What are the potential side effects of Bedaquiline, moxifloxacin, pretomanid, and linezolid in a patient with drug-resistant tuberculosis?

Side Effects of Bedaquiline, Moxifloxacin, Pretomanid, and Linezolid in Drug-Resistant Tuberculosis

When treating drug-resistant tuberculosis with these medications, linezolid causes the most concerning toxicities—particularly peripheral neuropathy and myelosuppression—while bedaquiline's primary risk is QTc prolongation requiring cardiac monitoring, moxifloxacin adds additional QTc risk, and pretomanid contributes to hepatotoxicity when used in combination. 1, 2

Linezolid Side Effects

Linezolid is the most toxic component of the BPaL/BPaLM regimen and requires the most intensive monitoring and dose adjustments. 3, 4

Hematologic Toxicity

• Myelosuppression including anemia occurs frequently, with rates of 22% at 1200 mg daily for 26 weeks, 15% at 1200 mg for 9 weeks, 2% at 600 mg for 26 weeks, and 7% at 600 mg for 9 weeks 3
• The 600 mg daily dose for 26 weeks demonstrates significantly lower myelosuppression rates compared to higher doses 3, 4
• Hemoglobin <7 g/dL or platelets <75,000/mm³ at baseline warrant preferring alternative regimens, though BPaLM can still be used with close monitoring 5

Neurologic Toxicity

• Peripheral neuropathy is dose-dependent: 38% at 1200 mg for 26 weeks, 24% at 1200 mg for 9 weeks, 24% at 600 mg for 26 weeks, and 13% at 600 mg for 9 weeks 3
• In structured dose reduction studies, peripheral neuropathy occurred in 30% with continuous 600 mg dosing versus 17-19% with dose reduction to 300 mg after initial weeks 4
• Optic neuropathy occurred in 9% of patients receiving 1200 mg for 26 weeks; all cases resolved after discontinuation 3
• Pre-existing peripheral neuropathy Grade III-IV warrants preferring other regimens, though BPaLM remains an option 5
• Visual function monitoring is mandatory in all patients receiving linezolid, with prompt ophthalmologic evaluation for any visual symptoms 2

Other Linezolid Toxicities

• Serotonin syndrome, lactic acidosis, and convulsions are additional serious adverse reactions requiring awareness 2
• Linezolid dose modifications (interruption, reduction, or discontinuation) occurred in 51% at 1200 mg for 26 weeks, 30% at 1200 mg for 9 weeks, and only 13% at 600 mg for 26 weeks 3

Optimal Dosing Strategy

• The 600 mg daily dose for 26 weeks is preferred over 1200 mg based on superior risk-benefit ratio with 91% favorable outcomes and significantly fewer adverse events 3
• Structured dose reduction to 300 mg after initial weeks (9-13 weeks) is as effective as continuous 600 mg but with fewer peripheral neuropathy cases 4
• US implementation data using 600 mg adjusted by therapeutic drug monitoring showed only 4.4% hematologic toxicity and 5.9% neurotoxicity requiring dose changes 6

Bedaquiline Side Effects

Cardiac Toxicity

• QTc prolongation is the primary cardiac concern, requiring baseline ECG and repeat monitoring at 2,12, and 24 weeks minimum 1
• Weekly ECG monitoring is required when bedaquiline is combined with other QTc-prolonging drugs (fluoroquinolones, clofazimine), in patients with cardiac history, or with electrolyte abnormalities 1
• Discontinue bedaquiline if QTcF >500 ms (confirmed by repeat ECG) or clinically significant ventricular arrhythmia develops 1
• Patients with cardiac disease or concomitant QTc-prolonging medications are eligible for BPaLM but require close monitoring 5
• Electrolyte monitoring (potassium, calcium, magnesium) at baseline and whenever QTc prolongation detected; correct all abnormalities promptly 1

