Résumé
To assess the relationship between renal function and efficacy/safety of imipenem/cilastatin/relebactam for the treatment of hospital-acquired/ventilator-associated pneumonia (HABP/VABP) from RESTORE-IMI 2 and determine the PTA.
Adults with HABP/VABP were randomized 1:1 to IV imipenem/cilastatin/relebactam 1.25 g or piperacillin/tazobactam 4.5 g every 6 h for 7-14 days. Initial doses were selected by CL
and adjusted thereafter, as appropriate. Outcomes included Day 28 all-cause mortality (ACM), clinical response, microbiological response and adverse events. Population pharmacokinetic modelling and Monte Carlo simulations assessed PTA.
The modified ITT population comprised those with normal renal function (
= 188), augmented renal clearance (ARC;
= 88), mild renal impairment (RI;
= 124), moderate RI (
= 109) and severe RI (
= 22). ACM rates were comparable between treatment arms among all baseline renal function categories. Clinical response rates were comparable between treatment arms for participants with RI and normal renal function but were higher (91.7% versus 44.4%) for imipenem/cilastatin/relebactam-treated versus piperacillin/tazobactam-treated participants with CL
≥250 mL/min (
= 21). Microbiologic response rates were comparable between treatment arms for participants with RI but higher among those treated with imipenem/cilastatin/relebactam in participants with CL
≥90 mL/min (86.6% versus 67.2%). Adverse events were comparable between treatment arms across renal function categories. Joint PTA was >98% for key pathogen MICs for susceptible pathogens (MIC ≤2 mg/L).
Prescribing information-defined dose adjustments in participants with baseline RI and full dosing of imipenem/cilastatin/relebactam 1.25 g every 6 h for participants with normal renal function or augmented renal clearance achieved sufficiently high drug exposures and favourable safety and efficacy profiles.