Second-line Anti-TB drugs

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Second-line Anti-TB drugsSession 5

USAID TB CARE II PROJECT

The five drug groups

• Group 1: First-line oral drugs• Group 2: Injectables• Group 3: Fluoroquinolones• Group 4: Other second-line drugs• Group 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)


Kanamycin (Km)

GROUP 2 — INJECTABLE• Aminoglycoside• Interferes with protein synthesis

through disruption of ribosomeDose: 1 g IM/IV (15-20 mg/kg)Side effects:

• Nephrotoxicity• Ototoxicity• Electrolyte wasting

Adjust dose for renal failure


Amikacin (Amk)

GROUP 2 — INJECTABLE• Aminoglycoside• Highly similar to kanamycin (can

be essentially considered the same drug)

Dose: 1 g IM/IV (15-20 mg/kg) daily

Side effects: • Same as kanamycin; renal failure

and ototoxicityHigh cross-resistance with

kanamycinAdjust dose in renal failure

(same as kanamycin)


Capreomycin (Cm)

GROUP 2 — INJECTABLE• Polypeptide • Structurally and functionally

similar to aminoglycosidesDose: 1 g IM/IV (15-20 mg/kg)

dailySide effects

• same as Km/AmkSome cross-resistance with

Km/AmkAdjust dose for renal failure


Ofloxacin (Ofx)

GROUP 3 — FLUOROQUINOLONE

• Inhibits DNA-gyraseDose: 800 mg dailySide effects

• Generally well-tolerated• GI upset, rash, CNS disturbance

Avoid antacids around time of ingestion (reduces absorption)

Near complete cross-resistance with other fluoroquinolones


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 effects

• Generally well-tolerated• GI upset, rash, CNS disturbance

Adjust dose in renal failure


Moxifloxacin (Mfx)

GROUP 3 — FLUOROQUINOLONE

• May be more active than earlier generation quinolones

Dose: 400 mg dailyNear complete cross-resistance

with other fluoroquinolones• Moxifloxacin may have limited

efficacy against some strains resistant to ofloxacin

No dose adjustment in renal failure• Hepatically cleared


Ethionamide (Eto)

GROUP 4 — OTHER SECOND LINE DRUGS

• Derivative of isonicotinic acid (same family as isoniazid)

Dose: 500-1000 mg daily in divided doses

Side effects• GI upset, hypothyroidism,

peripheral neuropathyPartial cross-resistance with

isoniazid, complete with prothionamide

Hepatically excretedCo-administer vitamin B6


Prothionamide (Pto)


• Structurally similar to ethionamide


Overall side effect profile similar to ethionamide• Slightly less GI side effects

Complete cross-resistance with ethionamide


Cycloserine (Cs)


• Alanine analogue• Interferes with cell-wall

proteoglycan synthesisDose: 500-1000 mg daily in

divided dosesSide effects:

• Seizures, psychosis, depression, irritability, headache

Renally excretedEffective CNS penetrationCo-administer B6


Terizidone (Trd)


• Structure is composed of two connected molecules of cycloserine

• Commonly used in South Africa in place of cycloserine


Possibly less side effects than cycloserine

Not yet recommended by the WHO• There is less information on terizidone

than cycloserine and no direct studies comparing the two


Para-aminosalicylic acid (PAS)


• Various formulations; delayed-release microcapsules (PASER) best tolerated

Dose of PASER is 4 g (1 sachet) twice daily

Side effects• GI upset, hypothyroidism• Hepatitis, electrolyte abnormalities

Hepatic metabolism, renal excretion

Administer with acidic food or drink


Group 5: Possible reinforcing agentsMinimal clinical data to support use in MDR-TB therapy. Should only be used in cases of extreme drug resistance (XDR-

TB):• Amoxicillin/clavulanic acid• Clofazamine• Linezolid• High dose isoniazid• Imipenem


Amoxicillin-clavulanic acid (AMX-CLV)

GROUP 5• Beta-lactam antibiotic with beta-

lactamase inhibitorDose

• 1000/250 mg twice daily or• 875/125mg twice daily

Side effects• GI upset, rash

Contraindicated: Penicillin allergy


Clofazimine (CFZ)

GROUP 5• Substituted iminophenazine

Usual adult dose is 100 mg daily

Side effects• Bronzing of skin• Malabsorption• Abdominal pain (can be severe)


Linezolid (LZD)GROUP 5

• Oxazolidinone: inhibits protein synthesis, interacting with ribosomal RNA

Dosing • Coated tablets: 400 and 600 mg• Intravenous solution: 2 mg/ml;

100, 200, or 300 mg bags• Usual 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.


Linezolid (LZD) (Continued)

Side effects• Generally 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


Linezolid (LZD) (Continued)

Monitoring • CBC 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 diarrhea• Unusual bleeding or bruising• Extreme tiredness or weakness• Numbness, tingling, or burning pain in your hands, arms, legs, or

feet• Change in visual acuity, vision blurring, or visual field defect • Headache, nausea, or vomiting


High-dose isoniazid (H)

GROUP 5 (AT HIGH DOSES)Dosing

• 16 to 18 mg/kg per day, typically 600 mg to 1200 mg per week

• Some clinicians give it three times a week instead of daily at the 16 to 18 mg/kg dosing


Imipenem/Cilastin

GROUP 5—BETA-LACTAM/CARBAPENEMIn vitro activity—very limited clinical

experienceDosing

• Adults: 1000 mg IV every 12 hours• In children, meropenem preferred: 20-

40 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 meningitis

Side effects• Diarrhea, nausea, vomiting• Seizure noted in CNS infections


Global TB drug pipeline


Weight-based dosing

Second-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.


Cross-resistance

Aminoglycosides• Minimal cross resistance between SM and other aminoglycosides• KM and AM have almost complete cross resistance• Cross resistance between CM and KM and/or AM has been

documentedFluoroquinolones

• Mutations 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).

Second-line Anti-TB drugs

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