Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance

Jason A Roberts; David P Nicolau; Ignacio Martin-Loeches; C Andrew Deryke; Maria C Losada; Jiejun Du; Munjal Patel; Matthew L Rizk; Amanda Paschke; Luke F Chen

doi:10.1093/jacamr/dlad011

Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance

JAC Antimicrob Resist. 2023 Mar 4;5(2):dlad011. doi: 10.1093/jacamr/dlad011. eCollection 2023 Apr.

Authors

Jason A Roberts^{1

2

3

4}, David P Nicolau⁵, Ignacio Martin-Loeches⁶, C Andrew Deryke⁷, Maria C Losada⁷, Jiejun Du⁷, Munjal Patel⁷, Matthew L Rizk⁷, Amanda Paschke⁷, Luke F Chen⁷

Affiliations

¹ Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Brisbane, Australia.
² Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia.
³ Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.
⁴ Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
⁵ Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT, USA.
⁶ Department of Intensive Care Medicine, St James's Hospital, Dublin, Ireland.
⁷ Merck & Co., Inc., Rahway, NJ, USA.

Abstract

Objectives: 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.

Methods: 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_CR 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.

Results: The modified ITT population comprised those with normal renal function (n = 188), augmented renal clearance (ARC; n = 88), mild renal impairment (RI; n = 124), moderate RI (n = 109) and severe RI (n = 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_CR ≥250 mL/min (n = 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_CR ≥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).

Conclusions: 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.