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1. Antibacterial Drug Development: A New Approach Is Needed for the Field to Survive and Thrive

Author: M. Courtney Safir, Sujata M. Bhavnani, Christine M. Slover, Paul G. Ambrose, and Christopher M. Rubino
Subjects: antibiotic development, monoclonal antibodies, antibiotic marketplace, Therapeutics. Pharmacology, RM1-950
Abstract: It is often said that the marketplace for new antibiotics is broken. This notion is supported by the observation that many recently-approved antibiotics to treat drug-resistant bacteria have failed commercially in a spectacular fashion. Today, companies with peak market-cap values in excess of USD 500 million to 1 billion prior to product launch regularly sell for pennies on the dollar a few years after market introduction. It is possible, however, that the market is not as broken as we perceive. That is, in the collective mind of the clinician, recently-approved antibiotics may be too-poorly differentiated to justify their broad use and inordinate cost relative to those already existing. Perhaps we in the antibacterial drug development field must change our way of thinking if we are to survive and thrive. Rather than reflexively developing new β-lactam-β-lactamase inhibitor combinations for every new enzyme that evades our current inhibitors, we should focus discovery and development efforts on agents that revolutionize how we potentiate antibiotics. To this end, there has been renewed interest in phage therapies, virulence inhibitors, bacterial growth rate modulators, monoclonal antibodies, and other approaches to augment antibiotic effects. Herein, we suggest that the unmet medical need is less about adding poorly-differentiated antibiotics to our armamentarium and more about the need for innovation in how we augment antibiotic regimen effects.
Published: 2020
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2. The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex

Author: John P O’Donnell and Sujata M Bhavnani
Subjects: Microbiology (medical), Infectious Diseases
Abstract: Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a β-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of β-lactamase–mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed β-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine β-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through β-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.
Published: 2023

3. Pharmacokinetic-Pharmacodynamic Target Attainment Analyses Evaluating Omadacycline Dosing Regimens for the Treatment of Patients with Community-Acquired Bacterial Pneumonia Arising from Streptococcus pneumoniae and Haemophilus influenzae

Author: Sujata M. Bhavnani, Jeffrey P. Hammel, Elizabeth A. Lakota, Michael Trang, Justin C. Bader, Catharine C. Bulik, Brian D. VanScoy, Christopher M. Rubino, Michael D. Huband, Lawrence Friedrich, Judith N. Steenbergen, and Paul G. Ambrose
Subjects: Pharmacology, Infectious Diseases, Pharmacology (medical)
Abstract: Omadacycline, a novel aminomethylcycline with in vitro activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and Haemophilus influenzae , is approved in the United States to treat patients with community-acquired bacterial pneumonia (CABP). Using nonclinical pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy and in vitro surveillance data for omadacycline against S. pneumoniae and H. influenzae , and a population pharmacokinetic model, PK-PD target attainment analyses were undertaken using total-drug epithelial lining fluid (ELF) and free-drug plasma exposures to evaluate omadacycline 100 mg intravenously (i.v.) every 12 h or 200 mg i.v. every 24 h (q24h) on day 1, followed by 100 mg i.v. q24h on day 2 and 300 mg orally q24h on days 3 to 5 for patients with CABP.
Published: 2023

4. 619. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Epetraborole Dose Selection for the Treatment of Patients with Mycobacterium avium Complex (MAC) Lung Disease

Author: Sujata M Bhavnani, Jeffrey P Hammel, Harish Ganesan, M Courtney Safir, Christopher M Rubino, Paul G Ambrose, and Kevin M Krause
Subjects: Infectious Diseases, Oncology
Abstract: Background Epetraborole (EBO) is an orally available, bacterial leucyl transfer RNA synthetase inhibitor that concentrates in alveolar macrophages and exhibits potent activity against nontuberculous mycobacteria. PK-PD target attainment (PTA) analyses using plasma exposures were performed to support the selection of an EBO oral (PO) dosing regimen for clinical development in MAC lung disease. Methods Hill-type models were used to characterize the PK-PD relationships between EBO free-drug plasma AUC:MIC ratio and change in log10 CFU from baseline for 5 MAC isolates (EBO MIC range 2-8 mg/L) in a murine chronic MAC lung infection model. Change in log10 CFU was calculated by comparing lung CFUs after 56 days of EBO dosing (100 to 300 mg/kg/day) to CFUs of untreated controls prior to dosing. Data from PK studies were used to determine AUC by EBO dose. EBO PK parameters were calculated for 10,000 simulated MAC lung disease patients using an EBO population PK model with inflated PK variance to generate total-drug plasma concentration-time profiles at steady-state after administration of EBO 250 mg and 500 mg PO q24h for 21 days in a fasted state. Free-drug plasma AUC values were calculated using a human protein binding estimate of 0%. Percent probabilities of PTA were assessed using median, randomly assigned, and the highest of the free-drug plasma AUC:MIC ratio targets from the Hill models developed using the above-described in vivo efficacy study data. Results Table 1 summarizes the free-drug plasma AUC:MIC ratio targets for each MAC isolate. For EBO 250 mg q24h, percent probabilities of PTA were ≥ 90% for a 1-log10 CFU reduction (Figure 1) at an MIC of 4 mg/L (all PK-PD targets) or 8 mg/L (median target only) and for a 2-log10 CFU reduction (Figure 2) at an MIC of 2 mg/L (all PK-PD targets) or 4 mg/L (median target only). For EBO 500 mg q24h, percent probabilities of PTA were ≥ 90% for a 1-log10 CFU reduction at an MIC of 8 mg/L (all PK-PD targets) or 16 mg/L (median target only) and for a 2-log10 CFU reduction at an MIC of 4 mg/L (median and randomly assigned PK-PD targets) or 8 mg/L (median target only). Conclusion The high PTA associated with plasma exposures after oral EBO 500 mg q24h support advancing this dosing regimen into clinical studies in patients with MAC lung disease. Disclosures Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Jeffrey P. Hammel, MS, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma,: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A,: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Harish Ganesan, MS, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co.Meiji Seika Pharma Co., Ltd: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support M. Courtney Safir, PharmD, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited,: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Paul G. Ambrose, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Kevin M. Krause, MBA, AN2 Therapeutics: Employee|AN2 Therapeutics: Stocks/Bonds.
Published: 2022

5. 592. Impact of Elevated MIC Values on Echinocandin Pharmacokinetic-Pharmacodynamic (PK-PD) Candida glabrata Target Attainment (TA)

Author: Christopher M Rubino, Shawn Flanagan, Jeffrey B Locke, and Sujata M Bhavnani
Subjects: Infectious Diseases, Oncology
Abstract: Background Given the increasing prevalence of non-albicans Candida species, including C. glabrata and C. auris, which have higher predisposition to develop antifungal resistance (e.g., fks mutations conferring reduced susceptibility to echinocandins), disparities in PK-PD TA of currently approved echinocandins warrant further attention. Rezafungin (RZF) is a novel, next-generation echinocandin in development for treatment and prevention of invasive fungal disease. The completed Phase 3 treatment trial (ReSTORE; NCT03667690) demonstrated non-inferiority of RZF once weekly to caspofungin (CAS) once daily in patients with candidemia and invasive candidiasis. Here we revisit the challenge for echinocandins in achieving TA against C. glabrata with elevated MIC values and build on previous analyses using RZF patient data. Methods Monte Carlo simulations were conducted using published population PK models for anidulafungin (AFG), micafungin (MFG), CAS, and RZF (Bader et al 2018, Rubino and Flanagan 2021). Dosing regimens were as labeled for candidemia for once-daily echinocandins and as studied for RZF (400 mg Week 1, 200 mg once weekly thereafter). Individual free-drug plasma AUC values from time zero to the end of the dosing interval of 24 or 168 h (AUC0-tau) were calculated for each drug for 2 weeks. MIC values corresponding to observed C. glabrata MIC90 and MIC100 values for each drug were derived from 2018-2020 SENTRY surveillance data (Pfaller et al 2020, Carvalhaes et al 2022). Free-drug AUC0-tau:MIC targets associated with return to baseline colony-forming units (CFU) (stasis) of C. glabrata, derived from neutropenic murine disseminated candidiasis models, were used (Table). Simulated echinocandin free-drug AUC0-tau:MIC ratio distributions relative to the MIC90 and MIC100 were generated. Results The FDA-approved dosing regimens for CAS, MFG and AFG failed to achieve adequate TA at higher C. glabrata MIC values associated with their respective MIC90 (AFG only) and/or MIC100 (all three). In contrast, the Phase 3 RZF dosing regimen achieved excellent TA at both the MIC90 and MIC100 (Figure). Conclusion Projected enhanced TA for RZF once weekly may result in clinical efficacy in patients infected with less susceptible C. glabrata isolates. Disclosures Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Shawn Flanagan, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Jeffrey B. Locke, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support.
Published: 2022

