Abstract
Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis
Journal of the Pediatric Infectious Diseases Society, Vol.12(Supplement_1), pp.S8-S8
11/20/2023
DOI: 10.1093/jpids/piad070.015
Abstract
Abstract Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. The management of these infections becomes increasingly complex due to decreased antimicrobial susceptibility and inadequate pharmacokinetic/pharmacodynamic (PK/PD) characterization of the most commonly used antimicrobial agents in this population. Methods One hundred fifty-five pediatric and adult participants receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK (PopPK) analysis was conducted using nonlinear mixed effects modeling in NONMEM, and clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) for different dosing regimens. Multiple targets, defined as percentage of a 24-h time period that the free drug concentration exceeds the MIC (fT> MIC), were selected based on prior studies of beta-lactam antibiotics. Results Preliminary PopPK modeling results show that lean body weight, creatinine clearance, daily dose, mode of administration (standard vs. extended infusion), and age affect PK parameters, with varying effects by drug. As anticipated, extended or continuous infusions resulted in higher PTA (Table 1). In the cefepime group, the 3-h infusion regimen achieved higher PTAs than the 0.5-h regimen across all age groups. Estimated breakpoints (in which ≥ 90% of patients are expected to achieve a PK/PD target) were 2-4 fold higher in pediatric participants receiving a 3-h infusion vs. 0.5-h infusion, based on age and target fT> MIC. In the meropenem group, increased creatinine clearance led to reduced PTA, and in the piperacillin-tazobactam group, total daily dose and interval were the principal drivers of PTA. Conclusions To our knowledge, this is the largest PopPK study to date of these antimicrobials in individuals with CF. Clinicians should incorporate local antibiograms with these PopPK models to determine optimal dosing in patients with CF, since standard dosing regimens may fail to achieve specific PK/PD targets. This population may also benefit from beta-lactam therapeutic drug monitoring.
Details
- Title: Subtitle
- Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis
- Creators
- Stephanie L Rolsma - Vanderbilt University Medical CenterAndrew G Sokolow - Vanderbilt University Medical CenterGuohua An - University of IowaNick FishbaneWilliam Fissell - Vanderbilt University Medical CenterKenan Gu - National Institute of Allergy and Infectious DiseasesNatalia Jimenez - Vanderbilt UniversityCarl KirkpatrickCornelia B Landersdorfer - Monash UniversityRoger L Nation - Monash UniversityPratish C Patel - Vanderbilt University Medical CenterKatherine Sokolow - Vanderbilt UniversityMary E Teresi - University of IowaMarissa KontosAmy Watanabe - EmmesPatricia Winokur - University of IowaC Buddy Creech - Vanderbilt University Medical Center
- Resource Type
- Abstract
- Publication Details
- Journal of the Pediatric Infectious Diseases Society, Vol.12(Supplement_1), pp.S8-S8
- DOI
- 10.1093/jpids/piad070.015
- ISSN
- 2048-7207
- eISSN
- 2048-7207
- Language
- English
- Date published
- 11/20/2023
- Academic Unit
- Medicine Administration; Internal Medicine; Pharmaceutical Sciences and Experimental Therapeutics; Infectious Diseases
- Record Identifier
- 9984539759602771
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