Drug-Resistant Tuberculosis

Richard E. Chaisson, MD
Center for TB Research
Center for AIDS Research
Johns Hopkins University
Baltimore, MD USA
Tuberculosis Drug Resistance - Definitions

• Acquired drug resistance

– Selection of resistant mutants by inadequate treatment
– Requires sufficient AFB load for selection of resistant
mutants (106–1010 organisms)
• Primary drug resistance
– Disease caused by an organism that was resistant when
infection was acquired
• Multi-drug resistant TB (MDR TB)
– Resistance to at least INH and rifampin
• eXtensively-drug resistant TB (XDR TB)
– MDR TB plus resistance to fluoroquinolones and an
injectable agent (amikacin, kanamycin, capreomycin)
 12 Month Results of the Medical Research
Council Streptomycin Trial
(BMJ 1948;2:769-82)
No
Treatment No. Improved Change Worse Death
Streptomycin 55 31 4 8 (15%) 12
(56%) (7%) (22%)

Control 52 16 5 7 24
(bed rest) (31%) (10%) (13%) (46%)

Streptomycin resistance in 35/41 Strept-treated patients at 6 months

 MDR and XDR TB
• Drug resistant TB arises from improper
treatment
– Wrong selection of drugs by doctors
– Poor adherence to treatment by patients
• Patients with M/XDR TB can spread infection
to others causing primary resistance
• Diagnosis and management of M/XDR TB is
challenging
• Control of DR TB requires both:
– rapid diagnosis and treatment of cases
– preventing creating new cases through improper treatment
Spectrum and Variability of TB Resistance
China CDC National Survey
• Prevalence of MDR TB
– 5.7% in never-treated patients
– 25.6% in retreatment cases

• Among MDR patients:

– 11% of new and 18% of retreatment ‘simple MDR’
– 55% of MDR patients had ethambutol resistance
– 32% with resistance to kanamycin or ofloxacin
– 8.2% with XDR TB

Zhao et al. NEJM 2012:366:2161-70;

 Prevalence of additional drug resistance in 1278
patients with MDR TB – The PETTS Study
First-line drugs
Ethambutol 826 (64·6%)
Streptomycin 881 (69·0%)
Four first-line drugs 625 (49·0%)
Second-line drugs
Any second-line drug 559 (43·7%)
At least one fluoroquinolone 165 (12·9%)
Injectable drugs
Kanamycin 237 (18·5%)
Amikacin 205 (16·0%)
Capreomycin 152 (12·0%)
At least one 255 (20·0%)
All 134 (10·5%)
Other oral second-line drugs
Ethionamide 249 (19·5%)
Aminosalicylic acid 137 (10·7%)
At least one 346 (27·1%)
XDR tuberculosis 86 (6·7%)
Dalton et al., Lancet 2012:380:1406-17
 Treatment of MDR Tuberculosis
Principles of Treatment

• Use 3-4 drugs active against the strain

• Supervise treatment to ensure adherence
• Continue treatment for at least 12-18
months after conversion of cultures to
negative
• Consider surgical removal of affected
segments or lobe(s) after several months of
antibiotic therapy
 Drugs for MDR-TB
Group Drugs
Group 1: First-line oral drugs Ethambutol (E)
Pyrazinamide (Z)
High dose INH (H)
Group 2: Injectable drugs Kanamycin (Km)
Amikacin (Am)
Capreomycin (Cm)
Group 3: Fluoroquinolones Moxifloxacin (Mfx)
Levofloxacin (Lev)
Ofloxacin (Ofx)
Group 4: Oral bacteriostatic second line Ethionamide (Eto)
drugs Prothionamide (Pro)
Cycloserine (Cs) OR
Terizidone (Trd)
Para-aminosalicylic acid (PAS)
Group 5: Drugs of unclear efficacy Clofazimine (Clo)
Clarithromycin (Cla)
Amoxacillin-clavulanate (Aug)
Linezolid (Lz)
Thiocetazone (T)
 Potency and tolerability of existing TB drugs

Dorman and Chaisson, Nature Medicine 2007;13:295

Indian RNTCP MDR Treatment Regimen

• 6 – 9 months
• Kanamycin, Ofloxacin (or Levo), Ethionamide,
Cycloserine, PZA, Ethambutol

• 18 months
– Ofloxacin (or Levo), Ethionamide,
Cycloserine, Ethambutol
 ‘Bangladesh’ Regimen
4-month intensive High-dose INH*
phase Prothionamide*
Kanamycin
Gatifloxacin
Ethambutol*
Pyrazinamide*
Clofazimine
5-month Gatifloxacin
continuation phase Ethambutol*
Pyrazinamide*
Clofazimine

*Resistance likely for many MDR patients

van Deun, et al. AJRCCM 2010:182:684-92
 Additional Options for Treating Drug-
Resistant TB
• New products (approved or via compassionate use)
– Bedaquiline
– Delaminid
– PA824
• Old products
– Imipenem/cilastin
– ?Inhaled colistin
Treatment of MDR TB can be successfully
implemented by a well-functioning TB
Control Progam

However, it can also be badly done,

making drug resistance worse and creating
a bigger public health nightmare.
 Treatment Outcomes in DOTS-Plus
Programs Supported by WHO “Green Light Committee”

Retreatment
Outcome New Patients Patients
Treatment Success 92 (77.3) 637 (68.6)
Defaulted 18 (15.1) 92 (9.9)
Failed 5 (4.2) 65 (7.0)
Died 4 (3.4) 132 (14.2)
Transferred 0 2 (0.2)
Total 119 (100.0) 928 (100.0)

Nathanson et al., 2005

 Outcomes of Treatment for MDR TB in the
South African DOTS-Plus Program, 2002-2004

Outcome HIV + HIV –/unknown P value

(N=327) (N=875)
Successful Rx 38.5% 49.3% <0.001
Failed 4.3% 11.4% <0.001
Defaulted 21.4% 22.6% 0.65

Died 35.8% 16.7% <0.001

Farley et al., IUATLD World Conference, 2007

 Important Rules to Remember

• Supervise treatment
• Never add a single drug to a failing regimen
• Treat the patient, but don’t ignore the lab
• Anticipate side effects
• Ask for help – use an expert panel
 Major Points
• There is a wide variety in patterns of resistance
among ‘MDR’ and ‘XDR’ patients
• Treatment decisions often made in absence of full
susceptibility data
• Standardized regimens are not effective for all
patients and may amplify resistance
• ‘Untreatable’ TB is a function of resistance
patterns of the strain and drugs available to treat it
 Selected Research Questions

• How infectious is MDR TB and where is it

transmitted?
• What is the best diagnostic strategy for
detecting MDR TB?
• What treatment regimens are most effective
and safe for treating MDR TB?
• How should contacts of MDR TB patients
be managed?
Thank you