Hepatotoxicity

• Monitor AST, ALT, bilirubin, and alkaline phosphatase at baseline, monthly, and if symptomatic 1
• More frequent monitoring needed with other hepatotoxic medications or underlying liver disease 1
• Discontinue if aminotransferases >3× ULN with bilirubin >2× ULN, or aminotransferases >8× ULN 1
• Avoid alcohol and other hepatotoxic drugs during treatment 1
• Can be used in Child-Pugh A or B hepatic impairment but avoid in Child-Pugh C 1

Common Symptoms Requiring Weekly Monitoring

• Nausea, headache, hemoptysis, chest pain, arthralgia, and rash should be monitored weekly with treatment modification as clinically indicated 1

Drug Interactions

• Avoid use with rifamycins or CYP3A4 inducers/suppressors unless benefits outweigh risks; monitor serum drug levels if combined 1
• The extremely long half-life (4-5 months) requires discontinuing bedaquiline 4-5 months before other drugs to avoid monotherapy 1

Moxifloxacin Side Effects

Cardiac Effects

• Moxifloxacin prolongs QTc interval, adding to the cardiac risk when combined with bedaquiline 1
• Requires the same intensive cardiac monitoring as described for bedaquiline when used in combination 1
• Weekly ECG monitoring mandatory when combined with bedaquiline and other QTc-prolonging agents 1

General Fluoroquinolone Toxicities

• Fluoroquinolones as a class carry risks of tendinopathy, peripheral neuropathy, and central nervous system effects 1
• Moxifloxacin is part of Group A drugs (fluoroquinolones) in WHO classification and considered a core agent for MDR-TB 1

Pretomanid Side Effects

Hepatotoxicity

• Liver enzyme abnormalities occur as part of the combination regimen with bedaquiline and linezolid 2
• Contributes to the overall hepatotoxic potential of the BPaL/BPaLM regimen 2
• Patients should inform physicians of any liver disease history 2

Combination Regimen Considerations

• Pretomanid must always be used in combination with bedaquiline and linezolid, never as monotherapy 2
• If bedaquiline or pretomanid is permanently discontinued, the entire combination regimen must be stopped 2
• Safety and effectiveness in hepatic or renal impairment populations have not been established 2

Critical Monitoring Algorithm

Baseline Assessment

• ECG, electrolytes (potassium, calcium, magnesium), complete blood count, liver function tests (AST, ALT, bilirubin, alkaline phosphatase), visual acuity, and peripheral neuropathy assessment 1, 2

During Treatment

• Weekly: Symptom monitoring (nausea, headache, chest pain, arthralgia, rash, visual changes, paresthesias) 1
• Every 2 weeks initially, then at 12 and 24 weeks: ECG monitoring (weekly if high-risk cardiac features) 1
• Monthly: Liver function tests, complete blood count 1
• As needed: Electrolytes when QTc prolongation detected, visual function testing if symptoms develop 1, 2

Dose Modification Triggers

• Linezolid: Reduce or interrupt for myelosuppression, peripheral neuropathy, or optic neuropathy; doses missed due to adverse reactions should not be made up 2
• Bedaquiline: Discontinue for QTcF >500 ms, ventricular arrhythmia, or severe hepatotoxicity 1
• Entire regimen: Discontinue if bedaquiline or pretomanid permanently stopped 2

Common Pitfalls to Avoid

• Do not use 1200 mg linezolid daily—the 600 mg dose for 26 weeks is preferred with better safety profile and equivalent efficacy 3, 6
• Do not skip cardiac monitoring—QTc prolongation is cumulative with multiple agents and can be life-threatening 1
• Do not continue linezolid at full dose if peripheral neuropathy or myelosuppression develops—early dose reduction or interruption prevents irreversible toxicity 2, 3, 4
• Do not forget the long half-life of bedaquiline—cardiac and hepatic monitoring effects persist months after discontinuation 1
• Therapeutic drug monitoring for linezolid, when available, significantly improves safety outcomes 6