Transcript Session 5 Presentation 2: Second-line Anti

Second-line Anti-TB drugs
Session 5
1
The five drug groups
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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)
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Kanamycin (Km)
GROUP 2 — INJECTABLE
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Aminoglycoside
Interferes with protein synthesis
through disruption of ribosome
Dose: 1 g IM/IV (15-20 mg/kg)
Side effects:
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Nephrotoxicity
Ototoxicity
Electrolyte wasting
Adjust dose for renal failure
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Amikacin (Amk)
GROUP 2 — INJECTABLE
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Aminoglycoside
Highly similar to kanamycin (can
be essentially considered the
same drug)
Dose: 1 g IM/IV (15-20 mg/kg)
daily
Side effects:
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Same as kanamycin; renal failure
and ototoxicity
High cross-resistance with
kanamycin
Adjust dose in renal failure
(same as kanamycin)
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Capreomycin (Cm)
GROUP 2 — INJECTABLE
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Polypeptide
Structurally and functionally
similar to aminoglycosides
Dose: 1 g IM/IV (15-20 mg/kg)
daily
Side effects
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same as Km/Amk
Some cross-resistance with
Km/Amk
Adjust dose for renal failure
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Ofloxacin (Ofx)
GROUP 3 —
FLUOROQUINOLONE
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Inhibits DNA-gyrase
Dose: 800 mg daily
Side effects
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Generally well-tolerated
GI upset, rash, CNS disturbance
Avoid antacids around time of
ingestion (reduces absorption)
Near complete cross-resistance
with other fluoroquinolones
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Levofloxacin (Lfx)
GROUP 3 —
FLUOROQUINOLONE
Dose: 750 mg daily for <50 kg
(1000 mg daily for > 75kg)
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A higher dose for tuberculosis is
used than for other infections
Side effects
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Generally well-tolerated
GI upset, rash, CNS disturbance
Adjust dose in renal failure
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Moxifloxacin (Mfx)
GROUP 3 —
FLUOROQUINOLONE
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May be more active than earlier
generation quinolones
Dose: 400 mg daily
Near complete cross-resistance
with other fluoroquinolones
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Moxifloxacin may have limited
efficacy against some strains
resistant to ofloxacin
No dose adjustment in renal
failure
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Hepatically cleared
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Ethionamide (Eto)
GROUP 4 — OTHER SECOND
LINE DRUGS
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Derivative of isonicotinic acid
(same family as isoniazid)
Dose: 500-1000 mg daily in
divided doses
Side effects
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GI upset, hypothyroidism,
peripheral neuropathy
Partial cross-resistance with
isoniazid, complete with
prothionamide
Hepatically excreted
Co-administer vitamin B6
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Prothionamide (Pto)
GROUP 4 — OTHER SECOND
LINE DRUGS
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Structurally similar to
ethionamide
Dose: 500-1000 mg daily in
divided doses
Overall side effect profile
similar to ethionamide
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Slightly less GI side effects
Complete cross-resistance with
ethionamide
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Cycloserine (Cs)
GROUP 4 — OTHER SECOND
LINE DRUGS
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Alanine analogue
Interferes with cell-wall
proteoglycan synthesis
Dose: 500-1000 mg daily in
divided doses
Side effects:
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Seizures, psychosis, depression,
irritability, headache
Renally excreted
Effective CNS penetration
Co-administer B6
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Terizidone (Trd)
GROUP 4 — OTHER SECOND LINE
DRUGS
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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
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There is less information on terizidone
than cycloserine and no direct studies
comparing the two
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Para-aminosalicylic acid (PAS)
GROUP 4 — OTHER SECOND
LINE DRUGS
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Various formulations; delayedrelease microcapsules (PASER)
best tolerated
Dose of PASER is 4 g (1 sachet)
twice daily
Side effects
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GI upset, hypothyroidism
Hepatitis, electrolyte abnormalities
Hepatic metabolism, renal
excretion
Administer with acidic food or
drink
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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 (XDRTB):
• Amoxicillin/clavulanic acid
• Clofazamine
• Linezolid
• High dose isoniazid
• Imipenem
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Amoxicillin-clavulanic acid (AMX-CLV)
GROUP 5
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Beta-lactam antibiotic with betalactamase inhibitor
Dose
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1000/250 mg twice daily or
875/125mg twice daily
Side effects
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GI upset, rash
Contraindicated: Penicillin
allergy
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Clofazimine (CFZ)
GROUP 5
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Substituted iminophenazine
Usual adult dose is 100 mg
daily
Side effects
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Bronzing of skin
Malabsorption
Abdominal pain (can be severe)
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Linezolid (LZD)
GROUP 5
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Oxazolidinone: inhibits protein
synthesis, interacting with ribosomal
RNA
Dosing
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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.
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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
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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
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High-dose isoniazid (H)
GROUP 5 (AT HIGH DOSES)
Dosing
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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—BETALACTAM/CARBAPENEM
In vitro activity—very limited clinical
experience
Dosing
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Adults: 1000 mg IV every 12 hours
In children, meropenem preferred: 2040 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
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Diarrhea, nausea, vomiting
Seizure noted in CNS infections
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Global TB drug pipeline
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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.
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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).
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