Multi-drug-resistant Tuberculosis

Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to isoniazid (INH) and rifampicin (RM )! the t"o most po"erful first-line anti-TB drugs# Isolates that are multipl$-resistant to an$ other combination of anti-TB drugs but not to INH and RM are not classed as MDR-TB# MDR-TB de%elops during treatment of full$-sensiti%e TB "hen the course of antibiotics is interrupted and the le%els of drug in the bod$ are insufficient to &ill '(() of bacteria# This can happen for a number of reasons* patients ma$ feel better and halt their antibiotic course! drug supplies ma$ run out or become scarce! or patients ma$ forget to ta&e their medication from time to time# MDR-TB is spread from person to person as readil$ as drug-sensiti%e TB and in the same manner#

+pidemiolog$
MDR-TB most commonl$ de%elops in the course of TB treatment! and is most commonl$ due to doctors gi%ing inappropriate treatment! or patients missing doses or failing to complete their treatment# MDR-TB strains are often less fit and less transmissible! and outbrea&s occur more readil$ in people "ith "ea&ened immune s$stems (e#g#! patients "ith HI,)# -utbrea&s among non.immunocompromised health$ people do occur! but are less common# / '001 sur%e$ of 23 countries found rates abo%e 4) in about a third of the countries sur%e$ed# The highest rates "ere in the former 566R! the Baltic states! /rgentina! India and 7hina! and "as associated "ith poor or failing national tuberculosis control programmes# It has been &no"n for man$ $ears that INH-resistant TB is less %irulent in guinea pigs! and the epidemiological e%idence is that MDR strains of TB do not dominate naturall$# / stud$ in 8os /ngeles found that onl$ 9) of cases of MDR-TB "ere clustered# 8i&e"ise! the appearance of high rates of MDR-TB in Ne" :or& cit$ in the earl$ '00(s "as associated "ith the e;plosion of /ID6 in that area#

Treatment of MDR-TB
5suall$! multidrug-resistant tuberculosis can be cured "ith long treatments of second-line drugs! but these are more e;pensi%e than firstline drugs and ha%e more ad%erse effects# The treatment and prognosis of MDRTB are much more a&in to that for cancer than to that for infection# It has a mortalit$ rate of up to <()! "hich depends on a number of factors! including '# Ho" man$ drugs the organism is resistant to (the fe"er the better)! 4# Ho" man$ drugs the patient is gi%en (patients treated "ith fi%e or more drugs do better)! 2# =hether an in>ectable drug is gi%en or not (it should be gi%en for the first three months at least)! ?# The e;pertise and e;perience of the ph$sician responsible! 3# Ho" co-operati%e the patient is "ith treatment (treatment is arduous and long! and re@uires persistence and determination on the part of the patient)! 9# =hether the patient is HI, positi%e or not (HI, co-infection is

associated "ith an increased mortalit$)# The ma>orit$ of patients suffering from multi-drug resistant tuberculosis do not recei%e treatment as the$ tend to li%e in underde%eloped countries or in a state of po%ert$# Denial of treatment remains a difficult human rights issue as the high cost of second-line medications often precludes indi%iduals "ho cannot afford therap$# Treatment courses are generall$ measured in months to $earsA MDR-TB ma$

re@uire surger$! and death rates remain high despite optimal treatment# That said! good outcomes are still possible# The treatment of MDR-TB must be underta&en b$ a ph$sician e;perienced in the treatment of MDR-TB# Mortalit$ and morbidit$ in patients treated in nonspecialist centres is significantl$ inferior to those patients treated in specialist centres# In addition to the ob%ious ris&s (i#e#! &no"n e;posure to a patient "ith MDRTB)! ris& factors for MDR-TB include HI, infection! pre%ious incarceration!

failed TB treatment! failure to respond to standard TB treatment! and relapse follo"ing standard TB treatment# Treatment of MDR-TB must be done on the basis of sensiti%it$ testing* it is impossible to treat such patients "ithout this information# If treating a patient "ith suspected MDR-TB! the patient should be started on 6HR+B (6treptom$cinCisonicotin$l H$drazineCRifampicinC+thambutolCp$raBinamide)