6. 593. Population Pharmacokinetic Model Development for Epetraborole and Mycobacterium avium Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

Author: Harish Ganesan, M Courtney Safir, Sujata M Bhavnani, Kevin M Krause, and Christopher M Rubino
Subjects: Infectious Diseases, Oncology
Abstract: Background Epetraborole (EBO), an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria, is under clinical development for treatment of MAC lung disease. A population pharmacokinetic (PK) model describing the disposition of EBO after oral (PO) and intravenous (IV) administration was developed to support EBO PK-PD analyses and dose selection for patients with MAC lung disease. Methods Model development was conducted using NONMEM (v.7.4.3). Models were attempted for oral absorption, systemic compartments, and linear vs. non-linear elimination. Model evaluation involved goodness-of-fit plots and prediction-corrected visual predictive plots, which describe the ability of model-based simulations to capture the observed data. Included were data from 5 Phase 1 (3 IV and 2 PO) and 2 Phase 2 studies (IV only) (Table 1). Results The pooled dataset included 2637 EBO PK samples from 138 subjects/patients. A robust fit to observed data across studies was obtained using a three-compartment model with linear elimination (Table 2). The impact of body weight on PK was included using an allometric scaling approach to accommodate observed lower body weight in MAC lung disease patients. PO dosing was modeled using an absolute bioavailability term (F) and transit compartments with separate absorption rates for fed and fasted administration. Interindividual variability (IIV) in systemic clearance was low (7.9%), but IIV in F (32.7%) contributed to slightly higher variability in PK for PO vs. IV administration. Moderate shrinkage was observed for the IIV in the model parameters. This was considered acceptable given inclusion of patients with limited PK data in the model and the objective to facilitate simulations designed to inform dose selection. The prediction-corrected visual predictive check plots for the data obtained from a recently completed Phase 1b study evaluating 28-day oral dosing regimens (NCT04892641) are provided in Figure 1. Conclusion This model is useful for describing expected PK in MAC lung disease patients and was used to conduct simulations for the advancement of the oral EBO 500 mg q24h dosing regimen into clinical studies in patients with MAC lung disease. Disclosures Harish Ganesan, MS, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co.Meiji Seika Pharma Co., Ltd: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support M. Courtney Safir, PharmD, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited,: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Kevin M. Krause, MBA, AN2 Therapeutics: Employee|AN2 Therapeutics: Stocks/Bonds Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support.
Published: 2022

7. LB2306. Population Pharmacokinetic (PPK), Pharmacokinetic/Pharmacodynamic attainment (PTA), and Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Sulbactam-Durlobactam (SUL-DUR) to Support Dose Selection for the Treatment of Acinetobacter baumannii-calcoaceticus Complex (ABC) Infections

Author: Sujata M Bhavnani, Christopher M Rubino, Jeffrey P Hammel, Anthony P Cammarata, Kajal Larson, Kathryn Liolios, Sarah McLeod, Alita Miller, Paul G Ambrose, Ruben Tommasi, and John O'Donnell
Subjects: Infectious Diseases, Oncology
Abstract: Background SUL-DUR is a β-lactam/β-lactamase inhibitor combination in development for the treatment of ABC infections, which are often severe and associated with substantial mortality. PPK, PTA, and clinical PK/PD analyses were conducted using all available PK and efficacy data to support SUL-DUR dose selection. Methods PPK analyses were performed using PK data from 373 subjects, including 110 patients who received SUL-DUR and underwent PK sampling in the pivotal Phase 3 (ATTACK) trial. SUL-DUR concentrations in epithelial lining fluid (ELF) from healthy subjects were utilized to predict SUL-DUR ELF concentrations in Phase 3 patients. Covariate analyses evaluated the impact of demographic factors on PK exposures. The PPK model, non-clinical PK/PD data, and in vitro surveillance data were used to assess the PTA by MIC in simulated patients with ABC infections. Clinical PK/PD relationships were assessed using dichotomous and time-to-event efficacy endpoints from the ATTACK trial. Results Two-compartment models with linear kinetics best characterized SUL and DUR PK. Consistent with high renal clearance of SUL-DUR, dose adjustments are needed in patients with renal impairment or augmented renal function. Body weight, site of infection, and East Asian region (which grouped patients from mainland China, Taiwan, and South Korea vs others) were statistically significant covariates in the PPK analysis but were not clinically relevant. No other statistical or clinically relevant covariates were identified. As shown in Figures A and B for plasma and ELF, respectively, the PTA was ≥ 90% for pathogens with an MIC ≤ 4 µg/mL across renal function categories in simulated patients, using PK/PD targets associated with a 1-log kill10. No relationships were observed between PK/PD indices and efficacy endpoints, consistent with most patients achieving SUL and DUR exposures above nonclinical PK/PD targets for efficacy. Percent PTA by MIC on Day 1 based on the assessment of sulbactam %T>MIC ≥ 50% and durlobactam AUC:MIC ratio ≥ 10 targets and free-drug plasma (A) and total-drug ELF (B) exposures among simulated patients by CLcr group after administration of sulbactam 1 g/ durlobactam 1 g IV q6h and dosing regimens adjusted for renal impairment and augmented renal function Abbreviations: %T>MIC, percentage of time on Day 1 that concentration exceed minimum inhibitory concentration; AUC, area under the concentration-time curve; CLcr, creatinine clearance; ELF, epithelial lining fluid; MIC, minimum inhibitory concentration; q6h, every 6 hours; PK-PD, pharmacokinetic/pharmacodynamic; PTA, probability of PK/PD target attainment Conclusion The simulated plasma and ELF exposures yielded a high PTA, which when combined with the favorable efficacy and safety findings from ATTACK (abstract #1266378), support a dose of 1.0 g sulbactam/1.0 g durlobactam via a 3-hour infusion, every 6 hours in patients with normal renal function and renal function-based dose adjustments. Disclosures Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Jeffrey P. Hammel, MS, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Anthony P. Cammarata, M.S., Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Kajal Larson, PhD, Entasis Therapeutics: Employee Kathryn Liolios, MA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sarah McLeod, PhD, Entasis Therapeutics: Employee Alita Miller, PhD, Entasis Therapeutics: Employee Paul G. Ambrose, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Ruben Tommasi, PhD, Entasis Therapeutics: Employee John O'Donnell, B.S, Entasis Therapeutics: Employee
Published: 2022

8. 1078. Optimization of a 96-well Plate Format Assay to Evaluate Concentration-Dependent Activity of a Monoclonal Antibody Against the O Antigen O25b from ST131-H30 Escherichia coli

