MDR TUBERCULOSIS

- An overview

Dr. Gyanshankar Mishra

MD (Pulmonary Medicine), DNB (Respiratory Diseases)
Assistant Professor ,
Department of Pulmonary Medicine,
GMC Nagpur
 Drug resistance - Types & Definitions
 Epidemiology
 Mechanism & Causes of drug resistance
 Management of MDR TB
 Clinical case illustration
Drug Resistant
TUBERCULOSIS
Types & Definitions
Drug resistance - types

 When drug resistance is demonstrated in a patient who has never

received anti-TB treatment previously, it is termed primary
(Initial) resistance, i.e. TB patient’s initial M.TB population
resistant to drugs

 Secondary (Acquired) resistance is that which occurs as a result

of specific previous treatment, i.e. Drug-resistant M. TB in initial
population, selected by inappropriate drug use (inadequate
treatment or non-adherence)
DRUG RESISTANT –TB (DR-TB)

 Drug resistant TB
 Mono resistance
 Poly resistance
 Multi Drug Resistant TB(MDR- TB)
 Extensive Drug Resistant TB (XDR-TB)
 Total Drug Resistance (TDR – TB)
 DRUG RESISTANT- TB(DR-TB)

 Mono Drug Resistance

 (Resistance to single first line ATT)
 Poly Drug Resistance
 (Resistance to two or more first line ATT except MDR-
TB)
DRUG RESISTANT- TB(DR-TB)

Multi-drug resistant tuberculosis (MDR TB) is defined as resistance

to isoniazid and Rifampicin (a laboratory diagnosis).

Extensively drug resistant TB (XDR-TB) is MDR + resistance to any

fluoroquinolone + resistance to at least one 2nd-line injectable drug
(amikacin, kanamycin, or capreomycin)
MDR TB

 Single Isoniazid or Rifampicin resistance is not MDR – TB.

 MDR TB is a laboratory diagnosis, Not a Clinical assumption.
TDR: Total Drug Resistance

 Resistance to all first-line anti-TB drugs (FLD) and

second-line anti-TB drugs (SLD) that were tested.
2012
Drug Resistant
TUBERCULOSIS
EPIDEMIOLOGY
In our country…
Global Data
India MDR TB Data

 State representative community based drug

resistance surveys estimate the prevalence of
Multidrug resistant TB (MDR-TB) to be ~3%
among new TB cases and 12-17% among
previously-treated TB cases.
 India XDR TB data

 *NDTB center, 18400 isolates, 0.89% of all MDR were XDR

 **Hinduja Hospital, Mumbai, 3204 samples, 32% MDR, 8%

of MDR were XDR

 *** KGMU, Lucknow: Among 68 MDR, 5 (7.4%) were XDR

* Ind J Tub 2008; 55:104

**Sushil Jain et al ATS 2007 meet Abstract 1398
***Mondal R et al. Em. Inf. Dis 2007; 13:9
Drug Resistant
TUBERCULOSIS
MECHANISMS & FACTORS
Mechanisims of Drug Resistance in Tuberculosis
DRUG RESISTANCE : MOLECULAR
BASIS

DRUG RESISTANT ISOLATES SHOW

MUTATION IN GENES
 INH : kat g, inhA

 RIFAMPICIN : rpoB

 STREPTOMYCIN : rpsL

 ETHIONAMIDE : inhA

 FLUOROQUINOLONES : gyrA, gyrB

DNA probes using genetic information have

been devised
 FACTORS RESPONSIBLE FOR
DEVELOPMENT OF DRUG RESISTANCE
 CLINICAL / OPERATIONAL FACTORS

 Unreliable treatment regimen by doctors

 Lesser number of drugs
 Inadequate dosage / duration

 Addition of a single drug in failing regimen

 Easy availability of drugs in private sector

 Poor drug supply

 Poor quality of drugs : poor bioavailability

Remember the correct doses of anti TB Drugs!
Why are correct doses important?

Ref: Mishra G, Mulani J. Tuberculosis Prescription Practices In Private

And Public Sector In India. NJIRM. 2013; 4(2): 71-78.
Why are correct doses important?

Ref: Mishra G, Mulani J. Tuberculosis Prescription Practices In Private

And Public Sector In India. NJIRM. 2013; 4(2): 71-78.
WHAT CAN BE DONE?

