Biliary pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime–avibactam in a case series of orthotopic liver transplant recipients

Objectives To assess the biliary pharmacokinetic/pharmacodynamic (PK/PD) of continuous infusion (CI) ceftazidime–avibactam in a series of critical orthotopic liver transplant (OLT) recipients having pre-emptive therapy during OLT because of carbapenemase-producing Enterobacterales (CPE) rectal colonization or targeted therapy of CPE intra-abdominal (IAIs) and/or biliary tract infections (BTIs). Methods We performed an exploratory, hypothesis-generating prospective case series including critical OLT recipients carrying a Kehr’s tube and undergoing therapeutic drug monitoring of ceftazidime and avibactam in both bile and plasma simultaneously while receiving CI ceftazidime–avibactam pre-emptive or targeted therapy. Biliary aggressive joint PK/PD target attainment [defined as a free ceftazidime steady-state concentrations fCss/MIC ratio >4 coupled with an avibactam fCss/target concentration (CT = 4 mg/L) ratio >1] was selected as optimal threshold of ceftazidime–avibactam efficacy, given this was previously shown to be independently associated with lower rates of microbiological failure and resistance development. Bile-to-plasma fCss ratios were calculated. Results Overall, four critical OLT recipients were included. Aggressive biliary ceftazidime–avibactam joint PK/PD target during treatment with CI 2 g/0.5 g q8 h over 8 h was attained in 2/4 cases (quasi-optimal and suboptimal in one case each). Median (range) fCss bile-to-plasma ratios were 0.28 (0.22–0.38) for ceftazidime and 0.24 (0.11–0.52) for avibactam. Conclusions Our limited cases series suggested that both ceftazidime and avibactam showed a moderate and broadly similar biliary penetration. Administration by CI may be helpful in attaining an aggressive biliary joint PK/PD target of ceftazidime–avibactam against pathogens with an MIC up to 8 mg/L.