CMDECc$closerine pending the result of laborator$ sensiti%it$ testing# There is e%idence that pre%ious therap$ "ith a drug for more than a month "as associated "ith diminished efficac$ of that drug regardless of in %itro tests indicating susceptibilit$! so! detailed &no"ledge of the treatment histor$ of that patient is essential# / gene probe for rpoB is a%ailable in some countries and this ser%es as a useful mar&er for MDR-TB! because isolated RM results of a to gene omit probe RM (rpoB) to are use &no"n to resistance is rare (e;cept be positi%e! The then it is for "hen patients ha%e a histor$ of being treated "ith rifampicin alone)# If the reasonable and 6H+BCMDECc$closerine# reason

maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffecti%e (e%en though isoniazid resistance so commonl$ occurs "ith rifampicin resistance)# =hen sensiti%ities are &no"n and the isolate is confirmed as resistant to both INH and RM ! fi%e drugs should be chosen in the follo"ing order (based on &no"n sensiti%ities)* an aminogl$coside (e#g#! ami&acin! &anam$cin) (e#g#! capreom$cin) B/ +MB a fluoro@uinolone* usedF'3G)A rifabutin c$closerine a thioamide* prothionamide or ethionamide e#g#! mo;iflo;acin (ciproflo;acin should no longer be or pol$peptide antibiotic

/6 a macrolide* e#g#! clarithrom$cin linezolid high-dose INH (if lo"-le%el resistance) interferon- thioridazine /mpicillin

Drugs are placed nearer the top of the list because the$ are more effecti%e and less to;icA drugs are placed nearer the bottom of the list because the$ are less effecti%e or more to;ic! or more difficult to obtain# Resistance to one drug "ithin a class generall$ means resistance to all drugs "ithin that class! not but a notable mean e;ception is rifabutin* and the rifampicinlaborator$ resistance does al"a$s rifabutin-resistance

should be as&ed to test for it# It is onl$ possible to use one drug "ithin each drug class# If it is difficult finding fi%e drugs to treat then the clinician can re@uest that high le%el INH-resistance be loo&ed for# If the strain has onl$ lo" le%el INH-resistance (resistance at '#( mg.l INH! but sensiti%e at (#4 mg.l INH)! then high dose INH can be used as part of the regimen# =hen counting drugs! sa$! "hen adding capreom$cin or B/ and interferon count as zeroA that is to B/ to a four drug regimen! $ou must still choose another ami&acin)! because the to;ic effect of these drugs is

drug to ma&e fi%e# It is not possible to use more than one in>ectable (6TM! additi%e* if possible! the aminogl$coside should be gi%en dail$ for a minimum of three months (and perhaps thrice "ee&l$ thereafter)# 7iproflo;acin should not be used in the treatment of tuberculosis if other fluoro@uinolones are a%ailable# There is no intermittent regimen %alidated for use in MDR-TB! but clinical e;perience is that gi%ing in>ectable drugs for fi%e da$s a "ee& (because there is no-one a%ailable to gi%e the drug at "ee&ends) does not seem to result in inferior results# Directl$ obser%ed therap$ certainl$ helps to impro%e outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB#

Response to treatment must be obtained b$ repeated sputum cultures (monthl$ if possible)# Treatment for MDR-TB must be gi%en for a minimum of '< months and cannot be stopped until the patient has been culture-negati%e for a minimum of nine months# It is not unusual for patients "ith MDR-TB to be on treatment for t"o $ears or more# atients possible# "ith MDR-TB should be (HI, of isolated infected MDR-TB (and in negati%e-pressure patients! some or rooms! if on on

atients "ith MDR-TB should not be accommodated on the same "ard as patients management patients insist

