, weakness, itching, unusual tiredness, loss of appetite, light-
colored bowel movements, dark-colored urine, yellowing of your skin or
the white of your eyes.
Refer to Annex 4.1 (p 341-368) of WHO MDR Guidelines 2014 for detailed description of Bdq
use.
A1.2. CAPREOMYCIN (CM)

Activity against Bactericidal; has strong anti-TB activity;
TB
Cross-resistance Amikacin and kanamycin. Variable frequency of cross-resistance has been
reported.
Dose (all once Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week
daily) 15 mg/kg/dose, 2–3 times per week after initial period of daily
administration
> 59 yrs of age: use a lower starting dose of 10 mg/kg/dose (max 750 mg)
5–7 times per week or 2–3 times per week after initial period.
Children: 15–30 mg/kg/day (max 1 gram) 5–7 days per week.
15–30 mg/kg/day (max 1 gram) 2–3 days per week after initial period daily.
In STR, 15-20 mg/kg/day is given.
Renal failure/dialysis: 12–15 mg/kg/dose 2–3 times weekly (not daily).
Markedly obese individuals: dose must be adjusted downwards.
Route of IV or IM.
administration
Preparation Capreomycin is available in vials of 1 gram for either IM or IV administration.
The contents of the vial should be reconstituted with 2 ml or more of Normal
Saline or sterile water.
Storage Package insert indicates that reconstituted capreomycin can be stored in
the refrigerator up to 24 hours prior to use. Other data suggest that it may be
held for 14 days in the refrigerator or 2 days at room temperature.
Oral absorption There is no significant oral absorption. Intramuscular absorption might be

delayed if the same site is used consistently.
CSF penetration There is a paucity of data regarding capreomycin’s penetration of the
meninges.
Use in pregnancy/breastfeeding: Generally avoided in pregnancy due
to congenital deafness. There are case reports of its safe use in pregnancy
Special (unaffected newborns). Can be used while breastfeeding.
circumstances Use in renal disease: Use with caution. Interval adjustment is
recommended for patients with impaired renal function.
Use in hepatic disease: Drug concentrations not affected by hepatic
disease . Presumed to be safe in severe liver disease; however, use with
caution—some patients with severe liver disease may progress rapidly to
hepato-renal syndrome.
Adverse Similar to the aminoglycosides.
reactions Nephrotoxicity: occurs in 20%–25%. Proteinuria, reduced creatinine
clearance, and depletion of potassium and magnesium.
Ototoxicity (hearing loss): Occurs more often in elderly persons or those with
pre- existing renal impairment; vestibular toxicity.
Local pain with IM injections.
Electrolyte abnormalities, including hypokalemia, hypocalcemia, and
hypomagnesemia. Liver function test abnormalities when used with other
TB drugs.
Contra- Hypersensitivity to capreomycin. Some experts would not use
indications capreomycin if vestibular side effects resulted from aminoglycoside use.
Generally avoided in pregnancy due to congenital deafness.
Monitoring Monitor renal function by documenting creatinine at least monthly (more
frequently if renal or hepatic impairment);
Document creatinine clearance if there is baseline renal impairment or any
concerns; Follow monthly electrolytes, magnesium, and calcium.
Document baseline and monthly audiology exam;
Question patient regularly about vestibular complaints and perform serial
vestibular exams.
Patient Call your doctor right away if you have:
instructions Rash / Fever or chills / Bleeding or bruising / Problems with
hearing, dizziness, or balance / Bleeding or a lump where the shot is given
/ Decreased urination / Trouble breathing / Muscle weakness
A1.3. CLOFAZIMINE (CFZ)

Activity against In vitro activity against M. tuberculosis without much in vivo data.
TB
Cross-resistance Bedaquiline.
Dose (all once Adults: 100 mg/day. (200 mg daily have been used. A regimen of 200 mg
daily) daily for 2 months, followed by 100 mg daily has been used.)
Children: Limited data. Suggested dose 2-3 mg/kg/day
Renal failure/dialysis: No adjustment required.
Route of Oral; not available parenterally.
administration
Preparation 50 and 100 mg capsules.
Storage Room temperature.
Oral absorption 70% absorption after an oral dose.
CSF penetration Limited data are available regarding CNS penetration.
Special Use in pregnancy/breastfeeding: Not recommended due to limited data.
circumstances Avoided with breastfeeding due to pigmentation of the infant.
Use in renal disease: No dosage adjustment required.
Use in hepatic disease: Partially metabolized by the liver; use caution and/
or adjust the dose for severe hepatic insufficiency.
Adverse Pink or red discoloration of skin, conjunctiva, cornea, and body fluids.
reactions Gastrointestinal intolerance.
Photosensitivity.
Other side effects include retinopathy, dry skin, pruritus, rash, ichthyosis,
xerosis, and severe abdominal symptoms, bleeding, and bowel obstruction.
Contra- Allergy to clofazimine.
indications
Monitoring Symptomatic monitoring.
Patient Take with food to avoid stomach upset and improve absorption.
instructions This medicine may discolor your skin and body secretions pink, red, or
brownish-black. This should go away after stopping the medicine, but may
take a long time. Avoid the sun and use strong sunscreens.
Call your doctor right away if you have:
• Bloody or black stools or diarrhea
• Yellowing of your skin or eyes
• Severe nausea, vomiting, abdominal pain, cramps, or burning
• Depression or thoughts of hurting yourself
A1.4. CYCLOSERINE (CS)

Activity against Bacteriostatic; inhibits cell wall synthesis.
TB
Cross-resistance None reported
Dose Adults: 10–15 mg/kg/day. Usually 250 mg twice a day or 500 mg in a single
dose; can increase to 250 mg 3 times a day or 250 mg in the morning and
500 mg in the evening. concentrations are kept below 35 mcg/ml. Some
patients may require only alternate day 250 mg and 500 mg dosing to
achieve desired blood levels.
Children: 10– 20 mg/kg/day divided every 12 hours (daily maximum 1 gram).
Vitamin B6: MDR-TB experts recommend that all patients should receive
vitamin B6 while taking cycloserine. Adults need 100 mg or more (or 50 mg
per 250 mg of cycloserine) and children should receive a dose proportionate
to their weight.
Renal failure/dialysis: 250 mg once daily or 500 mg 3 times per week;
Route of Oral; not available parenterally.
administration
Preparation 250 mg capsule.
Storage Room temperature in airtight containers.
Oral absorption Modestly decreased by food (best to take on an empty stomach); not
significantly affected by antacids or orange juice.
CSF penetration Concentrations approach those in serum.
Special Use in pregnancy/breastfeeding: Not well studied, but no teratogenicity
circumstances documented. Use if there are not better choices. Can be used while
breastfeeding (dose the infant with vitamin B6 if breastfed).
Use in renal disease: Cycloserine is cleared by the kidney and requires dose
adjustment for renal failure. Use with caution.
Use in hepatic disease: Not associated with hepatotoxicity.
Adverse CNS toxicity, including inability to concentrate and lethargy.
reactions More serious CNS side effects, including seizure, depression, psychosis, and
suicidal ideation, usually occur with high dosing, but may be seen in the
normal therapeutic range.
Other side effects include peripheral neuropathy and skin changes. Skin
problems include lichenoid eruptions and Stevens-Johnson syndrome.
Contra- Significant CNS disease, including seizure disorder, psychotic disease, or
indications alcohol abuse.
Monitoring Baseline and monthly monitoring for depression should be done.
Patient Best taken on an empty stomach, with juice or antacids. If food is taken,
instructions avoid a large fatty meal. Avoid alcohol.
You must also take a high-dose vitamin B6 supplement while on this drug.
• Seizures
• Shakiness or trouble talking
• Depression or thoughts of hurting yourself
• Anxiety, confusion, or loss of memory
• Personality changes, such as aggressive behavior
• Rash or hives
• Headache
A1.5. DELAMANID (DLM)

Activity against Bactericidal; has strong anti-TB activity. Inhibits mycolic acid biosynthesis.
TB
Cross-resistance Cross-resistance with investigational drug PA-824, also a Nitroimidazole
Dose Adults: 100 mg twice daily with food for 24 weeks. Administration for more
than 6 consecutive months has not been studied.
Children: The safety and efficacy in children under 18 years has not been
published. Based strictly on weight, converting from the adult doses in a 70
kg patient, estimated pediatric doses would be 1.5 mg/kg twice daily for 24
weeks. Studies are testing delamanid at 50 mg twice daily for ages 6-11 and
100 mg twice daily for ages 12-17.
Renal failure/dialysis: No dose adjustment needed for mild to moderate
renal insufficiency but there are no data regarding use in patients with
severe renal impairment. Therefore, delamanid is not recommended for
patients with severe renal impairment.
Route of Oral.
administration
Preparation 50 mg film coated tablets.
Storage Store at room temperature and in original package in order to protect from
moisture.
Oral absorption 25- 47% of the delamanid dose is absorbed following oral administration
with food.
CSF penetration No data are available. Also, there are no data on the treatment of
extrapulmonary TB (e.g., central nervous system, bone) with delamanid.
Special Use in pregnancy/breastfeeding: Delamanid may cause harm to a fetus.
circumstances It is usually not recommended for use during pregnancy. It is not known
if delamanid passes into breast milk in humans. Breastfeeding is not
recommended during treatment with delamanid.
Use in renal disease: No dose adjustment needed for mild to moderate
renal insufficiency, but not recommended for patients with severe renal
impairment.
Use in hepatic disease: No dose adjustment necessary in patients with mild
hepatic impairment, but not recommended in patients with moderate to
severe hepatic impairment. Contraindicated in patients with serum albumin
levels <2.8 g/ml.
Use in cardiac disease: Patients with various cardiac risk factors, including
QTc interval prolongation, should not receive delamanid unless the
potential benefits of treatment are expected to outweigh the possible
risks. Take ECG prior to starting delamanid, and then monthly throughout
treatment. Patients with serum albumin levels <3.4 g/ml (but at least
2.8 g/ml), or with cardiac risk factors, should receive more frequent ECG
monitoring. Serum electrolytes should be checked and corrected as needed.
Adverse The most frequent adverse drug reactions noted in controlled trials were
reactions nausea, vomiting, dizziness, insomnia, and upper abdominal pain.
QTc prolongation occurred in about 10% of patients receiving 100 mg twice
daily. However, no episodes were accompanied by clinical symptoms such
as arrhythmias or syncope.
Contra- Hypersensitivity to delamanid
indications Serum albumin < 2.8 g/ml because of an increased risk of QTc prolongation
Taking other medications that are strong inducers of CYP3A (e.g.
carbamazepine, rifamycins)
Monitoring ECG at baseline and monthly during treatment. Baseline electrolytes, repeat
if QTc prolongation occurs.
A1.6. Ethambutol
Activity against Bacteriostatic inhibitor of cell wall synthesis; bactericidal only at the high
TB end of the dosing range. At doses used over long periods of time, ethambutol
protects against further development of resistance.
Dose Adults: 15–25 mg/kg/day. Higher doses should be used only during the ini-
tial months of therapy. For prolonged therapy, the dose should be closer
to 15 mg/kg/day to avoid toxicity. Intermittent dosing at 50 mg/kg thrice or
twice weekly can be used.
Children: 15–25 mg/kg/day; doses closer to 15 mg/kg/day should be used if
the drug is used for more than 2 months
Renal failure/dialysis: 15–25 mg/kg/dose 3 times weekly (not daily).
Route of Oral; not available parenterally
administration
Preparation 400 mg tablets
Storage Room temperature
Oral absorption 80% bioavailability independent of food
CSF penetration Ethambutol penetrates meninges poorly
Special Use in pregnancy/breastfeeding: Safe in pregnancy; can be used while
circumstances breastfeeding.
Use in renal disease: Use with caution—cleared by the kidneys; dose
adjustment required for renal failure. Increased risk of toxicity with renal failure.
Use in hepatic disease: Safe in liver disease.
Adverse eactions Retrobulbar neuritis (dose-related—exacerbated during renal failure).
Contra- Pre-existing optic neuritis; visual changes on ethambutol
indications
Monitoring Patients should be counseled to report any changes in vision. Baseline
and monthly visual acuity and color discrimination monitoring should be
performed (particular attention should be given to individuals on higher doses
or with renal impairment).
Patient Can be taken with food or on an empty stomach.

instructions Call your doctor right away if you have:
• Any problems with your eyes: vision changes, blurring, color blind-
ness, trouble seeing, or eye pain
• Swelling of face
• Rash, hives, or trouble breathing
• Numbness, pain, or tingling in hands or feet
• Joint pain
• Fever or chills
• Nausea, vomiting, poor appetite, or abdominal pain
• Headache or dizziness
A1.7. Ethionamide
Activity against Weakly bactericidal; blocks mycolic acid synthesis.
TB
Cross-resistance Cross-resistance to isoniazid may occur when there is low-level resistance to
isoniazid due to mutation in inhA or the promoter region.
Dose Adults: 15–20 mg/kg/day (max dose 1 gram per day); usually 500–750 mg per
day in 2 divided doses or a single daily dose. Most patients will experience GI
intolerance with doses greater than 1 gram daily.
Children: 15– 20 mg/kg/day usually divided into 2–3 doses. A single daily
dose can sometimes be given at bedtime or with the main meal. Many indi-
viduals require gradual ramping up of the dose and treatment for GI upset.
Renal failure/dialysis: No change
Vitamin B6: Although there is little supporting data, most MDR-TB experts rec-
ommend that all patients should receive vitamin B6 while taking thionamide.
Adults need 100 mg and children should receive a dose proportionate to their
weight.
Route of Oral
administration
Preparation 250 mg tablet
Storage Store at room temperature
Oral absorption Erratic absorption, possibly due to GI disturbances associated with the
medication
CSF penetration Concentrations approach those in serum; one pediatric study evaluating
drug concentrations in the CSF suggests that ethionamide should be dosed
on the high end of the range for patients with meningitis.
Special Use in pregnancy/breastfeeding: Generally avoided during pregnancy due
circumstances to reports of teratogenicity; little data about use during breastfeeding (dose
the infant with vitamin B6 if breastfed).
Use in renal disease: No precautions are required for renal impairment
Use in hepatic disease: Can cause hepatotoxicity similar to that of INH— use
with caution in liver disease
Adverse Gastrointestinal upset and anorexia: Sometimes intolerable (symptoms are

