DRUG RESISTANT

TUBERCULOSIS

MDR-TB

XDR-TB

TDR-TB
Dr. Lalit Kumar
MBBS,MD,DTCD
 Multidrug-resistant TB (MDR-TB) :is a form
of TB caused by organisms that are resistant
to at least the two most effective anti-TB
drugs, isoniazid & rifampicin.
 Extensively drug-resistant TB (XDR-TB)
is a form of TB caused by organisms that are
resistant to isoniazid and rifampicin (i.e.
MDR-TB) as well as any fluoroquinolone and
any of the secondline anti-TB injectable
drugs (amikacin, kanamycin or capreomycin).
 These forms of TB do not respond to the
standard six month treatment with first-line
anti-TB drugs and can take two years or
more to treat with drugs that are less effective,
more toxic and more expensive.
 EPIDEMIOLOGY
ABOUT 3.6% OF NEW TUBERCULOSIS (TB) PATIENTS IN THE WORLD HAVE
MULTI-DRUG RESISTANT STRAINS (MDR-TB)

ABOUT 20% OF PREVIOUSLY TREATED PATIENTS OF TB HAVE MDR-TB

ABOUT 10% OF MDR-TB CASES ARE RESISTANT TO THE TWO MOST

IMPORTANT 2nd LINE DRUG CLASSES,OR EXTENSIVELY DRUG-RESISTANT
TB(XDR-TB)
 EPIDEMIOLOGY
WHO ESTIMATES THAT THERE WERE ABOUT 4,50,000 NEW(INCIDENT) MDR-TB CASES IN
THE WORLD IN 2012.

MORE THEN ONE HALF OF THESE CASES OCCURRED IN CHINA,INDIA & THE RUSSIAN
FEDERATION.

ONLY ABOUT 9% OF RETREATMENT TB CASES HAD DRUG SENSITIVITY TEST(DST)

RESULTS REPORTED WORLDWIDE!!

ENROLMENTS ON MDR-TB TREATMENT IN 2012: WERE EQUIVALENT TO ONE IN

FOUR OF THE MDR-TB CASES ESTIMATED TO OCCUR AMONG PULMONARY TB
PATIENTS NOTIFIED IN THE WORLD.

Treatment success: 48% of patients with MDR-TB enrolled on treatment in

2010 were reported to have been successfully treated

WHO estimates that there are about 650,000 MDR-TB cases in the world at any
one time. Only a small proportion of these cases are detected and treated
appropriately given that many low and lower middle-income countries still lack
sufficient diagnostic capacity to detect MDR/XDR-TB.
 INDIAN SCENARIO

India : Tuberculosis profile

High TB burden
High HIV burden
High MDR-TB burden
 MDR-TB(INDIA)
2.2% OF NEWLY DIAGNOSED TB CASES ARE MDR-TB
CASES
15 % OF PREVIOUSLY TREATED TB CASES ARE MDR-
TB CASES.
( Reported cases of MDR-TB 2012)
Total Cases tested for MDR-TB 55 611
Laboratory-confirmed MDR-TB cases 16 588
Patients started on MDR-TB treatment 14 143
GROSS NEGLIGENCE OF HIV+TB CASES IN INDIA

Tuberculosis is one of the earliest opportunistic diseases

to develop amongst persons infected with HIV. HIV
infection is the most powerful risk factor for the
progression of TB infection to TB disease. An HIV
positive person has many times higher risk of developing
TB disease in those infected with TB bacilli, as compared
to an HIV negative person.

TB PATIENTS WITH KNOWN HIV STATUS- 56%.....REST 44%...DONT

KNOW??

HIV POSITIVE TB PATIENTS ON ANTI RETROVIRAL THERAPY(ART)

59%!!.....61% OF HIV+VE TB PATIENTS ARE NOT ON ART!!
 WHY THIS EMERGENCE:CAUSES
MULTIPLE INEFFECTIVE TB REGIMENS
DELAYED DIAGNOSIS
WRONG DOSE
NON COMPLIANCE
WRONG DURATION OF TREATMENT
POOR QUALITY OF DRUGS
CONTACT WITH A DRUG RESISTANT TB PATIENT
CO-MORBIDITIES HIV POSITIVE
MDR-TB is a man-made phenomenon poor
treatment, poor drugs and poor adherence
lead to the development of MDR-TB.
 RISK FACTOR

THE MOST IMPORTANT RISK FACTOR

FOR THE DEVELOPMENT OF DR-TB IS
PREVIOUS TREATMENT
 MECHANISM OF DRUG RESISTANCE
In m. Tuberculosis, acquired drug resistance is caused mainly by spontaneous
mutations in chromosomal genes, producing the selection of resistant strains
during sub-optimal drug therapy.

