PHARMACOLOGY OF ANTITUBERCULAR DRUGS [MDR & XDR TB]

Dr.U.P.Rathnakar
MD.DIH.PGDHM K.M.C.Mangalore Visit: www.scribd.com

Antitubercular drugs-MDR TB
First-line oral antituberculosis agents Isoniazid Rifampicin Ethambutol Pyrazinamide (H) (R) (E) (Z)

Viomycin [Vi]

[Doubtful efficacy]

Ethionamide: ( Etm )
It is bacteriostatic. It acts on both extracellular and intracellular bacilli also effective against atypical mycobacteria. It blocks the synthesis of mycolic acid.

Adverse effects: Hepatotoxicity, gastric irritation, peripheral neuritis. Dose: 1 gm/day orally.(500mg 750mg/day).

Thiacetazone: ( Tzn )
It was once used as a first line drug. It is a tuberculostatic drug. Usually combined with INH.

Adverse effects: Hepatitis, Exfoliative dermatitis, StevensJohnson syndrome. Contraindicated in HIV positive cases. Dose: 150 mg/day.

Para-aminosalicylic acid (PAS):

Bacteriostatic drug. Similar to sulfonamides Least active but delays development of resistance. Prolongs the t1/2 of INH.

Adverse effects: Git symptoms, fever, goiter,liver dysfunction and blood dyscrasias Dose: 1012gms (200 mg/day) in

Cycloserine ( Cys ):
It is a tuberculostatic drug which inhibits cell wall synthesis. Rapidly absorbed from gut and achieves good concentration in the CSF when meninges are inflamed.

Adverse effects: Psychosis, Convulsions, Headache & Tremor.

Dose: 250 mg BD.

Capreomycin:
It is a polypeptide obtained from Streptomyces capreolus. It is similar to Streptomycin.

Dose: 15 20 mg per kg IM for 60 days and then twice weekly for 18 months. Clarithromycin and Azithromycin.

Macrolides: They are used to treat atypical mycobacterial

Fluoroquinolones
Ciprofloxacin, Ofloxacin, Moxifloxacin and

Sparfloxacin.

They are active against M.tuberculosis and some atypical mycobacteria. They are also effective in killing the bacilli lodged in the macrophages.

Aminoglycosides:

Kanamycin and Amikacin. They are used in resistant cases and against atypical mycobacteria.

Rifabutin:
Action is similar to Rifampicin. More active against MAC.

Adverse effects: Neutropenia, Myalgia, Impairment of taste Uses:1. Treatment and prophylaxis of Pulmonary MAC. 2. Pulmonary Tuberculosis.

Dose: 300 600 mg/day

Effective Diagnosis, Treatment, and Control of Tuberculosis

World Health Organization

Guidelines

RNTCP
National programme

DOTS
Implimentation

Sub-populations

Goals of therapy
Kill dividing bacilli Non contagious

Rapidly growing [Walls of cavity]

Slow growing[Macrophag es]

[Multiple drugs]

Intermittently growing [Spurters]

Kill persisting bacilli Prevent relapse Z Prevent

Not growing [Dormant]

Directly Observed Treatment Short course [RNTCP]

Categorization of Patients
Classified into two groups based on H/o previous treatment

New cases [CAT I]: All new pulmonary (sputum positive and negative) and extra pulmonary TB patients Previously treated cases [CAT II]: Patients who have more than one month Anti TB Rx previously (default, failure and relapse)

CATEGORIES AND TREATMENT REGIMENS UNDER RNTCP[2011]

Treatment regimen Category New Cases [I]
Previously Treated Cases

Characteristics All new cases sputum +ve or negative Patients who have more than one month Anti TB Rx previously (default, failure and relapse)

Intensive phase 2 H3R3Z3E3

Continuation phase 4 H3R3 5 H3R3E3

2 H3R3Z3E3S3 followed by 1 H3R3Z3E3

[II]

H[10mg/kg] R[10mg/kg] Z[35mg/kg] E[30mg/kg] S[15/kg]

Regimen for new cases[CAT I]

If sputum is + ve at the end of two months, IP is continued for another one month (12 doses) CP is for 4 months

Regimen for Previously treated cases[CAT II]

If sputum is + ve at the end of three months, IP is extended for another one month (12 doses, four weeks) If sputum remains +ve at the end of extended IP, sputum is send to an accredited RNTCP C&DST lab for C&S testing Relapse case have better outcome than Failure and Treatment after default cases

Intensive Phase
1.Aims for a rapid killing of bacilli 2.A state of non-infectiousness achieved within a short period 2/52 3.Quick relief of symptoms 4.Smear negativity by 2/12 5.Prevent development of drug resistance

Continuation Phase
Aims to eliminate remaining bacilli Killing of persisters prevents relapses

DOTS
All drugs can be given as a single daily dose. Direct observation is recommended for all patients Particularly essential when intermittent regimens are used.

