1095. Pharmacokinetics-Pharmacodynamics Evaluation of Tebipenem Pivoxil Hydrobromide Using the 10-Day Hollow-Fiber In Vitro Infection Model

Abstract Background Tebipenem pivoxil hydrobromide, an orally bioavailable prodrug of tebipenem, is currently in development for the treatment of complicated urinary tract infections. The spectrum of tebipenem activity against Enterobacterales is consistent with intravenous carbapenems such as ertapenem and meropenem including extended spectrum beta-lactamase (ESBL) and AmpC producing organisms. The goal of these studies was to determine the tebipenem exposure required to prevent on-therapy resistance and to evaluate the tebipenem regimen utilized in the recent Phase 3 clinical trial. Methods Three Escherichia coli clinical isolates (ESBL +, Sequence Type -131) (tebipenem MIC = 0.008 to 0.03 mg/L) were subjected to concentration-time profiles simulating free-drug plasma concentrations after oral administration of tebipenem regimens in a hollow-fiber in vitro infection model. Dose-ranging studies were completed using two isolates at an initial burden of 108 CFU/mL and with exposures for tebipenem regimens ranging from 4.69 to 1200 mg administered every eight hours (q8h). An additional isolate was subjected to only the tebipenem 600 mg q8h regimen evaluated in the Phase 3 trial. Samples were collected for the enumeration of bacterial burdens and evaluation of the simulated pharmacokinetic profile. Each sample for bacterial enumeration was suspended onto drug-free and tebipenem-supplemented agar plates in order to observe the density of the total- and drug-resistant subpopulations over the 10-day period. Results A full dose response, ranging from treatment failure to reductions in bacterial burden from baseline, were observed in the dose-ranging studies for the two E. coli isolates. Tebipenem consistently lowered bacterial burdens below that of the initial inoculum at a dose of 600 mg q8h for all three E. coli isolates. Amplification of resistance was observed intermittently for all regimens, but was never equal to that of the total population at the 600 mg q8h clinical dose. Tebipenem MIC values for isolates collected from the drug-supplemented agar ranged from 0.06 to 0.25 mg/L, representing four two-fold dilutions from baseline. Conclusion These data support the selection of tebipenem dosing regimens that minimize the potential for on-therapy drug-resistance amplification. Disclosures Brian D. VanScoy, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Haley Conde, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Sean Jones, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Ian A. Critchley, Ph.D., Spero Therapeutics (Employee, Shareholder) Thomas R. Parr, Ph.D., Spero Therapeutics (Employee, Shareholder) Nicole Cotroneo, Spero Therapeutics (Employee, Shareholder) Paul G. Ambrose, Pharm.D., FIDSA, 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Research Grant or Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support, Other Financial or Material Support, member/owner)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support)


Figure 1. Percent Free Dalbavancin vs Varying Concentrations of Tween 80 for Pretreatment of Tubes
Conclusion. By the ultracentrifugation method, dalbavancin's PB was estimated to be approximately 99%. Given dalbavancin's high PB, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should also determine if the active fraction is best predicted by the free or total fraction, as this remains a subject of debate.
Supported by NIAID/NIH grant UM1AI104681. Content is solely the authors' responsibility and does not represent official NIH views.
Disclosures. Thomas  Background. Tebipenem pivoxil hydrobromide, an orally bioavailable prodrug of tebipenem, is currently in development for the treatment of complicated urinary tract infections. The spectrum of tebipenem activity against Enterobacterales is consistent with intravenous carbapenems such as ertapenem and meropenem including extended spectrum beta-lactamase (ESBL) and AmpC producing organisms. The goal of these studies was to determine the tebipenem exposure required to prevent on-therapy resistance and to evaluate the tebipenem regimen utilized in the recent Phase 3 clinical trial.
Methods. Three Escherichia coli clinical isolates (ESBL +, Sequence Type -131) (tebipenem MIC = 0.008 to 0.03 mg/L) were subjected to concentration-time profiles simulating free-drug plasma concentrations after oral administration of tebipenem regimens in a hollow-fiber in vitro infection model. Dose-ranging studies were completed using two isolates at an initial burden of 10 8 CFU/mL and with exposures for tebipenem regimens ranging from 4.69 to 1200 mg administered every eight hours (q8h). An additional isolate was subjected to only the tebipenem 600 mg q8h regimen evaluated in the Phase 3 trial. Samples were collected for the enumeration of bacterial burdens and evaluation of the simulated pharmacokinetic profile. Each sample for bacterial enumeration was suspended onto drug-free and tebipenem-supplemented agar plates in order to observe the density of the total-and drug-resistant subpopulations over the 10-day period.
Results. A full dose response, ranging from treatment failure to reductions in bacterial burden from baseline, were observed in the dose-ranging studies for the two E. coli isolates. Tebipenem consistently lowered bacterial burdens below that of the initial inoculum at a dose of 600 mg q8h for all three E. coli isolates. Amplification of resistance was observed intermittently for all regimens, but was never equal to that of the total population at the 600 mg q8h clinical dose. Tebipenem MIC values for isolates collected from the drug-supplemented agar ranged from 0.06 to 0.25 mg/L, representing four two-fold dilutions from baseline.
Conclusion. These data support the selection of tebipenem dosing regimens that minimize the potential for on-therapy drug-resistance amplification. Disclosures

Evaluation of Vancomycin Pharmacokinetics in Intravenous Drug Users
Sayo Weihs, PharmD, MBA, BCPS, BCIDP 1 ; Gadison Quick, PharmD 2 ; Ivana Bogdanich, PharmD, BCPS, BCACP 2 ; 1 University Health Truman Medical Centers, Kansas City, Missouri; 2 Truman Medical Centers, Kansas City, Missouri Session: P-62. PK/PD Studies Background. People who inject illicit drugs (PWID) are 16 times more likely to develop methicillin-resistant Staphylococcus aureus (MRSA) infections including severe infections like bacteremia and endocarditis. Vancomycin is recommended as the drug of choice for empiric and targeted coverage in both severe and non-severe MRSA infections. Pharmacokinetic literature has suggested up to 31% higher renal clearance in intravenous drug users (IVDU) compared to non-IVDUs. This increased clearance may theoretically lead to more frequent sub-therapeutic troughs in otherwise standard dosing schemes. There is a paucity of data examining vancomycin pharmacokinetics following typical dosing schemes in IVDU population.
Methods. This was a single-center, retrospective chart review that examined therapeutic drug monitoring in patients treated with vancomycin between January 1 st , 2015 through July 31 st , 2020. Patients were identified as either IVDU or non-IVUD groups based on ICD-9/10 codes. The primary outcome was the difference between mean first vancomycin steady state troughs. Secondary outcomes were differences in time to first therapeutic trough, mean number of days on vancomycin based on infection, rate of acute kidney injury (AKI) after vancomycin, and rate of vancomycin failure.
Results. A total of 158 patients were included in the analysis (77 IVDU vs. 81 non-IVDU). Mean first vancomycin steady state trough were significantly less in IVDU group compared to non-IVDU group (11.85 vs. 13.98 mcg/mL P = 0.007). Mean time