2 The five drug groups Group 1: First-line oral drugs Group 2: InjectablesGroup 3: FluoroquinolonesGroup 4: Other second-line drugsGroup 5: Possible reinforcing drugs (drugs with unclear efficacy)An MDR-TB treatment regimen requires the use of at least four active medications against TB (but often involves five)
3 Kanamycin (Km) Group 2 — Injectable Dose: 1 g IM/IV (15-20 mg/kg) AminoglycosideInterferes with protein synthesis through disruption of ribosomeDose: 1 g IM/IV (15-20 mg/kg)Side effects:NephrotoxicityOtotoxicityElectrolyte wastingAdjust dose for renal failure
4 Amikacin (Amk) Group 2 — Injectable AminoglycosideHighly similar to kanamycin (can be essentially considered the same drug)Dose: 1 g IM/IV (15-20 mg/kg) dailySide effects:Same as kanamycin; renal failure and ototoxicityHigh cross-resistance with kanamycinAdjust dose in renal failure (same as kanamycin)
5 Capreomycin (Cm) Group 2 — Injectable PolypeptideStructurally and functionally similar to aminoglycosidesDose: 1 g IM/IV (15-20 mg/kg) dailySide effectssame as Km/AmkSome cross-resistance with Km/AmkAdjust dose for renal failure5
6 Ofloxacin (Ofx) Group 3 — Fluoroquinolone Dose: 800 mg daily Inhibits DNA-gyraseDose: 800 mg dailySide effectsGenerally well-toleratedGI upset, rash, CNS disturbanceAvoid antacids around time of ingestion (reduces absorption)Near complete cross-resistance with other fluoroquinolones
7 Levofloxacin (Lfx) Group 3 — Fluoroquinolone Dose: 750 mg daily for <50 kg (1000 mg daily for > 75kg)A higher dose for tuberculosis is used than for other infectionsSide effectsGenerally well-toleratedGI upset, rash, CNS disturbanceAdjust dose in renal failure
8 Moxifloxacin (Mfx) Group 3 — Fluoroquinolone Dose: 400 mg daily May be more active than earlier generation quinolonesDose: 400 mg dailyNear complete cross-resistance with other fluoroquinolonesMoxifloxacin may have limited efficacy against some strains resistant to ofloxacinNo dose adjustment in renal failureHepatically cleared
9 Ethionamide (Eto) Group 4 — Other second line drugs Derivative of isonicotinic acid (same family as isoniazid)Dose: mg daily in divided dosesSide effectsGI upset, hypothyroidism, peripheral neuropathyPartial cross-resistance with isoniazid, complete with prothionamideHepatically excretedCo-administer vitamin B69
10 Prothionamide (Pto) Group 4 — Other second line drugs Structurally similar to ethionamideDose: mg daily in divided dosesOverall side effect profile similar to ethionamideSlightly less GI side effectsComplete cross-resistance with ethionamide10
11 Cycloserine (Cs) Group 4 — Other second line drugs Alanine analogueInterferes with cell-wall proteoglycan synthesisDose: mg daily in divided dosesSide effects:Seizures, psychosis, depression, irritability, headacheRenally excretedEffective CNS penetrationCo-administer B611
12 Terizidone (Trd) Group 4 — Other second line drugs Structure is composed of two connected molecules of cycloserineCommonly used in South Africa in place of cycloserineDose: mg daily in divided dosesPossibly less side effects than cycloserineNot yet recommended by the WHOThere is less information on terizidone than cycloserine and no direct studies comparing the two12
13 Para-aminosalicylic acid (PAS) Group 4 — Other second line drugsVarious formulations; delayed-release microcapsules (PASER) best toleratedDose of PASER is 4 g (1 sachet) twice dailySide effectsGI upset, hypothyroidismHepatitis, electrolyte abnormalitiesHepatic metabolism, renal excretionAdminister with acidic food or drink13
14 Group 5: Possible reinforcing agents Minimal clinical data to support use in MDR-TB therapy.Should only be used in cases of extreme drug resistance (XDR-TB):Amoxicillin/clavulanic acidClofazamineLinezolidHigh dose isoniazidImipenem
16 Clofazimine (CFZ) Group 5 Usual adult dose is 100 mg daily Substituted iminophenazineUsual adult dose is 100 mg dailySide effectsBronzing of skinMalabsorptionAbdominal pain (can be severe)
17 Linezolid (LZD) Group 5 Dosing Oxazolidinone: inhibits protein synthesis, interacting with ribosomal RNADosingCoated tablets: 400 and 600 mgIntravenous solution: 2 mg/ml; 100, 200, or 300 mg bagsUsual dose: 600 mg twice daily.Some case series have successfully used daily half dosing (600 mg once daily) to decrease toxicity and maintain efficacy, however neuropathic reactions seem to be related to duration of therapy rather than dose.
18 Linezolid (LZD) (Continued) Side effectsGenerally well tolerated for treatment courses ≤28 days.Common: diarrhea, nausea, headache, insomnia, and rash.More serious:myelosuppression (generally reversible with discontinuation of the drug)optic neuropathy (usually resolved over time with drug discontinuation)peripheral neuropathy (possibly irreversible).Rare: hypertension, lactic acidosis, pancreatitis
19 Linezolid (LZD) (Continued) MonitoringCBC weekly during the initial period, then monthly, and then as needed based on symptoms.There is little clinical experience with prolonged use.Visual function should be monitored in all patients taking linezolid for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy.Alerting symptoms:Black, tarry stools or severe diarrheaUnusual bleeding or bruisingExtreme tiredness or weaknessNumbness, tingling, or burning pain in your hands, arms, legs, or feetChange in visual acuity, vision blurring, or visual field defectHeadache, nausea, or vomiting
20 High-dose isoniazid (H) Group 5 (at high doses)Dosing16 to 18 mg/kg per day, typically 600 mg to 1200 mg per weekSome clinicians give it three times a week instead of daily at the 16 to 18 mg/kg dosing
21 Imipenem/Cilastin Group 5—Beta-lactam/carbapenem In vitro activity—very limited clinical experienceDosingAdults: 1000 mg IV every 12 hoursIn children, meropenem preferred: mg/kg/dose IV every 8 hours up to 2 grams per day (high rates of seizures were seen in children treated with imipenem for TB meningitisSide effectsDiarrhea, nausea, vomitingSeizure noted in CNS infections
23 Weight-based dosingSecond-line anti-TB drugs are usually dosed based on weight according to the next three slides. If a patient gains weight during the treatment they move up a weight band and the dosage of drugs should be adjusted accordingly. Example: A patient who starts treatment at 45 kg will be started on 500 mg of ethionamide. Once the patient’s weight increases above 50 kg the dose should be adjusted to 750 mg per day.
24 Cross-resistance Aminoglycosides Minimal cross resistance between SM and other aminoglycosidesKM and AM have almost complete cross resistanceCross resistance between CM and KM and/or AM has been documentedFluoroquinolonesMutations that confer resistance to one fluoroquinolone will confer some degree of resistance to all, but the clinical significance of this is unclear (e.g. moxifloxacin may have limited efficacy against some strains resistant to ofloxacin).