reactions moderated by food or taking at bedtime). Premedication with an antiemetic
like ondansetron is often helpful.
Metallic taste. Hepatotoxicity.
Endocrine effects: Gynecomastia, hair loss, acne, impotence, menstrual irregu-
larity, and reversible hypothyroidism—treat with thyroid replacement.
Neurotoxicity (patients taking ethionamide should take high doses of vitamin
B6). Side effects may be exaggerated in patients also taking cycloserine.
Contra- Sensitivity to ethionamide.
indications
Monitoring Monitor TSH for evidence of hypothyroidism requiring replacement. Monitor
liver function tests.
Patient Take this medicine with food.
instructions You must also take a high-dose vitamin B6 supplement while on this drug.
• Any problems with your eyes: eye pain, blurred vision, color blindness, or
trouble seeing
• Numbness, tingling, or pain in your hands or feet
• Unusual bruising or bleeding
• Personality changes such as depression, confusion, or aggression
• Yellowing of your skin or eyes
• Dark-colored urine
• Nausea and vomiting
• Dizziness
• Swollen breasts (in men
A1.8. Isoniazid
Activity against Bactericidal, especially for rapidly dividing cells. Affects mycolic acid (cell
TB wall) synthesis. Inclusion of INH in the regimen of patients with strain W MDR-
TB and other strains with low-level INH resistance were also associated with
improved outcomes.
Cross-resistance Cross-resistance to ethionamide may occur when there is low-level resistance
to isoniazid due to a mutation in inhA or the promotor region
Dose Adults: high dose 10 mg/kg/day (maximum 600 mg)
Children: 10–15 mg/kg/day up to 300 mg
Renal failure/dialysis: 300 mg once daily or 900 mg thrice weekly.
Vitamin B6 should be used when high-dose INH employed and in patients
with diabetes, uremia, HIV infection, alcohol abuse, malnutrition, or peripheral
neuropathy. Additionally, pregnant and post-partum women and exclusively
breastfeeding infants should receive vitamin B6 while taking INH.
Route of Oral
administration
Preparation 100 mg, and 300 mg tablets
Storage Suspension must be kept at room temperature
Oral absorption Well absorbed orally or intramuscularly; best absorbed on an empty stomach;
up to 50% reduction in peak concentration with a fatty meal.
CSF penetration Concentration equivalent to plasma in inflamed meninges. 20% of
concentrations in plasma in non-inflamed meninges.
Special Use in pregnancy/breastfeeding: Safe during pregnancy; safe during
circumstances breastfeeding (both baby and mother should receive pyridoxine supple-
mentation). Up to 20% of the infant therapeutic dose will be passed to the
baby in the breast milk.
Use in renal disease: No dose adjustment for renal failure, but
pyridoxine supplementation should be used.
Use in hepatic disease: May exacerbate liver failure. Use with caution
Drug Interactions: INH may increase the concentrations of phenytoin and
carbamazepine.
Adverse Hepatitis (age-related).
reactions Peripheral neuropathy.
Hypersensitivity
reactions.
Other reactions, including optic neuritis, arthralgias, CNS changes, drug-
induced lupus, diarrhea, and cramping with liquid product.
Contra- Patients with high-level INH resistance who have failed an INH-containing
indications regimen should not receive INH.
Monitoring Clinical monitoring of all patients on INH is essential. Routine laboratory

monitoring is not recommended for patients receiving INH monotherapy.
For patients receiving multiple TB drugs or other hepatotoxic drugs, or with
underlying liver disease (including viral hepatitis), baseline liver function
testing is recommended. Follow-up liver function testing is determined by
baseline concerns and symptoms of hepatotoxicity.
Patient Do not take this medication with a large fatty meal. If you have an upset
instructions stomach, take the medicine with a snack. Avoid alcohol while taking
this medicine. If you need an antacid, don’t take it within an hour of this
medicine.
Call your doctor right away if you have any of these side effects:
• Loss of appetite for a few days that is not going away
• Tiredness, weakness
• Moderate stomach pain, nausea, or vomiting
• Numbness or tingling of your fingers or toes
• Blurred vision, eye pain
• Yellow skin or eyes or dark-colored urine
A 1.9. Kanamycin
Activity against Bactericidal; has strong anti-TB activity. Inhibits protein synthesis.
TB
Cross-resistance High likelihood of cross-resistance between kanamycin and amikacin
because it is associated with the same mutation (rrs). However, there are
some kanamycin mutations (eis) that do not cause amikacin resistance. Some
data suggests amikacin cross-resistance with capreomycin.
Dose Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week.
15 mg/kg/dose, 2–3 times per week after culture conversion is
documented following initial period of daily administration
> 59 yrs of age: Many experienced clinicians prefer to use a lower starting
dose of 10 mg/kg 5–7 times per week or 2–3 times per week after initial
period.
Children: 5–30 mg/kg/day (max 1 gram) 5–7 days per week.
15–30 mg/kg/day (max 1 gram) 3 days per week after initial daily
period
In STR: 15-20 mg/kg/day
Renal failure/dialysis: 12–15 mg/kg/dose 2–3 times weekly (not daily).
Markedly obese individuals should have an adjusted dose due to the de-
creased distribution of extracellular fluids in adipose tissues. Dosing based
on actual weight will give supratherapeutic concentrations.
Route of Intravenous or intramuscular; not absorbed orally.
administration
Preparation Clear colorless solution stable at room temperature; 250 mg/ml in vials of 1
gram. Can be mixed with D5W or normal saline for intravenous infusion. Adult
doses should be mixed in at least 100 ml of fluid, and pediatric doses should
be mixed to a concentration of at least 5 mg/ml.
Storage Kanamycin supplied by the Global Drug Facility does not need
storage in in the refrigerator.
Oral absorption Not absorbed orally; 40–80% of the dose is absorbed intramuscularly.
Intramuscular absorption might be delayed if the same site is used
consistently.
CSF penetration Minimal and variable CSF penetration—slightly better with inflamed
meninges.
Special Use in pregnancy/breastfeeding: Generally avoided in pregnan-
circumstances cy due to documented congenital deafness. Can be used while
breastfeeding.
Use in renal disease: Use with caution. Concentrations should be
monitored for patients with impaired renal function. Interval adjustment is
recommended in case of renal impairment.
disease. Presumed to be safe in severe liver disease; however, use with cau-
tion—some patients with severe liver disease may progress rapidly to hepato-
renal syndrome.
Diuretic use: Coadministration of loop diuretics and aminoglycoside
antibiotics carries an increased risk of ototoxicity
Adverse Nephrotoxicity.
reactions Ototoxicity (hearing loss) and vestibular toxicity: Increased with advanced
age and prolonged use;
Local pain with IM injections.
Electrolyte abnormalities, including hypokalemia, hypocalcemia, and
hypomagnesemia
Contra- Pregnancy (congenital deafness seen with kanamycin use in pregnancy);
indications Hypersensitivity to aminoglycosides;
Caution with renal, vestibular, or auditory impairment;
Patients with intestinal obstructions.
Monitoring Monitor renal function by documenting creatinine at least monthly (more
frequently if renal or hepatic impairment);
Document creatinine clearance if there is baseline renal impairment or any
concerns;
Document baseline and monthly audiology exam.
Question patient regularly about vestibular complaints and perform serial
vestibular exams.
Patient Call your doctor right away if you have:
instructions • Problems with hearing, dizziness, or balance
• Rash or swelling of your face
• Trouble breathing
• Decreased urination
• Watery or bloody diarrhea
• Swelling, pain, or redness at your IV site
• Muscle twitching or weakness
A1.10. Levofloxacin
Activity against Bactericidal; has strong anti-TB activity. Data suggests greater activity than
TB ciprofloxacin or ofloxacin. Inhibits DNA gyrase.
Cross-resistance In general, there is a complete class effect cross-resistance among
fluoroquinolones in vitro.
Dose Adults: 15-25 mg/kg/ day (maximum 1000 mg).
Children: 15-20 mg/kg/day once daily if ≥5 years; 2 divided doses if <5 years
Renal failure/dialysis: 750–1000 mg/dose 3 times weekly (not daily) for
creatinine clearance < 30ml/min.
Route of Oral
administration
Preparation tablets 500 mg
Storage Oral forms, undiluted solution, and pre-mixed solutions are stored at room
temperature.
Oral absorption Excellent oral absorption. Should not be administered within 2 hours of
ingestion of milk-based products, antacids, or other medications containing
divalent cations (iron, magnesium, calcium, zinc, vitamins, didanosine,
sucralfate).
CSF penetration Concentrations are 65% of that in the serum.
Special Use in pregnancy/breastfeeding: Fluoroquinolones are generally
circumstances avoided in pregnancy and breastfeeding due to observation of ar-
thropathy in puppy models. However, there are a few case reports of
fluoroquinolones being used safely in pregnancy.
Use in renal disease: Dosage adjustment is recommended if creatinine
clearance is < 50 ml/min.
disease. Presumed to be safe in severe liver disease.
Adverse Nausea and bloating.
reactions Headache, dizziness, insomnia, or tremulousness.
Rare tendon rupture, arthralgias (can usually be treated symptomatically).
QTc prolongation, hypoglycemia.
Contra- Fluoroquinolone intolerance, prolonged QTc, pregnancy (relative
indications contraindication)
Monitoring Side effect monitoring, but no specific laboratory monitoring required.
Patient Avoid caffeinated foods and beverages while taking this medicine; you can
instructions take levofloxacin with food. Drink plenty of beverages. Do not take milk-
based products, antacids (especially aluminum-containing), mineral supple-
ments such as iron or magnesium, or multivitamins within 2 hours of this
medication. This medicine may cause sun sensitivity; use sunscreens. Do not
undertake new strenuous activities.
Call your doctor and stop the medicine right away if you have:
• Pain, swelling or tearing of a tendon (such as the back of your ankle, elbow,
etc.), or muscle or joint pain
• Rashes, hives, bruising or blistering, trouble breathing, or tightness in your
chest
• Diarrhea
• Yellow skin or eyes
• Anxiety, confusion, or dizziness
A1.11. Linezolid
Activity against Has in vitro bactericidal activity; inhibits protein synthesis.
TB
Dose Adults: 600 mg once daily.
Children: If ≥12 years: 10 mg/kg/day single dose; if <12 years: 10 mg/kg
every 12 hours
Renal failure/dialysis: No dose adjustment required.
Vitamin B6: All patients should receive vitamin B6 while receiving linezolid
Route of Oral
administration
Preparation tablets 600 mg;
Storage Store at room temperature.
Oral absorption Nearly complete oral absorption
CSF penetration CSF concentrations are about 1/3 of those in serum in animal models, and
linezolid has been used to treat meningitis in humans.
Special Use in pregnancy/breastfeeding: Not recommended during
circumstances pregnancy or breastfeeding due to limited data.
Use in renal disease: No dose adjustment is recommended,
Use in hepatic disease: Rarely associated with increased transaminases
Adverse Myelosuppression. Diarrhea and nausea.
reactions Optic and peripheral neuropathy – may be irreversible.
Contra- Hypersensitivity to oxazolidinones.

indications Symptoms of neuropathy (pain, numbness, tingling or weakness in the
extremities).
Drug Interactions: Linezolid should generally not be administered to pa-
tients taking antidepressants such as monoamine oxidase inhibitors orselective
serotonin reuptake inhibitors due to the potential for serious CNS reactions,
such as serotonin syndrome or neuroleptic malignant syndrome-like reactions
Monitoring Monitor for peripheral neuropathy and optic neuritis. Monitor CBC weekly
during the initial period, then monthly, and then as needed based on
symptoms; there is little clinical experience with prolonged use.
Patient This medicine may be taken with or without food. Try taking it with food
instructions if it bothers your stomach. Make sure your doctor knows if you’re taking
medicines for colds, congestion, or depression.
• Pain, numbness, tingling or weakness in the extremities
• Black, tarry stools or severe diarrhea
• Unusual bleeding or bruising
• Unusual tiredness or weakness
• Headache, nausea, or vomiting
• Changes in vision
A1.12.a. Meropenem
Activity against In vitro activity—very limited clinical experience
TB
Cross-resistance Imipenem
Dose Adults: 1000 mg every 8 or 12 hours. Must be given with clavulanate (avail-
able as amoxicillin / clavulanate ) 125 mg every 8 –12 hours
Children: Not established for TB. Suggested dose 20-40mg/kg IV every 8
hours.
Renal failure/dialysis: Adjustment in dose and interval based on severity
of renal failure and body weight—for example, 750 mg every 12 hours for
creatinine clearance 20–40 ml/min, 500 mg every 12 hours for creatinine
clearance < 20 ml/min.
Route of IV only
administration
Preparation Vial 1 gram
Oral absorption No
CSF penetration Adequate
Special Use in pregnancy/breastfeeding: Little information known

circumstances Use in renal disease: Dose adjustment required,
Use in hepatic disease: Liver disease does not alter the pharmacodynamics
of meropenem
Adverse Diarrhea, nausea, or vomiting.
reactions
Seizure (noted with CNS infection), but rare
Rarely elevated LFTs, hematologic toxicity, hypersensitivity.
Contra- Carbapenem intolerance
indications
Monitoring Symptomatic
Patient Make sure your doctor knows if you are also taking valproic acid or have
instructions allergy to penicillins or cephalosporins
• Severe diarrhea (watery or bloody)
• Skin rash, hives, or itching
• Swelling in the face, throat, or lips
• Wheezing or trouble breathing
A1.12.b. Amoxicillin – clavulanic acid