 Treatment:
 Daily regime / Once a day dosing/ Dose as per weight/Baseline LFT, KFT
 New TB cases:
 2(EHRZ) + 4(HR)
 Retreatment TB cases:
 2(SHERZ)+1(EHRZ)+5(HRE)
What can be done?..

 Treatment….
 Daily Dose (mg/kg) as per weight (WHO Recommended):
 FACTORS RESPONSIBLE FOR
DEVELOPMENT OF DRUG RESISTANCE

 BIOLOGICAL FACTORS :

 Initial bacillary population

 Local factors in host favourable for multiplication of bacilli

 Presence of drug in insufficient concentration

Why this information?

 Suspect MDR TB if:

 There is extensive tuberculosis at the start of treatment.
 The patient is suffering from immunocompromised state like HIV.
 The patient has received ATT in suboptimal dosing.
 FACTORS RESPONSIBLE FOR
DEVELOPMENTOF DRUG RESISTANCE

 SOCIOLOGICAL FACTORS :

 Irregular intake
 inadequate duration
 Neglect of disease
 Ignorance
What can be done?

Patient counseling at the start

of treatment
Genesis of MDR TB

 Resistance is a man-made amplification of a natural phenomenon. i.e. Selection &

proliferation of pre existing mutants due to man made factors leads to drug resistance.

 Inadequate drug delivery is main cause of secondary drug resistance.

 Secondary drug resistance is the main cause of primary drug resistance due to
transmission of resistant strains.
 MDR due to spontaneous mutations is not possible as the genes encoding resistance
for anti TB are unlinked.
Drug Resistant
TUBERCULOSIS

MANAGEMENT PRINCIPLES
Suspicion, Diagnosis & Treatment
Suspicion of MDR TB

 When should we suspect drug resistant TB?

 A close contact of Drug Resistant TB case.
 Treatment failures.
 All retreatment cases.
 No sputum conversion after initial 2 months of ATT.
 Extensive disease at start of treatment.
 All HIV patients with TB.
 Extrapulmonary TB not responding to standard ATT regime.
In an Ideal setting..

Baseline culture dst

(1 & 2 line ATT)
st nd

for all TB patients

Culture dst of all 1st and 2nd line drugs prior to Treatment of MDR
TB. + Individualised treatment.
= Success rates of 68% …..Lung India. 31(4) Oct-Dec 2014.
Delay of culture dst : Patient’s all culture dst (1st and 2nd line ATT) available 7 years after
initial diagnosis of PTB + Standardised Regime.
Success rate - patient not cured till date…IJME. Vol XI No 1 January-March 2014
Diagnosis – Accredited laboratory
Diagnosis…

 Tests available are:

 Conventional LJ culture DST – Gold standard

 DST- modified proportion method. (4 to 6 weeks for culture & 3 weeks post culture for dst).
 PCR based LPA (line probe assay) – DST result within 72 hours.
 Other methods – (Liquid cultures)BACTEC 460, MGIT 960 (14 days + 9 days for dst) ,
etc.
The Xpert MTB/RIF

 The Xpert MTB/RIF is a cartridge-

based, automated diagnostic test that
can identify Mycobacterium
tuberculosis (MTB)DNA and resistance
to rifampicin (RIF)by nucleic acid
amplification technique(NAAT )

 Result within 2 hours.

Treatment – why important?
Treatment…

 “Recently, a letter to Clinical Infectious Disease Journal in

December 2011 described 4 patients from Mumbai, India with
“totally drug resistant” tuberculosis (coined “TDR-TB” from earlier
reports) i.e. resistant to all first line and second-line drugs tested.”
 “A careful audit of their prescriptions revealed that these 3 patients
had received erratic, unsupervised second line drugs, added
individually and often in incorrect doses, from multiple private
practitioners (on average from 4 physicians during a 18-month
period) in an attempt to cure their multi-drug resistant (MDR)
tuberculosis.”
Most efficacious and best
tolerated

