1080. Relebactam Increases Imipenem Activity Against Imipenem-Nonsusceptible and -Susceptible Pseudomonas aeruginosa and Enterobacterales: Assessment of Isolates from RESTORE-IMI 2

Abstract Background Relebactam (REL) inhibits class A and C β-lactamases (BLs) and is approved in the US in the combination imipenem/cilastatin/REL (IMI/REL) for hospital acquired bacterial pneumonia (HABP) and ventilator associated bacterial pneumonia (VABP), and also in patients with limited treatment options for complicated urinary tract infections and complicated intraabdominal infections. The objective of this study was to evaluate the potentiation of imipenem (IMI) by REL in baseline respiratory isolates from the recently completed Phase 3 RESTORE-IMI 2 study that demonstrated efficacy and safety of IMI/REL in the treatment of patients with HABP/VABP. Methods Baseline lower respiratory tract (LRT) isolates were evaluated for IMI MICs in the presence and absence of REL using broth microdilution and CLSI interpretive criteria. All Pseudomonas aeruginosa and Enterobacterales for which IMI/REL is either indicated or the MIC90 is less than or equal to the susceptibility breakpoint were evaluated. Results Summary statistics and the MIC distribution for P. aeruginosa are shown in the figure. For P. aeruginosa, REL reduces the IMI mode MIC of IMI-nonsusceptible (IMI-NS) (MIC >2) isolates ≥8-fold (from 16-32 to 2 µg/mL) and that of IMI-susceptible (IMI-S) (MIC ≤2) isolates ≥2-fold (from 1 to ≤0.5 µg/mL). Among Enterobacterales, the IMI mode MIC of IMI-NS (MIC >1) isolates was reduced ≥4-fold (from 2 to ≤0.5 µg/mL). REL enhanced the activity of IMI among IMI-S isolates (MIC ≤1), most notably observed in Enterobacterales species that produce a chromosomal AmpC, increasing the proportion with MIC ≤0.5 µg/mL from 76% to 98%. MIC Distribution and Summary Statistics of RESTORE IMI-2 Isolates Conclusion Among baseline LRT isolates from RESTORE-IMI 2 the potentiation of IMI by REL results in the restoration of susceptibility among IMI-NS P. aeruginosa and Enterobacterales and enhanced IMI activity among IMI-S isolates. This enhanced activity among IMI-S Enterobacterales is most notable among species with reported chromosomal expression of AmpC. This lowering of IMI MICs upon addition of REL contributes to the high probability of target attainment (≥90%) observed following administration of IMI/REL 1.25g every 6 hours, further supporting the IMI/REL efficacy data observed in RESTORE-IMI 2. Disclosures David W. Hilbert, PhD, Merck (Employee) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck (Employee) Pamela Moise, PharmD, Merck (Employee) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee) Katherine Young, MS, Merck (Employee)


Development of Tebipenem MIC Antimicrobial Susceptibility Test for Gram-negative Bacteria on MicroScan Dried Gram-negative MIC Panels
Jose Enrique Fernandez, n/a 1 ; Robert L. Williams, n/a 1 ; Vasna Carr, n/a 1 ; Renae Miller, n/a 1 ; 1 Beckman Coulter, West Sacramento, California Session: P-61. Novel Agents Background. Development of a tebipenem antimicrobial susceptibility test was completed for the MicroScan Dried Gram-negative MIC (MSDGN) Panel when compared to CLSI broth microdilution reference panels.
Methods. Development was conducted by comparing MICs obtained using the MSDGN panel to MICs using a CLSI broth microdilution reference panel. A total of 669 Enterobacterales isolates were tested at 16, 18, and 20 hour incubation times using the turbidity and Prompt ®* methods of inoculation. MSDGN panels were incubated at 35 ± 2 º C and read on the WalkAway System, the autoSCAN-4 instrument, and read visually. Frozen reference panels, prepared according to ISO/CLSI methodology, were inoculated using the turbidity inoculation method. All frozen reference panels were incubated at 35 ± 2ºC and read visually. Dilution sequence evaluated is 0.03-32 µg/mL.
Results. When compared to frozen reference panel results, essential agreement for all isolates tested during development are as follows: Background. Relebactam (REL) inhibits class A and C β-lactamases (BLs) and is approved in the US in the combination imipenem/cilastatin/REL (IMI/REL) for hospital acquired bacterial pneumonia (HABP) and ventilator associated bacterial pneumonia (VABP), and also in patients with limited treatment options for complicated urinary tract infections and complicated intraabdominal infections. The objective of this study was to evaluate the potentiation of imipenem (IMI) by REL in baseline respiratory isolates from the recently completed Phase 3 RESTORE-IMI 2 study that demonstrated efficacy and safety of IMI/REL in the treatment of patients with HABP/ VABP.

Essential
Methods. Baseline lower respiratory tract (LRT) isolates were evaluated for IMI MICs in the presence and absence of REL using broth microdilution and CLSI interpretive criteria. All Pseudomonas aeruginosa and Enterobacterales for which IMI/REL is either indicated or the MIC 90 is less than or equal to the susceptibility breakpoint were evaluated.

MIC Distribution and Summary Statistics of RESTORE IMI-2 Isolates
Conclusion. Among baseline LRT isolates from RESTORE-IMI 2 the potentiation of IMI by REL results in the restoration of susceptibility among IMI-NS P. aeruginosa and Enterobacterales and enhanced IMI activity among IMI-S isolates. This enhanced activity among IMI-S Enterobacterales is most notable among species with reported chromosomal expression of AmpC. This lowering of IMI MICs upon addition of REL contributes to the high probability of target attainment (≥90%) observed following administration of IMI/REL 1.25g every 6 hours, further supporting the IMI/ REL efficacy data observed in RESTORE-IMI 2. Disclosures