Activity against Only to be used because of the Clv component in combination with
TB meropenem
Cross-resistance None
Dose Adults: 250mg/day of Clv in 2 divided doses
Children: 5 mg/kg/day of Clv in 2 divided doses
Renal failure/dialysis: For creatinine clearance 10 – 30 ml/min dose 1000
mg as amoxicillin twice daily; for creatinine clearance < 10 ml/min dose 1000
mg as amoxicillin once daily.
Route of Oral
administration
Preparation Various combinations of amoxicillin and clavulanate.
Oral absorption Good oral absorption, best tolerated and well absorbed when taken at the
start of a standard meal.
CSF penetration Poor
Special Use in pregnancy/breastfeeding: No known risk
circumstances Use in renal disease: Dose adjustment required,
Use in hepatic disease: Clavulanate is cleared by the liver, so care should be
used when using in patients with liver failure.
Adverse Diarrhea and abdominal discomfort are most
reactions common. Hypersensitivity.
Nausea, vomiting, and rash are also common.
Rare side effects have been reported in all other organ systems
Contra- Penicillin allergy; use with caution with cephalosporin allergies

indications
Monitoring No specific monitoring is required
Patient Take at the beginning of a meal.
instructions Store tablets at room temperature
• Rash or swelling
• Trouble breathing
• Severe diarrhea
A1.13. Moxifloxacin
Activity against Bactericidal; inhibits DNA gyrase; may be more active than other
TB fluoroquinolones based on in vitro data.
Cross-resistance In general, there is a complete class effect cross-resistance among
fluoroquinolones in vitro. However, data suggest that moxifloxacin may
continue to demonstrate some activity despite in vitro resistance to ofloxacin.
Dose Adults: standard dose 400 mg daily; high dose in STR 10-15mg/kg/day
Children: No established dose. Suggested standard dose 7,5-10mg/kg/day;
high dose in STR 10-15mg/kg/day
Renal failure/dialysis: No dose adjustment required
Route of Oral or IV.
administration
Preparation Tablets 400 mg
Storage Store oral and IV products at room temperature (do not refrigerate).
Oral absorption Good oral absorption (90% bioavailable). Should not be administered within
2 hours of ingestion of milk-based products, antacids, or other medications
containing divalent cations (iron, magnesium, calcium, zinc, vitamins,
didanosine, sucralfate).
CSF penetration Good penetration in animal model studies.
Special Use in pregnancy/breastfeeding: Fluoroquinolones are generally avoided
circumstances in pregnancy and breastfeeding due to observation of arthropathy in puppy
models. However, there are a few case reports of fluoroquinolones being
used safely in pregnancy.
Use in renal disease: Excretion unchanged in the face of renal failure;
Use in hepatic disease: Rarely associated with hepatotoxicity; use with
caution. No dose adjustment required for mild or moderate liver disease.
Adverse Nausea and diarrhea.
reactions Headache and dizziness.
Rare tendon rupture; arthralgias. Rare hepatotoxicity.
QTc prolongation, hypo/hyperglycemia.
Contra- Fluoroquinolone intolerance, prolonged QTc, pregnancy (relative contrain-
indications dication).
Monitoring Symptomatic monitoring.
Patient Keep moxifloxacin at room temperature. Moxifloxacin can be taken with food,
instructions but do not take milk-based products, antacids (especially aluminum-coating),
vitamin supplements, or sucralfate within 2 hours of this medication. Do not
undertake new strenuous activities.
Call your doctor and stop the medicine right away if you have:
• Pain, swelling or tearing of a tendon (such as the back of your ankle, elbow,
etc.), or muscle or joint pain
• Rashes, hives, bruising or blistering, trouble breathing, or tightness in your
chest
• Diarrhea
• Yellow skin or eyes
• Anxiety, confusion, or dizziness
A1.14. Para-aminosalicylic acid

Activity against Bacteriostatic.
TB
Dose Adults: 150-200mg/kg/day in 2-3 divided doses per day. Maximum 12 grams
daily.
Children: 200 –300 mg/kg/day divided 2–4 times per day
Renal failure/dialysis: No change.
Route of Oral; should be given sprinkled on or stirred into yogurt or similar food. Do not
administration chew the granules; they should be swallowed whole.
Preparation 4 grams per sachet.
Storage Sachets should be kept in the refrigerator or freezer.
Oral absorption Incomplete absorption—sometimes requires increased doses to achieve
therapeutic concentrations.
CSF penetration Poorly penetrates the meninges (somewhat better with inflammation).
Special Use in pregnancy/breastfeeding: Not studied, but no teratogenicity
circumstances known. There is little data regarding use during breastfeeding
Use in renal disease: Inactive metabolite is cleared by the kidneys.
The package insert says to avoid with severe renal failure. Other authorities
believe it can be used with caution (no toxicity of metabolite known).
Use in hepatic disease: Use with caution; 0.5% incidence of hepatotoxicity
Adverse Gastrointestinal distress
reactions Rare hepatotoxicity and coagulopathy.
Reversible hypothyroidism (increased risk with concomitant use of
ethionamide)—treat with thyroid replacement.
Contra- Pregnancy (relative)
indications
Monitoring Monitor TSH, electrolytes, blood counts, and liver function tests.
Patient Keep the product in the refrigerator or freezer.

instructions Sprinkle granules over applesauce or yogurt or swirl in acidic juices (tomato,
grape, grapefruit, cranberry, apple, or orange).
Do not chew the granules.
Take with food if desired.
Do not use the packet if expanded or if the granules are discolored.
Gastrointestinal discomfort and diarrhea usually improve over time.
The shells of the granules may be seen in the stool— this is normal.
• Skin rash, severe itching, or hives
• Severe abdominal pain, nausea, or vomiting
• Unusual tiredness or loss of appetite
• Black stools or bleeding
A1.15. Pyrazinamide
Activity against Bactericidal for semi-dormant M. tuberculosis. Mechanism unclear.
TB
Cross-resistance None reported.
Dose Adults: 20-30 mg/kg/day.
Children: 30–40 mg/kg/day.
Route of Oral;
administration
Preparation 500 mg tablet.
Storage Store the tablets at room temperature.
Oral absorption Well absorbed from the GI tract.
CSF penetration Concentrations equivalent to serum.
Special Use in pregnancy/breastfeeding: no known teratogenicity but lack of data
circumstances regarding teratogenicity. Can be used while breastfeeding.
Use in renal disease: Cleared by the kidneys; dose 3 times a week
Use in hepatic disease: Use with caution; pyrazinamide is associated with
hepatotoxicity in about 1% of patients. It can be quite severe and worsen off
treatment.
Adverse Gout (hyperuricemia) and arthralgias.
reactions Hepatotoxicity.
Rash.
Photosensitivity.
Gastrointestinal upset.
Contra- Allergy to pyrazinamide; severe gout.
indications
Monitoring Monitor transaminases and uric acid.
Patient May be taken with or without food.

instructions This medicine may cause a rash after sun exposure: limit your sun exposure.
• Skin rash, severe itching, or hives
• Pain or swelling in the joints
• Yellowing of the skin or eyes or dark urine
• Nausea or vomiting
• Unusual tiredness or loss of appetite
Annex 2. Grading of the severity of Adverse Drug Events
N = normal value; N.A. = not applicable
Grade 1 Grade 2 Grade 3 Grade 4

Mild Moderate Severe Life threatening
Hemoglobine (g/dl) 8,0 – 9,40 7,0 – 7,99 6,5 – 6,99 < 6,50
Leucocytes (/mm3) 3 000 – 3 900 2 000 – 2 999 1 000 – 1 999 < 1 000
Neutrophiles (/mm) 1 000 – 1 500 750 – 999 500 – 749 < 500
Plateletss (/mm3) 75 000 – 99 000 50 000 – 74 999 20 000 – 49 999 < 20 000 or diffuse petechiae
Serum bilirubine (μmol/l) 1,25 – 2,50 x N > 2,50 – 5,00 x N > 5,00 – 10,00 x N > 10,00 x N
SGOT (IU/l) 1,25 – 2,50 x N > 2,50 – 5,00 x N > 5,00 – 10,00 x N > 10,00 x N
SGPT (IU/l) 1,25 – 2,50 x N > 2,50 – 5,00 x N > 5,00 – 10,00 x N > 10,00 x N
Alkaline phosphatase (IU/l) 1,25 – 2,50 x N > 2,50 – 5,00 x N > 5,00 – 10,00 x N > 10,00 x N
Gamma GT (IU/l) 1,25 – 2,50 x N > 2,50 – 5,00 x N > 5,00 – 10,00 x N > 10,00 x N
Serum creatinine (μmol/l) 1,00 – 1,50 x N > 1,50 – 3,00 x N > 3,00 – 6,00 x N > 6,00 x N or dialysis required
glycemia, fasting (mmol/l) 6,1 – 7,0 > 7,0 – 16,5 > 16,5 without ketosis Acidoketosis or hyperosmolarity
(>27,8 mmol/l without acidosis)
Serum potassium (mEq/l) 3,2 – 3,4 2,8 – 3,1 2,5 – 2,7 < 2,5
Serum calcium (mmol/l) 1,95 – 2,10 1,75 – 1,94 1,50 – 1,74 < 1,50
Uric acid (TU/l) 1,25 – 2,5 x N 2,6 – 5,0 x N 5,1 – 10 x N > 10 x N
Nausea Transient; normal food intake Food intake compromised for less Food intake compromised for more Food intake limited to liquids;
than 3 days than 3 days hospitalisation required
Vomiting Transient; 2 – 3 episodes/ day or Repeated; 4 – 5 episodes/day or Solid/liquid vomiting for 24 hours; Hospitalisation for hypovolemic
duration ≤ 1 week duration > 1 week orthostatic hypotension; perfusion shock
required
Hearing problems Mild hearing deficiency: 20 to 40 Moderate hearing deficiency: 40 to 70 Severe hearing deficiency: 70 to 90 Extreme hearing deficiency: > 90 dB
dB of hearing loss; difficulty to hear dB of hearing loss; speach is heard dB of hearing loss; speach is heard of hearing loss; speach cannot be
sounds of weak intensity, complex but poorly understood or only under- only if spoken loudly close to the ear heard at all
noises and low or distant voices stood through lip reading
Lengthening of the QT N.A. Male: 450< <500 ms > 500ms > 500ms with clinical signs (venticu-
interval Female: 470< <500 ms lar arrythmia, syncope, torsade de
pointe)
125
126
Annex 2. Grading of the severity of Adverse Drug Events

N = normal value; N.A. = not applicable
Grade 1 Grade 2 Grade 3 Grade 4

Mild Moderate Severe Life threatening
Hypothyroidism Infraclinical Manifest hypothyroidism without Severe hypothyroidism with multiple Myxoedematous coma
complications; treatment required clinical signs; to be treated urgently;
hospitalisation may be required
Cutaneous and/or mucous Moderate erythema and itching Extended maculopapular eruptions Extended papular-vesicular or oozing Any bullous condition of skin or
eruptions with or without itching eruptions; palpable purpura mucosa (type Lyell or Stevens-
Johnson); diffuse erythema
with fever, with or without other
hypersensitivity signs; necrosis of the
skin, reuiring surgical excision
Acute hypersensitivity, with N.A. Acute localised urticaria Giant urticaria; Quincke’s oedema Anaphylactic shock
or without dermatological
signs
Psychosis Minor anxiety Anxiety requiring treatment or Major anxiety or manifest depression Acure psychosis with suicidal
moderate depression requiring treatment tendencies, manic state
and hallucinatory delirium;
hospitalisation required
Arthritis Joint pain Joint pain with or without joint Manifest arthritis with or without N.A.
effusion or presenting moderate joint effusion or presenting
functional loss important functional loss
Loss of vision Subjective complaints; can count Can count fingers at 3m but not at Cannot count fingers at 3m Blindness
fingers at 6m 6m
Uncontrolled movements Occational clumsiness; mild tremors or dyskinesia or dysmetria Ataxia of upper or lower limbs or Inability to stand, total dependency
coordination problems or dysarthria; moderate impact on abnormal movements; impact on
daily activity daily activity
Annex 3. Calculating the QT interval
Note: The information below is about QTcF measurement and for management please see the
relevant information in aDSM chapter
What is QT Interval and measuring QTc (Ref: E. Burns 2017)

• QT Interval is the time measurement from the start of Q wave to the end of T wave
• It tells us the time taken for ventricular depolarization and ventricular repolarisation-means
ventricular contraction to relaxation
• QT interval is inversely proportional to Heart Rate-----,QT shortens at faster heart rate and QT
lengthens at slower heart rate
• Abnormally prolonged QT wave is associated with sudden arrhythmias and leading to Torsade
de pointes(Tdp)
Measuring QTc: Standardization

• The QT interval should be measured in Long lead II, V5, V6
• Several successive beats should be measured with the maximum interval taken
• Large U waves(more than 1 mm) that are fuse to the T wave should be included in measurement
• Small U waves and those which are separate from T should be excluded
• The maximum slope intercept method is used to define the end of T wave
Corrected QT– is called QTc

• With Irregular Rhythms (such as Atrial Fibrillation) always note the general(average) ventricular
rate (QRS’s per 6-sec. strip ✕ 10)
Rule of Thumb: Always remember

1. Use triplets method quickly to estimate heart rate, one larger square is 300, 2 LSs = 150,
3LSs=100,4 LSs=75,5LSs =60 all per minute
2. The normal QT interval is between 7-11 small squares
3. The normal QT is less than half of the preceding RR interval
QTcF Nomogram
How to use the QTcF Nomogram
1. Identify the patient’s HR or RR interval on the top of the table.
2. Identify the measured QT (uncorrected) interval on the left of the table.
3. Find the corresponding calculated QTcF in the cell below the HR (or RR) and to the right of the
QT interval.
The Framingham Formula

Calculation of QTcFra
QTFra(s)= QT +0.154 [1-RR(s)]
QT: distance between start of QRS complex and end of T wave, in seconds (number of small
squares x 0.04)
RR: distance between two R waves: R et R’ in seconds (number of small squares x 0.04)
QTcFra(sec) x 1000= QTcFra(ms)
Annex 4. Calculating the creatinine clearance
The estimated creatinine clearance is calculated based on the Cockcroft-Gault equation and is
expressed in ml/minute.
140 – age Weight

Creatinine clearance (CreatClear) = constant * ( )*( )
Serum creatinine 72
The constant is dependent on the sex: male = 1; female = 0.85
The serum creatinine should be expressed in mg/dl. If the laboratory gives the result in µmol/l, it
can be converted into mg/dl by dividing the µmol/l by 88.4.
Example: 212µmol/l = 212/88.4 = 2.398 mg/l.
A calculator to convert a serum creatinine result expressed in µmol/L to mg/dL can be found on
the internet: http://www.endmemo.com/medical/unitconvert/Creatinine.php
Example: a female patient (age = 46 years, weight = 50 kg) has serum creatinine = 212 µmol/l.
140-46 50 94 50
CreatClear = 0.85 * ( )*( ) = 0.85 * ( )*( ) = 0.85*39.2*0.694 = 23.1ml/min
2.398 72 2.398 72
A calculator to calculate the estimated creatinine clearance based on the Cockcroft-Gault equation
can be found on the internet: http://reference.medscape.com/calculator/creatinine-clearance-
cockcroft-gault.
Normal values for creatinine clearance are:
Men: 97 to 137 ml/min

Women: 88 to 128 ml/min
Annex 5: Peripheral Neuropathy Diagnostics
Note: Please use this with relevant chapter of aDSM to follow gradings and management
It is characterized by a decline and damage of nerve function leading to loss of sensation, ulceration
and subsequent amputation.
There is a common misconception that diabetic neuropathy is a phenomenon limited largely

to the lower limbs, which is not really true. About 40% of patients with neuropathy have upper
limb involvement in addition and the associated symptoms could be positive with that of pain,
paresthesias and dysesthesias, typically glove and stocking distribution.
There is probability that in some TB, HIV, Diabetic patients there is some level of pre-existing
peripheral neuropathy and use of toxic drugs may further exacerbate the situation leading to grade
1 or grade 2 of PN, which limits the use of such toxic drugs(for example Lzd, Cs, high dose INH)
Table; Distal symmetrical Polyneuropathy, small fiber and large fiber neuropathy (Source: A Practical
guide to DM,7th edition, © 2016, Jaypee Brothers Medical Publishers
Small fiber neuropathy Large fiber neuropathy

