Mdr tuberculosis

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

TUBERCULOSISTypes & 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

TUBERCULOSISEPIDEMIOLOGY

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

TUBERCULOSISMECHANISMS & 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):


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.


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 PRINCIPLESSuspicion, 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..

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.”

Drugs in MDR TB

Management

Most efficacious and best

tolerated

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 TBThe 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

TUBERCULOSISCASE 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


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)


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

Better to Prevent MDR-TB

Regular Drugs

Appropriate Dosages

Full Duration

Health Education

Direct Supervision

Carry Home Message

Some useful resources on MDR TB

Mdr tuberculosis

Health & Medicine