Principles of Management of

Multi Drug Resistant (MDR) TB

Advanced Clinical Care

MDRTB and HIV Management Workshop
Dr Rochelle Adams
ACC Program Manager
 Definitions
Type of TB Definition Treatment
Drug Sensitive MTB sensitive to standard TB RHZE
drugs
INH Mono- Resistance to INH only RHZE
resistant
RR TB MTB Resistant to Rifampicin +/ - R H Z E (treat
resistance to other TB medicines as MDRTB)

MDR-TB MTB Resistant to Rifampicin & RHZE

INH, with/without resistance to Quinolone
other first line anti-TB drugs Injectable, other
Core drugs
XDR TB MTB Resistant to Rifampicin, Individualised
Extensive INH, the Quinolones AND at least regimen
Drug Resistant one 2nd line Injectable drugs
Pre-XDR TB MTB Resistant to Rifampicin, Individualised
INH, the Quinolones OR at least regimen
one 2nd line Injectable drug
1. Current Standard MDR-TB treatment is

1. Kanamycin, Moxifloxacin, Ethionamide

Terizidone, Pyrazinamide,
2. Capreomycin, Moxifloxacin, Ethionamide
Terizidone, Pyrazinamide
3. Streptomycin, Moxifloxacin, Ethionamide
Terizidone, Pyrazinamide,
 Levofloxacin
GROUP A Moxifloxacin
Fluoroquinolones Gatifloxacin
Amikacin
GROUP B Capreomycin
Second-line injectable agents Kanamycin
(Streptomycin)
Ethionamide / Prothionamide
GROUP C Cycloserine / Terizidone
Other Core Second-line Linezolid
Clofazimine
Agents
Pyrazinamide
GROUP D D1 Ethambutol
Add-on agents High-dose isoniazid
Bedaquiline
(not core MDR-TB regimen components) D2 Delamanid
p-aminosalicylic acid
Imipenem-Cilastatin
D3 Meropenem; Amoxicillin-
Clavulanate; (Thioacetazone)
Principles of Current Long MDR-TB
regimen
• Use a minimum of 5 effective drugs
• Use 4 core drugs
• 1 Fluoroquinolone (Group A)
• 1 Injectable agent (Group B)
• 2 from group C (Other core 2nd line agents:
(Ethionamide/Terizidone/Linezolid/ Clofazamine)
• Use PZA from Group D1
• Use Injectable agents for a minimum of 6 months (ideally 4 months
after culture conversion)
• Don’t rely on drugs the patient has had before or to which resistance
is suspected
• Never add a single drug to a failing regimen
Current Standard MDR treatment
• Intensive phase (KMETZI)
 Kanamycin / Amikacin (minimum 6 months)
 Moxifloxacin
 Ethionamide
 Terizidone
 PZA
 May add INH if no katG mutation
• Continuation Phase (min 18 months)
• Moxifloxacin / Ethionamide / Terizidone /
PZA (+/- INH)
Bangladesh regimen
 9/12 regimen in low burden MDR/HIV countries
has shown to be successful
• Treatment success > 80%
• Implemented in some African countries
• Is being implemented in the STREAM study in
South Africa
• Not much data in HIV positive patients (Swaziland)
• Outcomes in 2017
 Differences essentially
• Duration of Rx 9 /12 vs 18/12
• Use of Clofazimine and EMB against Terizidone
• Higher dose Quinolones
 May impact on option of BDQ based regimen
Choosing the treatment regimen for RR-/MDR-TB
• Confirmed resistance or suspected ineffectiveness to a medicine in the
shorter MDR-TB regimen (except INH resistance)?
• Exposure to >1 second-line medicines in the shorter MDR-TB regimen
for >1 month?
• Intolerance to >1 medicines in the shorter MDR-TB regimen or risk of
toxicity (e.g. drug-drug interactions)?
• Pregnancy?
• Extrapulmonary disease?
• At least one medicine in the shorter MDR-TB regimen not available?

FAILING REGIMEN, DRUG

NO INTOLERANCE, RETURN YES
AFTER INTERRUPTION >2
Shorter MDR- MONTHS, EMERGENCE OF Longer
TB regimen ANY EXCLUSION CRITERION MDR-TB regimens
 MDRTB New Short Regimen
Category Phase 9 month Regimen
Children < 8 Intensive Phase Kanamycin, Levofloxacin
years Ethionamide, PZA,
Clofazamine; (hd) INH, Ethambutol
(4-6 months)

Continuation Phase Levofloxacin, PZA

Clofazamine, Ethambutol
(5 months)

Adults and Intensive Phase Kanamycin, Moxifloxacin

children > 8 Ethionamide, PZA,
years Clofazamine; INH, Ethambutol
(4-6 months)
Continuation Phase Moxifloxacin, PZA
Clofazamine, Ethambutol
(5 months)
 MDRTB New Long Regimens
Category Phase Old Regimen New Regimen
Adults and Intensive Kanamycin; Kanamycin,
children > 8 Phase Moxifloxacin Moxifloxacin
years Ethionamide; Ethionamide,
PZA PZA,
Terizidone Clofazamine;
(min 6 months ; 4 (hd) INH,
months post culture Ethambutol
conversion) (6-8 months)
Continuatio Moxifloxacin Moxifloxacin
n Phase PZA PZA
Ethionamide Clofazamine
Terizidone Ethambutol
(18 months) (12-14 months)
 Conditions for use of short MDR-TB regimen (2)
• Standardized regimen; limited modifications are possible
• 4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E / 5 Mfx-Cfz-Z-E