Fiber C-fiber type Delta type (Aδ)
Sensory loss 0 to + (Warm thermal perception) 0 to +++ (touch, vibration perception)–
Pinprick hypoesthesia checked with biothesiometer and tuning
Light touch sensation ↓↓ fork (128 Hz)
Monofilament testing–1 and 50 g) ↓ position sense and muscle strength
↓ sharp-dull and two-point
discrimination.
Prominent Hyperalgesia-superficial pain (+ to +++) Deep-seated, dull aching pain (+ to +++)
symptoms Constant burning Sensory ataxia → falls → minor trauma/
Allodynia– ↓ sweating → dryness fractures → ulcers/amputation
Severe hyperesthesia
Shock-like sensations
Hypoalgesia–late
ACTG Brief Peripheral Neuropathy Screening Tool(Source: NIAID Adult AIDS Clinical Trials Group)
Following are the step wise approaches to detect peripheral neuropathy in patients. Please
remember that this assessment is subjective and may lead to wrong scoring if not properly carried
out. Therefore, it is imperative that doctors/nurses/health care workers should be appropriately
trained to carry out below assessments.
1: Elicit Subjective Symptoms
Ask the subject to rate the severity of each symptom listed in Question 1 on a scale of 01 (mild) to
10 (most severe) for right and left feet and legs. Enter the score for each symptom in the columns
marked R (right lower limb) and L (left lower limb). If a symptom has been present in the past, but
not since the last visit, enter "00 - Currently Absent." If the symptom has never been present, enter
"11 - Always Been Normal."
Always Been Normal Currently Absent Mild Severe

11 00 01 02 03 04 05 06 07 08 09 10
Symptoms R L
a. Pain, aching or burning in feet, legs
b. “pins and needles” in feet, legs
c. Numbness (lack of feeling) in feet, legs
2. Grade Subjective Symptoms
Use the single highest severity score from Question 1 above to obtain a subjective sensory neuropathy
score. If all severity scores are "00" or "11," the subjective sensory neuropathy score will equal "0."
Subjective Sensory Neuropathy Score (based on highest severity rating)
01- 03 = grade of 1
04- 06 = grade of 2
07- 10 = grade of 3
11 or 00 = grade of 0
R L
3. Evaluate Perception of Vibration
Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch. Place the vibrating
tuning fork on a bony prominence on the subject's wrist or hand to be sure that he/she can recognize
the vibration or "buzzing" quality of the tuning fork. Again, compress the ends of the tuning fork just
hard enough that the sides touch. Immediately place the vibrating tuning fork gently but firmly on
the top of the distal interphalangeal (DIP) joint of one great toe and begin counting the seconds.
Instruct the subject to tell you when the "buzzing" stops. Repeat for the other great toe.
Vibration perception
a. Great toe DIP joint perception of vibration in seconds

b. Vibration perception score
0 = felt >10 seconds (normal)
1 = felt 6-10 seconds (mild loss)
2 = felt <5 seconds (moderate loss)
3 = not felt (severe loss)
8 = unable to or did not assess
R L
Picture: Adopted from , End TB Guidelines 2018
Vlbration perception Result Score

Felt > 10 seconds Normal 0
Felt 6-10 seconds Mild loss 1
Felt <S seconds Moderate loss 2
Not felt Severe loss 3
4. Evaluate Deep Tendon Reflexes
With the subject seated, the examiner uses one hand to press upward on the ball of the foot,
dorsiflexing the subject's ankle to 90 degrees. Using a reflex hammer, the examiner then strikes the
Achilles tendon. The tendon reflex is felt by the examiner's hand as a plantar flexion of the foot,
appearing after a slight delay from the time the Achilles tendon is struck. Use reinforcement by
having the subject clench his/her fist before classifying the reflex as absent.
Ankle Reflexes Score
0 = absent
1 = hypoactive
2 = normal deep tendon reflexes
3 = hyperactive
4 = clonus
8 = unable to or did not assess
R L
Nylon Monofilament Test (Source: a practical guide to DM, 7th edition)
The Semmes-Weinstein monofilament: The standard American Diabetes Association (ADA) criteria
will mention that it is only necessary to do a 2 g and a 10 g monofilament testing. In leprosy or TB,
up to 300 g may be utilized.
Form to be completed on monthly visit while patient is on Lzd/Cs and or Diabetics : The Brief
Peripheral Neuropathy Screen Tool (Refer to next page)
BRIEF PERIPHERAL NEUROPATHY SCREENING

NIAID ADULT AIDS CLINICAL TRIALS GROUPS
Patient number date of patient visit

Protocol Number Institution Code
Form week key operator code
INSTRUCTIONS FOR RECORDING SUBJECTIVE ELICITED SYMPTOMS:

• Ask the subject to rate the severity of each symptom listed in question 2 (a-c) on a scale of 01 (mild)
to 10 (most severe) for right and left feet, legs.
• Enter the score for each symptom in the column marked Presence/Severity.
• If a symptom has been present in the past, but not since the last visit, enter ‘00-Currently Absent’
• If the symptom has never been present enter ‘11-Always Been Normal.’
• The use of “-1” is not acceptable as an answer to any question.
1. Was a subjective elicited peripheral neuropathy evaluation completed?..........(1-Yes, 2-No)

If Yes, go to question 2.
If No, complete ‘a’ and go to question 4
a. If not completed, indicate reason why: ………..............……1 - Subject declined, specify

2 - Subject missed clinic visit
9 - Other reason, specify
If ‘1-Subject declined’ or ‘9-other reason’,
specify [30]:
Always Been Normal Currently Absent Mild Severe
11 00 01 02 03 04 05 06 07 08 09 10
2. SYMPTOMS PRESENCE/SEVERITY
Right Left
a. Pain, aching, or burning in feet, legs: .......................................................................
b. ‘Pins and needles’ in feet legs: ...................................................................................
c. Numbness (lack of feeling) in feet, legs: ..................................................................
INSTRUCTIONS FOR GRADING SUBJECTIVE ELICITED SYMPTOMS:
Use the single highest severity score from 01-10 In question 2 (a-c) above to obtain a subjective
peripheral neuropathy grade.
If all severity score is ‘00’ or ‘11’, the subjective peripheral neuropathy grade will equal ‘0.’
Presence/Severity score of:

01 – 03 = Grade of 1
04 – 06 = Grade of 2
07 – 10 = Grade 3
11 or 00 = Grade 0
3. Subjective peripheral neuropathy grade …………………………………………………
Source: JH McArthur
Annex 6. Forms, records and registers
Government of Nepal
Ministry of Health & Population
National Tubeculosis Center
DRTB 05
aDSM Adverse Event Reporting Form - Nepal
A. Patient and Health Facility Information
Patient ID number (as in DRTB
Treatment Centre:
Register:
Date of Birth (or Age): Province:
Sex:  Male  Female
HIV status:  Non-reactive  Reactive
Pregnancy:  No  Yes Trimester:
Weight (kg): Height (cm): BMI:
B. Adverse events experienced by patient (including abnormal investigations)
Adverse event Onset date End date Severity grade Seriousness * Outcome §
* Please select: D died LT life threatening HA caused or prolonged hospital admission PD permanent disability
OS other medically serious CA congenital abnormality NS not serious
§ Please select: A recovered B recovering C recovered with residual effects D died E not recovered F unknown
Detailed description of adverse event(s):
Was treatment of adverse event required?  No  Yes (please specify):
C. Laboratory assessment: Results of tests and procedures

Test performed Test date Result Unit Reference range
D. Medicines: DR-TB Regimen and other concomitant medicines, vaccines, traditional / herbal medicines and dietary supplements
 Tick if medicine suspected of causing adverse event
Medicine Dose Frequency Route Start date Stop date Reason for use Action taken † Response ‡











† Action taken in response to AE: DW drug withdrawn DR dose reduced DI dose increased DNC dose not changed UK unknown NA not applicable
‡ Response to action taken: RA recovered NE no effect on AE FA fatal AE UN unknown NA not applicable
E. Re-challenge information
List any medicines that were restarted and indicate effect on adverse event
Medicine adverse event recurred adverse event did not recur unknown
  
  
  
  
  
  
  
F. Other relevant information e.g. medical history, concurrent illnesses, smoking, alcohol use and Hospital Management
G. Causality Assessment at Treatment Center Level
1. Certain 2. Probable 3. Possible 4. Unlikely 5. Unassessed 6. Un-assessable
Comments:
H. Final AE/SAE Summary
Adverse Events Description:

Event Start date
Event End date
Severity Grading
Event classified: 1. Serious 2. Not – Serious (Based on Annex 2)
Narrative / Additional information (Final Result):
G. Reporter Information
Name: Phone number:
Email:
Occupation:  Doctor  Nurse  Paramedics  Other (please specify):
Signature: Date
Submit form to:

Email to: M&E Unit, NTC: aDSMNTC@gmail.com
NTC Use Only:

Date received by NTC:
Causality assessment:  Certain  Probable  Possible  Unlikely  Unassessed  Un-assessable
Comment:
Reported to DDA:  No  Yes Date reported to DDA:

Annex 7: Gastric aspirate Job aid:

Annex 8: Monitoring and Evaluation Checklist (Programmatic &

Clinical) for DR-TB Treatment Site
National TB Control Program, Nepal

Monitoring and Evaluation Checklist (Programmatic & Clinical) for DR-TB Treatment Site
Name of DR-TB Treatment Site: District/ Region:

Name & Designation of Visitor & Co-visitor Date of Visit:
Objective of the Visit: Period covered for review:
Yes (report
Observations/
# Indicators to Monitor is attached if No
Remarks
applicable)
1 Meeting with Stake Holders
1.1 Hospital Administration ( MS/ DMS)
1.2 DR-TB Site Focal Person
1.3 DR-TB Site Supporting Staff
1.4 SLDs Pharmacist
1.5 Others
2 DR-TB Management Site
Site Identified as DR-TB care service provider
2.1
(Board Displayed)
Facility visited by NTP/RTO/MDR-focal in
2.2
Reviewing Period
Updated DR-TB National Guidelines
2.3
available on site
2.4 DR-TB National Guidelines implemented
Staff Trained on the National Guidelines?
2.5 if not please provide names of and
designation
TB and DR-TB Related IEC Material on
2.6
display
DR TB ward available (#of beds), if in the
2.7
hospital
3 Infection Control
An Infection Control Committee or Person is
3.1
designated in this site
A written Infection Control (IC) plan or check
3.2
list is available for this site
3.3 TB-IC training for all staff has been done.
Facility design and patient flow have been
3.4
assessed (best use of space & ventilation).
IC measures in ward (ventilation, distance
3.5
between beds etc
Yes (report
Observations/
Remarks
applicable)
Triage of Patients with cough more than 2
3.6
weeks is done upon entering facility.
Patients with cough more than 2 weeks are
3.7 separated from others and "fast tracked" to
caregivers
Natural and/or mechanical airflow is
monitored daily by staff (especially in
3.8
waiting rooms, sputum collection room if
available, and at least one exam room).
Regular maintenance for directional and
3.9
extractor fans is conducted.
Signage is in place to keep doors and
3.10
windows open when feasible.
If UV lighting is used, routine maintenance is
3.11
scheduled.
Patients are not crowded in hallways or
3.12
waiting areas.
N95 or FFP2 respirators are readily available
3.13
for staff.
Staff has been trained on proper fit of
3.14
respirators.
Supplies are available to coughing patients
3.15 (tissues, cloths,surgical masks, trash bins,
etc.).
Staff is provided continuing education
3.16
opportunities and annual exams on TB-IC.
4 DR-TB Management
DR-TB 01 Patient’s Treatment Card
4.1 Adequately Filled and updated (check
random cards)
Past TB history mentioned, Supporting
4.2
Documents are attached with DR-TB 01
Treatment regimens designed correctly and
4.3
appropriately as per guidelines
Practices to stop Injectable are as per
4.4
guidelines?
Are side effects being identified timely and
4.5
managed appropriately?
Audiometry, baseline and follow up
investigations done, reports available?
4.6
Who is performing audiometry and is
trained?
DR-TB 03 ENRS Register adequately Filled
4.7 and updated(lab results, smear, xpert, CL/
DST),body weight recorded correctly
DR-TB 01 and DR-TB 03 tallies with each
4.8
other
Yes (report
Observations/
Remarks
applicable)
Patients files maintained properly in serial
4.9
order
DR-TB 04 Laboratory Register adequately
4.10
filled and maintained
DR-TB 03(patient identity booklet) and DR-
4.11 TB 04(lab register for DR TB) tallies with each
other
Number of MDR TB patients with Diabetes,
4.12
outcomes and glycemic control status
Treatment outcomes declared and
4.13
mentioned appropriately as per guidelines
Quarterly and Annual Reports are
4.14
maintained
Total Number of Cases Detected last Quarter
4.15
(DR-TB 04) and total enrolled
Time lapse between G. Xpert result and
Enrolment
(Please check 4 files of last quarter)
RR detected Date:
Enrolment Date:
1.
2.
3.
Reasons for delay of enrolment:
4.16
Time lapse between baseline /3rd month CL/
DST requested and reports available
CL/DST request Date:
Result Date:
1.
2.
3.
Reasons for delay of results:
Number of results with contaminated
4.17
cultures and or not done
Number of patients with missed
4.18 appointments and loss of follow up and
what actions have been taken for retrieval?
Post treatment outcome follow up being
4.19
done and recorded?
5 Contact Screening
Staff receives an evaluation for TB at least
9.1
annually.
Close contact screening for DR-TB patients
9.2
are done and documented on DR-TB 01
Number of patients enrolled through contact
9.3
screening
10 MDR TB/HIV
Yes (report
Observations/
Remarks
applicable)
10.1 All DR-TB patients are tested for HIV
MDR TB/HIV co-morbid patients are referred
10.2
for ART
11 SLD Management
Drugs Standard Storage Condition in
practice (comment on General condition of
11.1
stores and availability of racks for stacking
drugs etc)
SLDs available for current patients on
11.2
treatment for the next 3 months
11.4 Store Temperature maintained and recorded
11.5 SLDs arranged in FEFO manner
Stock Status Record maintained properly,
7.6
main, daily stock books
7.7 Consumption Matrix maintained properly
7.8 Consumption Matrix tallies with DR-TB 03
SLDs Stock out Reported for on treatment
7.9 Cases (GLC) – name of drug and Days out of
stock
7.10 Ancillary Drugs in Stock
Stock Status Record cross checked with
7.11
physical stock available on shelves
8 DR-TB Laboratory
Is the Laboratory register filled in correctly
8.1
and up to date?
Number of patients smear/CL positive at
8.2 the end of intensive phase and Smear/CL
positive at month 3,4?
Facility linked for xpert and Culture/DST?
8.2
please mention linked Laboratory.
How is the system of sample transportation
8.3 to labs(xpert,CL,DST),how often samples re
sent to next level labs
Monthly Smear, Culture and other
8.4 Laboratory Tests performed for patients who
are on treatment (DR-TB 01 &DR-TB 03)
Sputum samples are collected in a
8.5
designated area and away from others.
Health care workers which assist during
8.6
sputum collection take precautions.
Processing of sputum samples is expedited
8.7 to lab. There is a tracking mechanism to
monitor the turn-around time of lab results.
8.8 Gene Xpert available and functional
Yes (report
Observations/
Remarks
applicable)
8.9 Electricity Backup System in place
Laboratory Reagents and other stock
8.10
available
Laboratory under External Quality Assurance
8.11
System
8.12 Laboratory wastes properly disposed
Interview with MDR TB patients (please randomly select 2 patients)
1: Do you know how MDR TB is spread and how to prevent spread?
2: How many tablets are you taking every day, when do you take the medicine and does anyone
observe you when you take the medicine?
9 3: When do you take injection, by whom?
4: Do you know name of your DOT supervisor?
5: Do you receive socio-economic support during your Treatment?
Other Activities Undertaken:

