Second doses of drug resistance

1. MANAGEMENT OF
DRUG-RESISTANT
TUBERCULOSIS
Dr. Irfan Ahmad Khan
JR-2

2. INTRODUCTION
 DR-TB is a disease caused by M. tuberculosis strains resistant to one
or more anti-TB drugs.
 Mono-resistant: Resistance to a single drug
 Poly-resistant: Resistance to more than one drug, but not the
combination of isoniazid and rifampicin
 Multi-drug-resistant tuberculosis (MDR-TB) is defined as
resistance to rifampicin and isoniazid, with or without resistance
to other first-line anti-TB drugs.
 Extensively drug-resistant tuberculosis (XDR-TB) is defined as
resistance to rifampicin, isoniazid, any fluoroquinolone and
resistance to one or more of the following injectable anti-TB
drugs: kanamycin, amikacin and capreomycin.

3.  Classified according to the history of previous TB treatment:
• Resistance in new patients (previously called ‘primary
resistance’) is resistance in the cultures from patients with no
history of previous TB treatment or patients who have
received TB treatment for less than one month previously.
• Resistance in previously treated patients (previously called
‘acquired resistance’) refers to resistance in cultures from
patients with one or more previous TB treatment episodes, of
more than one month each.

4.  MDR-TB develops in otherwise treatable TB when:
 Patients do not receive effective therapy.
 Poor adherence
 ADRs due to drugs
 Drug supplies may run out or become scarce
 XDR-TB arises after the mismanagement of individuals with
multidrug-resistant TB (MDR-TB).

5. EPIDEMIOLOGY
 > 450,000 TB cases identified every year and causing 150,000
deaths/year
 Globally, 3.7% (2.1–5.2%) of new cases and 20% (13–26%) of
previously treated cases are estimated to have MDR-TB.
 In India, 1-3% of new cases and 12% of previously treated cases are
estimated to have MDR-TB.
 The average proportion of MDR-TB cases with XDR-TB is 9.0%
(6.7–11.2%).
 Transmitted from persons with active, pulmonary tuberculosis caused
by a drug-resistant strain if they are alive and coughing.

6. MECHANISMS OF DRUG RESISTANCE
1) Cell wall: The cell wall of M. tuberculosis consists of complex
lipids, and it acts as a permeability barrier from drugs.
2) Drug modifying & inactivating enzymes: The enzymes
usually phosphorylate, acetylate, or adenylate the drug
compounds.
3) Drug efflux systems
4) Mutations: Spontaneous mutations in the M. tuberculosis
genome can give rise to proteins that make the bacterium drug
resistant, depending on the drug action.

7. Drugs Mutations
Isoniazid (INH/H) •Mutation or deletion of katG gene (MC).
•Mutation in kasA gene.
Rifampicin (R) •Mutation at codon 526 & 531 site of rpoB gene.
•Mutation in DNA repair genes mut & ogt also reported.
Pyrazinamide (Z) Point mutation in pncA gene (encodes Pyrazinamidase )
Ethambutol (E) •Mainly by mutation in codon 306 of embB gene.(arabinosyl
transferase)
•katG 315 mutation – Co-occurance of Ethambutol &
Isoniazide resistance.
Streptomycin (S) •Mutation in rpsL gene (code for 16S mRNA) & rrs gene
(code for S12 ribosomal protein)
•Mutation in GidB gene (rRNA methyltransferase for 16S
rRNA)
PAS Mutation in thymidylate synthase gene(thyA gene)
Ethionamide (Etm) •Mutation in etaR gene (transcriptional repressor gene)
•Mutation in inhA gene (co-resistance with INH)

8. CLINICAL FEATURES
 Cough (usually productive and maybe bloody)
 Low-grade fever
 Sweating
 Chills at night
 Fatigue
 Malaise
 Anorexia
 Weight loss
 Dull, aching chest pain or tightness

9. DIAGNOSIS
 History
 Physical examination
 Radiology
 Sputum microscopy
 Culture and drug susceptibility testing
Line Probe Assay (LPA)
 Cartridge-Based Nucleic Acid Amplification Testing (CB-NAAT)
For follow-up

10. TREATMENT

11. GROUPING OF ANTI-TB DRUGS

12. AMINOGLYCOSIDES
 Streptomycin (S); Kanamycin (Km); Amikacin (Am)
 Tuberculocidal.
 Acts only on extracellular bacilli.
MECHANISM OF ACTION:
Binds with 30s ribosomal subunit
↓
Misreading of genetic code
↓
Inhibit protein synthesis

