What is the dosage of second-line injectables, such as amikacin (amikacin), kanamycin (kanamycin), and capreomycin (capreomycin), in the treatment of tuberculosis (TB)?

Second-Line Injectable Dosages in Tuberculosis

For drug-resistant tuberculosis, use amikacin 15 mg/kg/day (maximum 1 g/day) or capreomycin 15 mg/kg/day (maximum 1 g/day) as single daily doses 5-7 days per week initially, then reduce to 2-3 times weekly after 2-4 months or culture conversion. 1

Standard Dosing Regimens

Amikacin and Kanamycin

• Adults: 15 mg/kg/day (maximum 1 g/day) intramuscularly or intravenously as a single daily dose, given 5-7 days per week initially 1
• Elderly (>59 years): Reduce dose to 10 mg/kg/day (maximum 750 mg) 1
• Children: 15-30 mg/kg/day (maximum 1 g/day) as single daily dose 1
• Continuation phase: After 2-4 months or culture conversion, reduce frequency to 2-3 times weekly while maintaining the 12-15 mg/kg per dose 1

Capreomycin

• Adults: 15 mg/kg/day (maximum 1 g/day) as single daily dose 5-7 days per week initially 1
• Elderly (>59 years): Reduce to 10 mg/kg/day (maximum 750 mg) 1
• Children: 15-30 mg/kg/day (maximum 1 g/day) as single daily or twice weekly dose 1
• Continuation phase: After 2-4 months or culture conversion, reduce to 2-3 times weekly at 12-15 mg/kg per dose 1

Critical Dosing Principles

Concentration-Dependent Killing

Maintain the full mg/kg dose (12-15 mg/kg) even when reducing frequency to preserve the concentration-dependent bactericidal effect—smaller doses reduce efficacy 1. This principle applies particularly to patients with renal insufficiency where frequency is reduced but individual doses remain high 1.

Special Populations

Renal Insufficiency and Dialysis

• Reduce dosing frequency to 2-3 times weekly, but maintain dose at 12-15 mg/kg per administration 1, 2
• Administer after dialysis to facilitate directly observed therapy and prevent premature drug removal 1, 2
• Monitor serum drug concentrations to avoid toxicity 1, 2
• Dosing adjustments are essential because these drugs are almost exclusively cleared by the kidneys 1

Hepatic Disease

• No dose adjustments necessary for amikacin, kanamycin, or capreomycin 1
• However, patients with severe hepatic disease have increased risk of hepato-renal syndrome and require close renal function monitoring when receiving amikacin/kanamycin 1

Comparative Effectiveness and Drug Selection

Choose amikacin or streptomycin over kanamycin or capreomycin when drug susceptibility testing supports their use. Recent meta-analysis of 12,030 patients showed amikacin was associated with 6 more cures per 100 patients compared to kanamycin, and 9 more cures compared to capreomycin 3. Streptomycin performed even better, with 10 more cures and 10 fewer deaths per 100 patients compared to capreomycin 3.

Notably, patients treated with kanamycin or capreomycin did not fare better than those receiving no injectable drugs, while amikacin and streptomycin showed clear benefits 3.

Monitoring Requirements

Baseline Assessment

• Audiogram and vestibular testing 1
• Romberg testing 1
• Serum creatinine measurement 1
• For capreomycin: baseline potassium and magnesium levels 1

Ongoing Monitoring

• Monthly: Renal function assessment and questioning about auditory/vestibular symptoms 1, 4
• For capreomycin: Monthly serum potassium and magnesium measurements 1
• Repeat audiogram/vestibular testing if symptoms of eighth nerve toxicity develop 1, 4
• Serum drug concentrations when available, particularly for amikacin 1, 2
  • Target peak concentrations: <35 mcg/mL 5
  • Target trough concentrations: <10 mcg/mL 5

Toxicity Profile and Drug Choice

Ototoxicity

Capreomycin causes significantly less ototoxicity than amikacin. In UK cohorts, patients starting amikacin were 5 times more likely to experience ototoxicity compared to capreomycin (HR 5.2; 95% CI 1.2-22.6) 6. Overall, 55% of patients experienced ototoxicity, with 40% discontinuing the injectable due to hearing loss 6.

• Amikacin: High-frequency hearing loss in up to 24% of patients, with higher rates at higher cumulative doses 1, 4
• Kanamycin: Similar ototoxicity profile to amikacin but less vestibular dysfunction than streptomycin 1
• Capreomycin: Vestibular disturbances, tinnitus, and deafness occur more often in elderly or those with preexisting renal impairment 1

Nephrotoxicity

• Amikacin/Kanamycin: Renal impairment in 8.7% of patients, higher with elevated baseline creatinine or concurrent nephrotoxic agents 1
• Capreomycin: Significant renal toxicity requiring discontinuation in 20-25% of patients; proteinuria is common 1
• Capreomycin causes more electrolyte disturbances: 14% of patients stopped capreomycin due to recurrent hypokalemia and hypomagnesemia, compared to less frequent electrolyte loss with amikacin 6

Clinical Pitfalls to Avoid

• Never reduce the mg/kg dose when adjusting for renal insufficiency—only reduce frequency while maintaining 12-15 mg/kg per dose to preserve bactericidal activity 1
• Never administer before dialysis—this causes premature drug removal and treatment failure 2
• Do not use in pregnancy—all second-line injectables cause fetal nephrotoxicity and congenital hearing loss 1
• Avoid concurrent loop diuretics—significantly increases ototoxicity risk 1
• Monitor cumulative dose—ototoxicity risk increases substantially above 100-120 g total cumulative dose 1, 4

Duration of Injectable Therapy

• Standard MDR-TB: Continue injectable for at least 2-4 months after culture conversion, typically 6-8 months total 1
• XDR-TB: May require prolonged injectable use up to 18-24 months 6
• Treatment duration depends on efficacy of companion drugs in the regimen 1