P-1512. Partnering Imipenem/Relebactam (I/R) with Fosfomycin (FOS): Restoring Susceptibility Against Multi-Drug-Resistant <i>Pseudomonas aeruginosa</i>

Abstract Background Pseudomonas aeruginosa (Pae) is a significant pathogen causing up to 10% of hospital-acquired infections. Contributing to Pae’s multidrug-resistant (MDR) phenotype is the inducible Pseudomonas-derived cephalosporinase (PDC), low permeability outer membrane, multiple efflux systems, and loss of porins that yield resistant phenotypes. e.g. loss of OprD yields resistance to imipenem. Thus, the design of novel antibiotics or combination therapies that do not induce expression of blaPDC, are stable to PDC hydrolytic activity, bypass impermeability, and/or are not susceptible to efflux is essential for combating MDR Pae infections. Ceftazidime-avibactam (CZA), and imipenem/cilastatin/relebactam (I/R) were approved by the FDA for the treatment of infections caused by Pae; however, gaps in their efficacy against Pae remain. Previously, Winkler et al. analyzed a group of archived Pae and found that 20% of the isolates were resistant to CZA (PMID 25451057). By combining CZA with fosfomycin (FOS) and targeting multiple cell wall synthetic pathways, susceptibility was restored to most of the CZA resistant MDR Pae (PMID: 31099835). Based upon a similar mechanism of action, we propose that the combination of I/R+FOS will also restore susceptibility to I/R resistant Pae. Methods 149 isolates of Pae were used in this analysis. Minimum inhibitor concentrations (MICs) of IMI, I/R, and I/R+FOS against 150 P. aeruginosa isolates were determined following CLSI’s approved methods. To interpret the results better, genetic analysis of the resistomes was performed. Results The addition of FOS was found to shift the I/R MICs towards the susceptible range (Fig.1A). Moreover, the isolates tested with I/R+FOS possessed overall lower MICs (MIC50/90 I/R 8/256 mg/L vs. MIC50/90 I/R+FOS 8/64 mg/L) (Fig. 1B). The isolates have diverse resistance mechanisms including KPC-producers (3/149; 4.5%), VIM-producers (19/150; 28.3%), and isolates that carry mutations in ampR, ampD, oprD, and/or pbp genes. Conclusion I/R + FOS lowers MICs against MDR Pae. These results lead us to postulate that inhibiting MurA enzyme that catalyzes the first committed step in peptidoglycan synthesis with FOS adds to the potency of I/R even against VIM producers. Disclosures Robert Bonomo, MD, Merck: Grant/Research Support|Shionogi: Grant/Research Support Gauri G. Rao, PharmD, MS, Merck: Grant/Research Support