immunosuppressed crucial to the

immunosuppressi%e drugs)# 7areful monitoring of compliance "ith treatment is ph$sicians hospitalisation if onl$ for this reason)# 6ome ph$sicians "ill insist that these patients are isolated until their sputum is smear negati%e! or e%en culture negati%e ("hich ma$ ta&e man$ months! or e%en $ears)# Heeping these patients in hospital for "ee&s (or months) on end ma$ be a practical or ph$sical impossibilit$ and the final decision depends on the clinical >udgement of the ph$sician treating that patient# The attending ph$sician should ma&e full use of therapeutic drug monitoring (particularl$ of the aminogl$cosides) both to monitor compliance and to a%oid to;ic effects# 6ome supplements ma$ be useful as ad>uncts in the treatment of tuberculosis! but the for the purposes of counting drugs for MDR-TB! the$ count as zero (if $ou alread$ ha%e four drugs in the regimen! it ma$ be beneficial to add arginine or %itamin D or both! but $ou still need another drug to ma&e fi%e)# arginine (peanuts are a good source) ,itamin D

The drugs listed belo" ha%e been used in desperation and it is uncertain "hether the$ are effecti%e at all# The$ are used "hen it is not possible to find fi%e drugs from the list abo%e# imipenem co-amo;icla% clofazimine prochlorperazine metronidazole

The follo"ing drugs are e;perimental compounds that are not commerciall$ a%ailable! but "hich ma$ be obtained from the manufacturer as part of a clinical trial or on a compassionate basis# Their efficac$ and safet$ are un&no"n* /-<4?F4<G (manufactured =ashington) R4(10'(F40G (Hoen /ndries et al#! under de%elopment b$ Johnson K Johnson) b$ athoIenesis 7orporation! 6eattle!

In cases of e;tremel$ resistant disease! surger$ to remo%e infection portions of the lung is generall$ the final option# The centre "ith the largest e;perience in this is the National Je"ish Medical and Research 7enter in Den%er! a 2#2) 7olorado# operati%e '4) In '1 $ears "ith of an e;perience! additional the$ 9#<) ha%e d$ing performed follo"ing '<( the operationsA of these! 0< "ere lobectomies! <4 "ere pneumonectomies# There is mortalit$! e;perienced operationA significant morbidit$ (particularl$ e;treme

breathlessness)# -f 0' patients "ho "ere culture positi%e before surger$! onl$ ? "ere culture positi%e after surger$#

Luestions Eacing Modern Medicine

The destitute patients "ho suffer from multi-drug resistant tuberculosis face the problem of not recei%ing proper treatment# This in>ustice pertains to the issue of human rights# Treatment and medication for chronic infectious diseases are accessible to those "ho can afford it! "hile others! li&e those "ho li%e in impo%erished countries do not ha%e access to this care# Eor e;ample! areas such as /frica and Haiti! "here there is not a strong foundation for healthcare! treatment is una%ailable# 7onse@uentl$! onl$ a small minorit$ of affected people are treated#F'4G

+;tensi%el$ drug-resistant Tuberculosis

+;tensi%el$ drug-resistant tuberculosis (DDR-TB) is a form of TB caused b$ bacteria that are resistant to the most effecti%e anti-TB drugs# 6ome contend that DDR-TB TB strains (MDR-TB) ha%e and emerged once from the can mismanagement spread from of one multidrugperson to resistant created!

another# The e;act nature of this mismanagement is not $et &no"n! but origin

of DDR-TB ma$ coincide "ith the institution of ne" policies to promote drug compliance! such as D-T6# -ne in three people in the "orld is infected "ith TB bacteria# -nl$ "hen the