10 Issues/Challenges Identified:
11 Actions Taken:
12 Follow-up on the Recommendation of Pervious Visit:
13 Recommendation to the Site:
Submitted By:
Annex 9: Modified Shorter Regimen and Future STR Options
People living with DR-TB, their doctors, and treatment programs face important and difficult
decisions because there is no clear evidence that one regimen is better than another. Both the
shorter and longer regimen performed much better in the STREAM trial than the average MDR-TB
treatment success rate of about 50% normally observed worldwide in regular treatment programs.
Now WHO has recommended all Injectable free longer RR/MDR TB regimen and advised shared
based decisions with patients to choose right regimen. WHO has also now recommended that NTPs
should move forward with operational research on modified injectable free shorter regimens.
Futures focus globally is on STRs and many Trials are ongoing around the globe because; STRs are
of much less duration, equally effective, cheaper, promising to scale up DR TB program for NTPs.
Following is the information on studies being conducted and planned around the globe for shorter
regimens even for pre-XDR and XDR TB.
STR New Studies
Globally now all studies are focusing on all oral STR with different drug combinations and searching
for effective, safer and shorter treatment option for MDR, Pre XDR and XDR TB patients (6 months, 9
months, 11 months)
Nix TB clinical study- with combination of Pretomanid, Bedaquiline and Linezolid (6-9 months) for
MDR, Pre XDR and XDR showing high treatment success rates.
TB PRACTECAL- Bdq, Pretomanid in combination with preexisting new and repurposed drugs for
treatment of MDR,Pre XDR,XDR TB.
End TB clinical Trial part 1: from 2015-2019, nearly 750 patients, different combinations of Bdq, Dlm,
Lzd, FQs, CFZ, Z in FQ susceptible patients.
End TB Clinical trial part 2: duration 2017-2019, combination of Bdq, Lzd, Dlm, Cfz in different arms
for 6 months, 9 months and 20-24 months in FQ resistant TB
Bpal Trial: with addition of Pretomanid in combination with Lzd, Bdq(after FDA approval of
Pretomanid)
Modified shorter treatment regimen – MSTR Under OR

1. 9 Bdq, 9-12 Lfx, Lzd, Cfz,Z(Destroy TB operational research)
2. 6-8 Bdq,Lfx(high dose)hh, Cfz, Cs, INHh, E, Z/5 Mfxh,Cfz,Cs, Z,E
3. 6-8 Bdq,Lfx(high dose)hh, Cfz, Eto, INHh, E, Z/5 Mfxh,Cfz, Z,E
Option 1 regimen contains all best bactericidal, sterilizing activity and resistance prevention
characteristics with extended use of Bdq
Option 2 is with adjustments, bdq can be extended to 8 months if delayed response and if Bdq is
stopped by month 6 then switch Lfx to high dose Mfx, Cs replaces Eto.
Option 3, is just replacing Inj with Bdq, but after Bdq is stopped switch Lfx to high dose Mfx
Maximum duration for all three regimens is 12 months (9-12)
The cost of all these three regimens varies.

Annex 10 : Triple Layer Packaging of Samples

Transport conditions
 Sputa should be transported to the laboratory as soon as possible with in 24-72 hours.
 Keep specimens cool (refrigerated but not frozen). Specimens should preferably be kept in a
refrigerator at 4C. If none is available then cold boxes can be used with a small amount of dry ice,
as long as it is ensured specimens do not freeze. Refer to below for packaging instructions.
 Up to a week in cold conditions will not significantly affect the positivity rate of smear
microscopy/Xpert test; however, the additional growth of contaminants will result in an increased
contamination rate on culture media after 7 days.
Transport packaging
The basic packaging system for local surface transport of all specimens consists of three layers
1)
Primary receptacle –
the specimen container
Primary receptacle
– packaged with enough (leakproof or siftproof )
Waterproof
absorbent material to absorb Cap
all fluid in case of breakage. Rack-type holder
(styrofoam, sponge)
Absorbent
2) Secondary packaging – a packing
second durable, watertight, material Itemized list of
contents
leak-proof packaging to (specimen record)
enclose and protect the
primary receptacle(s).
Several cushioned primary Secondary Rigid outer
packaging ) packaging
receptacles may be placed
leakproof or
in one secondary packaging, siftproof )
Proper shipping
but sufficient additional name
absorbent material must be Package marking
used to absorb all fluid in
To/From labels
case of breakage. For cold
transportation conditions,
ice or dry ice shall be placed
outside the secondary
receptacle. Wet ice shall be placed in a leak-proof container;
3) Outer packaging – secondary packaging are placed in outer shipping packaging with suitable
cushioning material. Outer packaging protects its contents from external influences, such as
physical damage, during transit.
Annex 11: Forms, Records and Registers

The following documents for recording and reporting are used are:
S.N TB Number Tools

1 TB 01 Presumptive TB register
2 TB 02a Laboratory Request Form
3 TB 02b Laboratory Report Form (LPA and Culture DST)
4 TB 03a Laboratory Register (Microscopy)
5 TB 03b Laboratory Register (GeneXpert)
6 TB 03c Laboratory Register (Culture DST)
7 TB 03d Laboratory Register (LPA)
8 TB 03e Culture / DST Reporting Form
9 DRTB 01 DR-TB Register
10 DRTB 02 DR-TB Treatment Card
11 DRTB 03 DR-TB Patient Identity Card
12 TB 07 Contact Investigation Form
13 TB 08 Contact and TBPT Register
14 TB 10 Referral / Transfer Slip
15 TB 11 Referral Form (Community, Private, Contact)
16 DRTB 04 Commitment Form
17 DRTB 05 aDSM Recording and Reporting Form
18 DRTB 06 DR-TB Drug Order Form
19 DRTB 07 DR-TB Reporting Form (for cohort reporting)
20 DRTB 08 Six-monthly Report on Detection and Enrolment of DR-TB
148
TB 01 Presumptive TB Register
Name of Patient Referred to(for Referred to(For

Diagnosis) Treatment)
Age Screened By Lab result received TB Diagnosis
Screened
Types of
SN Date OPD Number Address Contact No Name of Lab Status of Treatment Remarks
Presumptive TB
(DD/MM/YY)
Surname Name of DOTs Center
F M Symptom X-ray Tests requested Yes No Yes No
Ethnicity Code
Name of Patient Referred to(for Referred to(For
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Age Screened By Lab result received TB 1Diagnosis
Screened Name of Patient 1. Enrolled in Tx
Types of
1. DS TB Name of Lab
Presumptive TB 1. PBC 1. DS TB
(DD/MM/YY) 1
Surname DD/MM/YY Name
CodeCode
DD /MM/ YY 1 2 2 2 NameofofDOTs
DOTs Center
Center 2. Not Enrolled in Tx
Surname DD/MM/YY 2. PCD
F M 2. DR TB Symptom X-ray Tests requested Yes No Yes 2. DR TB No
Ethnicity
Name of Patient S Referred
/X/C / L to(for
/ Other Referred to(For 3. Died
3. EP
Ethnicity
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Types of
(DD/MM/YY) 1
CodeCode
DOTs Center
Ethnicity
/X/C / L to(for
3. EP
Ethnicity
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Types of
(DD/MM/YY) 1
CodeCode
DOTs Center
Ethnicity
/X/C / L to(for
3. EP
Ethnicity
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Types of
(DD/MM/YY) 1
CodeCode
DOTs Center
Ethnicity
/X/C / L to(for
3. EP
Ethnicity
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Types of
(DD/MM/YY) 1
CodeCode
DOTs Center
Ethnicity
/X/C / L to(for
3. EP
Ethnicity
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Types of
(DD/MM/YY) 1
CodeCode
DOTs Center
Ethnicity
S / X / C / L / Other 3. Died
3. EP
Ethnicity
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1
Name of Patient Name of Lab 1. Enrolled in Tx
1. DS TB
1. PBC 1. DS TB
1
DD /MM/ YY 1 2 DD/MM/YY 2 2 Name of DOTs Center 2. Not Enrolled in Tx
2. DR TB 2. DR TB
S / X / C / L / Other 3. Died
3. EP
Ethnicity Code
TB 02 Laboratory Request and Reporting Form
HMIS 6.1
Government of Nepal
Health Management Information System
Laboratory Request and Reporting Form
Date…………/………/…..
1. Name of Health Facility………………………………….2. Presumptive/OPD/Contact Reg No… 3.DR/ TB Reg. No………..…..
4. Name of Patient………………………………………………………….. 5. Age……………. 6. Sex………..…………...
7. Ethnicity …………………………………. 8. Code ………………………
9. Address: Province………District……….M/RM…………………………………. ward……………… Tole …………………………..
10. Name of Guardian ………………………………………………………………….…11. Contact no………………………………
12. Purpose for Examination. i- Diagnosis. ii- Follow-up (...................month) iii- RR detection:
1-LABORATORY REQUEST
Part (A)-for Detection of TB

Microscopy and Xpert/MTB RIF
(to be filled at OPD/DOTS centre)
13. History of Treatment for TB: (a) No previous Treatment (b) Previous History of Treatment
(c) Current on Treatment- (i- New ii- Retreatment iii- Others)
14. Specimen Type: i- Sputum ii- Other (specify)......................................
15. Test Request for: i- Microscopy ii-. Xpert MTB/RIF
Part (B)-For INH Resistance identification

For patients who meet all three below mentioned criteria;
i. Retreatment cases, ii. Rifampicin Sensitive (via Xpert MTB/RIF), iii. Smear Positive
16. Test Requested: i. LPA
17. Specimen Type: 1. Sputum 2. Other(specify)......................................
18. Details of Past TB Treatmen: i. New ii- Relapse ii- Tx After Failure iii- Tx After LTFU
iv- Others Previously Treated vi. Unknown Previous TB Treatment History
19. History of Contacts with known TB: 1. Yes 2. No
If yes, Mention DST result of: i- INH…………. ii-Rif…………iii- Others:………..
20. Retro Status: i – Reactive ii – Non-reactive iii- Unknown
Part (C)- For Presumptive DR TB cases

MTB not detected, or MTB detected with Rif Indeterminant through Xpert MTB/RIF testing
21. Test Requested: i. Culture/DST
22. Specimen Type: 1. Sputum 2. Others (specify)......................................
23. Details of Past TB Treatment: i- New ii- Relapse iii- Tx After Failure iv- Tx After LTFU
v- Others Previously Treated vi – Unknown Previous TB Treatment History
24. Retro Status: i – Reactive ii – Nonreactive iii- Unknown
Part (D) – For DR TB Baseline and follow up cases

25 i ) Routine collection for 0 month: Collect 2 samples
ii) Routine collection for follow up months : …….. Collect 1 sample
26. Specimen Type: 1. Sputum 2. Others (specify)......................................

27. Details of Past TB Treatment: i- New ii- Relapse iii- Tx After Failure iv- Tx After LTFU
v- Others Previously Treated vi – Unknown Previous TB Treatment History
Date of Sample Collection: ………………………
Part (E)- For all cases Detected with TB (All Forms of TB)
28. Test Request for HIV o (“ü” if HIV Test Requested)
Requested by:
Name:...................................................................
Designation:..........................................................
Contact Number:..................................................
Signature:.............................................................
2- LABORATORY TEST RESULT
Name of Laboratory/GeneXpert Site:……………………………………………………………………………………..

Lab no. ... ... ... ... Result Date:………./………../…..
1. Microscopy Test Results
Visual Appearance Result Examined by:

Sample
Neg () Positive (circle the grading) Name Signature and date
NHPC No
A B M S Scanty 1+ 2+ 3+
B B M S Scanty 1+ 2+ 3+
(B) blood-stained (M) mucopurulent (S) saliva
Neg.=(0 AFB/100 OF), Scanty= (1-9 AFB /100 OF) 1+=(10−99 AFB/100 OF),2+ = (1−10 AFB/ OF), 3+=(>10 AFB/ OF),
2. Xpert MTB/RIF test result
Mycobacterium tuberculosis: 1. Detected 2. Not detected 3. Invalid / No result / Error

Rifampicin Resistance: 1. Detected 2. Not detected 3. Indeterminate
3. HIV Test Result

a) (A1) Determine Test i - Reactive ii- Non-Reactive
b) (A2) Uni-Gold Test ii- Reactive ii- Non-Reactive
c) (A3) Stat pack Test iii- Reactive ii- Non-Reactive
Examined by: Name:............................................................