The rate of mutation depends on the nature of the drug selection, but for
most of the main anti-tb drugs, this occurs at a rate of 109 mutations per cell
division. This is the main reason why anti-tb drugs are given as a combination,
as the risk of a mutant containing two resistance mutations is <1018
Drugs and associated mutations
DRUG ASSOCIATED GENE MUTATION

ISONIAZID (H) katG, inh A

RIFAMPICIN (R) rpoB

PYRAZINAMIDE (Z) pncA

STREPTOMYCIN (S) rrs,rpsl

ETHAMBUTOL (E) embB

DIAGNOSIS

INCLUSION
CRITERIA

PREVIOUSLY
TREATEDe.g A
PATIENT ON DOTS CAT
2(T/T
FAILURE,RELAPSED,DE
FAULTER)

A CLOSE CONTACT

PATIENT WITH A
IMPROPER
HISTORY OF ATT

ALL SPUTUM SMEAR +VE AT

THE END OF 4th MONTH OF
DOTS REGIMEN
 MDR TB SUSPECT CRITERIA

MDR Suspect Criteria

Criteria A

All failures of new TB cases

Smear +ve previously treated cases who remain smear +ve at 4th month onwards

All pulmonary TB cases who are contacts of known MDR TB case

Criteria B in addition to Criteria A:

All smear +ve previously treated pulmonary TB cases at diagnosis

Any smear +ve follow up result in new or previously treated cases

Criteria C in addition to Criteria B

All smear -ve previously treated pulmonary TB cases at diagnosis,

HIV TB co-infected cases at diagnosis

 DIAGNOSTICS

Currently 3 technologies are available for diagnosis

of MDR TB viz.
The conventional solid egg-based lowenstein-
jensen (LJ) media
The liquid culture (MGIT),
The rapid molecular assays such as line probe assay
(LPA) and similar nucleic acid Amplification Tests
like Xpert MTB/Rif.
 PHENOTYPIC DST : CONVENTIONAL DST(C-DST)
MOLECULAR DST : LPA,NAAT
C-DST MOLECULAR/GENOTYPIC DST

SENSITIVITY TEST FOR MANY 1ST LINE SENSITIVITY TESTS FOR RIFAMPICIN
ATT CAN BE DONE ARE RELIABLE

VERY SLOW RESULTS FAST RESULTS

MEDIA TURNAROUND TIME

C-DST(SOLID LJ MEDIA) 84 DAYS

C-DST(LIQUID MEDIA MGIT) 42 DAYS

MOL/GENO DST LPA-72 HOURS

CBNAAT-2 HOURS
MDR Diagnostic Technology Choice

Molecular DST (e.g. LPA DST) First

Liquid culture isolation and LPA DST Second

Solid culture isolation and LPA DST Third

Liquid culture isolation and Liquid DST Fourth

Solid culture isolation and DST Fifth

A NEWER CHEAP AND EFFECTIVE APPROACH IN TB
DIAGNOSTICS IS THE MODS(microscopic observation drug
sensitivity assay)

ADVANTAGE---
CHEAPER,
REQUIRES MINIMAL STAFF TRAINING
CONSIDERABLY FASTER COMPARED TO
CONVENTIONAL LIQUID CULTURE BASED TESTS,
CAN BE IMPLEMENTED ON A LARGER SCALE VERY
RAPIDLY AS COMPARED TO THE VERY VERY COSTLY
EQUIPMENTS USED FOR LPA OR NAAT
TREATMENT

DOTS PLUS(CAT
4) REGIMEN
FOR MDR TB

DOTS CAT 5
REGIMEN FOR
XDR TB
 PRE-TREATMENT EVALUATION
The pre-treatment evaluation will include the following:

1. Detailed history (including screening for mental illness, drug/alcohol abuse etc.)

2. Weight

3. Height

4. Complete Blood Count with platelets count

5. Blood sugar to screen for Diabetes Mellitus

6. Liver Function Tests

7. Blood Urea and S. Creatinine to assess the Kidney function

8. TSH levels to assess the thyroid function

9. Urine examination Routine and Microscopic

10. Pregnancy test (for all women in the child bearing age group)

11. Chest X Ray

 GROUPING OF ANTI-TB DRUGS

Group 1: First-line oral anti-TB agents

Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z)

Group 2: Injectable anti-TB agents

Streptomycin (S); Kanamycin (Km); Amikacin (Am);Capreomycin (Cm); Viomycin (Vm).

