What are the alternatives to fluoroquinolones (FQs) for treating tuberculosis (TB)?

Alternatives to Fluoroquinolones for Treating Tuberculosis

Moxifloxacin or levofloxacin should be included in a regimen to achieve a total of five effective drugs for the treatment of patients with multidrug-resistant tuberculosis (MDR-TB), but when fluoroquinolones cannot be used, several effective alternatives exist. 1

First-Line Alternatives to Fluoroquinolones

• Injectable agents (Group 2) are the primary alternatives to fluoroquinolones and include aminoglycosides (streptomycin, amikacin, kanamycin) and the polypeptide capreomycin 1
• These injectable agents block protein synthesis at the ribosomal level and demonstrate concentration-dependent killing, a postantibiotic effect, and synergism with other antibacterial drugs 1
• Aminoglycosides are administered parenterally through slow intravenous infusion or intramuscular injection due to their poor absorption from the gastrointestinal tract and limited ability to cross lipid membranes 1

Second-Line Oral Alternatives

• Ethionamide or prothionamide (15-20 mg/kg) can be used if no inhA mutation is documented, as their metabolic pathways are similar and cross-resistance is total 1
• Cycloserine or terizidone (15-20 mg/kg) can be added, but only one of these two should be used due to complete cross-resistance 1
• Para-aminosalicylic acid (PAS) (150 mg/kg) can be included if there are not sufficient effective drugs, though gastrointestinal intolerance may limit its use 1

Building an Effective Regimen Without Fluoroquinolones

When designing a regimen without fluoroquinolones, follow this approach:

1. Include any first-line drugs to which the organism is still susceptible 1

   • Even when the organism is resistant to isoniazid, higher doses (15–20 mg/kg) may overcome resistance in some cases 1

2. Add an injectable agent from Group 2 1

   • Kanamycin (15-30 mg/kg)
   • Amikacin (15-22.5 mg/kg)
   • Capreomycin (15-30 mg/kg)
   • Streptomycin (15-20 mg/kg)

3. Add drugs from Group 4 until you have at least four likely effective drugs 1

   • Ethionamide/prothionamide
   • Cycloserine/terizidone
   • PAS

4. Consider Group 5 agents if needed 1

   • Clofazimine (3-5 mg/kg)
   • Linezolid
   • Other agents with unclear efficacy against TB

Special Considerations

• For patients with HIV coinfection, careful attention must be paid to potential drug-drug interactions, especially if rifampin is included in the regimen 1
• For children, the long-term use of fluoroquinolones has traditionally been limited due to concerns about effects on bone and cartilage growth, making alternative regimens particularly important 1
• When treating MDR-TB without fluoroquinolones, extended treatment duration (18-24 months) may be necessary to lessen the risk of relapse 1
• For patients with extensive disease, the use of additional agents may be prudent to lessen the risk of failure and additional acquired drug resistance 1
• Resectional surgery may be appropriate in some cases of MDR-TB when fluoroquinolones cannot be used 1

Monitoring and Adverse Effects

• Injectable agents require monitoring for ototoxicity and nephrotoxicity 1
• Ethionamide/prothionamide can cause gastrointestinal disturbance, metallic taste, and hypothyroidism 1
• Cycloserine/terizidone may produce neurological and psychological effects 1
• PAS commonly causes gastrointestinal intolerance and may lead to hypothyroidism and hepatitis 1

Common Pitfalls to Avoid

• Avoid using a single new drug in a failing regimen, as this can lead to additional resistance 1
• Do not rely on drug susceptibility testing alone; consider the patient's treatment history and potential cross-resistance patterns 1
• Remember that high-level isoniazid resistance (katG mutations) differs from low-level resistance (inhA promoter mutations), with the latter often conferring ethionamide resistance as well 1
• Ensure adequate dosing of all drugs, as underdosing can lead to treatment failure and development of additional resistance 1