Abstract
Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese; 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3–4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%fT>MIC). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27; 1.61), higher in plasma versus target-site, supporting targets of %fT>2×MIC instead of %fT>4×MIC during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %fT>MIC = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %fT>MIC = 98) of piperacillin/tazobactam.
Highlights
In recent decades, obesity has increased in prevalence globally
Figure S2) with none of the patients requiring haemodialysis. Both lean body weight (LBW, Supplementary Figure S3) and fat mass were higher in obese compared to nonobese patients (Table 3)
1069/1128 piperacillin concentrations were available, comprising total (n = 237/240) and unbound (n = 114/116) plasma concentrations, microdialysate concentrations collected via two catheters in the interstitial space fluid (ISF) of subcutaneous adipose tissue over 8 h (n = 285/300 + 272/300; Supplementary Figure S4), and retrodialysate concentrations (n = 80/86 + 81/86)
Summary
In the United States, over 40% of adults are obese [2] with projections of up to 50% in 2030 [3]. Previous investigations on the effect of body mass on the PK of piperacillin, a β-lactam antibiotic with bactericidal activity against a broad spectrum of Gram-negative and Grampositive bacteria [13], have been compromised by inconsistent scaling approaches of PK parameters with body mass [8,14]. This has hindered their implementation in modelinformed personalization of antimicrobial dosing
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