Second-line Anti-TB drugs

Session 5

1

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) USAID TB CARE II PROJECT

Kanamycin (Km)

GROUP 2 — INJECTABLE

• • Aminoglycoside Interferes with protein synthesis through disruption of ribosome

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

• • • Nephrotoxicity Ototoxicity Electrolyte wasting

Adjust dose for renal failure USAID TB CARE II PROJECT

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 ototoxicity

High cross-resistance with kanamycin Adjust dose in renal failure (same as kanamycin) USAID TB CARE II PROJECT

Capreomycin (Cm)

GROUP 2 — INJECTABLE

• • Polypeptide Structurally and functionally similar to aminoglycosides

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

• same as Km/Amk

Some cross-resistance with Km/Amk Adjust dose for renal failure USAID TB CARE II PROJECT

Ofloxacin (Ofx)

GROUP 3 — FLUOROQUINOLONE

• Inhibits DNA-gyrase

Dose: 800 mg daily Side effects

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

Avoid antacids around time of ingestion (reduces absorption) Near complete cross-resistance with other fluoroquinolones USAID TB CARE II PROJECT

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 infections

Side effects

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

Adjust dose in renal failure USAID TB CARE II PROJECT

Moxifloxacin (Mfx)

GROUP 3 — FLUOROQUINOLONE

• May be more active than earlier generation quinolones

Dose: 400 mg daily Near 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

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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 neuropathy

Partial cross-resistance with isoniazid, complete with prothionamide Hepatically excreted Co-administer vitamin B6 USAID TB CARE II PROJECT

Prothionamide (Pto)

GROUP 4 — OTHER SECOND LINE DRUGS

• Structurally similar to ethionamide

Dose: 500-1000 mg daily in divided doses Overall side effect profile

•

similar to ethionamide

Slightly less GI side effects

Complete cross-resistance with ethionamide USAID TB CARE II PROJECT

Cycloserine (Cs)

GROUP 4 — OTHER SECOND LINE DRUGS

• • Alanine analogue Interferes with cell-wall proteoglycan synthesis

Dose: 500-1000 mg daily in divided doses Side effects:

• Seizures, psychosis, depression, irritability, headache

Renally excreted Effective CNS penetration Co-administer B6 USAID TB CARE II PROJECT

Terizidone (Trd)

GROUP 4 — OTHER SECOND LINE DRUGS

• Structure is composed of two connected molecules of cycloserine • Commonly used in South Africa in place of cycloserine

Dose: 500-1000 mg daily in divided doses 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

USAID TB CARE II PROJECT

Para-aminosalicylic acid (PAS)

GROUP 4 — OTHER SECOND LINE DRUGS

• 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 USAID TB CARE II PROJECT

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 acid Clofazamine Linezolid High dose isoniazid Imipenem

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Amoxicillin-clavulanic acid (AMX-CLV)

GROUP 5

• Beta-lactam antibiotic with beta lactamase inhibitor

Dose

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

Side effects

• GI upset, rash

Contraindicated: Penicillin allergy USAID TB CARE II PROJECT

Clofazimine (CFZ)

GROUP 5

• Substituted iminophenazine

Usual adult dose is 100 mg daily Side effects

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

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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.

USAID TB CARE II PROJECT

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

USAID TB CARE II PROJECT

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

USAID TB CARE II PROJECT

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

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Imipenem/Cilastin

GROUP 5 —BETA LACTAM/CARBAPENEM In vitro activity —very limited clinical experience Dosing

• • 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

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Global TB drug pipeline

USAID TB CARE II PROJECT

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.

USAID TB CARE II PROJECT

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 documented

Fluoroquinolones

• 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).

USAID TB CARE II PROJECT