MANAGEMENT OFDRUG-RESISTANT

TUBERCULOSIS

Dr. Irfan Ahmad KhanJR-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.

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.

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).

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.

MECHANISMS OF DRUG RESISTANCE1) 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.

Drugs MutationsIsoniazid (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)

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

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

TREATMENT

GROUPING OF ANTI-TB DRUGS

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

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

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

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

PHARMACOKINETICS:• Oral bioavailabilty >50%• Most are excreted through kidney as such (except

Moxifloxacin- metabolized by liver)

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

PHARMACOKINETICS:• Oral bioavailability ~100%.• T1/2~ 2hrs.• Metabolised by liver & excreted in urine.

ADRs:• Anorexia, nausea & vomiting (Common)• Postural hypotension , neurological & psychiatric symptoms• Hepatitis

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

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.

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).

PHARMACOKINETICSOral bioavailability is highly variable, 45-60%;

bioavailability is increased 2-fold by high-fat meals and decreased 30% by antacids.

t1/2 is ~70 daysMetabolized in the liver.

ADRsabdominal pain, diarrhoea, nausea, and vomiting.Body secretion discoloration, eye discoloration, and skin

discoloration.

LINEZOLID(LZD)

• Oxazolidinone

• Very effective against drug susceptible + resistant cases

• Inhibits bacterial protein synthesis (binding to 50S

Ribosomal unit)

• 100 % oral bioavailabilityADRs• Bone marrow suppression, peripheral neuropathy

THIOACETAZONE only weak activity against M.tuberculosis Only useful in preventing resistance to more powerful drugs

like isoniazid and rifampicin.

ADRsOtotoxicitysevere (sometimes fatal) skin reactionsHepatitis, neutropenia and thrombocytopenia

MANAGEMENT OF DR-TBAS PER

RNTCP Guidelines on Programmatic Management of Drug Resistant TB

(PMDT) in India

PRE-TREATMENT EVALUATION1. Detailed history2. Weight3. Height4. Complete Blood Count with platelets count5. Blood sugar to screen for Diabetes Mellitus6. Liver Function Tests7. Blood Urea and S. Creatinine to assess the Kidney function8. TSH levels to assess the thyroid function9. Urine examination – Routine and Microscopic10. Pregnancy test (for all women in the child bearing age group)11. Chest X-Ray12. HIV counselling and testing

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.

INTEGRATED ALGORITHM FOR DR-TB TREATMENT

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

DR-TB case

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.

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)

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

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.

REGIMEN FOR XDR TB DOSAGE AND WEIGHT BAND RECOMMENDATIONS

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......

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.

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.

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 monthsReturn for treatment after 6 months

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

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

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.

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

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

MDR-TB IN SPECIAL SITUATIONS

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

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.

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.

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

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.

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.

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.

THANK YOU

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.

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.