Designation: ........................................................................
NHPC No..............................................................................
Signature and date ..............................................................
TB 02b Laboratory Report Form (LPA and Culure DST)

TB O2b
National Tuberculosis Programme Nepal
National Tuberculosis Centre
National T.B. Reference Laboratory
Thimi, Bhaktapur (Phone no. 01-6630706, 6630832, Ext no. 107)
LABORATORY REPORT (LPA and Culture DST)

1. Name of Health Facility…………....................………… 2. Presumptive/OPD Reg No./Contact No…..
3. DR/TB Reg. No……..
4. Name of Patient………………………………….. 5. Age. 6. Sex……
7. Address: Province……… District……………..M/RM……………… ward…. Tole …..
8. Specimen Type: 1. Sputum 2. Other (specify)..................................................................
11. Date of Sample Collection: ……………….. 12. Date of Sample Receipt: …………………………..
12. If for Follow up (Month): …………..
REPORTS ON CULTURE
Lab No. :
Tests Smear Microscopy (Concentrated Sample) Culture*
Result
*Please see remarks below
REPORT ON LPA
Result on LPA from: i) Direct Specimen ii) Culture
Identification M. tuberculosis Complex

Drugs Genes Mutation Result/ Interpretation*
Rifampicin rpoB
Isoniazid KatG
Inh A
Fluoroquinolones gyr A
gyr B
Second Line Injectable rrs
eis
Drug Susceptibility Test (Phenotypic)

Drugs H Z Lfx Mfx 0.25 Mfx 1.0 Cfz Lnz Am Bdq Dmn Other
µg/ml µg/ml
Result*
Interpretation:
Note: S: Susceptible
H-Isoniazid , Z-Pyrazinamide, R: Resistance
Eto-Ethionamide, Lfx-C: Contaminated
Levofloxacin, ND: Not Bdq-Bedaquiline,
Mfx- Moxifloxacin, Done. Lnz- Linezolid, Cfz-Clofazimine,
Am- Amikacin, Dmn- Delamanid
Remarks:
Reported By: ………......……………… Verified By: ….....…………………. Date: .......………………………………

152
TB 03a Laboratory Register (Microscopy) HMIS 6.2
Tuberculosis Laboratory Register (Microscopy)

TB 03a
Month
Purpose of Result and date
Sample collection Date Name of Patient Age Address Name of Health Previous Treatment History Tested by
test Specimen A Specimen B
Institution
Name of requesting for test
District M/RM Current on Treatment Result Result Name post
Lab no Guardian/ HIV Status HIV Test Result Remarks
Family Member
DD MM YY Surname Presumptive/ OPD
Male
Female
Contact no /Contact TB Test date Test date Signature
Diagnosis
Follow up
Treatment
New
No previous
Others
of Treatment
ward no
Ethnicity Code
Registration no
Previous History
Retreatment
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Name of Health 1.Reactive
Name of Patient District M/RM Institution requesting Result Result Name post Reactive
for test 2.Non- …….
Lab no Ethni Reactive 1 2 3 4 5 1
Presum/ OPD /TB Month
Surname city ward no Contact no Test date Test date Signature Non Reactive
Registration no
code 3.Unknown
Name of Health
Name of Patient District M/RM Institution requesting 1.Reactive Result Result Name post Reactive
for test
2.Non- …….
Lab no Ethni 1
OPD दतार् नं.÷�यरोग Reactive Month
Surname city ward no Contact no Test date test date Signature Non Reactive
दतार् नं
code 3.Unknown
Lab no Ethni 1
Presum/ OPD /TB Reactive Month
Surname city ward no Contact no Test date Test date Signature Non Reactive
Registration no
code 3.Unknown
Lab no Ethni 1
OPD दतार् नं.÷�यरोग Reactive Month
Surname city ward no Contact no Test date test date Signature Non Reactive
दतार् नं
code 3.Unknown
(TALF) Treatment after lost follow up, (OPT) Other previously Treated, (OTHU) Other treatment History Unknown
TB 03b Tuberculosis Laboratory Register (GeneXpert)
TB 03b
Tuberculosis Laboratory Register (GeneXpert)
HMIS 6.2
Tuberculosis Laboratory Register (GeneXpert)
TB 03b
Month
Name of Patient Age Address Name of Health History of Treatment for TB Purpose of test
Institution
requesting for test
District M/RM Name of Current on Treatment Specimen
Lab no Guardian/ HIV Status
Family Member
No Previous Type
Ethnicity
Surname previous History of
Male
code Presumptive/ OPD MTB Not MTB + Rif
Female
Contact no Treatment Treatment
Diagnosis
New
Detected sensitive
Sample received date
/TB Registration no
Others
RR Detection
ward no
Retreatment
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Name of Health
Name of Patient District M/RM Institution requesting 1.Reactive
for test
Lab no DD/MM/YY
2.Non-
Ethnicity reactive
Presum/ OPD /TB
Surname ward no Contact no DD/MM/YY DD/MM/Y
code Registration no
3.Unknown
Name of HealthHMIS 6.2

1.Reactive
Name of Patient District M/RM Institution requesting
Lab no for test DD/MM/YY
2.Non-
reactive
Ethnicity Presum/ OPD /TB
pert) Surname ward no Contact no DD/MM/YY DD/MM/Y
code Registration no 3.Unknown
Tested by
Test Result
imen Name post

Remarks
pe
MTB Not MTB + Rif MTB+Rif MTB+Rif Test Failure (No
Error/Code Signature
Detected sensitive resistance indeterminate result/Invalid)
Sample received date

8 19 20 21 22 23 24 25 26 27
Name post
DD/MM/YY
DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Signature
Name post
DD/MM/YY
DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Signature

153
154
TB 03c Laboratory Register (Culture DST) Tuberculosis Laboratory Register (C

TB
TB 03c
03c
Month
Month
Tuberculosis Laboratory Register (Culture)
Sample Collection Date Name of Patient Age Address Name of Health
Institution
Name of requesting for Refrigerated/
District M/RM
Visual Dates of Dates of Smear
Guardian/ test HIV Test Category & Non- Date of
Lab no Specimen Appeara sample Sample Microscopy:
Ethnicity Family Result month refrigerated/ Processing
DD MM YY Surname Female Male Member nce collection Receive Result
code Presum/ OPD /TB Cold chain
Ward no Contact no
Registration no
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Name of Health
Name of Patient District M/RM Institution 1. Reactive
requesting for test 2. Non
Lab no DD MM YY
culosis Laboratory Register (Culture) Reactive
Ethnicity Presum/ OPD /TB 3. Unknown
Surname ward no Contact no
code Registration no
Refrigerated/ MGIT: DST

es of Smear MGIT DST
Non- Date of MGIT: MGIT: Date L J: L J: Date of
ple Microscopy: Date of Remarks
refrigerated/ Processing Result of reporting Result reporting
eive Result Inoculation
Cold chain
R H Z Am Bdq Cfz Lzd Mfx (H) Mfx (L) Eto Lfx Dlm Others
17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
TB 03d Laboratory Register (LPA)
National Tuberculosis Centre National Tuberculosis Centre
Thimi, Bhaktapur Thimi, Bhaktapur
TB 03d Laboratory Register (Line Probe Assay)
TB 03d Laboratory Register (Line Probe Assay)
Sample Collection
Name of Patient Age Address Sm
Date
Lab no HIV Test Result Treatment Centre Category & month Specimen Type Date of sample collection Date of Sample Received Date of Processing Micro
District M/RM
DD MM YY Surname Ethnicity code Female Male Re
Ward no Contact no
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1
Name of Patient District M/RM
1. Reactive
Lab no DD MM YY 2. Non Reactive
Surname Ethnicity code ward no Contact no 3. Unknown
Name of Patient District M/RM

1. Reactive
Lab no DD MM YY 2. Non Reactive
Surname Ethnicity code ward no Contact no 3. Unknown
LPA DST
Smear
Specimen Type C)Culture R H FLQ AMG LPA: Date of
e of Sample Received Date of Processing Microscopy Culture Result Identification Interpretation Remarks
D)Direct rpob KatG Inh A gyrA gyrB rrs eis reporting
Result
WT Mut WT Mut WT Mut WT Mut WT Mut WT Mut WT Mut
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
155
156
TB 03e Culture / DST Reporting Format

TB 03e Culture/Dst Reporting Format
Name of Reporting Unit: _______________________________________________ Reporting Period:_________________ to____________________
Report Prepared by:___________________________________________________
Report Verified by_________________________________________
Report submission date:___DD/MM/YYY_____________________________________________
1 Results of first-line drug susceptibility testing in pulmonary TB patients
Previous anti-TB treatment status
New Previously treated [A] Unknown treatment history [B] Total
F M F M F M
i) Number of pulmonary TB patients with positive identification for M. Tuberculosis complex
confirmed by culture and/or line-probe assay. (Use line (vi) below for patients confirmed by Xpert 0
MTB/RIF only)
(ii) Among patients reported in (i), number of patients with available DST results for
0
isoniazid (H) and rifampicin (R)
(iii) Among patients reported in (ii), number of patients with resistance to H but not R 0
(iv) Among patients reported in (ii), number of patients with resistance to R but not H 0
0
(v) Among patients reported in (ii), number of patients with resistance to H and R (MDR-TB)
(vi) Number of pulmonary TB patients with positive identification for M. Tuberculosis complex
confirmed by Xpert MTB/RIF alone and who are not confirmed by culture and/or line-probe assay 0
(these cases should be additional to those reported in i)
(vii) Among patients reported in (vi), number of patients with resistance to R (these cases should be
0
additional to those reported in iv and v)
2 Among patients with DST results in 1 line (ii): association between MDR-TB and HIV status (number of patients)
HIV Test Result
Reactive Non Reactive Unknown Total
F M F M F M
(a) MDR-TB (resistant to both H and R) 0
(b) Not MDR-TB (drug susceptible plus any resistance that is not MDR-TB) 0
Grand Total 0 0 0 0 0 0 0
3 Among patients with DST results in 1 line (ii): association between MDR-TB and age (number of patients)
Age
0–14 ≥15 Unknown Total
F M F M F M
(a) MDR-TB (resistant to both H and R) 0
(b) Not MDR-TB (drug susceptible plus any resistance that is not MDR-TB) 0
Grand Total 0 0 0 0 0 0 0
4 Results of second-line drug susceptibility testing

F M Total
(i) Total number of pulmonary MDR-TB patients with DST results for any fluoroquinolone
(FQ) and any second-line injectable agent (2LI) 0
(ii) Among MDR-TB patients reported in (i), number of patients susceptible to both FQ and
2LI 0
(iii) Among MDR-TB patients reported in (i), number of patients with any resistance to FQ
0
(iv) Among MDR-TB patients reported in (i), number of patients with any resistance to 2LI
0
(v) Among MDR-TB patients reported in (i), number of patients with any resistance to both
FQ and 2LI (XDR-TB) 0
DRTB 1 DRTB Register
DRTB Register DRTB 01
Registration No: Registration Date Treatment start date: DST Status: H R Z E Mfx Lfx Am Bdq Lzd Eto Cfz Others
Name: Ethnicity code Sex: 1. Female 2. Male Age: R/S R/S R/S R/S R/S R/S R/S R/S R/S R/S R/S R/S
M/RM : Ward/ tole: Contact no. DM HIV Status ART CPT CBDOTS
Treatment Center: Treatment sub Center: Tin /Institution 1. Yes 2. No 1. Reactive 2. Non-Reactive 3. Unknown 1. Yes 2. No 1. Yes 2. No 1. Yes 2. No
Tobacco Smoking Registration Category (Circle) Patients Referred / Diagnosed by (Circle) Disease Type (Circle) Total no.of household member No. of household members screened for TB
Status of Smoking (S,R,Q,) 1. New 1 Private Health Facility 1 Pulmonary 1
Status of Exposure to smoking inside the home (Y or N)
Smoking Tobacco (Current) S: Current Smoker, R: Relapsed Smoker, Q: Quitter
F/U Months F/U Months 2. Relapse 2 Community 2 Extra Pulmonary 2
Yes No 0 1st 2nd End 0 1st 2nd End 3.1. After failure of first line Treatment with FLD 3 Contact Investigation 3
1 2 3.2. After failure of Re-Treatment with FLD 4
1 2 3.3. After failure of Treatment with Hr TB Regimen 5
1 2 3.4. After failure of Treatment with SLD 6
1 2 4. TALFU 7
1 2 5. Other Previously Treated 8
1 2 6. Unknown Previous TB Treatment History 9
Type of DR Regimen/Lab result Adverse event (Severity)

Months Number of Number of Not-
RR MDR Pre- XDR XDR Regimen: Regimen: Regimen: Regimen:
Serious Event Serious Event
S.MC Result C. Result S.MC Result C. Result S.MC Result C. Result S.MC Result C. Result Total Number in a Total Number in a
0 month Lab No. Lab No Lab No. Lab No Lab No. Lab No Lab No. Lab No Month Month
Enrolment Date/ Type of Test/ Result

12 month DR TB regimen
Lab No. Lab No Lab No. Lab No Lab No. Lab No Lab No. Lab No Month Month
4-6 Am,Mfxh, Cfz, Eto, INHh, E, Z/ S.MC Result C. Result S.MC Result C. Result S.MC Result C. Result S.MC Result C. Result Total Number in a Total Number in a
13 month SSTR Lab No. Lab No Lab No. Lab No Lab No. Lab No Lab No. Lab No
5 Mfxh,Cfz, Z,E Month Month
14 month LR1 Bdq(6), 18 Lfx,Lzd,Cfz,Z
15 month LR2 Bdq (12),18Lzd, Cfz, Cs,Z
6 Am, Dlm, Eto, PAS (Cs) Cfz (Mfx/lfx) 12 Dlm S.MC Result C. Result S.MC Result C. Result S.MC Result C. Result S.MC Result C. Result Total Number in a Total Number in a
16 month LR3 Lab No. Lab No Lab No. Lab No Lab No. Lab No Lab No. Lab No
(6) Eto PAS (Cs) Cfz, (Mfx/Lfx) Month Month
17 month LR4.1 18 Dlm(12),Cs, Imp/Clv (10),Eto,PAS,Cfz, Z
18 month LR4.2 18 Dlm(12), Imp/Clv (10) ,Eto,PAS, Cfz, Z
19 month Modified LR2 18 Bdq (12), Dlm(6), Lzd,Cs,Cfz,PAS Lab No. Lab No Lab No. Lab No Lab No. Lab No Lab No. Lab No Month Month
20 month CLR1 18 Lfx, Lzd,Cfz,Cs, Z
21 month CLR2.1 18 Lzd,Cfz,Cs,INHh,Z,Eto
22 month CLR2.2 18 Lzd,Cfz,Cs,Dlm(6),Z
PLR1 18Lfx, Cfz, Cs, PAS, Z
Outcome 1. Cured / Date 2. Completed / Date 3. Failed / Date 4. Died / Date 5. LTFU / Date 6. Not evaluated / Date
157
158
DRTB 02 DRTB Treatment Card

