Chemotherapy of Chemotherapy of tuberculosistuberculosis

Chemotherapy of Chemotherapy of tuberculosistuberculosis

F. A. FehintolaF. A. Fehintola

Burden of TB• TB is found globally • About a third of the World population is

infected• ~ 1 person is infected per second• Most are asymptomatic and only about

10% of those infected are likely to develop active disease

• Burden is worse in poorer countries

Burden of TB• Untreated, Mortality ~ 50-67%• Treated and well supported mortality ~

5%• Relapse rate of 2-3% amongst those

considered cured after standard therapy

• Major drain on economy: loss of man-hour and school absenteeism

Burden of TB• About 8 m of nearly 2 billion infected

individuals become symptomatic every year

• Accounts for ~ 2m deaths per year, 90% of this occurs in developing countries

• Age 15-54 years mostly affected (75% of cases)

Burden of TB• WHO declared TB as an emergency in

1993• HIV/AIDS has compounded the problem

of TB• Drug resistance is very high ~ 20%• Multiple drugs: HAART and anti TB

– Interactions– expense

Burden of TB

Re-emergence of TB due to: • Poverty• Neglect of the disease• Collapse of health facilities in

depressed economy• HIV/AIDS scourge

The organism• Causative organism: Mycobacteria

spp. (tuberculosis>>>> bovis>> africanum > microti)*

• An obligate aerobic organism– Acid fast Bacilli (due to presence of mycolic acid**

in the cell wall) • *others are called non tuberculous mycobacteria e.g. M.

leprae, MAC etc• ** mycolic acid is also responsible for caseous granuloma

The organism•Organism is slow growing

(division: 15-20 hours vs ~20min. in E. coli)

•Discovered by Robert Koch in 1882

•Genome sequenced in 1998

Transmission and organ involvement

• Transmission of TB usually by inhalation of aerosols

• At risk people include:– Immuno-compromised people

• HIV/AIDS, severe malnutrition, immuno-supressant, DM, leukaemia, lymphomas

– Close contacts including health care workers

Transmission and organ involvement

• M. bovis usually by ingestion of un-pasteurised infected milk

• Organ involvement is broadly divided into: – Pulmonary (75%) or – extra-pulmonary (considering

transmissibility)

• Sites other than lung = Extra-pulmonary TB

Diagnosis• Lung mostly involved and

symptoms of respiratory dysfunction predominate

• Systemic symptoms like fever, weight loss, anorexia, fatigue, night sweats

• Miliary TB or Disseminated TB? (involvement of circulatory system)

Diagnosis• TB the great imitatus• Symptoms and signs depend on site

of involvement• Sometimes only systemic features like

prolonged fever and weight loss • Not uncommonly other common

bacterial pathogens may be present

DiagnosisInvestigations may include but not limited

to:• Microscopy: Ziehl-Neelsen staining• Culture* (and sensitivity) takes time• CXR and other radiodiagnostic tests• Haematology etc• Tuberculin test (? )• *Lowenstein-Jensen medium and Middlebrook)

Ziehl-Nelsen stain of M. tuberculosis

Drug classes• Drugs are grouped as first-line or

second line based on:• Availability e.g. Fluoroquolones • Toxicity e.g cycloserine• Efficacy e.g PAS

chemotherapy• Prolonged therapy is the rule!• Hitherto,• INH + PAS for 18-24 months• Even short course lasts 6 months!• Short course consists of 4 initial

drugs for the first 2 months

First line drugs• INH• Ethambutol• Streptomycin• Rifampicin• Pyrazinamide

First line drugs: INHHydrazide of isonicotinic acid• Inhibits mycolic acid synthesis• An essential component of anti TB• Undergoes acetylation• Poor acetylators at increased risk of

neuropathy• Usual dose is 5 mg per kg body weight• Conc in csf varies widely 20~100% of

plasma conc

First line drugs: INH• Uses:

– All forms of TB– Chemoprophylaxis

• ADRs• Hepatitis ~ 1% (vs 10-20% cases of asymptomatic elevated

transaminases); increases with age, pregnancy, alcohol are also predisposing factors.

• Neuropathy- peripheral neuropathy is common with slow acetylators

• Allergy• anaemia

First line drugs: Rifampicin

• Semi-synthetic agent• Essential component of anti TB drugs• Inhibits RNA polymerase• Accesses every site and bactericidal for

Mycobacteria• Resistance is by alteration of target

following point mutation on the polymerase gene

First line drugs: Rifampicin

• Well absorbed following oral medication

• Excretion mainly in bile• Undergoes entero-hepatic recirculation• Dosage adjustment for renal

impairment is unnecessary• Poorly penetrates CNS ~ 10-20%

First line drugs: Rifampicin

• Indications– Treatment of TB– Alternative chemoprophylaxis– Elimination of meningococcal carriage– Elimination of staph. Carriage (only in

combination)– Chemoprophylaxis of H. influenzae

First line drugs: Rifampicin

• ADRs– Thrombocytopenia– Nephritis– Hepatitis (Z>>H>>R)– Flu-like syndromeInteractions: Rifampicin induces

microsomal enzymes

First line drugs: Ethambutol

– Inhibits arabinosyl transferase preventing proper formation of cell-wall

– Over-expression of the this enzyme is found in the resistant strains

• Well absorbed from gut• Accumulates in renal failure requiring

reduced dose• Poorly penetrates CNS 4-64%• Most disturbing ADR: retrobulbar neuritis