13.  PHRAMACOKINETICS:
• Very poor oral bioavailability hence given in injectable form.
• Distributed extracellularly mainly
• Excreted unchanged in urine
 ADRs:
• Nephrotoxicity
• Ototoxicity
• Neuromuscular blockade- ↓release of Ach by inhibiting fusion
of vesicles with terminal membrane

14. CAPREOMYCIN (CPR)
• Tuberculocidal cyclic polypeptide antibiotic
• Consists of four active components-ΙA,ΙB,ПA & ΠB
• IA & IB important for anti-mycobacterial effect
• Resistance develops when given alone and such
microorganisms show cross-resistance with kanamycin and
neomycin
• Poor oral absorption
 ADRs: Hearing loss, Tinnitus, Transient proteinuria, nitrogen
retention, eosinophilia

15. FLUOROQUINOLONES
 FQs used as 2nd line anti-TB drugs are- Ciprofloxacin,
Ofloxacin, Levofloxacin, Moxifloxacin
 Moxifloxacin addition of C8 halogen and C8 methoxy
groups decreases drug resistance.
 Tuberculocidal
 Active against intracellular as well as extracellular bacilli.
 MECHANISM OF ACTION:
• Inhibit DNA gyrase →Impaired transcription & translation

16.  PHARMACOKINETICS:
• Oral bioavailabilty >50%
• Most are excreted through kidney as such (except
Moxifloxacin- metabolized by liver)

17. ETHIONAMIDE (ETM)
• Congener of thioisonicotinamide.
• Tuberculostatic , acts on both extra and intracellular bacilli.
 MECHANISM OF ACTION:
• Inhibit enoyl-ACP reductase of Fatty acid synthase II (inhA
gene product) → ↓ Fatty acid synthesis → Impaired cell wall
synthesis

18.  PHARMACOKINETICS:
• Oral bioavailability ~100%.
• T1/2~ 2hrs.
• Metabolised by liver & excreted in urine.
 ADRs:
• Anorexia, nausea & vomiting (Common)
• Postural hypotension , neurological & psychiatric symptoms
• Hepatitis

19. CYCLOSERINE (CYS)
• Is D-4-amino-3-isoxazolidone.
• Tuberculostatic
 MECHANISM OF ACTION:
L-alanine
alanine recemase↓
D-alanine
D-alanine ligase↓
Incorporated to cell wall
CYCLOSERINE
CYCLOSERINE

20.  PHARMACOKINETICS:
• Almost completely absorbed orally.
• Food ↓absorption.
• T1/2 ~ 9 hrs.
• ~50% excreted unchanged in urine.(accumulate to toxic levels
in renal failure)
 ADRs:
• Neuropsychiatric symptoms (common) →“Psych-serine”
• Headache, somnolence, convulsion
 CONTRAINDICATION:
• H/o depression, Psychosis & Epilepsy.

21. PARA-AMINO SALICYLIC ACID (PAS)
• 1st effective drug discovered for TB
• Tuberculostatic drug
MECHANISM OF ACTION:
• Inhibit folate synthesis in bacteria by inhibiting
dihydropteroate synthase (folP1).

22.  PHARMACOKINETICS
 Oral bioavailability is highly variable, 45-60%;
bioavailability is increased 2-fold by high-fat meals and
decreased 30% by antacids.
 t1/2 is ~70 days
 Metabolized in the liver.
 ADRs
 abdominal pain, diarrhoea, nausea, and vomiting.
 Body secretion discoloration, eye discoloration, and skin
discoloration.

23. LINEZOLID(LZD)
• Oxazolidinone
• Very effective against drug susceptible + resistant cases
• Inhibits bacterial protein synthesis (binding to 50S
Ribosomal unit)
• 100 % oral bioavailability
ADRs
• Bone marrow suppression, peripheral neuropathy

24. THIOACETAZONE
 only weak activity against M.tuberculosis
 Only useful in preventing resistance to more powerful drugs
like isoniazid and rifampicin.
 ADRs
 Ototoxicity
 severe (sometimes fatal) skin reactions
 Hepatitis, neutropenia and thrombocytopenia

25. MANAGEMENT OF DR-TB
AS PER
RNTCP Guidelines on Programmatic
Management of Drug Resistant TB
(PMDT) in India

26. PRE-TREATMENT EVALUATION
1. Detailed history
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
12. HIV counselling and testing

27.  For XDR TB, an ECG, serum electrolytes, and surgical
evaluation is added to the pre-treatment evaluation
 Patients should receive counselling on
1) the nature and duration of treatment,
2) need for regular treatment,
3) possible side effects of these drugs
4) the consequences of irregular treatment or pre-mature cessation of
treatment.
5) Female patients for family planning.

