Could an optimized joint pharmacokinetic/pharmacodynamic target attainment of continuous infusion ceftazidime-avibactam be a way to avoid the need for combo therapy in the targeted treatment of deep-seated DTR Gram-negative infections?

The objective of this study was to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome of documented difficult-to-treat resistant (DTR) Gram-negative infections. A 2-year retrospective cohort study was performed in patients receiving CI ceftazidime-avibactam mono- or combo therapy for documented DTR Gram-negative infections and undergoing therapeutic drug monitoring of both ceftazidime and avibactam. The free fractions of steady-state concentrations ( f C _ss ) of ceftazidime and avibactam were calculated. The joint PK/PD target was considered optimal when both the f C _ss /MIC ratio for ceftazidime ≥4 (equivalent to 100% f T _>4xMIC ) and the f C _ss /C _T ratio for avibactam >1 (equivalent to 100% f T >C _T of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two and suboptimal if neither of the two was achieved). Multivariate logistic regression analysis was applied for testing potential variables associated with microbiological failure. Fifty-eight patients were treated with CI ceftazidime-avibactam mono- (36) or combo therapy (22) for documented DTR Gram-negative infections [74.2% for primary or secondary bloodstream infections (BSIs)]. Combo therapy was administered more frequently to intensive care unit (ICU) patients ( P = 0.023) or for pneumonia ( P = 0.001) and less frequently for intra-abdominal infections and BSIs ( P = 0.04). Microbiological failure occurred in five cases (8.6%, three in mono- and two in combo therapy). In the multivariate analysis, the suboptimal/quasi-optimal joint PK/PD target emerged as the only independent predictor of microbiological failure (odds ratio [OR] 11.11; 95% confidence interval [CI] 1.31-93.98; P = 0.023), whereas monotherapy was not ( P = 0.99). Optimized joint PK/PD target attainment of CI ceftazidime-avibactam monotherapy could represent a way forward for allowing microbiological eradication of DTR Gram-negative infections and could render unnecessary combo therapy.
Competing Interests: M.G. received personal fees from Angelini, outside the submitted work; P.V. has served as a consultant for Biomerieux, Gilead, Merck Sharp & Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx and received payment for serving on the speaker's bureau for Correvio, Gilead, Merck Sharp & Dohme, Nordic Pharma, and Pfizer, outside the submitted work; F.P. participated in the speaker's bureau for Advanz Pharma, Angelini, BeiGene, Gilead, InfectoPharm, Merck Sharp & Dohme, Menarini, Pfizer, and Shionogi and in the advisory board for Advanz Pharma, Angelini, Gilead, Merck Sharp & Dohme, and Pfizer, outside the submitted work. The authors report no other conflicts of interest in this work.