# P-1229. Characterization of Ampicillin (AMP) and Vancomycin (VAN) Pharmacokinetics-Pharmacodynamics (PK-PD) in a Neutropenic Murine Invasive Enterococcal Infection Model

## TL;DR

This study characterizes the effectiveness of ampicillin and vancomycin against enterococcal infections in a mouse model, providing new pharmacokinetic-pharmacodynamic targets for treatment decisions.

## Contribution

The study provides novel PK-PD targets for ampicillin and vancomycin against Enterococcus species using a newly developed neutropenic murine infection model.

## Key findings

- Ampicillin f %T >MIC targets for bacterial stasis and 1-log reduction were 25.5% and 44.7% for E. faecalis, and 16.5% and 20.3% for E. faecium.
- Vancomycin fAUC:MIC ratio targets for these endpoints were 9.61 and 25.5 for E. faecalis, and 6.62 and 18.3 for E. faecium.
- The model enabled robust PK-PD characterization of both drugs against enterococcal isolates.

## Abstract

AMP and VAN were developed in the 1950s and have remained important therapies for enterococcal infections. Current treatment decisions are based on in vitro susceptibility test interpretive criteria (STIC) using epidemiology data rather than robust PK-PD data due to the poor growth of Enterococcus species in standard pre-clinical infection models. The goal of these studies was to characterize the PK-PD of AMP and VAN against panels of Enterococcus faecalis and E. faecium isolates using a neutropenic murine invasive enterococcal infection model that we developed.

Single-dose PK studies were completed in neutropenic mice infected with E. faecalis ATCC 29212. Plasma samples were collected over 7 time points following subcutaneous administration of 4 doses of AMP (4.50, 37.5, 150, and 600 mg/kg) or VAN (0.35, 7.00, 64.0, and 200 mg/kg). 24-hour dose-ranging studies were completed using 5 isolates of each of E. faecium and E. faecalis exposed to 7 different AMP or VAN dosing regimens administered every 6 hours. Population PK models were used to determine AMP free-drug plasma percent time above MIC (f %T >MIC) and VAN free-drug plasma area under the concentration-time curve over 24 hours (fAUC) values for these doses. Relationships between change in log10 CFU/g from baseline at 24 hours and each respective PK-PD index were fit using Hill-type models to determine the magnitude of the index required to achieve net bacterial stasis and a 1-log10 CFU/g reduction from baseline at 24 hours for each isolate and pooled by species.

Relationships between change in log10 CFU/g and each of AMP f %T >MIC and VAN fAUC:MIC ratio described the data well for E. faecalis and E. faecium (Figures 1 and 2). Median AMP f %T >MIC targets associated with net bacterial stasis and a 1-log10 CFU reduction from baseline were 25.5 and 44.7%, respectively, for E. faecalis, and 16.5 and 20.3%, respectively, for E. faecium. Median VAN fAUC:MIC ratio targets associated with these endpoints were 9.61 and 25.5, respectively, for E. faecalis, and 6.62 and 18.3, respectively, for E. faecium.

Data from these neutropenic murine invasive enterococcal infection model studies allowed for the PK-PD characterization of AMP and VAN against E. faecalis and E. faecium, the PK-PD targets for which will support STIC evaluations.

Brian D. VanScoy, B.S., A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals, Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support Allison N. Seyfried, M.S., A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics, Inc.: Grant/Research Support|Excalibur Pharmaceuticals, Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support Alexander S. MacGregor, B.S., A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals, Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support Micah Nasman, B.S., A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals, Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support Christopher M. Rubino, PharmD, A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences,: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals, Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Ownership Interest|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|pRxcision, Inc.: Ownership Interest|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support Rodrigo E. Mendes, PhD, GSK: Grant/Research Support|Shionogi & Co., Ltd.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140 Helio Sader, United States Food and Drug Administration: FDA Contract Number: 75F40123C00140 Paul G. Ambrose, PharmD; MS; FIDSA, A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals, Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Ownership Interest|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|pRxcision, Inc.: Ownership Interest|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Advisor/Consultant|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, A&G Pharma: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany College of Pharmacy and Health Sciences: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|Aurobac Therapeutics: Advisor/Consultant|B. Braun Medical, Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Cumberland Pharmaceuticals, Inc.: Grant/Research Support|Debiopharm: Grant/Research Support|Elion Therapeutics, Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Excalibur Pharmaceuticals, Inc: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|Global Antibiotic Research & Development Partnership: Grant/Research Support|Inotrem: Grant/Research Support|Insmed, Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics: Ownership Interest|Invivyd, Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics, Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|National Institutes of Health: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|pRxcision, Inc.: Ownership Interest|PTC Therapeutics: Grant/Research Support|PureTech LYT 100, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sagimet Biosciences, Inc.: Grant/Research Support|Schrodinger, Inc.: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi, Inc.: Advisor/Consultant|Shionogi, Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences, Inc.: Grant/Research Support|UCB Biosciences, Inc.: Grant/Research Support|United States Food and Drug Administration: FDA Contract Number: 75F40123C00140|University of Wisconsin: Grant/Research Support|UT Southwestern: Grant/Research Support|VenatoRx Pharmaceuticals, Inc.: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support|Zogenix International: Grant/Research Support