Treatment of TB: Current Drugs in UseSlide Number 2OutlineTB Drugs in UsePrinciplesLimitationsSlide Number 7First Line DrugsIsoniazid (INH)RifampinOther rifamycinsPyrazinamide (PZA)EthambutolStreptomycinExample CaseFixed Dose Combinations (FDC)Slide Number 17Treatment Regimens: LTBITreatment Regimens: Culture + Pulmonary TB DiseaseAlternative RegimensSlide Number 21Commonly Used 2nd line DrugsFluoroquinolonesInjectables (Aminoglycosides)Slide Number 25Other 2nd line DrugsCycloserineEthionamidePara-aminosalicylate (PAS)LinezolidAmoxicillin-ClavulanateClofazamineImipenem-cilastatinSlide Number 34Cross-ResistanceTreatment of Drug Resistant TBSlide Number 37Treatment of TB: Current Drugs in UseAdrian Gardner MD, MPHAssistant Professor of Medicine (Research)Alpert Medical School of Brown UniversityApril, 2011Outline• Principles• First-line drugs– Fixed-dose combinations• Commonly used Second-line drugs•Other Second-line drugsTB Drugs in UseIsoniazidRifampin/RifabutinEthambutolPyrazinamideFirst-lineOther 2nd-lineInjectablesQuinolonesOfloxacinLevofloxacinMoxifloxacinStreptomycinKanamycinAmikacinCapreomycinEthionamideCycloserinePASLinezolid Amox-ClavClofazamineImipenemClarithromycinPrinciples• Combination therapy– Eradicate TB infection– Protect against resistance– Prevent Relapse• Weight-based dosing– All first-line TB drugs are dosed based on patient’s weight• Directly Observed TherapyLimitations• Lack of good information on pediatric pharmacokinetics– Utility of serum drug levelsFirst Line DrugsIsoniazid (INH)• Mechanism: Affects cell wall synthesis (Bactericidal)• Dosing• Adults: 5 mg/kg/d to max 300mg/d; “high dose”: 900-1500 mg twice/thrice weekly•Children: 10-15 mg/kg/d to max 300mg/d; 20-30 mg/kg/dose twice/thrice weekly• Route: oral, IV, IM• Oral Preparations: 50/100/300mg scored tablets; 50mg/5ml solution (sorbitol)• Metabolism: Hepatic (cytochrome p450)• Adverse Reactions:• Hepatitis (age-related), peripheral neuropathy, hypersensitivity• Common Drug Interactions:• Seizure meds: ↑ phenytoin (dilantin); carbamazepine (tegretol)  hepatotoxicity• Special circumstances:• Safe during pregnancy, breastfeeding•Vitamin B6 (pyridoxine) supplementationRifampin• Mechanism: inhibits protein synthesis (Bactericidal)• Dosing• Adults: 10 mg/kg/d to max 600mg/d• Children: 10-20 mg/kg/d to max 600mg/d• Route: oral, IV• Oral Preparations: 150/300mg capsules• Metabolism: Hepatic (cytochrome p450)• Adverse Reactions:• Rash, pruritis, orange body fluids, hepatotoxicity, hematologic, GI upset, flu-like syndrome• Common Drug Interactions:• Many HIV medications (protease inhibitors), oral contraceptives, warfarin, methadone, corticosteroids• Special circumstances:• Safe during pregnancy, breastfeedinghttp://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/default.htmOther rifamycins• Rifabutin– 5mg/kg (max 300mg/d)–Fewer problematic drug interactions• Rifapentine– Drug interactions similar to rifampin– Once weekly regimen with INH for continuation phase for…• HIV neg adults, non-cavitary dz, cx neg at 2 monthsPyrazinamide (PZA)• Mechanism: Unclear (Bactericidal inside cells (acidic