Chap 47: Antimycobacterials

INTRODUCTION
- mycobacteria intrinsically resistant to most abx

• grow slowly - abx act on dividing cells
• can be dormant - completely resistant or killed very slowly
• lipid rich cell wall - impermeable to many agents
• intracellular pathogen - organism residing in macrophages are difficult to be entered
• development of resistance is notorious

- combination >2 drugs needed + long term treatment


ANTUBERCULOUS DRUGS
Introduction
- 1st line agents - RIPES
- I+R - 2 most active drugs - 9 months of both will cure 95-98% of cases
- addition of pyrazinamide to above for 1st 2 mths --> reduce duration to 6 mths
- ethambutol and streptomycin

• does not reduce duration of rx
• for coverage of resistant bugs while culture pending

- prevalance of resistance

• INH resistance in US 10%
• both INH and R resistance (MDR) 3%

Isoniazid (INH)
- most active drug
- less effective for atypicals
- penetrates into macrophages --> extracellular and intracellular microbes
- MOA

• inhibit mycolic acid synthesis - components of mycobacterial cell wall - cell death

- resistance

• drug resistance happens in 1 x 10*6
• TB lesions has 1 x 10*8 bacilli - resistant mutants are readily selected
• adding rifampicin - resistance 1 x 10*6 x 10*6 - much higher

- pharmacokinetics

• po - well absorbed
• penetrates all tissue including CNS
• metabolised by liver, renally excreted
• don't need to adjust dose in renal pt

- SE

1. hepatitis - commonest, up 3-4x normal - dont need to stop drugs, if clinically symptoms occur (loss of appetite, n/v, jaundice, RUQ pain - stop drugs promptly (causes liver cell necrosis)
2. peripheral neuropathy - due to relative pyridoxine deficiency (INH promotes pyridoxine excretion) - hence higher risk for alcoholic/malnutrition/DM/AIDS/uremia
3. immunologic - rash, fever, SLE
4. blood disorders - pyridoxine def anemia, tinnitus, GI discomfort

Rifampicin
- semisynthetic abx of rifamycin, produced by Streptomyces mediterranei
- g+ve/-ve, enteric bacteria, mycobacteria (bactericidal), chlamydia
- readily penetrates tissues, phagocytes --> enters abscess and lung cavities
- MOA

• binds to B-subunit of RNA polymerase --> (-) RNA synthesis
• resistance - point mutation - reduction in binding to polymerase

- clinical uses

1. mycobacteria infection
2. others - meningococcal carriage, Hib in kids, + fusidic acid = against staph carriage

- SE

1. orange tinge to bodily fluid
2. hepatitis
3. allergic type - rash, fever, thrombocytopenia

Ethambutol
- synthetic agent
- inhibits mycobacterial arabinosyl transferases --> needed for polymerization of arabinoglycan (component of cell wall)
- resistance - due to mutation unable to bind to transferases
- SE - retrobulbar neuritis - loss of visual acuity, red-green color blindness --> C/I in children too young to allow visual assessment

Pyrazinamide
- exact mechanism unknown
- use - important as 1st line agent to reduce rx time 6mths - as 'sterilizing' agent
- SE - liver toxicity, hyperuricemia (may provoke gout)

Streptomycin
- aminoglycoside - see chapter 45
- penetrate into cells poorly - mainly against extracellular tubercle bacilli

ALTERNATIVE 2ND LINE AGENTS
Introduction
- considered only

1. resistance to 1st line
2. failure of lcinical response
3. serious drug reactions
4. expert guidance to deal with the SE of the agents listed

- examples

• Ethionamide - related to INH - blocks mycolic acid
• Capreomycin - peptide protein synthesis inhibitor
• Cycloserine - inhibit cell wall synthesis
• Aminosalicylic acid (PAS) - anti-folate exclusively against TB
• Kanamycin & amikacin
• Fluoroquinolone
• Linezolid
• Rifabutin
• Rifapentine

DRUGS FOR ATYPICAL MYCOBACTERIA
- 10% of clinical practice in US - not M tuberculosis or M tuberculosis complex

• M avium complex - M avium, M intracellulare

- characteristics of atypical mycobacteria

• special lab characteristic
• present in environment
• not communicable btw person
• less susceptible to normal antiTB drugs

- usually need atypicals - tetracycline, macrolide, sulfonamides
- M kansasii - INH, R, ethambutol
- M avium

• common - important in AIDS
• combination agents - azythro/clarithro + ethambutol +- ciprofloxacin

DRUGS USED IN LEPROSY
- M leprae
- dapsone + other sulfones

• closely related to sulfonamides - same MOA
• resistance issue - used in combination with 3 agents - dapsone, rifam, clofazimine
• NB: dapsone can be used for PCP
• SE: hemolysis (common, esp in thos with G6PD deficiency), metHb, erythema nodosum (can be rx with steroids/thalidomide)

- rifampicin - usually in combination
- clofazimine

• phenazine dye - alternative to dapsone
• MOA unknown - DNA binding
• SE: skin discoloration - red brown to nearly black