Open forum infectious diseases · 2026
Cerebrospinal Fluid Concentrations of Bedaquiline, Pretomanid, and Linezolid During Curative Treatment of Fluoroquinolone-Resistant Pre-Extensively Drug-Resistant Tuberculous Meningitis.
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Tramontana Adrian Robert, Burke Andrew, Globan Maria, McWhinney Brett, Bloch Aaron E, Smith Benjamin J, Denholm Justin T, Wright Connor James, Molton James S
Аннотация
BACKGROUND: Bedaquiline, pretomanid, and linezolid (BPaL) is a 6-month regimen that has revolutionized treatment of multidrug-resistant (MDR) tuberculosis (TB). However, there is limited evidence of using BPaL to treat MDR tuberculous meningitis (TBM), a devastating illness that has high risk of mortality and permanent disability.
METHODS: A patient with fluoroquinolone-resistant pre-extensively drug-resistant (pre-XDR) TBM was cured with a 10-month regimen based on BPaL with clofazimine and cycloserine. Total concentrations of bedaquiline, pretomanid, and linezolid were measured in plasma and cerebrospinal fluid (CSF) via ultraperformance liquid chromatography. Unbound concentrations were estimated from plasma concentrations and CSF concentrations normalized to plasma protein concentrations using the Winter-Tozer formula. AUC24 (24-hour area under the curve) was calculated using the trapezoidal method.
RESULTS: The CSF:plasma unbound AUC24 was 1.48 and 0.99 for pretomanid and linezolid, respectively. Pharmacokinetic/pharmacodynamic targets were achieved for pretomanid with CSF concentration above the critical concentration of 0.5 mg/L throughout most of the dosing interval and linezolid AUC24/minimum inhibitory concentration (MIC) of 171 for an MIC of 0.5 mg/L. However, CSF concentrations of pretomanid and linezolid may be below target for strains with MICs >0.5 mg/L. Estimated unbound peak concentrations in CSF in week 21 were comparable to plasma (0.0034 mg/L and 0.0032 mg/L, respectively), suggesting that therapeutic central nervous system concentrations of bedaquiline were achieved.
CONCLUSIONS: Fluoroquinolone-resistant pre-XDR TBM was cured with 10 months of treatment based on BPaL with clofazimine and cycloserine. BPaL achieved therapeutic concentrations in CSF for most TB strains. Further research is required into optimal treatment and dosing of drug-resistant TBM.
METHODS: A patient with fluoroquinolone-resistant pre-extensively drug-resistant (pre-XDR) TBM was cured with a 10-month regimen based on BPaL with clofazimine and cycloserine. Total concentrations of bedaquiline, pretomanid, and linezolid were measured in plasma and cerebrospinal fluid (CSF) via ultraperformance liquid chromatography. Unbound concentrations were estimated from plasma concentrations and CSF concentrations normalized to plasma protein concentrations using the Winter-Tozer formula. AUC24 (24-hour area under the curve) was calculated using the trapezoidal method.
RESULTS: The CSF:plasma unbound AUC24 was 1.48 and 0.99 for pretomanid and linezolid, respectively. Pharmacokinetic/pharmacodynamic targets were achieved for pretomanid with CSF concentration above the critical concentration of 0.5 mg/L throughout most of the dosing interval and linezolid AUC24/minimum inhibitory concentration (MIC) of 171 for an MIC of 0.5 mg/L. However, CSF concentrations of pretomanid and linezolid may be below target for strains with MICs >0.5 mg/L. Estimated unbound peak concentrations in CSF in week 21 were comparable to plasma (0.0034 mg/L and 0.0032 mg/L, respectively), suggesting that therapeutic central nervous system concentrations of bedaquiline were achieved.
CONCLUSIONS: Fluoroquinolone-resistant pre-XDR TBM was cured with 10 months of treatment based on BPaL with clofazimine and cycloserine. BPaL achieved therapeutic concentrations in CSF for most TB strains. Further research is required into optimal treatment and dosing of drug-resistant TBM.