Author: Jill Lindley, Timothy B Doyle, Brian D VanScoy, Christopher M Rubino, Sujata M Bhavnani, Paul G Ambrose, and Mariana Castanheira
Subjects: Infectious Diseases, Oncology
Abstract: Background Escherichia coli ST131 is a major challenge for global human health. Among ST131 isolates, the H30 type is prevalent and displays multiple drug resistance to classes. A monoclonal antibody (mAb) specific for the O antigen, O25b, which is conserved in ST131-H30 clonal lineage, was developed for diagnostic and prophylactic therapy. We optimized a 96-well plate assay to test different concentrations of the mAb against E. coli clinical isolates. Methods Initial growth curves were performed against 69 ST131-O25b, 9 ST131-O25a, 32 ST131 non-O25, and 29 non-ST131 E. coli isolates in 40% active human serum (HS). Additional conditions evaluated for growth inhibition by the mAb included 3 media types, 3 HS sources, pH variations, addition of polysorbate 80 (P80), inoculum concentration, length of incubation, and varying calcium and magnesium concentrations. Once optimal parameters were established, the assay was miniaturized into a 96-well format and 12 ST131-O25b and 5 non-ST131 were tested. Fluorescence and visual reading using alamarBlue (AB), a cell metabolism indicator, were performed at 8 and 10h in addition to plating for viable colonies. Results After 10h incubation, only 36/69 (52.2%) ST131-O25b isolates exhibited visible growth in BHI plus 40% HS. A 2-part growth inhibition assay using BHI plus 50% HS and BHI with 25% HS without the addition of P80, calcium, or magnesium was considered the optimal growth condition for EC strains to test the effect of the mAb. By 10 hours, all ST131-O25b strains displayed a visual inhibition of growth between 0.3-5 mg/L of α-ST131 mAb and zero non-ST131 strains were inhibited (Figure). While reading AB on a fluorometer was more sensitive and less subjective than visual interpretation, both reading methods allow for endpoint determinations. Additionally, panels were able to go through one freeze-thaw cycle and still retain α-ST131:O25b mAb activity. Conclusion Concentration-dependent activity of a α-ST131:O25b mAb can be measured in vitro in a microtiter format; however, the growth inhibition by HS, while still providing enough complement for complement-mediated mAb killing, might be an obstacle. Additionally, assay reproducibility may be difficult without a consistent source of active HS. Figure Disclosures Jill Lindley, Bravos Biosciences (Research Grant or Support)ContraFect Corporation (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) 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) Christopher M. Rubino, Pharm.D., 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 (Research Grant or 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 (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, 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) Sujata M. Bhavnani, Pharm.D., M.S., 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 (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, 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) 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) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors (Individual(s) Involved: Self): Research Grant or Support; Allergan (Individual(s) Involved: Self): Research Grant or Support; Amicrobe, Inc (Individual(s) Involved: Self): Research Grant or Support; Amplyx Pharma (Individual(s) Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc. (Individual(s) Involved: Self): Research Grant or Support; Astellas (Individual(s) Involved: Self): Research Grant or Support; Basilea (Individual(s) Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center (Individual(s) Involved: Self): Research Grant or Support; BIDMC (Individual(s) Involved: Self): Research Grant or Support; bioMerieux Inc. (Individual(s) Involved: Self): Research Grant or Support; BioVersys Ag (Individual(s) Involved: Self): Research Grant or Support; Bugworks (Individual(s) Involved: Self): Research Grant or Support; Cidara (Individual(s) Involved: Self): Research Grant or Support; Cipla (Individual(s) Involved: Self): Research Grant or Support; Contrafect (Individual(s) Involved: Self): Research Grant or Support; Cormedix (Individual(s) Involved: Self): Research Grant or Support; Crestone, Inc. (Individual(s) Involved: Self): Research Grant or Support; Curza (Individual(s) Involved: Self): Research Grant or Support; CXC7 (Individual(s) Involved: Self): Research Grant or Support; Entasis (Individual(s) Involved: Self): Research Grant or Support; Fedora Pharmaceutical (Individual(s) Involved: Self): Research Grant or Support; Fimbrion Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Fox Chase (Individual(s) Involved: Self): Research Grant or Support; GlaxoSmithKline (Individual(s) Involved: Self): Research Grant or Support; Guardian Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Hardy Diagnostics (Individual(s) Involved: Self): Research Grant or Support; IHMA (Individual(s) Involved: Self): Research Grant or Support; Janssen Research & Development (Individual(s) Involved: Self): Research Grant or Support; Johnson & Johnson (Individual(s) Involved: Self): Research Grant or Support; Kaleido Biosceinces (Individual(s) Involved: Self): Research Grant or Support; KBP Biosciences (Individual(s) Involved: Self): Research Grant or Support; Luminex (Individual(s) Involved: Self): Research Grant or Support; Matrivax (Individual(s) Involved: Self): Research Grant or Support; Mayo Clinic (Individual(s) Involved: Self): Research Grant or Support; Medpace (Individual(s) Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd. (Individual(s) Involved: Self): Research Grant or Support; Melinta (Individual(s) Involved: Self): Research Grant or Support; Menarini (Individual(s) Involved: Self): Research Grant or Support; Merck (Individual(s) Involved: Self): Research Grant or Support; Meridian Bioscience Inc. (Individual(s) Involved: Self): Research Grant or Support; Micromyx (Individual(s) Involved: Self): Research Grant or Support; MicuRx (Individual(s) Involved: Self): Research Grant or Support; N8 Medical (Individual(s) Involved: Self): Research Grant or Support; Nabriva (Individual(s) Involved: Self): Research Grant or Support; National Institutes of Health (Individual(s) Involved: Self): Research Grant or Support; National University of Singapore (Individual(s) Involved: Self): Research Grant or Support; North Bristol NHS Trust (Individual(s) Involved: Self): Research Grant or Support; Novome Biotechnologies (Individual(s) Involved: Self): Research Grant or Support; Paratek (Individual(s) Involved: Self): Research Grant or Support; Pfizer (Individual(s) Involved: Self): Research Grant or Support; Prokaryotics Inc. (Individual(s) Involved: Self): Research Grant or Support; QPEX Biopharma (Individual(s) Involved: Self): Research Grant or Support; Rhode Island Hospital (Individual(s) Involved: Self): Research Grant or Support; RIHML (Individual(s) Involved: Self): Research Grant or Support; Roche (Individual(s) Involved: Self): Research Grant or Support; Roivant (Individual(s) Involved: Self): Research Grant or Support; Salvat (Individual(s) Involved: Self): Research Grant or Support; Scynexis (Individual(s) Involved: Self): Research Grant or Support; SeLux Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Shionogi (Individual(s) Involved: Self): Research Grant or Support; Specific Diagnostics (Individual(s) Involved: Self): Research Grant or Support; Spero (Individual(s) Involved: Self): Research Grant or Support; SuperTrans Medical LT (Individual(s) Involved: Self): Research Grant or Support; T2 Biosystems (Individual(s) Involved: Self): Research Grant or Support; The University of Queensland (Individual(s) Involved: Self): Research Grant or Support; Thermo Fisher Scientific (Individual(s) Involved: Self): Research Grant or Support; Tufts Medical Center (Individual(s) Involved: Self): Research Grant or Support; Universite de Sherbrooke (Individual(s) Involved: Self): Research Grant or Support; University of Iowa (Individual(s) Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics (Individual(s) Involved: Self): Research Grant or Support; University of Wisconsin (Individual(s) Involved: Self): Research Grant or Support; UNT System College of Pharmacy (Individual(s) Involved: Self): Research Grant or Support; URMC (Individual(s) Involved: Self): Research Grant or Support; UT Southwestern (Individual(s) Involved: Self): Research Grant or Support; VenatoRx (Individual(s) Involved: Self): Research Grant or Support; Viosera Therapeutics (Individual(s) Involved: Self): Research Grant or Support; Wayne State University (Individual(s) Involved: Self): Research Grant or Support
Published: 2021

9. Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease

Author: Dayton W. Yuen, Nikolas J. Onufrak, Christopher M. Rubino, Jakko van Ingen, David E. Griffith, Kevin C. Mange, Kevin L. Winthrop, and Sujata M. Bhavnani
Subjects: medicine.medical_specialty, Population, Cmax, Urine, 030226 pharmacology & pharmacy, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Medicine, Pharmacology (medical), Dosing, Original Research Article, education, Pharmacology, education.field_of_study, Inhalation, business.industry, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Amikacin, 030220 oncology & carcinogenesis, Sputum, medicine.symptom, business, medicine.drug
Abstract: Background and Objectives Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease. Methods In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg. Results Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (Cmax) was < 2 mg/L and median area under the concentration-time curve (AUC0–24) was
Published: 2021

10. Gepotidacin Pharmacokinetics-Pharmacodynamics against Escherichia coli in the One-Compartment and Hollow-Fiber In Vitro Infection Model Systems

Author: Haley Conde, Brian VanScoy, Sujata M. Bhavnani, Nicole E. Scangarella-Oman, Steven Fikes, Elizabeth A Lakota, Philippa Elefante, and Paul G. Ambrose
Subjects: Gepotidacin, medicine.drug_class, gepotidacin, Antibiotics, Microbial Sensitivity Tests, medicine.disease_cause, Microbiology, Pharmacokinetics, Escherichia coli, medicine, Humans, pharmacokinetics-pharmacodynamics, Pharmacology (medical), Escherichia coli Infections, Pharmacology, Acenaphthenes, Chemistry, Liter, In vitro, Anti-Bacterial Agents, Infectious Diseases, Mechanism of action, Pharmacodynamics, medicine.symptom, Heterocyclic Compounds, 3-Ring
Abstract: Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action with an in vitro spectrum of activity that includes Escherichia coli. Our objectives herein were the following: (i) to identify the pharmacokinetic-pharmacodynamic (PK-PD) index associated with the efficacy of gepotidacin against E. coli; (ii) to determine the magnitude of the above-described PK-PD index associated with various bacterial reduction endpoints for E. coli; and (iii) to characterize the relationship between gepotidacin exposure and on-therapy E. coli resistance amplification. A 24-h one-compartment in vitro infection model was used to investigate the first two study objectives, and a 10-day hollow-fiber in vitro infection model was used to evaluate the third objective. For the dose-fractionation studies (objective i) in which E. coli NCTC 13441 (gepotidacin MIC, 2 mg/liter) was evaluated, gepotidacin free-drug area under the concentration-time curve (AUC) from 0 to 24 h to the MIC (AUC/MIC ratio) was identified as the PK-PD index most closely associated with change in bacterial burden (r2 = 0.925). For the dose-ranging studies (objective ii), in which four E. coli isolates (gepotidacin MIC range, 1 to 4 mg/liter) were studied, the magnitude of the median gepotidacin free-drug AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log10 CFU reductions for the pooled data set was 33.9, 43.7, and 60.7, respectively. For the hollow-fiber in vitro infection model studies (objective iii), in which one isolate (E. coli NCTC 13441; gepotidacin MIC, 2 mg/liter) was evaluated, gepotidacin free-drug AUC/MIC ratios of 275 and greater were sufficient to suppress on-therapy resistance amplification. Together, the data generated from these studies will be useful to support discrimination among candidate dosing regimens for future clinical study.
Published: 2021

11. Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Noninfected Subjects and Infected Patients

Author: Michael Trang, Sujata M. Bhavnani, Paul G. Ambrose, Jeffrey S Loutit, Michael N. Dudley, David C. Griffith, and Christopher M. Rubino
Subjects: Pharmacology, Body surface area, medicine.medical_specialty, education.field_of_study, business.industry, Urinary system, Population, Urology, Renal function, Meropenem, Boronic Acids, End stage renal disease, NONMEM, Anti-Bacterial Agents, Drug Combinations, Heterocyclic Compounds, 1-Ring, Infectious Diseases, Pharmacokinetics, Medicine, Humans, Pharmacology (medical), business, education, medicine.drug
Abstract: Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the USA and Europe to treat patients with complicated urinary tract infections and in Europe, other serious bacterial infections, including hospital- acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time-course of meropenem and vaborbactam using pooled data from two Phase 1 and two Phase 3 studies. Multi-compartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different in Phase 1 non-infected subjects relative to Phase 3 infected patients, respectively. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.
Published: 2021

12. 1105. Population Pharmacokinetic Analyses for Tebipenem After the Administration of Tebipenem Pivoxil Hydrobromide

Author: Harish Ganesan, Vipul Kumar, Sujata M Bhavnani, David Melnick, and Christopher M Rubino
Subjects: Infectious Diseases, AcademicSubjects/MED00290, Oncology, Poster Abstracts
Abstract: Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety. TBP is a carbapenem with activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum-β-lactamase-producing Enterobacterales and is being developed for treating complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). Data from three Phase 1 studies and one Phase 3 study in patients with cUTI/AP were used to develop a population pharmacokinetic (PPK) model for TBP and identify covariates that described the variability in TBP pharmacokinetics (PK). Methods The PPK model was developed using TBP plasma and urine concentration-time data from the above-described Phase 1 and 3 studies. TBPPI-HBr doses, which ranged from 100 to 900 mg, were administered as single or multiple doses every 8 hours. After development of the structural model, stepwise forward and backward selection procedures were used to identify significant covariate relationships. The robustness of the final PPK model was assessed using a prediction-corrected visual predictive check (PC-VPC). Results The final dataset included 3448 plasma concentrations from 99 Phase 1 subjects and 647 Phase 3 patients and urine concentrations from 128 Phase 1 subjects. A two-compartment model with linear, first-order elimination and transit compartments to describe the rate of drug absorption after oral administration of TBP-PI-HBr best described TBP PK. The most clinically significant covariate effect, which would warrant dose adjustment, was the relationship between apparent oral clearance and creatinine clearance. In contrast, age, body size, sex, and fed status each had a minimal impact on TBP exposure. The PC-VPC showed good agreement between median simulated plasma concentrations based on the final PPK model and the median observed plasma concentrations for the pooled dataset (Figure 1). Figure 1. Prediction-corrected visual predictive check plot for the final population PK model using the pooled analysis dataset Conclusion A robust description of TBP plasma PK in subjects and patients with cUTI/AP was achieved, such that derived measures of TBP plasma exposure are expected to be both accurate and precise. The population PK model was considered appropriate for model-based simulations and the assessment of PK-PD relationships for TBP. Disclosures Harish Ganesan, M.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) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Sujata M. Bhavnani, Pharm.D., M.S., 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 (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, 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) David Melnick, MD, Spero Therapeutics (Employee, Shareholder) Christopher M. Rubino, Pharm.D., 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 (Research Grant or 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 (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, 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)
Published: 2021

13. Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber In Vitro Infection Model

Author: Sujata M. Bhavnani, Sharon Min, Nicole E. Scangarella-Oman, Karen A. Ingraham, Haley Conde, Jianzhong Huang, Paul G. Ambrose, Brian VanScoy, and Steven Fikes
Subjects: Pharmacology, Drug, 0303 health sciences, Gepotidacin, 030306 microbiology, business.industry, media_common.quotation_subject, Gonorrhea, Liter, medicine.disease, medicine.disease_cause, Microbiology, Ciprofloxacin, 03 medical and health sciences, Regimen, 0302 clinical medicine, Infectious Diseases, medicine, Neisseria gonorrhoeae, Ceftriaxone, Pharmacology (medical), 030212 general & internal medicine, business, medicine.drug, media_common
Abstract: Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 106 CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 108 CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections.
Published: 2020

14. Antibacterial Drug Development: A New Approach Is Needed for the Field to Survive and Thrive

Author: Christine M. Slover, Paul G. Ambrose, Christopher M. Rubino, M Courtney Safir, and Sujata M. Bhavnani
Subjects: Microbiology (medical), 2019-20 coronavirus outbreak, Antibiotic regimen, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Collective mind, Communication, Antibiotics, lcsh:RM1-950, Biochemistry, Microbiology, Infectious Diseases, lcsh:Therapeutics. Pharmacology, antibiotic marketplace, medicine, Pharmacology (medical), Business, monoclonal antibodies, General Pharmacology, Toxicology and Pharmaceutics, Marketing, Antibacterial drug, health care economics and organizations, antibiotic development
Abstract: It is often said that the marketplace for new antibiotics is broken. This notion is supported by the observation that many recently-approved antibiotics to treat drug-resistant bacteria have failed commercially in a spectacular fashion. Today, companies with peak market-cap values in excess of USD 500 million to 1 billion prior to product launch regularly sell for pennies on the dollar a few years after market introduction. It is possible, however, that the market is not as broken as we perceive. That is, in the collective mind of the clinician, recently-approved antibiotics may be too-poorly differentiated to justify their broad use and inordinate cost relative to those already existing. Perhaps we in the antibacterial drug development field must change our way of thinking if we are to survive and thrive. Rather than reflexively developing new β-lactam-β-lactamase inhibitor combinations for every new enzyme that evades our current inhibitors, we should focus discovery and development efforts on agents that revolutionize how we potentiate antibiotics. To this end, there has been renewed interest in phage therapies, virulence inhibitors, bacterial growth rate modulators, monoclonal antibodies, and other approaches to augment antibiotic effects. Herein, we suggest that the unmet medical need is less about adding poorly-differentiated antibiotics to our armamentarium and more about the need for innovation in how we augment antibiotic regimen effects.
Published: 2020

15. Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Author: Judith N. Steenbergen, Scott A. Van Wart, Elizabeth A Lakota, M Courtney Safir, Evan Tzanis, Sujata M. Bhavnani, Lawrence V. Friedrich, Christopher M. Rubino, Michael Trang, and Paul G. Ambrose
Subjects: Male, medicine.drug_class, Urinary system, Antibiotics, Population, Physiology, Absorption (skin), patients, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, population pharmacokinetics, Medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dosing, education, Pharmacology, 0303 health sciences, education.field_of_study, Clinical Trials, Phase I as Topic, 030306 microbiology, business.industry, Bacterial pneumonia, omadacycline, medicine.disease, Bioavailability, Anti-Bacterial Agents, Community-Acquired Infections, Infectious Diseases, Clinical Trials, Phase III as Topic, Tetracyclines, Administration, Intravenous, Female, business
Abstract: Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies., Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.
Published: 2020

16. Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model

Author: Elizabeth A Lakota, Haley Conde, Judith N. Steenbergen, Lawrence V. Friedrich, Sujata M. Bhavnani, Jennifer McCauley, Paul G. Ambrose, and Brian VanScoy
Subjects: Pharmacology, 0303 health sciences, 030306 microbiology, Pharmacokinetic pharmacodynamic, Epithelial lining fluid, Bacterial pneumonia, Liter, Biology, medicine.disease, medicine.disease_cause, Antimicrobial, 030226 pharmacology & pharmacy, In vitro, Haemophilus influenzae, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Infectious Diseases, chemistry, Omadacycline, medicine, Pharmacology (medical)
Abstract: Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r 2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.
Published: 2020

17. Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber

Author: Brian D, VanScoy, Nicole E, Scangarella-Oman, Steven, Fikes, Sharon, Min, Jianzhong, Huang, Karen, Ingraham, Sujata M, Bhavnani, Haley, Conde, and Paul G, Ambrose
Subjects: Gonorrhea, Acenaphthenes, Ciprofloxacin, Ceftriaxone, Drug Resistance, Bacterial, Humans, Microbial Sensitivity Tests, Heterocyclic Compounds, 3-Ring, Neisseria gonorrhoeae, Anti-Bacterial Agents
Abstract: Multidrug-resistant
Published: 2020

18. Methodological features of clinical pharmacokinetic–pharmacodynamic studies of antibacterials and antifungals:a systematic review

