Adequacy of the Dosing and Infusion Time of Ceftazidime/Avibactam for the Treatment of Gram-Negative Bacterial Infections: A PK/PD Simulation Study

Yun Han,1,* Jianping Zhu,1,* Jieqiong Liu,2 Ying Zheng,2 Gang Liang,1 Yi Yang,1 Lingyan Yu,3 Zhenwei Yu,1 Gang Han1 1Research Center for Clinical Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China; 2The 903rd Hospital of PLA Joint Logistic Support Force, Hangzhou, People’s Republic of China; 3Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenwei Yu; Gang Han, Email yzw_srrsh@zju.edu.cn; 3199022@zju.edu.cnIntroduction: Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets.Methods: This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR.Results: Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ CT=1.0 mg/L (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ CT=1.0 mg/L. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ CT=4.0 mg/L targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions.Conclusion: The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.Keywords: ceftazidime, avibactam, pharmacokinetic/pharmacodynamic, probability of target attainment