Group 3: Fluoroquinolones

Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lvx);Moxifloxacin (Mfx); Gatifloxacin (Gfx)

Group 4: Oral second-line anti-TB agents

Ethionamide (Eto); Prothionamide (Pto); Cycloserine (Cs); Terizadone (Trd); para-aminosalicylic acid (PAS)

Group 5: Agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients)

Clofazimine (Cfz); Linezolid (Lzd); Amoxicillin/Clavulanate(Amx/Clv); thioacetazone (Thz); imipenem/cilastatin

(Ipm/Cln) ,high-dose isoniazid (high-dose H); Clarithromycin (Clr)
DOTS PLUS REGIMEN FOR MDR-TB

[6(9) KM LFX ETO CS Z E / 18 LFX ETO CS E]

 FOLLOW UP SMEAR AND CULTURE EXAMINATION DURING TREATMENT

The most important objective evidence of response to M/XDR treatment

is the conversion of sputum culture to negative. Smear conversion is less
reliable than culture conversion, which reflects viability of tubercle bacilli
and is a more accurate reflection of response to treatment.
Good quality sputum is essential to get proper results.
Patients will be considered culture converted after having two
consecutive negative cultures taken at least one month apart.
Time to culture conversion is calculated as the interval between the date
of MDR-TB treatment initiation and the date of the first of these two
negative consecutive cultures (the date that the sputum specimens are
collected for culture should be used).
Patients will be considered smear converted after having two consecutive
negative smears taken at least one month apart.
For follow up examination the required number of
sputum specimens will be collected and
examined by smear and culture at least 30 days
apart from the 3rd to 7th month of treatment
(i.e. at the end of the months 3, 4, 5, 6 and 7) and at
3-monthly intervals from the 9th month
onwards till the completion of treatment (i.e. at the
end of the months 9, 12, 15, 18, 21 and
24).
 RNTCP REGIMEN FOR XDR-TB

Intensive phase (6-12 months) consist of 7

drugs
capreomycin (cm), PAS,moxifloxacin (mfx),
high dose-inh, clofazimine, linezolid, and
amoxyclav
Continuation phase (18 months) consist of 6
drugs
PAS, moxifloxacin (mfx),high dose-inh,
clofazimine, linezolid, and amoxyclav
 TREATMENT ALGORITHM OF DRUG RESISTANT TB

STARTRNTCP
START RNTCP MDR
MDR TB TB AT THE END OF IP THE RESULT OF MOST
MDR TB
MDR TB REGIMENREGIMEN RECENT CULTURE

POSITIVE NEGATIVE

EXTEND IP FOR 1 MONTH AT A TIME, FOR UP TO 3 MONTHS MAX, START CP

TILL AT LEAST A SUBSEQUENT NEGATIVE FOLLOW-UP CULTURE RESULT
IS OBTAINED.

CULTURE POSITIVE EVEN AFTER 9 MONTHS OR

CULTURE RE-VERSION
CONTINUE
MDR TB
IF OFX & KM REGIMEN
SECOND LINE DST SENSITIVE

START REGIMEN
IF OFX &/or
KM RESISTANT FOR XDR TB
 M/XDR TB TREATMENT OUTCOME DEFINITIONS

Cure: A patient who has completed treatment and has been consistently culture negative
(with at least 5 consecutive negative results in the last 12 to 15 months). If one follow-up
positive culture is reported during the last three quarters, patient will still be considered
cured provided this positive culture is followed by at least 3 consecutive negative
cultures, taken at least 30 days apart, provided that there is clinical evidence of
improvement.

Treatment completed: A patient who has completed treatment according to guidelines

but does not meet the definition for cure or treatment failure due to lack of
bacteriological results.

Treatment failure: Treatment will be considered to have failed if two or more of the five
cultures recorded in the final 12-15 months are positive, or if any of the final three
cultures are positive

Treatment default: A patient whose treatment was interrupted for two or more
consecutive months for any reasons.
 MDR-TB IN SPECIAL SITUATIONS
PREGNANCY
All women of childbearing age who are receiving MDR-TB
therapy should be advised to use birth control measures
because of the potential risk to both mother and foetus

CONSENT FOR
MTP? YES

NO

<12 WEEKS >12 WEEK

GESTATION GESTATION

Km & ETO ARE REPLACED ONLY Km IS REPLACED

WITH PAS WITH PAS

REPLACE PAS WITH Km AFTER DELIVERY

 HIV POSITIVE AND MDR TB

THE CLINICAL PRESENTATION IS PROPORTIONELY

MORE EXTRAPULMONARY MAKING DIAGNOSIS OF
TB MORE DIFFICULT .

ART SHOULD BE STARTED AS SOON AS POSSIBLE

IRRESPECTIVE OF THE CD4 COUNTS

ART TO BE STARTED WITHIN 8 WEEKS OF START OF

ATT

CO-TRIMOXAZOLE PROPHYLAXIS

PREDNISONE THERAPY IF IRIS OCCURS .