HMIS 6.3
DR TB 02
NATIONAL TUBERCULOSIS CONTROL PROGRAMME
DRUG RESISTANT TUBERCULOSIS TREATMENT CARD
Photo
Name of Patients Name of Treatment Center:
Sex 1. Female 2. Male Age: Phone No: Name of Treatment Sub Center Referred for Treatment:
Address: Province Districts: Type of DOT: Health Facility Based  Community Based 
M/RM: Ward No / Tole : Name of DOT Provider
Initial Weight (Kg): Contact Number:
Guardian's Name Contact Investigation:
Total no.of household member No. of household members screened for TB i - No. of close contact
ii -No. Traced
Type of resistance: Site iii -No. Diagnosed with TB
RR 1 Pulmonary 1 iv -No. Linked to Treatment
MDR TB 2 Extra-pulmonary 2
Pre-XDR 3 If extra-pulmonary, specify site:
XDR 4 OTHER INFORMATION
Retro Status: 1. Reactive 2. Non-Reactive 3. Unknown
Registration Group (Circle) Date of Test: DD/MM/YY Result:
1. New 1 Started on ART: Y / N Date: DD/MM/YY
2. Relapse 2 Started on CPT: Y / N Date: DD/MM/YY
3.1. After failure of first line Treatment with FLD 3
3.2. After failure of Re-Treatment with FLD 4
3.3. After failure of Treatment with Hr TB Regimen 5 Risk Category of DR-TB suspects(Circle): Previous Tuberculosis Treatment History
3.4. After failure of Treatment with SLD 6 New 1 No. Start Date (if unknown put year)

Regimen (write regimen in drug abbreviations)

Outcome
4. TALFU 7 Re-treatment 2
5. Other previously treated 8 Non- Converter 3
6. Unknown Previous TB Treatment History 9 DR-TB contact 4
TB/ HIV 5
Initial Lab Results Chest X-Ray at Start Health Care Worker 6
Smear 1.Normal 1 Others (Specify): 7
Xpert 2.Abnormal 2
LPA 3.Not Done 3 Used second-line drugs previously?
Culture DST Date: DD/MM/YY If Yes, specify: _______________________
Expert Group meetings:

Date Decision Remarks
Sputum Microscopy / Culture Base line Investigations and Results

Month of Treatment Weight Regimen
Date Lab No. Smear Result Culture result CBC
0 DR TB regimen Blood Glucose
1 SSTR 4-6 Amk,Mfxh, Cfz, Eto, INHh, E, Z/ 5 Mfxh,Cfz, Z,E LFT
2 LR1 Bdq(6), 18 Lfx,Lzd,Cfz,Z RFT
3 LR2 Bdq (12),18Lzd, Cfz, Cs,Z Hep B
4 LR3 6 Am, Dlm, Eto, PAS (Cs) Cfz (Mfx/lfx) 12 Dlm (6) Eto PAS (Cs) Cfz, (Mfx/Lfx) Hep C
5 LR4.1 18 Dlm(12),Cs, Imp/Clv (10),Eto,PAS,Cfz, Z ECG
6 LR4.2 18 Dlm(12), Imp/Clv (10) ,Eto,PAS, Cfz, Z Audiometry
7 Modified LR2 18 Bdq (12), Dlm(6), Lzd,Cs,Cfz,PAS Pregnancy
8 CLR1 18 Lfx, Lzd,Cfz,Cs, Z Visual Acuity
9 CLR2.1 18 Lzd,Cfz,Cs,INHh,Z,Eto Uric Acid
10 CLR2.2 18 Lzd,Cfz,Cs,Dlm(6),Z Others:
11 PLR1 18Lfx, Cfz, Cs, PAS, Z
12 Drug Abbreviations
13 First-line drugs Second-line drugs
14 H=Isoniazid Am=Amikacin Eto=Ethionamide
15 R=Rifampicin CS=Cycloserine Cfz- Clofazimine
16 E=Ethambutol Lfx=Levofloxacin PAS=p -aminosalicylic acid
17 Z=Pyrazinamide Mfx=Moxifloxacin Lzd=Linezolid
18 Bdq=Bedaquiline Imp/Cln=Imipenem / Cilastatin
19 Dlm=Delamanid
20 Amx/Clv=Amoxicillin/Clavulanate
21
22
23
24
DRUG SUSCEPTIBILITY TESTING (DST) RESULTS

Date sputum collection DST method (liquid solid, LPA, X-pert) Date DST result H R Z E Am Bdq Cfz Lzd Mfx(H) Mfx(L) Eto Lfx Dlm Notation method for DST:
Other
R=resistant,
S=susceptible,
C=contaminated
TREATMENT REGIMEN for each month of treatment; dosages (mg or gm); comments
DRUG SUSCEPTIBILITY TESTING (DST) RESULTS
Date sputum collection DST method (liquid solid, LPA, X-pert) Date DST result H R Z E Am Bdq Cfz Lzd Mfx(H) Mfx(L) Eto Lfx Dlm Notation method for DST:
Other
R=resistant,
S=susceptible,
C=contaminated
TREATMENT REGIMEN for each month of treatment; dosages (mg or gm); comments
Others Comments
Months Weight (KG) Lfx Bdq Lnz Mfx Cfz Cs Dlm Am Amx-Clv E Eto Imp-Cln H PAS Z 1)........................................ (Reasons for changes in dosage,
2)......................................... regimen, etc.)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
SO = stockout AE = adverse effect
ADMINISTRATION OF DRUGS (one line per month):
Month
Day
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 COMMENTS
Mark in √= Directly observed (if split dose is used for Cs, Eto or PAS, mark √ for morning dose and √ for evening dose)
N = Not supervised
φ = Drugs Not Taken
Comments: OUTCOME Circle one DATE
_______________________________________________________________________________________ Cured 1
_______________________________________________________________________________________ Completed 2
_______________________________________________________________________________________ Died 3
_______________________________________________________________________________________ Failed 4
_______________________________________________________________________________________ Lost to follow-up 5
_______________________________________________________________________________________ Not evaluated 6
159
160
Section on ABC Smoking Cessation
At start of TB treatment
Brief advice given to patient (30 seconds- Cessation support provided to patient (1-
then at follow-up Ask
1 minute) 3 minutes)
examination visit:
Date Do you smoke?* Yes / No

Yes
Does anyone smoke inside
Month of How soon after you wake do your home? Yes / No Yes / No
Have you smoked at all—even a Comments Comments
Treatment DD/MM/YY No you usually have your first Yes / No 1 = yes 2 = no 1 = yes 2 = no
puff—in the last 2 1 = yes 2 = no
cigarette? 1 = <30 min or 2 =
weeks?(months 0, 2, 5, End)
>30 min
0 S 1 2 1 2 1 2
1st follow up S ,R ,Q ,L,D 1 2 1 2 1 2
2nd follow up S ,R ,Q ,L,D 1 2 1 2 1 2
End S ,R ,Q ,L,D 1 2 1 2 1 2
*Definitions for status of smoking
For month 0, S for current smoker (has smoked in the last 3 months)
For months 2, 5, End, enter one of S, R, Q, D or L:
S = current smoker: has smoked in the last 2 weeks before the visit and has not made any quit attempt since the last visit (quit attempt = patient tried to quit and succeeded for at least 24 hours).
R = relapsed smoker: has smoked in the last 2 weeks before the visit but has made at least one quit attempt of at least 24 hours since the last visit.
Q = quitter: has not smoked at all in the last 2 weeks before the visit, not even a puff
D = died.
L = lost to follow-up: did not attend their appointment.
Note: If a patient is registered after month 0, draw a line through the month(s) when patient was not registered.
TB-07
TB 07 Contact Investigation forms
National TB Program
National
TB 07 Contact Investigation
TB ProgramForm
TB 07 Contact Investigation Form
TB / DRTB Registration Number (Index case): Date enrolled: __
Name (Index Case): ________________________________________________________________________ Age:_________Sex: 1. Male 2. Female Total Number of Household Member: ______________
Address: Telephone Number/s: _________________________________
TB Type: i. Drug Sensitive TB ii. Drug Resistant TB
Age Referred to further diagnosis If no symptoms of TB among

children (<5 years), referred for
SN Name(s) of contacts Relationship with index case TB Symptoms, If Yes then Mention Coode (eg. 1, 2, etc) Remarks
Sputum Patient TBPT?
F M
courier Referred
Yes No
1 1, 2 etc 1 2 1 2
2 1, 2 etc 1 2 1 2
3 1, 2 etc 1 2 1 2
4 1, 2 etc 1 2 1 2
5 1, 2 etc 1 2 1 2
6 1, 2 etc 1 2 1 2
7 1, 2 etc 1 2 1 2
8 1, 2 etc 1 2 1 2
9 1, 2 etc 1 2 1 2
10 1, 2 etc 1 2 1 2
DEFINITIONS Symptoms for Children(0-14 years old) (code) Symptoms for Adult (15 years =>) (code)
Household contact: 0 - None 0. None

Someone who sleeps and eats in the same house with Persistence of: Persistence of:
the Index TB case. 1.Cough 1. Cough
2. Fever 2. Fever (Evening Rise / Low Grade) / Night
3. Not eating well Sweats
4. Weight Loss \ Failure to thrive 3. Loss of Appetite
5. Fatigue 4. Weight Loss
6. Reduce playfulness 7. Chest Pain
8. Coughing Blood/Sputum
Interviewer: Remarks: Signature:

161
1
162
TB 08 Contact and TBPT Register

TB 08_Contact and TBPT Register
Name of Health Facility
Year
Month
Contact Tracer Name
Contact Number
Type of Contact Tracer (√): Health Worker FCHV Others......................................

Index TB Cases Contacts of the IndexTB Cases
Age Type of Contact Investigation: or Presumptive TB If Presumptive TB (HB)

No. of Family
Type of TB
Name of Index TB Members Microscopy / GeneXpert Center
S.N TB Reg. No (DS TB, Hr TB or DR Name of Family Members Address Contact Numbers Guardian's Name Contacts Directly Sputum
Health Facility for Sputum Test
TB) F M Home Based (HB) Yes No Referred to Health Transported to
Based (HFB)
facility Health Facility
1 2 1 2 3 4
1 2 1 2 3 4
1 2 1 2 3 4
1 2 1 2 3 4
egister 1 2 1 2 3 4
1 2 1 2 3 4
1 2 1 2 3 4
1 2 1 2 3 4
1 2 1 2 3 4
Cases
Enrolled in TB Child Eligible for TBPT Collection Date
Date of home
If Presumptive TB (HB) Sputum Results
Treatment? TBPT? visit of health
Date TBPT Started worker to Outcome Remarks
Microscopy / GeneXpert Center GeneXpert
tacts Directly Sputum Microscopy Lab No. monitor TBPT
for Sputum Test 1.MTB not Detected
rred to Health Transported to 1.Neg Yes No Yes No 1 Month 2 Month 3 Month intake (D/M/Y)
2.MTB Rif Sensitive
ity Health Facility 2.Pov
3. MTB Rif Resistant
DD/MM/YY Wt. Wt. Wt.

3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY DD/MM/YY
No. Tab No. Tab No. Tab
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY
No. Tab No. Tab No. Tab DD/MM/YY
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY DD/MM/YY
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY

3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY DD/MM/YY
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY DD/MM/YY
3 4 1 / 2 1 / 2 / 3 1 2 1 2 DD/MM/YY DD/MM/YY
TB 10 Referral / transfer Slip
Government of Nepal Government of Nepal
Health Management Information System Health Management Information System
…………..District …………..District
…………..Municipality/ Rural Municipality …………..Municipality/ Rural Municipality
………………………………...Hospital/ PHC/HP/HC/CHU …………...Hospital/ PHC/HP/HC/CHU
Referral/Transfer slip Acknowledgement slip
TB 10
Name of Client/ Patient Sex Age Date … … / … … / ……..…
Address Province District M/RM ward no Dear sir
Contact no of Patient: ………………………………………….Name of Referred institution
………………………………………….Address of institution
Drug Provided for …… days to the patient while being transferred The client/patient referred by your institution reached this institution and we are
continuing TB treatment as Transfer in case in this institution.
Transfer/ Referral
Further examination needed …………… Reasons (Specify)………………………………………………………… Name of client /patient
sex age
Vital signs and other condition of Patient Address
BP Pulse Temp Respiration Weight (kg) Height (cm) MUAC (mm) Edema on both Feet Other District
(+ / + + / + + +) Local Level ward no
(For TB Patient only)

Type of TB: 1. PBC, 2. PCD , 3. EP (Site……………………) Examination and Result Date of contact … … / … … / …..…
lab no / Service provided
Registration Category Date Result
Test Institution
1. New 2. Relapse 3. T. after Failure 4. TALFU Sputum
5. Other previously Tx Pt. 6. Unknown previous TB Tx history
Xpert MTB/RIF
Treatment Regimen:…………………………………….
X-ray
Others
Dear sir
………………………………………….....................…(Name of Referred Institution)
…………………………………………........................................…(Address of Referred Institution)
we are sending the above detailed client/ patient to your institution for further service. Please inform us after referred client/patient
reaches your institution. Name of Responder….. signature Date
Referred by Position:
Name Position: Signature Contact no

-- -- -- -- -- -- -- -- -- - -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --
Contact no Date:
163
प�रमािजर्त: २०७०/७१ Print FY: 2070/71

164
TB 11 Referral forms (Community, Private, Contact)
TB 11 - Referral Form (Community / Private / Contact)
Date: .........../............../..............
1. Name of Health facility referred to: .....................................................
2. Name of the person referred: ..................................................... 3. Age .................. 4. Sex : M / F
5. Address Province District M / RM Ward Tole
6. Reason for referral 1. For further diagnosis of presumptive TB 2. TB cases follow up :
3. Others including SAEs:

...................................................................................................................................................
...................................................................................................................................................
*********************************************************************************************************************************
Referred by:
Type of Referral 1. Community 2. Private 3. Contact Investigation
Name: ............................................................. Address: ........................................
Signature .............................................................. Contact number: ...........................
Note: The original copy should be sent with the patient to the referred health facility and the carbon copy should be kept with the referring person
DRTB 04 Community form DRTB 04
Patient Commitment Form
Part 1: Signed at Treatment center

Patient commitment
I am aware that in order to be cured of this form of tuberculosis, I need to take anti-TB drugs
daily till the end of my treatment. If I do not take these drugs daily, I am putting my own
health at risk as well as the health of family and community members. I commit to taking
these drugs at this health center (sub-center) till the end of my treatment. If I decide to leave
this treatment, I understand the risk and consequences of this disease.
Name: Address:
Date: Signature:
Treatment center DR-TB focal person commitment
I have explained the importance of taking these drugs and potential difficulties during
treatment. I will do my best to support him/her in completing a full course of treatment and
ensuring cure/completion. I also commit to ensuring proper documentation and reporting as
per NTP guidelines
Name: Address:
Date: Signature:
Part 2: Signed at Treatment Sub-Center
Sub-centre DR-TB focal person commitment
I have explained the importance of taking these drugs and potential difficulties during
treatment. I will do my best to support him/her in completing a full course of treatment and
getting cured. I also commit to ensuring proper documentation and reporting as per NTP
guidelines
Name: Address:
Date: Signature:
Treatment provider Commitment