Drugs in MDR TB
Management

Less efficacious and

poorly tolerated
 Important principles of
MDR-TB regimen design

1. Use at least 4 reliable drugs .

2. Do not use drugs with cross resistance .
3. Eliminate drugs that are not safe for the patient.
4. Include drugs from Groups 1-5 in a hierarchical order.
5. Monitor and manage adverse effects of drugs.
6. Never add a single drug to failing regime.
General Treatment Principles
 Provide 18-24 months’ treatment, always with intensive phase of
at least 6 months ( current WHO guidelines -8 months).
 Provide DOT therapy.
 Warn patients about possible side-effects.
 Manage side-effects appropriately.
 Perform cultures monthly.
 Regimen under DOTS Plus
Programme in India (PMDT)
INITIAL INTENSIVE PHASE : 6- 9 months
 Inj. Kanamycin
 Tab Ethionamide
 Tab Ofloxacin
 Tab. Pyrazinamide
 Tab. Ethambutol
 Cap Cycloserine

CONTINUATION PHASE : 18 months

 Tab Ethionamide
 Tab Ofloxacin
 Tab Ethambutol
 Cap Cycloserine
DOTS PLUS DAILY REGIME
Be aware of the possible culprits in case of
ADR
 Nausea and vomiting - Eto, PAS, Z, E
 Giddiness - Aminoglycosides, Eto, Fq and/or Z
 Ocular toxicity - E
 Renal toxicity - Aminoglycosides
 Arthralgia - Z and/or Fq
 Cutaneous reactions - pruritis or rash- any of the drugs used.
 Hepatitis - Z & Eto
Be aware of the possible culprits in case of
ADR..
 Peripheral neuropathy - Cs, Eto
 Seizures - Fq and/or Cs
 Psychiatric disturbances – Cs, Fq and/or Eto
 Vestibulo-auditory disturbances - Aminoglycosides
 Hypothyroidism - PAS and/or Eto
Pre treatment evaluation for MDR TB
PMDT (Dots Plus)
CAT V- XDR TB
The Intensive Phase (6-12 months) will
consist of 7 drugs Capreomycin (Cm),
PAS, Moxifloxacin (Mfx), High dose-
INH, Clofazimine, Linezolid, and
Amoxyclav
The Continuation Phase (18 months)
will consist of 6 drugs –
PAS, Moxifloxacin (Mfx), High dose-
INH, Clofazimine, Linezolid, and
Amoxyclav
NEW DRUGS FOR MDR-TB

 Bedaquiline (diarylquinolone)and delamanid (oxazole) are

two new drugs for use in the treatment of MDR-TBand
WHO has developed interim guidance on their use.
 No four 2nd line drugs in MDR + FQ resistance.
 bedaquiline be used for a maximum duration of 6 months and at
suggested dosing (400 mg daily for the first 2 weeks, followed by
200 mg three times per week for the remaining 22 weeks
 Novel drug regimens for shortened treatment of drug-
resistant TB, including new or re-purposed drugs, are under
investigation.
Drug Resistant
TUBERCULOSIS
CASE ILLUSTRATION
Exercise
 Clinical Case

 50 years old, 62 Kg patient

 H/o Irregular ATT treatment for 6-7 months
 Now sputum AFB smear Positive
 Put on 4 drug ATT (H 300mg, R 450 mg, E 800 mg and Z 1500 mg).
 Clinical Case Contd...

 Sputum continues to be positive after 5 months of treatment

 Sputum sent for AFB culture/sensitivity and inj. kanamycin
added.
 Sputum continues to be positive after 3 months
 Clinical Case Contd...

 DST: MDR (resistance to H+R)

 INH and RIF stopped and ethionamide & ofloxacin added
 After 4 months sputum is still positive
 DST: resistance to H, R, Kana, Oflox (XDR-TB)
 Clinical Case Contd...

Lesson learnt from case

 Inadequate dosages.
 Wrong regime at the start .
 Lack of initial suspicion of MDR suspect and hence delay in sending
culture dst / and initiating correct regime.
 Adding only single drug to a failing regimen
 Improper regime of MDR TB: Regime did not include 4 reliable core
drugs after diagnosis of MDR TB.

Can lead to MDR / XDR -TB

Carry Home Message

Better to Prevent MDR-TB

Regular Drugs
Health Education
Appropriate Dosages Direct Supervision
Full Duration
Some useful resources on MDR TB