Author: Sujata M. Bhavnani, George L. Drusano, Paul G. Ambrose, Alexandra McAleenan, Johan W. Mouton, Alasdair P. MacGowan, William W. Hope, and Julian P T Higgins
Subjects: Microbiology (medical), medicine.medical_specialty, Antifungal Agents, pathogenic organism, medicine.drug_class, Antibiotics, MEDLINE, Recursive partitioning, Clinical pharmacokinetic, Logistic regression, antibiotics, antimicrobials, anti-bacterial agents, Anti-Infective Agents, Internal medicine, pharmacodynamics, Humans, Medicine, Pharmacology (medical), Dosing, infections, Pharmacology, business.industry, data mining, Regression, Anti-Bacterial Agents, Infectious Diseases, Area Under Curve, Pharmacodynamics, antifungal agents, business, serum
Abstract: Background Pharmacokinetic (PK)–pharmacodynamic (PD) indices relate measures of drug exposure to antibacterial effect. Clinical PK–PD studies aim to correlate PK–PD indices with outcomes in patients. Optimization of dosing based on pre-clinical studies means that PK–PD relationships are difficult to establish; therefore studies need to be designed and reported carefully to validate pre-clinical findings. Objectives To describe the methodological features of clinical antibacterial and antifungal PK–PD studies that reported the relationship between PK–PD indices and clinical or microbiological responses. Methods Studies published between 1980 and 2015 were identified through systematic searches. Methodological features of eligible studies were extracted. Results We identified 85 publications containing 97 PK–PD analyses. Most studies were small, with fewer than 100 patients. Around a quarter were performed on patients with infections due to a single specific pathogen. In approximately one-third of studies, patients received concurrent antibiotics/antifungals and in some other studies patients received other treatments that may confound the PK–PD–outcome relationship. Most studies measured antimicrobial concentrations in blood/serum and only four measured free concentrations. Most performed some form of regression, time-to-event analysis or used the Hill/Emax equation to examine the association between PK–PD index and outcome. Target values of PK–PD indices that predict outcomes were investigated in 52% of studies. Target identification was most commonly done using recursive partitioning or logistic regression. Conclusions Given the variability in conduct and reporting, we suggest that an agreed set of standards for the conduct and reporting of studies should be developed.
Published: 2020

19. Old In Vitro Antimicrobial Breakpoints Are Misleading Stewardship Efforts, Delaying Adoption of Innovative Therapies, and Harming Patients

Author: Robert K. Flamm, John S. Bradley, Jason M. Pogue, Sujata M. Bhavnani, Ronald N. Jones, Paul G. Ambrose, and David R. Andes
Subjects: 0301 basic medicine, medicine.medical_specialty, susceptibility breakpoints, incentives, in vitro antimicrobial susceptibility test interpretative criteria, 030106 microbiology, Appropriate use, 03 medical and health sciences, 0302 clinical medicine, medicine, Major Article, Antimicrobial stewardship, 030212 general & internal medicine, Intensive care medicine, Government, business.industry, antimicrobial drug development, Antimicrobial, antimicrobial stewardship, Infectious Diseases, Antimicrobial use, Innovative Therapies, Incentive, AcademicSubjects/MED00290, Oncology, Stewardship, business
Abstract: The current antimicrobial market and old (pre-2000) in vitro antimicrobial susceptibility test interpretative criteria (STIC) are not working properly. Malfunctioning susceptibility breakpoints and antimicrobial markets have serious implications for both patients (ie, from a safety and efficacy perspective) and antibiotic-focused pharmaceutical and biotechnology company economic viability. Poorly functioning STIC fail both patients and clinicians since they do not discriminate between likely effective and ineffective antimicrobial regimens. Poor economic viability fails patients and clinicians as it decreases the industry’s ability to develop antimicrobial agents that clinicians and patients urgently require now and in the future. Herein, we review how STIC for older antimicrobial agents were determined and how their correction can impact the perceived utility of old relative to new antimicrobial agents. Moreover, we describe the data and analysis needs to systematically reevaluate older STIC values. We call for professional infectious diseases societies, government agencies, and other consensus bodies interested in the appropriate use of antimicrobial agents to join an effort to systematically evaluate and, where warranted, correct STIC for all relevant antimicrobial agents. This effort will amplify the effects of other measures designed to increase appropriate antimicrobial use (ie, good antimicrobial stewardship), development, and regulation.
Published: 2020

20. A Broken Antibiotic Market: Review of Strategies to Incentivize Drug Development

Author: Kevin M Krause, Paul G. Ambrose, and Sujata M. Bhavnani
Subjects: 0301 basic medicine, susceptibility breakpoints, medicine.drug_class, in vitro antimicrobial susceptibility test interpretative criteria, media_common.quotation_subject, 030106 microbiology, Antibiotics, 03 medical and health sciences, 0302 clinical medicine, Antibiotic resistance, Tax credit, Milestone (project management), Major Article, Medicine, 030212 general & internal medicine, health care economics and organizations, media_common, Public economics, business.industry, push incentives, antimicrobial drug development, Payment, Antimicrobial, pull incentives, Infectious Diseases, Incentive, AcademicSubjects/MED00290, Oncology, Drug development, business
Abstract: The threat posed by infections arising from antimicrobial-resistant bacteria is a global concern. Despite this trend, the future development of new antimicrobial agents is currently very uncertain. The lack of commercial success for newly launched antimicrobial agents provides little incentive to invest in the development of new agents. To address this crisis, a number of push and pull incentives have been constructed to support antimicrobial drug development. Push incentives, which are designed to lower the cost of developing new antimicrobial agents, include grants, contracts, public-private partnerships, tax credits, and clinical trial networks. Pull incentives, which are designed to facilitate higher financial returns for a newly launched antimicrobial agent, include those that decrease the time for a regulatory review, extend patent exclusivity, or provide premium pricing. Such incentives may also include direct, advanced, or milestone payments or they may be insurance-based whereby healthcare systems pay for the right to access an antimicrobial agent rather than the number of units administered. Another strategy involves the re-evaluation of interpretive criteria for in vitro susceptibility testing (susceptibility breakpoints) of old antimicrobial agents using the same standards applied to that of new agents, which will allow for an accurate determination of antimicrobial resistance. Although each of the above-described strategies will be important to ensure that antimicrobial agents are developed in the decades to come, the update of susceptibility breakpoints for old agents is a strategy that could be implemented quickly and one that could be the most effective for incentivizing drug developers and financiers to reconsider the development of antimicrobial agents., The lack of commercial success for newly launched antimicrobial agents provides little incentive to develop new agents. To address this crisis, several financial incentives have been constructed. Correction of susceptibility breakpoints could be most impactful to incentivizing antimicrobial drug development.
Published: 2020

21. Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

Author: Jeffrey P. Hammel, Elizabeth A Lakota, Yu Nagira, Paul G. Ambrose, Kenichiro Kondo, Nobuo Sato, M Courtney Safir, Sujata M. Bhavnani, Tomokazu Koresawa, Brian VanScoy, and Christopher M. Rubino
Subjects: Staphylococcus aureus, Population, Renal function, Microbial Sensitivity Tests, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, In vivo, medicine, Humans, Pharmacology (medical), Arbekacin, 030212 general & internal medicine, education, 0303 health sciences, education.field_of_study, Inhalation, 030306 microbiology, business.industry, Aminoglycoside, Bacterial pneumonia, Dibekacin, Staphylococcal Infections, medicine.disease, Anti-Bacterial Agents, Infectious Diseases, business, medicine.drug
Abstract: ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m(2)) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log(10) CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PKPD target attainment based on PK-PD targets for a 1-log(10) CFU reduction from baseline at MIC values above the MIC(90) value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m(2). ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m(2), respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.
Published: 2019

22. Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment

Author: Brian D, VanScoy, Elizabeth A, Lakota, Haley, Conde, Jennifer, McCauley, Lawrence, Friedrich, Judith N, Steenbergen, Paul G, Ambrose, and Sujata M, Bhavnani
Subjects: Pharmacology, Mice, Streptococcus pneumoniae, Tetracyclines, in vitro infection model, Animals, Humans, omadacycline, pharmacokinetics-pharmacodynamics, Microbial Sensitivity Tests, Haemophilus influenzae, Anti-Bacterial Agents
Abstract: Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates., Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.
Published: 2019

23. Correction to: Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment‑Refractory Nontuberculous Mycobacterial Lung Disease