I commit to supporting his/her in completing a full course of treatment. I will
e n c o u r a g e h i m / h e r t o c o m p l y w i t h t h e t r e a t m e n t a n d commit to
informing the treatment sub-center if I know that s/he has stopped taking drugs.
Name: Address:
Date: Signature:
DRTB 05 aDSM Recording and Reporting Form
Government of Nepal
Ministry of Health & Population
National Tubeculosis Center
DRTB 05
aDSM Adverse Event Reporting Form - Nepal
A. Patient and Health Facility Information
Patient ID number (as in DRTB
Treatment Centre:
Register:
Date of Birth (or Age): Province:
Sex:  Male  Female
HIV status:  Non-reactive  Reactive
Pregnancy:  No  Yes Trimester:
Weight (kg): Height (cm): BMI:
B. Adverse events experienced by patient (including abnormal investigations)
Adverse event Onset date End date Severity grade Seriousness * Outcome §
* Please select: D died LT life threatening HA caused or prolonged hospital admission PD permanent disability
OS other medically serious CA congenital abnormality NS not serious
§ Please select: A recovered B recovering C recovered with residual effects D died E not recovered F unknown
Detailed description of adverse event(s):
Was treatment of adverse event required?  No  Yes (please specify):
C. Laboratory assessment: Results of tests and procedures

Test performed Test date Result Unit Reference range
D. Medicines: DR-TB Regimen and other concomitant medicines, vaccines, traditional / herbal medicines and dietary supplements
 Tick if medicine suspected of causing adverse event
Medicine Dose Frequency Route Start date Stop date Reason for use Action taken † Response ‡











† Action taken in response to AE: DW drug withdrawn DR dose reduced DI dose increased DNC dose not changed UK unknown NA not applicable
‡ Response to action taken: RA recovered NE no effect on AE FA fatal AE UN unknown NA not applicable
E. Re-challenge information
List any medicines that were restarted and indicate effect on adverse event
Medicine adverse event recurred adverse event did not recur unknown
  
  
  
  
  
  
  
F. Other relevant information e.g. medical history, concurrent illnesses, smoking, alcohol use and Hospital Management
G. Causality Assessment at Treatment Center Level
1. Certain 2. Probable 3. Possible 4. Unlikely 5. Unassessed 6. Un-assessable
Comments:
H. Final AE/SAE Summary
Adverse Events Description:

Event Start date
Event End date
Severity Grading
Event classified: 1. Serious 2. Not – Serious (Based on Annex 2)
Narrative / Additional information (Final Result):
G. Reporter Information
Name: Phone number:
Email:
Occupation:  Doctor  Nurse  Paramedics  Other (please specify):
Signature: Date
Submit form to:

Email to: M&E Unit, NTC: aDSMNTC@gmail.com
NTC Use Only:

Date received by NTC:
Causality assessment:  Certain  Probable  Possible  Unlikely  Unassessed  Un-assessable
Comment:
Reported to DDA:  No  Yes Date reported to DDA:

DRTB 06 DRTB Drug Order Form
National Tuberculosis Program

DR Drug Order Form DRTB 06
Treatment center: Order Period, FY: From: To:
Regimen SSTR LR1 LR2 LR3 LR4.1 LR4.2 Modify SSTR CLR1 CLR2.1 CLR2.2 Total Stock on hand Expiry date Total order
Adult LR2 Child requirement
No. of cases
Medicines Factors used for calculating total requirement
Amikacin 500 mg 200 288 120 0 0
Amoxycillin 875 mg+
240 240 0 0
Clavulanic acid 125 mg
Bedaquilline 100 mg 188 188 188 0 0
Clofazimine 100 mg 120 120 120 120 120 120 120 0 0
Cycloserine 250 mg 240 240 240 240 0 0
Delamanid 50 mg 480 480 480 480 240 0 0
Ethambutol 400 mg 360 0 0
Ethionamide 250 mg 360 360 360 360 0 0
Imipenem-Cilastatin 500
480 480 0 0
mg
Isoniazid 300 mg 120 0 0
Isoniazid 100 mg 240 0 0
Levofloxacin 250 mg 480 0 0
Linezolid 600 mg 120 120 120 120 120 120 0 0
Moxifloxacin 400 mg 240 112 0 0
PAS 4 g 240 240 0 0
Pyrazinamide 400 mg 480 480 480 480 480 0 0
Water for injection 5 ml 200 480 480 0 0
Moxifloxacin 150 mg DT 480 0 0
Clofazimine 50 mg 120 120 120 120 0 0
Ethionamide 125 mg DT 240 360 0 0
Isoniazid 100 mg DT 360 360 0 0
Ethambutol 100 mg DT 480 0 0
Pyrazinamide 150 mg DT 600 600 600 600 0 0
Levofloxacin 100 mg DT 360 0 0
Cycloserine 150 mg 360 360 360 0 0
Prepared By: Verified By: Approved By:

Signature: Signature: Signature:
Date: Date: Date:
Name: Name: Name:

Designation: Designation: Designation:
169
HMIS 9.3
170
DRTB 07 DRTB Reporting Form (for cohort reporting)
Nepal Government
Ministry of Health and Population
Department of Health Service
Health Management Information System
Province/ District/Local Level,…………………………..
… … … … … … … … … … … … … … … … … … … … … … … …
Monthly Progress Report
Health Facility Code
Fiscal Year 20.... /7... Date of Submission / / 207 ...
Ref. No Date of Recived: / / 207 ...

District D/PHO…..
Sub: Submission of Monthly Public Health Activities Progress report Month 207 ... Year
Number of New Client Number of Total Client Number of Referred Client Operation Total number of

Number of HFs within the Operated
Age Group (number) Clint recived
F M F M F M work area (number)
Health service
0‐9 Year Community Outreach Clinic
10‐19 Year Immunization Clinic
20‐59 Year Immunization Session
>= 60 Years FCHVs
SN Types of Health Facility Circle SN Available Services Circle SN Available Services Circle SN Available Services Circle

1 Primary Health Care Center 1 1 Birthing Centre 1 7 OPT Site 7 13 ART Site 13
2 Health Post 2 2 BEOC Site 2 8 DOTS Centre 8 14 Other …. 14
3 Sub‐Health Post 3 3 Safe Abortion Listed Site 3 9 Microscopy Site 9
4 Urban Health Clinic 4 4 IUCD Service Site 4 10 Laboratory Service 10

5 Community Health Unit 5 5 Implant Service Site 5 11 HTC Site 11
6 Institutional/Districts Health Clinic 6 6 Adolescent Friendly Site 6 12 PMTCT Site 12
Prepared By Approved By
Signature Signature
Name Name
Designation Designation
Revised: 2070/71 Print FY: 2070/71
DRTB 07 DRTB Reporting Format (For cohort reporting)
Block 4:Registration
After failure of After failure by Treatment SSTR LR1 LR2 LR3 LR4.1 LR4.2 Modified LR2 CLR1 CLR2.1 CLR2.2 PLR1
After failure of After failure of Other Unknown Previous
first line of Treatment Regimen [3]
New Relapse Re‐Treatment Treatment with TALFU previously TB Treatment
Block 1 : Case Registration Treatment with with Hr TB
with FLD SLD treated History
FLD Regimen
1 2 3 4 5 6 7 8 9 10 11 12
F M F M F M F M F M F M F M F M F M Female
Sex of
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Patient Male
RR Pulmonary
Block 6.1: Tobacco Smoking
Extra Pulmonary
At the Time after walking to first cigarette
Status of Exposure to smoking inside the home (Y
Pulmonary beginning of Smoking Tobacco (Current) 1= <=30 Min or
or N)
MDR 2=>30 Min
TB
Extra Pulmonary Treatment 1 2 3
Female
Pulmonary
Male
Pre‐XDR
Extra Pulmonary
Pulmonary Block 6.2:All DR TB patients (MDR,Pre‐Xdr, XDR‐ register for Outcome‐Status of Tobacco Smoking at End of Treatment
XDR
Status of Smoking at the END of Treatment
Extra Pulmonary No of Cases
(S,R,Q,D or L)
Registered S: Current Smoker, R: Relapsed Smoker, Q: Quitted, D: Died, L: LTFU
BLOCK 2: Age 0‐4 Years 5‐14 Years 15‐24 Years 25‐34 Years 35‐44 Years 45‐54 Years 55‐64 Years ≥ 65 Years
F M S R Q L D
Registration
1 2 3 4 5 6 7
[2] F M F M F M F M F M F M F M F M
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
RR
Block 5:HIV status
HIV +ve TB Patients on
MDR At the Time of TB Diagnosis [41] Patients Tested for HIV Total HIV Positive
ART CPT
1 2 3 4 5
Pre‐XDR
Female
Sex of
XDR
Patient
Male
Block 3:Sputum Conversion (Interim cohort analysis)
Smear result at 4 months (Cases Reg. at 8 Month Culture result at 6 months (Cases Reg. at 12 Switched to
Sputum Conversion of DR Register Died Lost to follow‐up Not Evaluated
ago Month Ago) MDR (LR) Pre‐XDR XDR Block 7:Contact Investigation
TB Cases: No of months
F M F M
completed treatment [3] F M F M F M F M F M F M F M Sex
Negative Positive Negative Positive
Contact Tracing of Registered Case
1 2 3 4 5 6 7 8 p 10 11 12 13 14 15 16 17 18 19 Female Male
MDR (SSTR) 1 2 3
MDR (LR) 1 Total number of close contacts
Pre‐XDR 2 Total number contact traced
XDR 3 Total number diagnosed with TB/DRTB
Block 7:Treatment Outcome 4 Total number linked to TB/DRTB treatment and care
Switched to
Types of DR TB [..] Register Cured Treatment Completed Lost to Follow up Died Not Evaluated
MDR LR Pre‐XDR XDR
F M F M F M F M F M F M F M F M F M
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
MDR SSTR (Cases Reg
16 Month Ago)
MDR LR (Cases Reg 24
Month Ago)
Pre‐XDR (Cases Reg 24
Month Ago)
XDR (Cases Reg 24
Month Ago)
171
172
DRTB 08 Six-monthly Report on Detection and Enrolment of DR-TB

DRTB 08
National Tuberculosis Program, Nepal

Six-monthly Report on Detection and Enrolment of DR-TB for the 6-month cohort that just ended
Name of Facility ____________________________________________Municipality/Rural Municipality________________________________
District:________________________________________ Name of PMDT Focal Person: ________________________________________
Cohort being assessed: ___________________ of ___ (Year) Date of Report: _______________________________________

(Months eg: Jan-June)
Summary of the six months that just ended:
Presumptive DR-TB Total Detection Enrolment

number
GeneXpert MTB/RIF test Culture/LPA
No. of tested RR-TB MDR On SSTR On LR
New
Retreatment
Non-converters at 2 months
Symptomatic contacts of DR-TB

Others
TOTAL (No. and %)

Age and Sex breakdown of the enrolled patient
<15 yrs >15 year
Male
Female
HIV positive among enrolled patient: ------------------------------------------

Patient started on Pre XDR-TB regimen ---------------------------------------
Patient started on XDR-TB regimen ---------------------------------------------
Current year
1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6
Reporting period Summary Report due

173
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2019

Drug Resistant Tuberculosis

3. REGISTRATION CATEGORY OF DR-TB 24

5. MANAGEMENT AND MONITORING ASPECTS OF DR-TB 58

6. ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (ADSM) 69

8. MONITORING AND EVALUATION FOR TB CONTROL PROGRAM 96

1. Dr. Bhim Singh Tinkari, (Previous NTC Director)

THE MAIN CHANGES IN THE WHO 2019

The overall objectives of NSP 2016-21 are as follows:

Objective 3: To provide DR TB diagnose services to 50% of the presumptive MDR TB patients

Objective 5: To gradually scale up Community System Strengthening Programme (CSS) at 60% of

Objective 6: To contribute to health system strengthening through HR management and

Objective 7: To develop comprehensive Monitoring and Evalutaion system

1.1.1 Multi Drug Resistant Tuberculosis (MDRTB) in the world

FIGURE 1.1: DR-TB burden

1.1.2 MDR in SEAR countries

FIGURE 1.2: Ranking of SEAR countries by MDR-TB incidence, 2015

1.1.3 MDR-TB in Nepal

TABLE 1.2: Estimates of MDR-TB disease burden in Nepal for 2016

1.2 KEY DEFINITIONS

Drug resistance is the result of inadequate therapy

TABLE 1.3: Causes of Resistance

How to prevent drug resistance?

There are five principal ways to prevent drug-resistant TB:

1.3 ORGANISATION OF DR-TB CONTROL IN NEPAL

1.4 ROLES AND RESPONSIBILITY

B. Provincial Health Directorate (PHD) Office

C. Local Level (Palikas)

• Manage drugs, reagents and required logistics for the programmeme

D. Treatment/Sub Centre Levels

F. Patient and Community Level

1. Close contact of DR-TB case

2.2 MANAGEMENT OF PRESUMPTIVE DR-TB

2.2.3. What needs to be done at the DR-TB Centre?

2.3 DIAGNOSTIC TESTS

2.3.2 Xpert MTB/RIF test

• the presence of DNA from the tubercle bacillus;

2.3.2.1 How to collect a sputum sample for Xpert MTB/RIF testing

D1. Falcon tube D2. Proper identification of Falcon tube

as shown in diagram and

2.3.2.4 Xpert MTB/RIF testing results

Label Result and Action to be taken

MTB detected, Diagnosis of TB confirmed. Treat with first-line TB regimen.

MTB detected, If presumptive MDR- TB case: send to DR-TB Centre.

MTB detected, Diagnosis of TB is confirmed. Start treatment with first-line TB

N MTB not detected Additional investigations required to exclude TB.

2.3.3 Line Probe Assay (LPA)

Interpretation of Second-Line (SL) LPA result:

Interpretation of Second Line (SL) LPA result for SLDs:

2.3.4 Culture and drug susceptibility testing (DST)

2.3.4.1 How to collect a sputum specimen for culture and DST?

To ensure the quality of sputum samples:

In case of EP DR-TB, other specimens can be collected

TB of the peripheral lymph adenitis Pus and/or excision biopsy Minimum 2 ml

Musculoskeletal TB, Osteo-articular Intra-articular Fluid Sterile

2.3.4.2 How to send the specimens for culture DST.

Transportation of the sputum samples, which is likely to contain drug

2.3.4.3 Culture result

Interpretation of Liquid Culture

Drug Susceptibility Testing (DST):

Xpert MTB/RIF Ultra assay

Next Generation Sequencing (NGS):

2.4 DIAGNOSIS OF EXTRAPULMONARY DR-TB IN THE