Population Pharmacokinetic Modeling of Cefepime, Meropenem, and Piperacillin-Tazobactam in Patients With Cystic Fibrosis

Abstract

Background: Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to β-lactam antibiotics. The pharmacokinetics (PK) of these agents are inadequately characterized in patients with CF.

Methods: This study enrolled 155 pediatric and adult participants with CF who were receiving the following β-lactam antibiotics: cefepime (n = 82), meropenem (n = 42), or piperacillin-tazobactam (n = 31). Opportunistic blood samples were obtained during hospitalization. Population PK analysis was conducted via nonlinear mixed effects modeling. Clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) for different dosing regimens.

Results: Estimated creatinine clearance and total or lean body weight affected the PK of cefepime and meropenem. No covariates were identified for piperacillin and tazobactam. In the cefepime group, a 3-hour infusion achieved a higher PTA than a 0.5-hour infusion for all participants. Estimated breakpoints-the respective minimum inhibitory concentration up to which ≥90% of patients are predicted to reach a PK/pharmacodynamic target-were 2- to 4-fold higher in pediatric participants receiving a 3- vs 0.5-hour infusion. In the meropenem group, increased creatinine clearance led to reduced PTA. In the piperacillin-tazobactam group, total daily dose and mode of administration were principal drivers of PTA.

Conclusions: Standard dosing regimens fail to achieve specific minimum inhibitory concentration targets in patients with CF. Therefore, clinicians should incorporate local antibiograms and PK models to determine optimal dosing. Further PK optimization to account for interindividual differences could be achieved by real-time β-lactam therapeutic drug monitoring.

Keywords: cystic fibrosis; pharmacokinetics; population pharmacokinetics; probability of target attainment; β-lactams.

Figure 1.

Comparison of cefepime probability of target attainment between the 2 durations of infusion for 50 mg/kg (age 3–11 years) or 2 g (age ≥12 years) every 8 hours at the target of 65% fT_>MIC (ie, percentage of the dosing interval where unbound plasma drug concentrations exceed the MIC of the causative pathogen). Dashed line indicates 90% probability of target attainment. MIC, minimum inhibitory concentration.

Figure 2.

Comparison of cefepime probability of target attainment between the 2 durations of infusion for 50 mg/kg (age 3–11 years) or 2 g (age ≥12 years) every 8 hours at the target of 100% fT_>MIC (ie, percentage of the dosing interval where unbound plasma drug concentrations exceed the MIC of the causative pathogen). Dashed line indicates 90% probability of target attainment. MIC, minimum inhibitory concentration.

Figure 3.

Comparison of meropenem probability of target attainment between renal function groups—creatinine clearance (CL_{CR, LBW}) <90 and ≥90 mL/min—for the dosing regimen of 2 g every 8 hours as a 3-hour infusion. fT_>MIC indicates the percentage of the dosing interval where unbound plasma drug concentrations exceed the MIC of the causative pathogen. Dashed line indicates 90% probability of target attainment. LBW, lean body weight; MIC, minimum inhibitory concentration; q8h, every 8 hours.

Figure 4.

Comparison of piperacillin probability of target attainment among different dosing regimens: 4 g every 8 hours as 4-hour infusions, 12 g/d as continuous infusion, 4 g every 6 hours as 4-hour infusions, and 16 g/d as continuous infusion. fT_>MIC indicates the percentage of the dosing interval where unbound plasma drug concentrations exceed the MIC of the causative pathogen. Dashed line indicates 90% probability of target attainment. MIC, minimum inhibitory concentration; q6h, every 6 hours; q8h, every 8 hours.