Pharmacokinetic-Pharmacodynamic Target Attainment Analyses to Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Cystic Fibrosis. [PublishAheadOfPrint]

Background: Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in CF. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF; including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF. Therefore, this study sought to characterize the PK of CZA and perform target-attainment analyses to determine the optimal treatment regimen.

Methods: The PK of CZA was determined from 12 adult CF patients administered 3 intravenous doses of 2.5g q8h infused over 2h. Population modeling utilized the maximum-likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). Exposure targets of free-ceftazidime (CAZ) above MIC (fT>MIC), and free-avibactam (AVI) above a 1 mg/L threshold concentration (fT>C_t) were evaluated. Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities.

Results: CAZ and AVI were best described by 1-compartment models. Total body clearances (CAZ CL_t: 7.53 ± 1.28 L/h, AVI CL_t: 12.30 ± 1.96 L/h) and volumes of distribution (CAZ V_d: 18.80 ± 6.54 L, AVI V_d: 25.30 ± 4.43 L) were broadly similar to published healthy adults. CAZ achieved a PTA (50% fT>MIC) > 0.9 for MICs ≤ 16 mg/L and AVI PTA (50% fT>C_t of 1.0) >0.99. The overall likelihood of treatment response was 0.82 with CZA vs. 0.42 for CAZ.

Conclusions: These data demonstrate improved pharmacodynamics of CZA in comparison with CAZ and provide guidance on optimal dosing of (CZA) for future studies.

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