Anti-TB Drugs

multidrug-resistant TB (MDR-TB)

resistance to both isoniazid and rifampin

extensively drug resistant TB (XDR-TB)

resistance to both isoniazid and rifampin and to all fluoroquinolones, and at least one injectable second line agent

directly observed therapy (DOT)

measure of promoting adherence; dosing in the presence of an observer, usually someone from the health department

intermittent dosing schedules

measure of promoting adherence; daily dosing vs dosing 2-3 times/week; decreases risk of resistance when combined with DOT

treatment for drug-sensitive TB

1. induction phase

2. continuation phase

drug-sensitive TB - induction phase

2 months duration; 4 agents (isoniazid, rifampin, pyrazinamide, ethambutol); daily, twice weekly, or 3 times weekly dosing schedules; goal is to eliminate actively-dividing extracellular tubercle bacilli

drug-sensitive TB - continuation phase

4 months duration; 2 agents (isoniazid and rifampin); daily, twice weekly, or 3 times weekly dosing schedules; goal is to eliminate intercellular persisters

single agent resistant infections

resistance to either isoniazid or rifampin; treatment is with other 3 drugs; duration of treatment 18-24 months; usually responds well to treatment

MDR / XDR TB infections

much harder to manage; treatment is prolonged (24+ months); initial therapy may require 5-7 agents; uses second and third line agents (more toxic / less effective); prognosis is poorer

TB and HIV co-infections

incidence of TB is higher in HIV patients; prolonged duration of TB treatment; rifampin (for TB) should not be given with protease inhibitors / NNRTIs (for HIV) → patients only receive optimal treatment for one of their infections

latent TB treatment

lengthy; risk for drug toxicity; limited to those who really need it; must rule out active TB before beginning treatment; options = isoniazid daily for 9 months (270 doses) or isoniazid + rifapentine weekly for 3 months (12 doses)

first-line agents

usually a combination of 3-4 are used to decrease risk of resistance

1. isoniazid

2. rifampin

3. rifapentine

4. rifabutin

5. pyrazinamide

6. ethambutol

second-line agents

always in combination with first-line; less effective, more expensive, and more toxic

1. fluoroquinolones (2) - levofloxacin, moxifloaxacin

2. injectable agents (4) - kanamycin, amikacin, capreomycin, streptomycin

3. others (3) - para-aminosalicylic acid, ethionamide, cycloserine

isoniazid (isotamine - INH)

primary agent for treating active / latent TB; inactivated in liver by acetylation; excreted in urine primarily as inactive metabolites; tablets, syrups, or solutions for IM injection; available in fixed dose combinations with rifampin / rifampin + pyrazinamide

isoniazid adverse effects

1. hepatotoxicity - signs of hepatitis

2. peripheral neuropathy caused by isoniazid/induced B6 deficiency

3. others - CNS manifestations, GI symptoms, anemia, urinary retention, allergic reactions

isoniazid drug/drug interactions

ingesting with rifampin, rifapentine, rifabutin, or pyrazinamide increases risk of hepatotoxicity; strong inhibitor of cytochrome P450 isoenzymes (raise levels of other drugs); phenytoin most concerning (excess → ataxia, incoordination)

rifampin (Rifadin)

used alongside isoniazid for TB; bactericidal to M. Tuberculosis; induces hepatic drug-metabolizing enzymes; best taken on empty stomach; hepatitis is most common adverse effect; discolors body fluids orange; available as oral capusle

rifampin drug/drug interactions

induces cytochrome P450 isoenzymes which can hasten the metabolism of many other drugs (contraceptives, warfarin, certain protease inhibitors and NNRTIs for HIV)

drugs related to rifampin

1. rifapentine (Priftin)

2. rifabutin (Mycobutin)

rifapentine (Pfiftin)

long-acting analogue of rifampin; same MOA, adverse effects, and drug interactions as rifampin; best absorbed when given with food

rifabutin (Mycobutin)

close chemical relative of rifampin; preferred to rifampin in patients with HIV infection; risk of uvelitis

other first-line agents

1. pyrazinamide

2. ethambutol

pyrazinamide

part of initial combination therapy along with rifampin, isoniazid, and ethambutol for active TB caused by drug-sensitive bacilli; adverse effects = hepatotoxicity, non-gouty polyarthralgia (pain in multiple joints)

ethambutol

bacteriostatic effects - dose related optic neuritis (clears upon discontinuation of drug treatment; drug should be withdrawn if this occurs)

bedaquiline

new anti-TB agent; first unique agent to be developed in 40+ years; works faster / better than all other anti-TB drugs; does not accelerate the metabolism of other drugs → useful for patients taking HIV drugs; warning - prolongs QT interval, risk of hepatotoxicity; use as last resort; administer under DOT and take with food