1. Second-line Anti-TB drugs
Session 5

2. 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)

3. Kanamycin (Km) Group 2 — Injectable Dose: 1 g IM/IV (15-20 mg/kg)
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

4. 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)

5. 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 5

6. Ofloxacin (Ofx) Group 3 — Fluoroquinolone Dose: 800 mg daily
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

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 infections
Side effects
Generally well-tolerated
GI upset, rash, CNS disturbance
Adjust dose in renal failure

8. Moxifloxacin (Mfx) Group 3 — Fluoroquinolone Dose: 400 mg daily
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

9. Ethionamide (Eto) Group 4 — Other second line drugs
Derivative of isonicotinic acid (same family as isoniazid)
Dose: 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 9

10. Prothionamide (Pto) Group 4 — Other second line drugs
Structurally similar to ethionamide
Dose: mg daily in divided doses
Overall side effect profile similar to ethionamide
Slightly less GI side effects
Complete cross-resistance with ethionamide 10

11. Cycloserine (Cs) Group 4 — Other second line drugs
Alanine analogue
Interferes with cell-wall proteoglycan synthesis
Dose: mg daily in divided doses
Side effects:
Seizures, psychosis, depression, irritability, headache
Renally excreted
Effective CNS penetration
Co-administer B6 11

12. 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: 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 12

13. 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 13

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 acid
Clofazamine
Linezolid
High dose isoniazid
Imipenem

15. 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

16. Clofazimine (CFZ) Group 5 Usual adult dose is 100 mg daily
Substituted iminophenazine
Usual adult dose is 100 mg daily
Side effects
Bronzing of skin
Malabsorption
Abdominal pain (can be severe)

17. Linezolid (LZD) Group 5 Dosing
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.

18. 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

19. 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

20. 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

21. 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: 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

22. Global TB drug pipeline

23. 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.

24. 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).