First line drugs• Pyrazinamide

– Exact mechanism of action unknown but mycobacteria converts it to the active form – pyrazinoic acid

– Resistance is expressed by reduced uptake

• Very active against intracellular bacteria• Well absorbed in GIT• Widely distributed; CNS penetration ~ 100%• ADRs: hepatotoxicity (1-5%); hyperuricaemia;

drug fever

Second line drugs

• Cycloserine• Amikacin• Kanamycin• Capreomycin

Second line drugs• Viomycin• Ethionamide• Ciprofloxacin• Moxifloxacin• Para-aminosalicylic Acid

Second line drugs• Para-aminosalicylic acid• Specific for Myco. Tuberculosis• Tuberculostatic• Very large dose reqd. and constantly • Mechanism of action may be similar to

sulphonamides in folate synthesis

Second line drugs• PAS is well absorbed from GIT• Achieves peak conc. Within 2 hours• Sufficient conc. in all body tissues

except CSF• Half life ~ 1 hour• Excretion in acetylated form in the urine• To be avoided in renally impaired

individuals

Second line drugs• PAS: displaced by Rifampicin and

ethambutol• Usual dose 10-12 g given after

meals and in divided doses (gastric irritation)

Second line drugs: PAS• ADR: • GIT upset is the most common

– Pain, nausea, diarrhoea

• Haematological: haemolytic anaemia, – Agranulocytosis, leukopenia, eosinophilia,

thrombocytopenia

• Hypersensitivity (5-10%)– Malaise, fever, joint pain

Second line drugs: cycloserine

• Broad spectrum antibiotics• Tuberculostatic• No cross resistance with other

tuberculostatic drugs• Also inhibitory to:

– E. coli, staph aureus, chlamydia

• Analogue of D-alanine and thus inhibits cell wall synthesis

Second line drugs: cycloserine

• Well absorbed when given orally (usual adult dose is 250-500mg bd)

• Peak conc. 3-4 hours• Distributed throughout body tissues

– CSF conc. ~ plasma conc.

• Elimination mainly as parent drug in urine– May accumulate in renal impairment

Second line drugs: cycloserine

• Mainly CNS disturbance:– Somnolence, headache– Dysathria, vertigo– Nervousness– Suicidal tendencies, paranoid symptoms– Hyper-reflexia, ankle clonus– seizure

Other drugs (+ adjunct)

• ‘Third-line’ drugs• Rifabutin• Linezolid• Thiacetazone• Arginine• Vitamin D• Thioridazine

The Rule: Drug combination

• Rationale– Reduce or prevent drug resistance

• An average PTB patient harbours ~ 1012 Bacilli• Thus, • 105 EMB- resistant bacilli• 104 STM- resistant bacilli• 104 INH- resistant bacilli• 102 RMP- resistant bacilli• Chances of spontaneous resistance to all the four drugs ~

1:1011

– Shortens duration of treatment

Standardised therapyRegimen Intensive

phaseDuration (months)

INH, Rif, PZM, Etham

2 months all drugs

4 months of INH & Rif

INH, Rif. - 9 months

INH, Rif, PZM, Strept.

2 months all drugs

4 months of INH & Rif.

DOTS• Was introduced in 1990s by WHO• Transmission of TB has declined

since inception in some areas (notably China, Peru)

• TB Mortality has also dropped in those countries that apply it

• Drug resistance has also reduced

DOTS

• Essential elements• political will and sustained fund• Case detection thru’ quality assured

bacteriology• Supervised standardised treatment with

patient support

DOTS• effective drug supply and

management system• monitoring and evaluation system,

and impact measurement

• DOTS plus!

Special cases• Pregnancy• Breast-feeding• Hepatic dysfunction• Renal dysfunction• CNS TB• Drug resistance

Special cases: Pregnancy

• Only streptomycin need be avoided of the first line drugs

• Breastfeeding: Provide drugs, – breastfeed child, – INH for the baby;

Special cases: Acute hepatitis plus TB

• Drug induced or non-drug hepatitis• Differentiate asymptomatic elevated

aminotransferases• Streptomycin plus Ethambutol for 12

months OR• Strept plus Ethambutol for 3 months

then 6 months of Rifampicin plus INH if the hepatitis has resolved

Special cases• Renal impairment:• INH, Rifampicin and Pyrazinamide

are eliminated largely by the Liver and can be used in normal dose

• Streptomycin and thiocetazone should be given at reduced doses

Special cases: MDR• By definition: Resistance to INH and

Rifampicin (INH + Strept = ? Poly-drug)

• Extensively resistant TB is resistant to > 3 second line drugs

• Management is very complex and may:– include at least 3 drugs to which the

organism is less likely or not resistant to (usually 2nd line drugs like cycloserine, ethionaide)

Special cases• Corticosteroid necessary: • CNS • Pericardium• Duration of treatment of TB

meningitis, cerebritis or myelitis: 2 years