pH))• Dosing• Adults: 25 mg/kg/d to max 2 g/d• Children: 20-40 mg/kg/d• Route: oral• Oral Preparation: 500mg scored tablets• Metabolism: Renal• Adverse Reactions:• GI upset, hepatitis, gout (hyperuricemia), rash, photosensitivity • Common Drug Interactions: none• Special circumstances:• Dose not protect against resistance, allows for short-course therapy• Dose-adjust with renal failure• Dose based on lean body weight•? Safety in pregnancyEthambutol• Mechanism: Inhibits cell wall synthesis (mostly bacteriostatic)• Dosing• Adults: 15-20 mg/kg/d • Children: 15-20 mg/kg/d • Route: oral• Oral Preparations: 100/400mg scored tablets• Metabolism: Renal• Adverse Reactions:• Optic neuritis (dose-related)• Common Drug Interactions: none• Special circumstances:• Baseline and monthly visual acuity, color-vision testing• Safe during pregnancy, breastfeeding•Dose adjust for renal diseaseStreptomycin• Mechanism: Inhibits protein synthesis (bactericidal)• Dosing• Adults: 15 mg/kg/d 5-7x/wk, then 2-3x/wk• Children: 20-40 mg/kg/d• Route: IV, IM• Oral Preparations: none• Metabolism: Renal• Adverse Reactions:• Nephrotoxicity, Ototoxicity/Vestibular toxicity (increased with age, prolonged use), Electrolyte abnormalities (hypokalemia, hypomagnesemia), local pain• Common Drug Interactions:• Careful with other nephrotoxins (diuretics, NSAIDS)• Special circumstances:• Avoided during pregnancy (congenital deafness), can be used during breastfeeding• Monitor serum levels, renal function•Dose adjust for renal disease, obesity (ideal body weight + 40% excess weight)Example Case• 32 yo F with AFB smear+ pulmonary TBPast Medical History: noneCurrent Medications: OCPWeight: 130 lbs (59 kg)TB med dosing:R 59kg x 10mg/kg = 590 ~ 600 mgI 59 kg x 5 mg/kg = 295 ~ 300 mgZ 59kg x 25mg/kg = 1475 ~ 1500 mgE 59kg x 15-20mg/kg = 885-1180 ~ 1200 mg600mg/59kg = 10.17 mg/kg300mg/59kg = 5.08 mg/kg1500mg/59kg = 25.4 mg/kg1200mg/59kg = 20.3 mg/kgBarrier contraception!Fixed Dose Combinations (FDC)• USA– Rifamate (RH)– Rifater (RHZ)• Worldwide– Many different combinations with different names• Rifafour (RHZE)• Rifater (RHZ)• Rifinah (RH)•Ethizide (HE)Treatment Regimens: LTBIAdults ChildrenINH 5mg/kg/d x 9 mo INH 10mg/kg/d x 9 moMax 300 mg/dINH 900 mg twice weekly* x 9 moINH 20-30 mg/kg twice weekly* x 9 moMax 900 mg/dALTERNATIVE REGIMENRifampin 600 mg daily x 4 monthsRifampin 10-20 mg/kg/d x 6 monthsMax 600 mg/d*Twice weekly must be administered by DOT?Treatment Regimens: Culture + Pulmonary TB DiseaseInitial phase(minimum # doses)Continuation phase(minimum # doses)EfficacyRHZE 5-7 d/wk x 8 wks(40 – 56 doses)RH 5-7 d/wk x 18 wks(90 – 126 doses)RH 2-3x/wk x 18 wks(36 - 54 doses)H/RPT weekly x 18 wks (18 doses)97-99%98%97%(HIV neg, non-cavitary, cx neg)•Patients with cavitation on CXR, + culture at 2 months require 7 month continuation phase (total 9 months)•2x/wk regimens not recommended in resource-limited settings (smaller margin for safety if doses missed) or for advanced HIV+ patientsAlternative RegimensInitial phase(minimum # doses)Continuation phase(minimum # doses)NotesRHZE 5 - 7 d/wk x 2 wks (10 - 14 doses), then 2x/wk x 12 wks (24