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

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.