Abstract
The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.
Highlights
Piperacillin/tazobactam (PIPC/TAZ, 8:1) is a β-lactam/β-lactamase inhibitor combination with in vitro activity against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative bacteria, including penicillinase, cephalosporinase, and extended-spectrum β-lactamase-producing bacteria
In Japan, increased mortality from pneumonia suggests that elderly patients and those with underlying diseases or deteriorated general conditions are recommended antimicrobial chemotherapy, which is effective against drug-resistant bacteria [7]
The aim of this study is to develop a population PK model for PIPC/TAZ in late elderly patients with pneumonia and to present optimized dosing regimens by applying PK/PD criteria
Summary
Piperacillin/tazobactam (PIPC/TAZ, 8:1) is a β-lactam/β-lactamase inhibitor combination with in vitro activity against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative bacteria, including penicillinase-, cephalosporinase-, and extended-spectrum β-lactamase-producing bacteria. In many guidelines for infectious diseases, including pneumonia, PIPC/TAZ, like fourth-generation cephems, carbapenems and new quinolones, is rated as a first-choice drug for a variety of patients at risk for resistant bacteria [1,2]. In Japan, increased mortality from pneumonia suggests that elderly patients and those with underlying diseases or deteriorated general conditions are recommended antimicrobial chemotherapy, which is effective against drug-resistant bacteria [7]. In many cases, the dosage regimen for the elderly is adjusted based on the package insert or books such as the Sanford Guide [8]. This dosage regimen recommended in such a way does not take into account bacterial susceptibility
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