28. INTEGRATED ALGORITHM FOR DR-TB
TREATMENT

29. REGIMEN FOR MDR-TB
 Intensive Phase (6-9 months) 6 drugs - Kanamycin,
Levofloxacin, Ethionamide, Pyrazinamide,Ethambutol and
Cycloserine
 Continuation Phase (18 months) 4 drugs-Levofloxacin,
Ethionamide, Ethambutol and Cycloserine
 Reserve/Substitute drugs: PAS, Moxifloxacin, Capreomycin

30. DR-TB case

32.  All drugs should be given in a single daily dosage under directly
observed treatment (DOT)
 All patients will receive drugs under direct observation on 6 days of
the week.
 On Sunday, the oral drugs will be administered unsupervised whereas
injection Kanamycin will be omitted.
 If intolerance occurs to the drugs, Ethionamide, Cycloserine and PAS
may be split into two dosages and the morning dose administered
under DOT. The evening dose will be self-administered.
 Pyridoxine is administered to all patients on Regimen for MDR TB.

33. REGIMEN FOR MDR TB DOSAGE AND WEIGHT BAND
RECOMMENDATIONS
 2 In case of PAS with 60% weight/volume the dose will be increased to 7 gm
(16-25 Kg); 14 gm (26-45 Kg) and 16 gm (> 45 Kg)

34.  If a patient gains/ loses 5 kgs or more in weight during treatment and crosses the
weight-band range, patient can be shifted to the higher/lower weight band drug
dosages.
 The dosages for higher weight patients (> 70 kg)  Kanamycin/Capreomycin
(1 gm), Ethionamide (1 gm), Cycloserin (1 gm), Ethambutol(1.6 gm) and
Pyrazinamide (2 gm). Other drugs dosages would remain the same.
 Dosage of Regimen for MDR TB for paediatric age group <16 kg

35. REGIMEN FOR XDR TB
 Intensive Phase (6-12 months) 7 drugs-Capreomycin (Cm), PAS,
Moxifloxacin (Mfx), High dose-INH, Clofazimine, Linezolid, and
Amoxyclav
 Continuation Phase (18 months) 6 drugs – PAS, Moxifloxacin (Mfx), High
dose-INH, Clofazimine, Linezolid, and Amoxyclav
 Reserve/Substitute drugs: Clarithromycin, Thiacetazone
 In case the patient was on PAS, PAS will be replaced with one of the
reserve drugs in the regimen for XDR TB
 If the patient is unable to tolerate one or more of the drugs
 If the patient is found to be resistant to Capreomycin
 All drugs are to be given on a daily basis. Injections of Capreomycin will be
given for 6 days/week (not on Sundays). All morning doses are to be
supervised except on Sundays.

36. REGIMEN FOR XDR TB DOSAGE AND WEIGHT BAND
RECOMMENDATIONS

37.  The change from IP to CP will be done only after achievement
of culture conversion i.e. 2 consecutive negative cultures taken
at least one month apart.
 In case of delay in culture conversion, the IP can be extended
from 6 months up to a maximum of 12 months.
 Consultation by a thoracic surgeon for consideration of surgery.
Regimen for XDR TB Contd......

38. ROLE OF SURGERY IN MANAGEMENT OF DR-TB
 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;
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.

39. MANAGEMENT OF TREATMENT INTERRUPTIONS AND
DEFAULT FOR M/XDR TB PATIENTS
 Patients in IP/CP who miss doses:
 All the missed doses during IP must be completed prior to switching
the patient to CP.
 Similarly all missed doses during CP must be administered prior to
ending treatment.
 Patients who interrupt treatment for less than 2 months
during IP:
 When the patient returns to resume treatment the IP will be continued,
however the duration of treatment will be extended to complete IP.

