Population Pharmacokinetic and Pharmacodynamic Prediction for Tebipenem Pivoxil Treatment of Pediatric Shigellosis
Abstract
Increasing antimicrobial resistance poses a serious challenge for the treatment of Shigella infections, and there is an urgent need for alternative antibacterial treatments. We conducted a clinical trial to investigate the efficacy of oral tebipenem pivoxil, compared to intravenous ceftriaxone, in Bangladeshi children with shigellosis. Using demographic data of 2249 Bangladeshi children with suspected shigellosis, population pharmacokinetic (PK) simulations were conducted to simulate tebipenem PK profiles in children with the proposed dosing regimen. Subsequently, the model predictions estimated each virtual participant's fraction of time over the 3-day treatment period during which simulated free tebipenem plasma concentration was above the minimum inhibitory concentration (fT > MIC). Variability associated with the prevalence of different Shigella species in Bangladeshi children and the MIC distributions were incorporated. Shigella treatment effect was assumed for participants that had fT > MIC for at least 40% of the 3-day treatment period (40% fT > MIC). The probability of achieving 40% fT > MIC was 86.4% for 4 mg/kg tebipenem pivoxil three times daily (TID) dosing and 92.4% with 3 mg/kg tebipenem pivoxil four times daily (QID) dosing. Lastly, the probability of tebipenem pivoxil being non-inferior to ceftriaxone, in a clinical trial containing 66 participants per arm, was evaluated for two dosing regimens. Three levels of ceftriaxone resistance were simulated to examine…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 2,249 participants or records.
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