Identification of Ampicillin and Vancomycin In Vitro Susceptibility Test Interpretive Criteria for Enterococcus faecalis and Enterococcus faecium

Abstract Background Ampicillin and vancomycin are used for the treatment of patients with enterococcal infections. In vitro STIC for these agents against Enterococcus species were established decades ago based on limited clinical and pharmacokinetic-pharmacodynamic (PK-PD) data. Using non-clinical PK-PD targets for efficacy, population PK models, simulation, and in vitro surveillance data, PK-PD target attainment analyses were performed to identify STIC for these agents against E. faecalis and E. faecium. Methods Population PK models for each agent were identified from the literature. PK-PD targets for efficacy were based on data from a neutropenic murine invasive enterococcal infection model. Using replication, simulated patients with demographic variables resembling a clinical trial population were generated. These variables with population PK models were used to generate ampicillin and vancomycin exposures after administration of ampicillin 2 g IV q4h adjusted for creatinine clearance (CLcr) and vancomycin weight-based loading doses followed by dosing regimens based on weight and CLcr. On Days 5 to 6, vancomycin AUC values were assigned from distributions assuming administration of dosing regimens adjusted using therapeutic drug monitoring. Percent probabilities of PK-PD target attainment by MIC based on median and randomly assigned ampicillin and vancomycin PK-PD targets associated with a 1-log10 CFU reduction from baseline for each pathogen were assessed in the context of in vitro surveillance data and any available clinical PK-PD and outcome by MIC data from the literature. Results Percent probabilities of PK-PD target attainment by MIC on Days 1 to 2 and 5 to 6 for ampicillin and vancomycin are shown in Figure 1 and Figure 2, respectively. Table 1 shows candidate susceptible breakpoints for E. faecalis and E. faecium based on these data, with recommended and existing STIC shown in Table 2. These data suggest ampicillin and vancomycin susceptible breakpoints of ≤ 8 and ≤ 4 mg/L for both species, respectively, consistent with CLSI STIC. In totality, the results from the literature search for clinical data did not provide meaningful information. Conclusion The results of these analyses provide support for recommendations for ampicillin and vancomycin STIC for E. faecalis and E. faecalis. Disclosures All Authors: No reported disclosures