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)
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
USAID TB CARE II PROJECT
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
USAID TB CARE II PROJECT
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)
USAID TB CARE II PROJECT
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
USAID TB CARE II PROJECT
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
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).