Imipenem/cilastatin/relebactam treatment of hospital-acquired/ventilator-associated bacterial pneumonia caused by imipenem-nonsusceptible pathogens: Subgroup analysis and molecular characterization of isolates from the RESTORE-IMI 2 clinical study

Background Additional treatment options are needed for patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by carbapenem-resistant pathogens. This subgroup analysis examined clinical and microbiologic outcomes in participants from RESTORE-IMI 2 treated with imipenem/cilastatin/relebactam (IMI/REL), stratified by baseline lower respiratory tract (LRT) isolate susceptibility to imipenem. Emergence of nonsusceptibility to IMI/REL during treatment was also evaluated. Methods Baseline LRT specimens were obtained ≤48 hours before screening, identified at a central laboratory, and susceptibility determined per the Clinical and Laboratory Standards Institute breakpoints. Outcomes for participants who received IMI/REL, with ≥1 imipenem-nonsusceptible, imipenem/REL-susceptible baseline LRT pathogen were compared with participants with imipenem-susceptible pathogens. Emergence of nonsusceptibility to imipenem/REL was also assessed, and isolates were characterized molecularly. Results In total, 215 participants in the microbiologic-modified intent-to-treat population received IMI/REL, of whom 112 were infected with imipenem-susceptible pathogens and 18 with imipenem-nonsusceptible, imipenem/REL-susceptible pathogens and were included in this analysis. Of these 18 participants, 88.9% were in the intensive care unit and 83.3% had one gram-negative baseline pathogen. Day 28 all-cause mortality was 22.2% and 18.8% (adjusted difference: 7.3 [−8.8 to 31.1]) for participants who received IMI/REL for the treatment of HABP/VABP caused by imipenem-nonsusceptible versus imipenem-susceptible pathogens, respectively. Of a total of 192 isolates, 59 gram-negative isolates (baseline isolates that were nonsusceptible to imipenem and subsequent isolates of the same species from the same participants) were characterized using multiplex polymerase chain reaction and sequencing techniques. Emergence of nonsusceptibility to imipenem/REL occurred in isolates from three of the 112 participants with indicated imipenem-susceptible baseline pathogens (two isolates of Pseudomonas aeruginosa and one isolate of Klebsiella pneumoniae ). Conclusions Day 28 all-cause mortality was similar among participants treated with IMI/REL, regardless of baseline pathogen susceptibility to imipenem. Emergence of nonsusceptibility to imipenem/REL on treatment was low. Clinical trials registration ClinicalTrials.gov ( NCT02493764 ).