Does the combination of bedaquiline, pretomanid, linezolid, moxifloxacin, and cycloserine cause gastrointestinal (GI) upset?

Gastrointestinal Side Effects of Bedaquiline, Pretomanid, Linezolid, Moxifloxacin, and Cycloserine

Yes, the combination of bedaquiline, pretomanid, linezolid, moxifloxacin, and cycloserine commonly causes gastrointestinal upset, with multiple drugs in this regimen having overlapping GI adverse effects. 1

Individual Drug GI Side Effect Profiles

Bedaquiline

• Common GI effects: Nausea 1
• Less common: Abdominal pain

Pretomanid

• Limited specific data on GI effects in the guidelines, but when used in the BPaL regimen (bedaquiline, pretomanid, linezolid), GI effects are reported 2

Linezolid

• Common GI effects: Diarrhea, nausea, headache 1
• Less common: Vomiting

Moxifloxacin

• Common GI effects: Gastrointestinal disturbance 1
• The American Thoracic Society guidelines specifically note that fluoroquinolones like moxifloxacin can cause sleep disturbance and gastrointestinal disturbance 1

Cycloserine

• Common GI effects: Gastrointestinal intolerance 1, 3
• The European Respiratory Society notes that cycloserine can cause central nervous system effects that may indirectly affect GI function 1

Combination Effects and Management

When these drugs are used together, as in regimens for drug-resistant TB, the risk of GI side effects is compounded. The 2022 WHO guidelines for drug-resistant TB management specifically recommend active TB drug safety monitoring and management (aDSM) for patients on these regimens due to the high likelihood of adverse events 1.

Risk Factors for Increased GI Intolerance

• Prior history of GI disorders
• Concomitant use of other medications that cause GI upset
• Inadequate food intake with medication administration (some drugs should be taken with food)
• Dehydration

Management Strategies

1. Timing of medication:

   • Some medications may be better tolerated when taken with food
   • Bedaquiline should specifically be taken with food 1
   • Spacing doses throughout the day when possible

2. Supportive care:

   • Adequate hydration
   • Anti-emetics if needed
   • Proton pump inhibitors or H2 blockers for acid-related symptoms (with caution regarding drug interactions)

3. Dose adjustments:

   • The ZeNix trial showed that lower doses of linezolid (600 mg vs 1200 mg) maintained efficacy while reducing adverse events 2
   • Individualized linezolid dosing with therapeutic drug monitoring has shown improved tolerability 4

Clinical Implications

The GI side effects of this drug combination can significantly impact:

• Treatment adherence
• Quality of life during treatment
• Nutritional status
• Absorption of the medications themselves

Recent evidence from implementation of the BPaL regimen (bedaquiline, pretomanid, linezolid) in the United States suggests that with careful monitoring and dose adjustments, particularly of linezolid, treatment completion rates can be high (97.1%) despite the potential for adverse effects 4.

Monitoring Recommendations

1. Baseline assessment of GI function and symptoms
2. Regular monitoring of symptoms during treatment
3. Nutritional assessment and support
4. Laboratory monitoring for electrolyte abnormalities secondary to GI losses
5. Therapeutic drug monitoring when available, particularly for linezolid 4

The combination of these drugs represents an important advance in treating drug-resistant TB, but clinicians must be vigilant about managing the expected GI side effects to ensure treatment success and maintain patient quality of life.