Principles DOTS
Sputum microscopy Domiciliary treatment Short course chemotherapy Intermittent chemotherapy Directly observed treatment

What is the need for DOT?

A

t least 1/3 of patients on self-administered Rx fail to adhere to Rx to predict which patients will take

Impossible

medicines
DOT

necessary at least in the Int.Phase of Rx

to ensure adherence and smear conversion

TB

patient missing 1 attendance can be

traced immediately and counseled.

Directly observed treatment

Ensures the best possible results in TB treatment Observer watches & assists patient swallow the tablets

Directly observed treatment.

Poor results and high death rates in the absence of DOT Observing the patients during the entire course
Ensures that the patient receives the right drugs Ensures the right doses Ensures the right intervals

Benefits of DOTS
Produces cure rates of up to 95 % Prevents new infections Prevents the development of MDR-TB Cost effective

Multi-drug resistant and Extensively drug resistant TB MDR-TB Defined as resistance to Isoniazid and Rifampicin XDR-TB Defined as resistance to at least Isoniazid and Rifampicin (i.e. MDR-TB) PLUS resistance to any of the Fluoroquinolones and any one of the second-line injectable drugs (Amikacin, Kanamycin, or

RNTCP MDR-TB Treatment Regimen [Daily DOTS]

RNTCP CATEGORY MDR REGIMEN: 6 (9) Km Ofx (Lvx) Eto Cs Z E / 18 Ofx (Lvx)Eto Cs E 6 Drugs for intensive phase [6-9 Months] 4 Drugs for intensive phase [18 Months]

Management Guidelines for Patients with XDR-TB

Use any Group 1 agents that may be effective. Use an injectable agent -an extended duration of use (12 months or possibly the whole treatment). If resistant to all injectable agents, it is recommended to use one the patient has never used before.* Use a later-generation fluoroquinolone such as moxifloxacin. Use all Group 4 agents that have not been used extensively in a previous regimen or any that are likely to be effective. Use two or more agents from Group 5. Consider high-dose isoniazid treatment if low-level resistance is documented. Consider adjuvant surgery if there is localized disease. Treat HIV

Can XDR-TB be cured or treated?

Yes, in some cases. Good TB control programmes -cure is possible up to 30% of affected people. Depends on the extent of the drug resistance, Severity of the disease Patients immune system Access to laboratories that can provide early and accurate diagnosis so that effective treatment is provided as soon as possible.

Chemoprophylaxis-Primary
To prevent latentActive 1. Contacts of open cases-recent Mx conversion 2. Children with +ve Mx with contacts 3. Neonates of tubercular mother 4. DM, HIV, Leukemia with contactsMx+ve 5. Who received inadequate therapy

Drugs used are: INH 300mg for 6 12 months OR INH ( 5mg/kg ) + Rifampicin ( 10 mg/kg ) for 6 months OR INH + Rifampicin + Pyrazinamide for 2 3 months.

Glucocorticoids in Tuberculosis:
Glucocorticoids must never be used without cover of effective antitubercular chemotherapy.

The indications for steroids are: 1.Miliary or severe pulmonary TB. 2.Hypersensitive reactions to anti TB drugs. 3.Meningeal and Renal TB. 4.Pleural and Pericardial effusion. 5.Rapidly enlarging mediastinal lymph node. 6.To prevent fibrosis in ocular & genitourinary TB.

Tt not to be with held Initial phase H R [Z] E for 2 months. Continuation phase H R for 7 months. [Ethambutol not added during early pregnancy] All drugs can be given to the mother during breast feeding

TB in pregnant women:

Only difference-Use Rifabutin [150mg/thrice weekly] whenever PI are used

Mycobacterium avium complex (MAC):

The most common drug regimens used are:

Clarithromycin + Ethambutol Azithromycin + Ethambutol Clarithromycin + Ethambutol + Ciprofloxacin OR Rifabutin Azithromycin + Ethambutol + Ciprofloxacin OR Rifabutin

Treatment should be continued for life.

For prophylaxis Clarithromycin or Azithromycin.