• Careful selection of patients by testing for resistance to

fluoroquinolones and second-line injectable drugs or
evaluation of previous history and drug resistant surveillance
data; not recommended in case of 2nd line drug resistance,
extrapulmonary disease and pregnancy
• Effective patient support to enable full adherence to
treatment
• Monitoring for effectiveness, relapse, and harms (active TB
drug safety monitoring and management (aDSM)) applies
• Recommendation applies to adults, children, PLHIV
Recommendation on longer MDR-TB regimen (2)
Group D2
- If the minimum number of five Bedaquiline,
effective TB medicines cannot be delamanid
composed as given above:
- an agent from Group D2 and
Group D3
- other agents from Group D3
P-aminosalicylic
may be added to bring the total
to five acid,
Imipenem–
- the regimen may be further
Cilastatin,
strengthened with high-dose
isoniazid and/or ethambutol Meropenem,
Amoxicillin–
Clavulanate,
(Thioacetazone)
2. In a patient with an inhA mutation what
MDRTB regimen would be used?

1. Kanamycin, Moxifloxacin, Ethionamide; High

dose INH, Terizidone, Pyrazinamide
2. Kanamycin, Moxifloxacin, Clofazamine;
High dose INH; Terizidone, Pyrazinamide
3. Kanamycin, Moxifloxacin, High dose INH;PAS
Terizidone, Pyrazinamide
3. Nephrotoxicity is a common side
effect with which drug below

1. Moxifloxacin
2. Kanamycin
3. Ciprofloxacin
4. Erythromycin
 Common Side Effects
Side Effect Drugs Monitoring
Nephrotoxicity Kanamycin Baseline U+E, Pregnancy Test +
Amikacin dipstix
Capreomycin Monitor U+E at least monthly

Ototoxicity Kanamycin Baseline Audiometry

Amikacin Monitor Audiometry at least
Capreomycin monthly
Check U+ E if hearing loss occurs

Hypo: K+, Ca, Capreomycin Baseline Calcium; Magnesium and

Mg, PO4 Phosphate
Monitor CMP at least monthly
Hepatitis Rif , INH, PZA, Baseline LFT
Moxifloxacin Monitor LFT at least monthly
Hypothyroidism Ethionamide, Baseline Thyroid Function Test
GIT ( Nausea + PAS Monitor TFT within the 1st 3 months
Vomiting) and then at 6 months then 6
monthly
 Common Side Effects
Side Effect Drugs
Peripheral Neuropathy Terizidone, INH, Linezolid
Psychosis Terizidone, INH
CNS- Depression, Seizures Terizidone
Arthralgia Fluoroquinolones, PZA
(↑ Uric acid)
Prolonged QTC interval Fluoroquinolones,
Bedaquiline, Clofazamine
Bone Marrow Suppression Linezolid
and Optic Neuritis
Skin discolouration Clofazamine
Regarding Monitoring after baseline
which is correct?
1. Do CXR at month 3 then 6 monthly or
when clinically indicated
2. Do CXR at month 6,12,24 or when
clinically indicated
3. Do CXR 3 monthly or when clinically
indicated
4. Do CXR 2 monthly or when clinically
indicated
Smear and culture after baseline is
done

1. Monthly
2. Monthly till culture conversion then every
2 months
3. Every 2 months
4. Every 3 months
 MDRTB and HIV Co-infection (1)
• 60-70% HIV Co-infection with MDRTB
• Outcomes improved with combined ART therapy
• Start ART within 8 weeks after MDRTB
treatment depending on CD4
• AZT + 3TC + EFV- recommended during
injectable phase1
• ABC + 3TC + EFV in renal impairment without
chronic HepB2

1- Management of Drug Resistant TB (2013)

2- National Consolidated Guidelines for PMTCT and the
management of HIV in children, adolescents and adults (2015)
 Shared Side Effects of ART and MDRTB
Drugs
Side Effect ART DRTB Drug
Nausea AZT, Protease Ethionamide, PZA,
Inhibitors Capreomycin, PAS
Hepatitis NVP, EFV, Protease INH, PZA,
Inhibitors (NRTI’s can Fluoroquinolones
cause steatohepatitis)
Renal Impairment TDF Kanamycin, Amikacin,
Streptomycin,
Capreomycin
Neuropsychiatric EFV Terizidone, Cycloserine,
Problems INH, Quinolones
Peripheral D4T,ddI INH, Terizidone,
Neuropathy Cycloserine, Linezolid
Rash NVP, EFV, ABC, RAL INH,PZA, Quinolones;
Streptomycin
 MDRTB and ART Failure
First Line ART Failure
Viral Load > 1000
• Adherence interventions
• Viral Load after 2 months
• Hep B, Hb & Lipids
• If repeat VL > 1000
• Change to AZT +
3TC + Aluvia if Hb
>8
• Discuss patients with
chronic Hepatitis B
Second Line ART Failure
Viral Load > 1000
• Adherence interventions
• Viral Load after 6 months
• If repeat VL > 1000
• Refer for
Genotype- NHLS
Virology Helpline
• New regimen
based on third line
committee
 Acknowledgments
• DRTB Guidelines
• National Consolidated ART Guidelines
• Dr Iqbal Master and Sunitha Chotoo
• Caprisa
 Dr Padayatchi
 Narissa Naidu
This training was supported by the Grant or Cooperative Agreement
Number U2G GH001142, funded by the Centers for Disease Control
and Prevention. Its contents are solely the responsibility of the
presenters and do not necessarily represent the official views of the
U.S. Centers for Disease Control and Prevention or the U.S.
Department of Health and Human Services