 RENAL IMPAIRMENT

Drugs, which might require dose or interval

adjustment in presence of mild to moderate
renal impairment,are: ethambutol,
quinolones, cycloserine and pas IN addition to
aminoglycosides
Blood and serum creatinine every month for
the first 3 months and then every 3 months
 Liver impairement
In the RNTCP Regimen for MDR TB,
Pyrazinamide, PAS and Ethionamide are
potentially hepatotoxic drugs.
The further management should be on the
same guidelines as in non- MDR-TB patients
Pyrazinamide should be avoided in such
patients.
 Seizure disorder
Among second line drugs, Cycloserine, Ethionamide
and fluoroquinolones have been associated with
seizures, and hence should be used carefully amongst
MDR-TB patients with history of seizures
Pyridoxine should be given with Cycloserine to prevent
seizures
Cycloserine should however be avoided in patients
with active seizure disorders that are not well
controlled with medication.
when seizures present for the first time during anti-TB
therapy, they are likely to be the result of an adverse
effect of one of the anti-TB drugs.
 psychosis
Fluoroquinolones ,cycloserine and Ethionomide
have been associated with psychosis.
Cycloserine may cause severe psychosis and
depression leading to suicidal tendencies.
If patient on Cycloserine therapy develops
psychosis, anti-psychotic treatment should be
started and Cycloserine therapy should be
temporarily suspended.
Pyridoxine prophylaxis may minimize risk of
neurologic and psychiatric adverse reactions.
 Extra pulmonary mdr tb
Treatment regimen and schedule for EP MDR
TB cases will remain the same as for
pulmonary MDR TB.
 Contacts of mdr tb
If the contact is found to be suffering from
pulmonary TB disease irrespective of the Smear
results, he/she will be identified as an MDR-TB
suspect
The patient will be initiated on Regimen for new
or previously treated case based on their history
of previous anti-TB treatment. Simultaneously
two sputum samples will be transported for
culture and DST to a RNTCP-certified C&DST
laboratory.
 FOR REGIMEN OF MDR TB

s.no drugs 16-25 Kg 26-45 Kg 46-70 Kg >70kg

1 Kanamycin(500&1G) 500 mg 500mg 750mg 1000mg
(IP)
2 Levofloxacin (250 & 250mg 750mg 1000mg 1000mg
500mg) (IP/CP)
3 Ethionamide 375mg 500mg 750mg 1000mg
(250mg) (IP/CP)
4 Ethambutol (200 & 400mg 800mg 1200mg 1600mg
800mg) (IP/CP
5 Pyrazinamide (500 & 500mg 1250mg 1500mg 2000mg
750mg) (IP)
6 Cycloserine (250mg) 250mg 500mg 750mg 1000mg
(IP/CP)
7 PAS (80% 5mg 10mg 12mg 12mg
Bioavailability)
8 Pyridoxine (100mg) 50mg 100mg 100mg 100mg
(IP/CP)
 DRUGS USED FOR XDR-TB

Dosage/day
DRUGS <= 45kgs >= 45kgs
Inj. Capreomycin(cm) 750mg 1g
PAS 10gm 12gm
Moxifloxacin (Mfx) 400mg 400mg
High dose INH (High 600mg 900mg
dose-H)
Clofazimine (Cfz) 200mg 200mg
Linezolid (Lzd) 600mg 600mg
Amoxyclav(Amx/Clv) 875/125mg bd 875/125 mg bd
Pyridoxine 100mg 100mg
 ROLE OF SURGERY

When unilateral resectable disease is present, surgery should be considered

for the following cases:

Absence of clinical or bacteriological response to chemotherapy

despite six to nine months of treatment with effective anti-
tuberculosis drugs;
High risk of failure or relapse due to high degree of resistance or
extensive parenchymal involvement;
Morbid complications of parenchymal disease e.g. haemoptysis,
bronchiectasis, bronchopleural fistula, or empyema;
Recurrence of positive culture status during course of treatment;
and
Relapse after completion of anti-tuberculosis treatment.
If surgical option is under consideration at least six to nine
months of chemotherapy is recommended prior to surgery.
 TOTALLY DRUG-RESISTANT TUBERCULOSIS/super extensively dr tb

Tdr-tb is the term used for tb strains that showed in vitro resistance to
all first and Second line drugs tested.

Even changing the treatment to reserve drugs namely co amoxiclav and

Clarithromycin showed little or no improvement in one study

Center for disease control and prevention termed the disease untreatable

In addition to mutation in the tdr strains,many morphological changes have

been found like budding or branching forms of MTB,MTB with thicker walls etc.