What is the role of streptomycin and amikacin in the treatment of tuberculosis?

Role of Streptomycin and Amikacin in Tuberculosis Treatment

Overview of Injectable Agents in TB Treatment

Streptomycin and amikacin should only be included in multidrug-resistant tuberculosis (MDR-TB) regimens when susceptibility has been confirmed and when more effective or less toxic therapies cannot be assembled to achieve a total of five effective drugs. 1

These injectable aminoglycosides have historically played an important role in tuberculosis treatment but are now considered second-line options due to their toxicity profiles and the availability of newer, less toxic agents.

Current Recommendations

Streptomycin

• Primarily used for drug-resistant TB when susceptibility is confirmed
• Dosing:
  • Adults: 15 mg/kg/day (maximum 1g/day) initially, then 2-3 times weekly 1
  • Children: 20-40 mg/kg/day (maximum 1g/day) 1
  • Reduced dosing (10 mg/kg/day) for patients over 59 years 1
• Should not be used in pregnancy due to risk of fetal hearing loss 1
• Limited usefulness in patients likely to have acquired TB in high-incidence countries due to resistance rates 1

Amikacin

• Slightly more effective than streptomycin in MDR-TB treatment
• Compared to streptomycin, amikacin shows:
  • Increased treatment success (aOR 1.7; 95% CI 1.3-2.2) 1
  • No significant difference in mortality (aOR 1.0; 95% CI 0.8-1.2) 1
• Particularly effective in quinolone-resistant TB and XDR-TB cases 1

Comparative Effectiveness

When comparing injectable agents:

• Amikacin is superior to kanamycin and capreomycin in treatment success rates and mortality 1
• Streptomycin shows better outcomes than kanamycin and capreomycin 1
• Current guidelines recommend against using kanamycin or capreomycin in MDR-TB treatment 1

Toxicity Considerations

Both drugs have significant toxicity profiles that limit their use:

1. Ototoxicity:

   • Can affect vestibular (balance) or cochlear (hearing) function
   • Risk increases with cumulative dose and duration
   • Hearing impairment can exceed 50% in some series 1
   • May be irreversible even after discontinuation

2. Nephrotoxicity:

   • Less common with streptomycin than with amikacin 1
   • Renal dysfunction approaches 50% in some reports 1
   • Risk factors include older age, dehydration, prior aminoglycoside treatment, and coexisting renal disease

3. Other adverse effects:

   • Electrolyte disturbances
   • Neurotoxicity (circumoral parasthesias with streptomycin) 1

Monitoring Requirements

Due to toxicity concerns, close monitoring is essential:

• Baseline audiogram, vestibular testing, and serum creatinine
• Monthly assessment of renal function
• Regular questioning about auditory or vestibular symptoms
• Repeat audiogram if symptoms of eighth nerve toxicity develop 1

Current Place in Therapy

The 2019-2021 guidelines from ATS/CDC/ERS/IDSA and WHO suggest:

1. Limited role: Use only when susceptibility is confirmed and more effective or less toxic drugs cannot be assembled to create an effective regimen 1

2. Duration of treatment:

   • When included in longer MDR-TB regimens, an intensive phase of 6-7 months is suggested 1
   • Total treatment duration typically 18-20 months for MDR-TB 1

3. Hierarchy of drug selection:

   • Newer agents like bedaquiline, linezolid, and fluoroquinolones are preferred before considering injectable agents 1
   • Streptomycin or amikacin should be considered only after exhausting other options 1

Special Considerations

1. Drug resistance patterns:

   • Cross-resistance between aminoglycosides is common but not universal 2
   • Some strains with low-level streptomycin resistance (via gidB mutations) may still respond to higher doses 3

2. Penetration into lesions:

   • Limited but rapid penetration to TB disease sites 4
   • This may explain their modest clinical utility

3. Pediatric use:

   • Injectable agents have shown improved treatment success in children with confirmed MDR-TB (aOR 2.94; 95% CI 1.05-8.28) 1
   • Careful dose adjustment and monitoring required

Practical Algorithm for Use

1. First determine if injectable agents are needed:

   • Confirm MDR-TB diagnosis
   • Attempt to construct a regimen with 5 effective drugs using oral agents first
   • Consider injectables only if unable to construct an adequate regimen

2. If injectable needed, choose between streptomycin and amikacin:

   • Check susceptibility testing results
   • Prefer amikacin if both are susceptible (higher treatment success)
   • Consider streptomycin if amikacin resistance is present

3. Assess patient factors before initiating:

   • Age (reduced dose for elderly)
   • Renal function (adjust dosing in renal impairment)
   • Pregnancy status (contraindicated)
   • Ability to monitor for toxicity

4. Implement monitoring protocol:

   • Baseline and monthly audiometry
   • Regular renal function tests
   • Electrolyte monitoring
   • Clinical assessment for vestibular symptoms

Conclusion

While streptomycin and amikacin remain in the armamentarium against drug-resistant TB, their role has diminished with the advent of newer, less toxic agents. They should be reserved for cases where susceptibility is confirmed and other options are limited, with careful attention to monitoring for their significant toxicities.