Author: Nikolas J. Onufrak, Kevin L. Winthrop, David E. Griffith, Jakko van Ingen, Dayton W. Yuen, Christopher M. Rubino, Kevin C. Mange, and Sujata M. Bhavnani
Subjects: Adult, Lung Diseases, Male, medicine.medical_specialty, Time Factors, Population, Gastroenterology, Young Adult, Pharmacokinetics, Double-Blind Method, Internal medicine, Administration, Inhalation, medicine, Humans, Pharmacology (medical), In patient, Tissue Distribution, Prospective Studies, education, Amikacin, Aged, Mycobacterium avium-intracellulare Infection, Pharmacology, Aged, 80 and over, Liposome, education.field_of_study, Inhalation, Treatment refractory, business.industry, Correction, Middle Aged, Mycobacterium avium Complex, Anti-Bacterial Agents, Treatment Outcome, Lung disease, Area Under Curve, Liposomes, Female, business, medicine.drug
Abstract: Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease.In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg.Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (CSystemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin.ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).
Published: 2021

24. Clinical pharmacokinetic–pharmacodynamic analyses: a critical element for developing antibacterial agents

Author: Jeffrey P. Hammel and Sujata M. Bhavnani
Subjects: 0301 basic medicine, Pharmacology, Drug, medicine.medical_specialty, Special populations, business.industry, media_common.quotation_subject, 030106 microbiology, Clinical pharmacokinetic, 030226 pharmacology & pharmacy, Anti-Bacterial Agents, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Pharmacodynamics, Drug Resistance, Bacterial, Drug Discovery, Humans, Medicine, business, Intensive care medicine, media_common
Abstract: In the current of era of developing antibacterial agents, including those for unmet medical need, Sponsors are required to submit a robust pre-clinical pharmacokinetic-pharmacodynamic (PK-PD) data package in exchange for limited clinical data. However, the clinical data package also needs to be as robust as possible. The clinical data package needs to include the Phase 1 pharmacokinetic (PK) studies conducted in the target patient populations and special populations. Additionally, PK data need to be collected from all patients enrolled in the pivotal trial(s). Such data are critical to confirm adequate drug exposures relative to non-clinical PK-PD targets for efficacy, explain unexpected clinical failures in individuals or groups of patients, and evaluate exposure-response relationships for safety.
Published: 2017

25. Editorial overview: Use of PK-PD for antibacterial drug development: decreasing risk and paths forward for resistant pathogens

Author: John H. Rex and Sujata M Bhavnani
Subjects: Risk, 0301 basic medicine, Drug, media_common.quotation_subject, 030106 microbiology, Drug resistance, Pharmacology, Models, Biological, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Drug Development, Drug Resistance, Bacterial, Drug Discovery, Animals, Humans, Medicine, Computer Simulation, Antibacterial drug, PK/PD models, media_common, Dose-Response Relationship, Drug, business.industry, Bacterial Infections, Anti-Bacterial Agents, Drug development, business, Introductory Journal Article
Published: 2017

26. Polymyxin Susceptibility Testing and Interpretive Breakpoints: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST)

Author: David R. Andes, Michael N. Dudley, John S. Bradley, George L. Drusano, Paul G. Ambrose, Keith A. Rodvold, Ronald N. Jones, Sujata M. Bhavnani, Jason M. Pogue, and Robert K. Flamm
Subjects: medicine.medical_specialty, medicine.drug_class, Polymyxin, Guidelines as Topic, Microbial Sensitivity Tests, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dosing, Polymyxins, Respiratory Tract Infections, Polymyxin B, Pharmacology, 0303 health sciences, biology, Respiratory tract infections, 030306 microbiology, Pseudomonas aeruginosa, business.industry, Colistin, Breakpoint, biology.organism_classification, bacterial infections and mycoses, United States, Acinetobacter baumannii, Anti-Bacterial Agents, Infectious Diseases, Urinary Tract Infections, Commentary, lipids (amino acids, peptides, and proteins), business, medicine.drug
Abstract: The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa , Acinetobacter baumannii , and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary.
Published: 2019

27. Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

Author: Elizabeth A Lakota, Helio S. Sader, Paul G. Ambrose, Justin C Bader, Sujata M. Bhavnani, John H. Rex, and Glenn E. Dale
Subjects: Ertapenem, medicine.medical_specialty, Klebsiella pneumoniae, Population, Microbial Sensitivity Tests, Clinical Therapeutics, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Pneumonia, Bacterial, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, education, Pharmacology, 0303 health sciences, education.field_of_study, Bacteria, biology, 030306 microbiology, business.industry, Pseudomonas aeruginosa, Bacterial pneumonia, Pneumonia, Ventilator-Associated, Antimicrobial, medicine.disease, biology.organism_classification, Anti-Bacterial Agents, Infectious Diseases, chemistry, Staphylococcus aureus, Pharmacodynamics, business
Abstract: Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa. A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 μg/ml, respectively (MIC(90) values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.
Published: 2019

28. Prediction of lefamulin epithelial lining fluid penetration after intravenous and oral administration using Phase 1 data and population pharmacokinetics methods

Author: Li Zhang, Christopher M. Rubino, Sujata M. Bhavnani, and Wolfgang W Wicha
Subjects: 0301 basic medicine, Microbiology (medical), Adult, Male, medicine.drug_class, 030106 microbiology, Antibiotics, Administration, Oral, Pharmacology, Epithelium, 03 medical and health sciences, Route of administration, Young Adult, 0302 clinical medicine, Pharmacokinetics, Oral administration, Predictive Value of Tests, medicine, Humans, Pharmacology (medical), Polycyclic Compounds, 030212 general & internal medicine, Cross-Over Studies, Models, Statistical, Chemistry, Epithelial lining fluid, Penetration (firestop), respiratory system, Middle Aged, Crossover study, Healthy Volunteers, Bioavailability, Anti-Bacterial Agents, Infectious Diseases, Thioglycolates, Supplement Papers, Administration, Intravenous, Female, Diterpenes, Bronchoalveolar Lavage Fluid, Tablets
Abstract: Objectives Lefamulin is a semi-synthetic intravenous and oral pleuromutilin antibiotic with activity against pathogens commonly associated with community-acquired bacterial pneumonia. Using data from two Phase 1 studies, a population pharmacokinetics (PPK) model for lefamulin in plasma and epithelial lining fluid (ELF) was constructed. Methods Plasma pharmacokinetic (PK) data from a crossover, bioavailability, food-effect study and plasma and ELF PK data from a tissue penetration study in normal healthy volunteers were used to construct a PPK model for lefamulin. Model development involved refinement of a previous PPK model for intravenous and oral administration, followed by application of the model to plasma and ELF data from the tissue penetration study. The ELF penetration ratio of lefamulin was determined using model-based simulations. Results The PPK analysis data set contained 1103 plasma and 12 ELF lefamulin concentrations from 32 subjects. A three-compartment model with non-linear protein binding and two parallel absorption processes provided precise and unbiased estimated plasma concentration–time profiles. The absorption rate was slower and bioavailability was decreased after a high-fat/high-calorie meal. ELF data were well described using first-order rate constants into and out of the ELF compartment. The median predicted lefamulin total-drug ELF AUC0–24/free-drug plasma AUC0–24 ratio was ∼5:1 after intravenous or oral administration. Conclusions The final PPK model allowed precise characterization of plasma and ELF exposures after intravenous and oral administration. The high ELF penetration ratio suggests that the penetration of lefamulin into the effect site is rapid and extensive, irrespective of route of administration.
Published: 2019

29. Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia

Author: Sujata M. Bhavnani, Christopher M. Rubino, Steven P Gelone, Li Zhang, Paul G. Ambrose, Helio S. Sader, Wolfgang W Wicha, Jeffrey P. Hammel, and Justin C Bader
Subjects: 0301 basic medicine, Microbiology (medical), Staphylococcus aureus, medicine.drug_class, 030106 microbiology, Antibiotics, Population, Administration, Oral, Microbial Sensitivity Tests, Pharmacology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Streptococcus pneumoniae, medicine, Pneumonia, Bacterial, Humans, Pharmacology (medical), Computer Simulation, Polycyclic Compounds, 030212 general & internal medicine, Dosing, education, education.field_of_study, Models, Statistical, Bacteria, business.industry, Bacterial pneumonia, Fasting, Staphylococcal Infections, medicine.disease, Anti-Bacterial Agents, Community-Acquired Infections, Regimen, Infectious Diseases, Pharmacodynamics, Thioglycolates, Supplement Papers, Administration, Intravenous, Diterpenes, business, Monte Carlo Method
Abstract: Objectives Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. Methods The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2 log10 cfu reductions from baseline. Results Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1 log10 cfu reduction from baseline for SP were ≥99.2% at the MIC90 of 0.12 mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25 mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12 mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%–100% for iv and oral dosing regimens. Conclusions These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.
Published: 2019