bacteria become acti%e do people become ill "ith TB# Bacteria become acti%e as a result of an$thing that can reduce the personMs immunit$! such as HI,! ad%ancing age! or some medical conditions# TB can usuall$ be treated "ith a course of four standard! or first-line! anti-TB drugs# If these drugs are misused or mismanaged! multidrug-resistant TB (MDR-TB) can de%elop# MDR-TB ta&es longer to treat "ith second-line drugs! "hich are more e;pensi%e and ha%e more side-effects# DDR-TB can de%elop "hen these second-line drugs are also misused or mismanaged and therefore also become ineffecti%e# DDR-TB raises concerns of a future TB epidemic "ith restricted treatment options! and >eopardizes the ma>or gains made in TB control and progress on reducing TB deaths among people li%ing "ith HI,./ID6# It is therefore %ital that TB control is managed properl$ and ne" tools de%eloped to pre%ent! treat and diagnose the disease# The true scale of DDR-TB is un&no"n as man$ countries lac& the necessar$ e@uipment and capacit$ to accuratel$ diagnose it# It is estimated ho"e%er that there are around ?(!((( cases per $ear# /s of June 4((<! ?0 countries ha%e confirmed cases of DDR-TB#

Definition
DDR-TB is defined as TB that has de%eloped or MDR-TB)! resistance as "ell as to to at an$ This also least rifampicin and isoniazid (resistance to these first line anti-TB drugs defines Multi-drug-resistant anti-TB -ctober in>ectable 4((9# The tuberculosis! member of the @uinolone famil$ and at least one of the follo"ing second-line drugs* &anam$cin! capreom$cin! definition of DDR-TB as or ami&acin# MDR-TB that is definition of DDR-TB "as agreed b$ the =H-Ilobal Tas& Eorce on DDR-TB in earlier resistant to three or more of the si; classes of second-line drugs! is no longer used! but ma$ be referred to in older publications#

Transmission
8i&e other forms of TB! DDR-TB is spread through the air# =hen a person "ith infectious TB coughs! sneezes! tal&s or spits! the$ propel TB germs! &no"n

as bacilli! into the air# / person needs onl$ to inhale a small number of these to be infected# eople infected "ith TB bacilli "ill not necessaril$ become sic& "ith the disease# The immune s$stem N"alls offN the TB bacilli "hich! protected b$ a thic& "a;$ coat! can lie dormant for $ears# The spread of TB of bacteria infectious depends people on in factors an$ one such place as the number "ith and the

concentration

together

presence of people "ith a higher ris& of being infected (such as those "ith HI,./ID6)# The ris& of becoming infected increases the longer the time that a pre%iousl$ uninfected person spends in the same room as the infectious case# The ris& of spread increases "here there is a high concentration of TB bacteria! such as can occur in closed en%ironments li&e o%ercro"ded houses! hospitals or prisons# The ris& "ill be further increased if %entilation is poor# The ris& of spread "ill be reduced and e%entuall$ eliminated if infectious patients recei%e proper treatment#

Diagnosis
6uccessful diagnosis of DDR-TB depends on the patientMs access to @ualit$ health-care ser%ices# If TB bacteria are found in the sputum! the diagnosis of TB can be made in a da$ or t"o! but this finding "ill not be able to distinguish bet"een drug-susceptible and drug-resistant TB# To e%aluate drug susceptibilit$! the bacteria need to be culti%ated and tested in a suitable laborator$# Einal diagnosis in this "a$ for TB! and especiall$ for DDR-TB! ma$ ta&e from 9 to '9 "ee&s# F1G To reduce the time needed for diagnosis! ne" tools for rapid TB diagnosis are urgentl$ needed#

Treatment
The principles of treatment for MDR-TB and for DDR-TB are the same# Treatment re@uires e;tensi%e chemotherap$ for up to t"o $ears# 6econd-line drugs are more to;ic than the standard anti-TB regimen and can cause a range of serious side-effects including hepatitis! depression and hallucinations# atients are often hospitalised for long periods! in isolation# In addition! second-line drugs are e;tremel$ e;pensi%e compared "ith the cost of drugs for standard TB treatment#

