P-1223. Mechanistic Insights to Combating Enterobacter cloacae in Deep Seated Infections

Abstract

Listen

Translate article

Abstract Background Enterobacter cloacae is a formidable pathogen in deep-seated infections. Increasing prevalence of carbapenem-resistant Enterobacterales exemplifies the need for optimizing non-carbapenem therapeutics. We aimed to evaluate cefepime (FEP) and meropenem (MEM) regimens against E. cloacae isolates in a pharmacokinetic/pharmacodynamic (PK/PD) ex vivo model.Table 1.CDC Antibiotic Resistance Isolate Bank Enterobacter cloacae Strains Tested in Ex vivo Models Methods E. cloacae isolates (CDC# 0032, 0060, Table 1) were evaluated in 96h simulated endocardial vegetation (SEV) high inoculum (109 CFU/g) models against humanized FEP (2g q8h via 30-min and 3h infusions) and MEM (2g q8h via 30-min and 3h infusions) regimens. SEV clot and planktonic samples were removed in duplicate from each model replicate at predefined time points and evaluated for bactericidal activity (defined as a ≥ 3 log10 CFU/g reduction from baseline), antibiotic PK target attainment, treatment-emergent resistance, and β-lactamase induction via RT-PCR. Significant differences between regimens were assessed by ANOVA with Tukey’s post hoc modification (α=0.05).Table 2.Beta-lactam PK/PD Targets and Achieved Concentrations in Ex vivo Models Results Against E. cloacae 0060, MEM via 3h infusion demonstrated bactericidal activity (-Δ4.79 log10 CFU/g) in SEV clots and greater killing than MEM via 30-min infusion (-Δ2.6 log10 CFU/g; p< 0.001) (Figure 1). Both MEM 3h and 30-min infusions suppressed bacterial growth at detection limits in planktonic samples through 96h against 0060. Against E. cloacae 0032, neither FEP nor MEM regimens demonstrated bactericidal activity or growth suppression at 96h in SEV clots and planktonic samples, respectively (Figure 2). β-lactam PK/PD targets and achieved concentrations in ex vivo models are displayed in Table 2. Treatment-emergent resistance was identified in 96h samples for FEP against 0060 and MEM against 0032 (3- and 5-fold MIC increase). FEP exposure in 0060 models induced ACT-89 β-lactamase expression while FEP and MEM in 0032 models induced ACT-16, KPC-3, and TEM-1.Figure 1.Efficacy of Beta-lactam Regimens in a SEV PK/PD Ex vivo Model Against E. cloacae Isolate 0060 Conclusion Against E. cloacae isolates in a PK/PD ex vivo model, MEM demonstrated bactericidal activity against E. cloacae 0060, with greater efficacy via 3h compared to 30-min infusion. However, neither FEP nor MEM showed bactericidal activity against E. cloacae 0032, with the emergence of treatment-resistant strains and induction of β-lactamase expression observed in some cases.Figure 2.Efficacy of Beta-lactam Regimens in a SEV PK/PD Ex vivo Model Against E. cloacae Isolate 0032 Disclosures All Authors: No reported disclosures