antimycobacterial

Question 1

mycobacterium clinical manifestations

Answer 1

TB (M. tuberculosis), Leprosy (M. leprae)

Pulomonary, intestinal mucosa and lymph nodes: M. avium-intracellulare (fatal in AIDS pts)

Question 2

challenges to antimycobacterial therapy

Answer 2

Cells grow slowly ( difficult to kill, grow, identify, and do susceptibility testing), very lengthy therapy, chronic disease, intracellular forms

Spontaneous resistance- requires multi drug therapy

goals- convert cultures to negative in shortest possible time, prevent emergence of drug resistance, assure complete cure without relapse

Question 3

tuberculosis

Answer 3

disease- primarily pulmonary can disseminate into CNS, M . tuberculosis is 90% the problem, M. avium intracellulare (MAI) is a serious problem in AIDS patients

Diagnosis- TB skin test (positive prior to symptoms), X-ray, acid fast stain/culture

Question 4

first line drugs used in TB

Answer 4

isoniazid, rifampin, rifabutin, ethambutol, pyrazinamide, streptomycin

Question 5

isoniazid

Answer 5

Nicotinic acid derviative,
MOA: bactericidal for actively growing bacilli, bacteriostatic for resting cells

Inhibits synthesis of mycolic acids- isoniazid is a prodrug that is activatated by catalase peroxidase (Kat G) of the tubercle bacillus, the activated drugs target is the enoyl- acyl carrier protein reductase (blocks InhA protein, blocking fatty acid elongation and therefore mycolic acid synthesis)

Resistant strains often result from mutation in KatG or InhA

Uses: all pts with INH-sensitive strains should receive INH if possible, for treatment always given w/ other agents

Absorption/excretion: rapidly absorbed, N- acetylation is under genetic control, N acetyltransferase-2 polymorphisms (slow acetylators longer half life, rapid acetylators short)

SEs: neurotoxicity esp peripheral neuritis- significantly improved with B6 admin, hepatotoxicity

Question 6

rifampin

Answer 6

MOA: inhibits bacterial RNA synthesis by binding to RNA Polymerase beta, bactericidal

never used alone always w/ isoniazid

SE: hepatotoxicity, potent inducer of multiple CYPs and metabolsim is increased of other drugs, orange-red color to bodily fluids

Question 7

Ethambutol

Answer 7

MOA: interferes arabinosyl transferase, blocking cell wall synthesis, tuberculostatic

Absorbed well into CSF

SE: not heptatotoxic , optic neuritis, uric acid increase

Question 8

Pyrazinamide

Answer 8

MOA: blocks mycolic acid synthesis by inhibiting fatty acid synthase 1, bactericidal

Uses: combination therapy, important component of short term multi drug therapy

absorption/excretion: widely distributed including CSF

SE: hepatic damage especially when combined with rifampin, drug fever, hyper uricemia

Question 9

Streptomycin

Answer 9

MOA: binds to several ribosomal sites, stops intiation, causes mRNA misreading

Uses: reserved for the most serious of TB

SE: ototoxicity, nephrotoxicity

Question 10

multi drug regimens for treating active TB

Answer 10

always use at least 2 drugs

importance of bactericidal and intracellular drugs for conventional TB: need a cidal plus intracellular drugs

Bacteriostatic are both intra and extra (ethambutol, and p-aminosalicylic acid

Bacteriocidals: (intra and extra- isoniazid, rifampin and pyrazinamide) Extra only: streptomycin

Question 11

Atypical mycobacterial infections

Answer 11

atypical= MOTT (mycobacteria other than tubercle bacilli)

treatment regiments: MOTTS are generally not sensitive to many anti - TB regimens

rifabutin and clarithromycin

Question 12

rifabutin

Answer 12

single- agent prophylaxis of M. avium intracellulare MAC in AIDS patients

multi-drug treatment of MAC alternative to rifampin

Toxicities- similar to rifampin (hepatotoxic) less severe, nausea and rash, drug interactions similar to rifampin but less potent CYP inducer

Question 13

Clarithromycin/azithromycin

Answer 13

part of multi drug regimen of M-avium-intracellulare in AIDS pts

also used for MAC prophylaxis Bactericidal

Question 14

leprosy hansens disease

Answer 14

disease: endemic areas ( 2 types lepromatous and tuberculoid) invitro growth and susceptibility testing hard

dapsone, clofazimine, and rifampin

Question 15

dapsone

Answer 15

MOA: same as sulfonamides, structural analog of paraaminobenzoic acid (PABA) inhibits synthesis of folic acid, bacteriostatic

uses: combination therapy with other drugs (rifampin) prophylaxis and treatment of pneumocystis jiroveci
absorption: slow and fast acetylators

SE: hemolytic anemia and methemoglobinemia

Question 16

Clofazimine

Answer 16

MOA: binds to mycobacterial DNA interfering with reproduction and growth

Use: combo chemotherapy

SE: red /brown skin and bodily fluids

Question 17

Treatment regimens for leprosy

Answer 17

lepromatous: dapsone + clofazimine + rifampin for 2 years daily

TB: dapsone and rifampin daily for 1 year