DDR-TB is associated "ith a much higher mortalit$ rate than MDR-TB! because of a reduced number of effecti%e treatment options# Despite earl$ fears that this strain of TB "as untreatable! recent studies ha%e sho"n that DDR-TB can be treated through the use of aggressi%e regimens# / stud$ in the Toms& oblast of Russia! reported that '? out of 40 (?<#2)) patients "ith DDR-TB successfull$ completed treatment#F0G 6uccessful outcomes depend on a number of factors including the e;tent of the drug resistance! the se%erit$ of the disease and "hether the patientMs immune s$stem is compromised# It also depends on access to laboratories that can pro%ide earl$ and accurate diagnosis so that effecti%e treatment is pro%ided as soon as possible# +ffecti%e treatment re@uires that all si; classes of second-line drugs are a%ailable to clinicians "ho ha%e special e;pertise in treating such cases#

re%ention
7ountries aim to pre%ent DDR-TB b$ ensuring that the "or& of their national TB control programmes! and all practitioners "or&ing "ith people "ith TB! is carried out according to the International and 6tandards for to TB 7are# TB These emphasize pro%iding proper diagnosis treatment all patients!

including those "ith drug-resistant TBA assuring regular! timel$ supplies of all anti-TB drugsA proper management of anti-TB drugs and pro%iding support to patients to ma;imize adherence to prescribed regimensA caring for DDR-TB cases in a centre "ith proper %entilation! and minimizing contact "ith other patients! particularl$ those "ith HI,! especiall$ in the earl$ stages before treatment has had a chance to reduce the infectiousness# /lso an effecti%e disease control infrastructure funding is for necessar$ research! for and the pre%ention of DDR tuberculosis# Increased strengthened laborator$

facilities are much re@uired# Immediate detection through drug susceptibilit$ testingMs are %ital! "hen tr$ing to stop the spread of DDR tuberculosis#

TB %accine
The B7I %accine pre%ents se%ere forms of TB in children! such as TB meningitis# It "ould be e;pected that B7I "ould ha%e the same effect in pre%enting se%ere forms of TB in children! e%en if the$ "ere e;posed to DDRTB! but it ma$ be less effecti%e in pre%enting pulmonar$ TB in adults! the

most common and most infectious form of TB# The effect of B7I against DDR-TB "ould therefore li&el$ be %er$ limited# Ne" %accines are urgentl$ needed! and =H- and members of the 6top TB %accines# artnership are acti%el$ "or&ing on ne"

DDR-TB and HI,./ID6

TB is one of the most common infections in people li%ing "ith HI,./ID6# In places "here DDR-TB is most common! people li%ing "ith HI, are at greater ris& of becoming infected "ith DDR-TB! compared "ith people "ithout HI,! because of their "ea&ened immunit$# If there are a lot of HI,-infected people in these places! then there "ill be a strong lin& bet"een DDR-TB and HI,# Eortunatel$! in most of the places "ith high rates of HI,! DDR-TB is not $et "idespread# Eor this reason! the ma>orit$ of people "ith HI, "ho de%elop TB "ill ha%e drug-susceptible or ordinar$ TB! and can be treated "ith standard first-line anti-TB drugs# Eor those "ith HI, infection! treatment "ith antiretro%iral drugs "ill li&el$ reduce the ris& of becoming infected "ith DDR-TB! >ust as it does "ith ordinar$ TB# / research stud$ titled NTB re%alence 6ur%e$ and +%aluation of /ccess to TB atients in /sembo and Iem! =estern

7are in HI,-Infected and 5ninfected TB

Hen$a!N sa$s that HI,./ID6 is fueling large increases in TB incidence in /frica! and a large proportion of cases are not diagnosed#

6$mptoms
6$mptoms of DDR-TB are no different from ordinar$ or drug-susceptible TB* a cough "ith thic&! cloud$ mucus (or sputum)! sometimes "ith blood! for more than 4 "ee&sA fe%er! chills! and night s"eatsA fatigue and muscle "ea&nessA "eight lossA and in some cases shortness of breath and chest pain# / person "ith these s$mptoms does not necessaril$ ha%e DDR-TB! but the$ should see doctor for a chec&-up# TB patients "hose s$mptoms do not impro%e after a fe" "ee&s of treatment "ith TB and are ta&ing treatment should inform their clinician or nurse#