40.  Patients who interrupt treatment for less than 2 months
during CP:
 When the patient returns to resume treatment, the CP will be
continued, however the duration of treatment will be
extended to complete the CP.
 Patients who default (interrupt treatment for 2 or more
months) and return back for treatment:
 Return for treatment within 6 months
 Return for treatment after 6 months

41. RETURN FOR TREATMENT WITHIN 6 MONTHS OF
DISCONTINUING REGIMEN FOR M/XDR TB

42. MANAGEMENT OF M/XDR PATIENTS WHO DEFAULT AND
RETURN FOR TREATMENT AFTER 6 MONTHS

43. MONITORING & OUTCOME DEFINITIONS
 Clinical monitoring
 at monthly intervals during the IP, and
 At 3-monthly intervals during the CP until the end of treatment.
 Follow-up investigations during treatment
 Chest radiograph
 Follow-up chest radiograph will be done at the end of the IP, end of
treatment, and whenever clinically indicated.
 Serum creatinine
 done every month for the first 3 months and every three months thereafter
whilst the patient is receiving kanamycin.
 Thyroid testing
 Thyroid testing after the baseline would be conducted as and when required.

44.  Follow up smear and culture examination during treatment
 Sputum specimens 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).
 In case of extension of IP, the follow up culture months will
shift by every month of extension of IP

45. 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).
 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

46. MDR-TB IN SPECIAL SITUATIONS

47. MDR-TB IN PREGNANCY
All women of childbearing age who are receiving MDR-TB therapy should
be advised to use birth control measures.

48. MDR-TB WITH HIV CO-INFECTION
 The treatment is the same as for HIV negative patients.
 ART should be initiated as soon as possible in all HIV/TB-co-
infected patients with active TB (within 8 weeks after the start of
TB treatment).
 Patients on ART at the time of MDR-TB diagnosis be continued
on ART when MDR-TB therapy is initiated.

49. MDR-TB IN PATIENTS WITH RENAL IMPAIRMENT
 In patients with mild renal impairment, the dose of
aminoglycosides may be reduced.
 In the presence of severe renal failure, the aminoglycoside
therapy should be discontinued and replaced with other potent
nonnephrotoxic antituberculosis drugs.

50. DOSE ADJUSTMENT OF ANTI-TB DRUGS IN
PRESENCE OF RENAL IMPAIRMENT

51. MDR-TB IN PATIENTS WITH PRE-EXISTING LIVER
DISEASE
 Pyrazinamide, PAS and Ethionamide are potentially hepatotoxic
drugs.
 In general, most of second line drugs can be safely used in presence of
mild hepatic impairment, as they are relatively less hepatotoxic than
the first-line drugs.
 MDR patients having deranged liver function test (LFT) during
pre-treatment evaluation should be strictly monitored through
monthly LFTs while on treatment.

52. MANAGEMENT OF CONTACTS OF MDR-TB
 All close contacts of MDR-TB cases should be identified through
contact tracing and evaluated for active TB disease.
 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” and regimen initiated.

53. PREVENTION OF DR-TB
1) Rapid diagnosis & treatment of TB: If TB is identified and
treated soon, drug resistance can be avoided.
2) Completion of treatment.
3) Patients with HIV/AIDS should be identified and diagnosed
as soon as possible.
4) Identify contacts who could have contracted TB: i.e. family
members, people in close contact, etc.
5) Research: Much research and funding is needed in the
diagnosis, prevention and treatment of DR TB.

54. THANK YOU

55. MDR-TB IN PATIENTS WITH SEIZURE DISORDERS
 If the seizures are not under control, initiation or adjustment of
antiseizure medications will be needed prior to the start of MDR-TB
therapy.
 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.
 Antiepileptic drugs may have drug interactions with Cycloserine and
fluoroquinolones. Hence close monitoring of serum levels of anti-
epileptic drugs should be done.

56. MANAGEMENT OF MDR TB IN EXTRA PULMONARY
TB CASES
 Treatment regimen and schedule for EP MDR TB cases will
remain the same as for pulmonary MDR TB.
 Treatment for Extra pulmonary MDR tuberculosis should be
given for 24 months strictly
 Regular patient monitoring and periodic follow up of nodes and
other extra-pulmonary symptoms with culture from the
discharging node/sinus is the key in monitoring of treatment in
Extra-pulmonary Lymph Nodal MDR-TB.