30. Population Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation Solution

Author: Elizabeth A Lakota, Christopher M. Rubino, Kenichiro Kondo, Paul G. Ambrose, Sujata M. Bhavnani, Tomokazu Koresawa, and Nobuo Sato
Subjects: Adult, Male, Adolescent, Population, Renal function, Pharmacology, 030226 pharmacology & pharmacy, Models, Biological, 03 medical and health sciences, Route of administration, Young Adult, 0302 clinical medicine, Pharmacokinetics, Administration, Inhalation, Medicine, Humans, Pharmacology (medical), Arbekacin, education, Aged, Aged, 80 and over, 0303 health sciences, education.field_of_study, Inhalation, 030306 microbiology, business.industry, Nebulizers and Vaporizers, Dibekacin, Middle Aged, Bioavailability, Anti-Bacterial Agents, Pharmaceutical Solutions, Infectious Diseases, Pharmacodynamics, Female, business, Bronchoalveolar Lavage Fluid, medicine.drug
Abstract: ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL = (weight/52.2)0.855·[(CLcrn–77)·0.0289 + 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.
Published: 2019

31. Pharmacokinetic/Pharmacodynamic Evaluation of Solithromycin against Streptococcus pneumoniae Using Data from a Neutropenic Murine Lung Infection Model

Author: David R. Andes, Alan Forrest, Prabhavathi Fernandes, Olanrewaju O. Okusanya, Sujata M. Bhavnani, and Paul G. Ambrose
Subjects: Solithromycin, Microbial Sensitivity Tests, Pharmacology, medicine.disease_cause, 03 medical and health sciences, Minimum inhibitory concentration, Mice, 0302 clinical medicine, Pharmacokinetics, Streptococcus pneumoniae, medicine, Animals, Pharmacology (medical), 030212 general & internal medicine, Lung, 0303 health sciences, 030306 microbiology, business.industry, Bacterial pneumonia, Staphylococcal Infections, Triazoles, Antimicrobial, medicine.disease, Anti-Bacterial Agents, Regimen, Infectious Diseases, Pharmacodynamics, Female, Macrolides, business
Abstract: Solithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with community-acquired bacterial pneumonia. Using a neutropenic murine lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with efficacy and the magnitude of such indices associated with solithromycin efficacy against Streptococcus pneumoniae. Plasma and epithelial lining fluid (ELF) samples for pharmacokinetics (PK) were collected serially over 24 hours from healthy mice administered single doses of solithromycin (0.625 to 40 mg/kg). Neutropenic CD-1 mice infected with 10(8) CFUs of one of five S. pneumoniae isolates were administered solithromycin (0.156 to 160 mg/kg/day) via oral gavage. Doses were administered in a fractionated manner for mice infected with one isolate, while mice infected with the remaining four isolates received solithromycin as either a regimen every 6 hours or every 12 hours. A three-compartment model best described solithromycin PK in the plasma and ELF (r(2) = 0.935 and 0.831, respectively). The ratio of total-drug ELF to free-drug plasma area under the concentration-time curve (AUC) from time 0 to 24 hours was 2.7. Free-drug plasma and total-drug ELF AUC to minimum inhibitory concentration ratios (AUC/MIC ratios) were most predictive of efficacy (r(2) = 0.851 and 0.850, respectively). The magnitude of free-drug plasma/total-drug ELF AUC/MIC ratios associated with net bacterial stasis and a 1- and 2-log(10) CFU reduction from baseline was 1.65/1.26, 6.31/15.1, and 12.8/59.8, respectively. These data provided dose selection support for solithromycin for clinical trials in patients with community-acquired bacterial pneumonia.
Published: 2018

32. 1304. Characterization of Tebipenem Pivoxil Hydrobromide Pharmacokinetics-Pharmacodynamics (PK-PD) in a Neutropenic Murine Acute Pyelonephritis (AP) Model

Author: Thomas R. Parr, Paul G. Ambrose, Brian VanScoy, Steven Fikes, Christopher M. Rubino, Ian A. Critchley, Sujata M. Bhavnani, and Nicole Cotroneo
Subjects: AcademicSubjects/MED00290, Infectious Diseases, Oncology, Pharmacokinetics, Hydrobromide, business.industry, Pharmacodynamics, Poster Abstracts, Medicine, Pharmacology, business, PK/PD models, TEBIPENEM PIVOXIL
Abstract: Background Tebipenem pivoxil hydrobromide (tebipenem HBr), an orally (PO) bioavailable prodrug of tebipenem, is a carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria that is being developed for the treatment of patients with complicated urinary tract infections, including AP. Data from a one-compartment in vitro infection model demonstrated that the ratio of free-drug plasma area under the curve (AUC) to MIC with adjustment for dosing interval (τ) (AUC:MIC ratio•1/τ) was the PK-PD index most associated with tebipenem HBr efficacy [VanScoy BD et al., IDWeek 2019, Poster 1565]. Studies were undertaken to characterize the magnitude of tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ associated with efficacy for Enterobacteriaceae using a neutropenic murine AP model. Methods A single dose pharmacokinetic study was completed in neutropenic mice infected via intra-renal injection with 104 CFU/kidney of Escherichia coli NCTC 13441. Following PO administration of 4 tebipenem HBr doses (1, 15, 45 and 100 mg/kg), plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-treatment initiation and drug concentrations were determined using LC/MS/MS. Dose-ranging studies were completed using a panel of 7 Enterobacteriaceae isolates (tebipenem HBr MIC values of 0.015 to 0.5 mg/L). Mice were infected with 104 CFU/kidney via intra-renal injection. Two hours post-incubation, 8 total daily tebipenem HBr doses (0.3 to 135 mg/kg) were fractionated into regimens given every 8 hours. The relationship between change in log10 CFU/g from baseline at 24 hours and free-drug plasma AUC:MIC ratio•1/τ was fit using a Hill-type model. Free-drug plasma AUC:MIC ratio•1/τ values associated with net bacterial stasis and 1- and 2-log10 CFU/g reductions from baseline at 24 hours were determined. Results The relationship between change in log10 CFU/g from baseline at 24 hours and tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ described the data well (r2 = 0.833). Free-drug plasma AUC:MIC ratio•1/τ values associated with net bacterial stasis and a 1-log10 CFU/g reduction from baseline were 26.2 and 54.1, respectively. A 2-log10 CFU/g reduction was not achieved. Relationship between change in log10 CFU/g from baseline at 24 hours and tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ based on data for a panel of Enterobacteriaceae isolates evaluated in the dose-ranging studies conducted using a neutropenic murine acute pyelonephritis model Conclusion These data will be useful to support tebipenem HBr dose selection for clinical studies in patients with AP. Disclosures Brian D. VanScoy, B.S., Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Steven Fikes, BA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Christopher M. Rubino, PharMD, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Sujata M. Bhavnani, PharMD, MS, FIDSA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Ian A. Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Thomas R. Parr, PhD, Spero Therapeutics (Employee, Shareholder) Paul G. Ambrose, PharMD, FIDSA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support)
Published: 2020

33. Gatifloxacin Pharmacokinetics/Pharmacodynamics–based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis

Author: Jotam G. Pasipanodya, Tawanda Gumbo, Thearith Koeuth, Shashikant Srivastava, Wynand Smythe, Paula Bendet, Paul G. Ambrose, Armand Van Deun, M Gumusboga, Helen McIlleron, Sujata M. Bhavnani, Guy E. Thwaites, and Devyani Deshpande
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Tuberculosis, Combination therapy, 030106 microbiology, Antitubercular Agents, Supplement Articles, Microbial Sensitivity Tests, Gastroenterology, Gatifloxacin, 03 medical and health sciences, Minimum inhibitory concentration, Pharmacokinetics, Internal medicine, Tuberculosis, Multidrug-Resistant, medicine, Humans, Dosing, Prospective Studies, Lung, Tuberculosis, Pulmonary, business.industry, Mycobacterium tuberculosis, medicine.disease, Infectious Diseases, Pharmacodynamics, Tuberculosis, Meningeal, Meningeal Tuberculosis, business, Monte Carlo Method, medicine.drug
Abstract: Background Gatifloxacin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The optimal dose is unknown. Methods We performed a 28-day gatifloxacin hollow-fiber system model of tuberculosis (HFS-TB) study in order to identify the target exposures associated with optimal kill rates and resistance suppression. Monte Carlo experiments (MCE) were used to identify the dose that would achieve the target exposure in 10000 adult patients with meningeal or pulmonary MDR-TB. The optimal doses identified were validated using probit analyses of clinical data from 2 prospective clinical trials of patients with pulmonary and meningeal tuberculosis. Classification and regression-tree (CART) analyses were used to identify the gatifloxacin minimum inhibitory concentration (MIC) below which patients failed or relapsed on combination therapy. Results The target exposure associated with optimal microbial kill rates and resistance suppression in the HFS-TB was a 0–24 hour area under the concentration-time curve-to-MIC of 184. MCE identified an optimal gatifloxacin dose of 800 mg/day for pulmonary and 1200 mg/day for meningeal MDR-TB, and a clinical susceptibility breakpoint of MIC ≤ 0.5 mg/L. In clinical trials, CART identified that 79% patients failed therapy if MIC was >2 mg/L, but 98% were cured if MIC was ≤0.5 mg/L. Probit analysis of clinical data demonstrated a >90% probability of a cure in patients if treated with 800 mg/day for pulmonary tuberculosis and 1200 mg/day for meningeal tuberculosis. Doses ≤400 mg/day were suboptimal. Conclusions Gatifloxacin doses of 800 mg/day and 1200 mg/day are recommended for pulmonary and meningeal MDR-TB treatment, respectively. Gatifloxacin has a susceptible dose-dependent zone at MICs 0.5–2 mg/L.
Published: 2018

34. Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis

Author: Scott K. Heysell, Paul G. Ambrose, Guy E. Thwaites, Pooi S Lee, Paula Bendet, Shashikant Srivastava, Tawanda Gumbo, Thearith Koeuth, Sujata M. Bhavnani, Devyani Deshpande, Jotam G. Pasipanodya, and Stellah G. Mpagama
Subjects: 0301 basic medicine, Microbiology (medical), Tuberculosis, medicine.drug_class, 030106 microbiology, Antibiotics, Antitubercular Agents, Supplement Articles, Drug resistance, Levofloxacin, Microbial Sensitivity Tests, Tuberculous meningitis, lung, Mycobacterium tuberculosis, 03 medical and health sciences, Moxifloxacin, Artificial Intelligence, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, pharmacodynamics, Medicine, Humans, Tuberculosis, Pulmonary, minimum inhibitory concentration measurement, biology, business.industry, Sputum, multidrug-resistant tuberculosis, medicine.disease, biology.organism_classification, probit trial, Infectious Diseases, tuberculosis, exposure, minimum inhibitory concentration result, tuberculous meningitis, Pharmacodynamics, Drug Therapy, Combination, Artificial intelligence, mutation, moxifloxacin, business, pharmacokinetics, pulmonary tuberculosis, Monte Carlo Method, Algorithms, medicine.drug
Abstract: Background Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however the optimal dose is unknown. Methods We used the hollow fiber system model of tuberculosis (HFS-TB) to identify 0–24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs) were used to identify doses best able to achieve the HFS-TB–derived target exposures in cavitary tuberculosis and tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI) algorithms to identify the most important predictors of sputum conversion, ADR, and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis treated with a levofloxacin-containing regimen. We also performed probit regression to identify optimal levofloxacin doses in Vietnamese tuberculous meningitis patients. Results In the HFS-TB, the AUC0-24/MIC associated with maximal Mtb kill was 146, while that associated with suppression of resistance was 360. The most common gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms identified an AUC0-24/MIC of 160 as predictive of microbiologic cure, followed by levofloxacin 2-hour peak concentration and body weight. Probit regression identified an optimal dose of 25 mg/kg as associated with >90% favorable response in adults with pulmonary tuberculosis. Conclusions The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for replacement of high-dose moxifloxacin in treatment of multidrug-resistant tuberculosis.
Published: 2018

35. Population Pharmacokinetic Analyses for Ertapenem in Subjects with a Wide Range of Body Sizes

Author: Li Zhang, Elizabeth A Lakota, Cornelia B. Landersdorfer, Anne N. Nafziger, Sujata M. Bhavnani, Joseph S. Bertino, and Alan Forrest
Subjects: Adult, Ertapenem, Male, 0301 basic medicine, medicine.medical_specialty, 030106 microbiology, Population, Urology, Renal function, Clinical Therapeutics, Body Mass Index, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Covariate, medicine, Body Size, Humans, Pharmacology (medical), 030212 general & internal medicine, education, Pharmacology, Body surface area, education.field_of_study, business.industry, Body Weight, NONMEM, Infectious Diseases, Carbapenems, chemistry, Female, business, Body mass index, Algorithms
Abstract: Despite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients from those in healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously described study in normal-weight, obese, and morbidly obese healthy volunteers. A single ertapenem 1-g dose administered intravenously was evaluated in 30 subjects within different body mass index (BMI) categories. The population pharmacokinetic model was developed using the first-order conditional estimation method with interaction (FOCE-I) algorithm within NONMEM. The ability of age, sex, renal function, and various body size measures (total body weight, height, body mass index, ideal body weight, fat-free mass, and body surface area [BSA]) to explain a portion of the interindividual variability on select pharmacokinetic parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The data were best described using a linear three-compartment model with total body weight as a covariate on clearance (CL = 1.79 · [weight/95.90](0.278)) and BSA as a covariate on central volume (Vc = 4.76 · [BSA/2.06](1.86)). After accounting for fixed effects, the estimated interindividual variability was very low (
Published: 2018

36. Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata

Author: Christopher M. Rubino, Paul G. Ambrose, Voon Ong, Taylor Sandison, Shawn Flanagan, Justin C Bader, Sujata M. Bhavnani, and Elizabeth A Lakota
Subjects: 0301 basic medicine, Antifungal Agents, Echinocandin, 030106 microbiology, Population, PK-PD target attainment, Candida glabrata, Microbial Sensitivity Tests, Pharmacology, Clinical Therapeutics, Drug Administration Schedule, 03 medical and health sciences, Echinocandins, Pharmacokinetics, Candida albicans, medicine, Candida species, Humans, Pharmacology (medical), Dosing, education, education.field_of_study, biology, business.industry, Candidiasis, Candidemia, biology.organism_classification, Corpus albicans, Regimen, Infectious Diseases, echinocandin, business, Monte Carlo Method, medicine.drug
Abstract: Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log 10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC 90 for C. albicans and C. glabrata , a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC 100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata .
Published: 2018

37. Norepinephrine in Combination with Antibiotic Therapy Increases both the Bacterial Replication Rate and Bactericidal Activity

Author: Brian VanScoy, Paul G. Ambrose, John H. Adams, Christopher M. Rubino, Steven Fikes, Justin C Bader, and Sujata M. Bhavnani
Subjects: 0301 basic medicine, Sodium, 030106 microbiology, chemistry.chemical_element, Levofloxacin, Microbial Sensitivity Tests, Pharmacology, medicine.disease_cause, Norepinephrine (medication), 03 medical and health sciences, Norepinephrine, Tandem Mass Spectrometry, medicine, Escherichia coli, Pharmacology (medical), Bacterial replication, Chemistry, Liter, Antimicrobial, In vitro, Anti-Bacterial Agents, Infectious Diseases, medicine.drug, Chromatography, Liquid
Abstract: We previously demonstrated that the rate and extent of an antimicrobial agent's bactericidal effects were coupled to the bacterial replication rate, the latter of which was modulated with the sodium chloride concentration. Herein, we describe the results from a 24-h one-compartment in vitro infection model study that was designed to demonstrate that an antimicrobial agent's bactericidal effects could be amplified when it is administered with a pharmaceutical agent that increases the bacterial replication rate. The antimicrobial and growth-promoting agents selected were levofloxacin and norepinephrine, respectively. The challenge isolate was Escherichia coli JMI 21711R (levofloxacin MIC, 8 mg/liter). Within the in vitro infection model, a human levofloxacin concentration-time profile (half-life, 7 h) was simulated and the challenge isolate was subjected to an ineffective monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC] ratio of 6) with and without norepinephrine as a continuous infusion (275 mg/liter). Samples were collected from the model during the course of the study for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). As expected, the norepinephrine and no-treatment control arms failed immediately, followed by the levofloxacin monotherapy arm, which failed slowly over time. The levofloxacin-epinephrine regimen resulted in a 2-log 10 CFU reduction in bacterial density over the first 6 to 8 h of the study, which was followed by regrowth of a highly levofloxacin-resistant subpopulation (MIC, 64 mg/liter). These data demonstrate that increasing the rate of bacterial replication with a pharmaceutical product in combination with antimicrobial therapy represents an opportunity to increase the rate and magnitude of bactericidal effect.
Published: 2018

38. Erratum for Drusano et al., 'Dilution Factor of Quantitative Bacterial Cultures Obtained by Bronchoalveolar Lavage in Patients with Ventilator-Associated Bacterial Pneumonia'

Author: Danijela Djureinovic, Michael L. Corrado, Evelyn J. Ellis-Grosse, Ronald N. Jones, Helen K. Donnelly, Michael Vicchiarelli, Krisztina Dorizas, Paul G. Ambrose, Hassan Alnuaimat, Lisa Mayfield, Gino Girardi, Brooks Edward Morgan, George L. Drusano, C. Mazo, Kenneth V. Leeper, Richard G. Wunderink, Alain Combes, Robert K. Flamm, Jordi Rello, Sujata M. Bhavnani, Tasnova Malek, Catharine C. Bulik, Robert Duncan Hite, Thomas J. Walsh, Colleen Berman, Michelle Ferrari, Ann Doyle, Leah N. Woosley, Arnold Louie, Mona Brown, Jean Chastre, Christopher M. Rubino, and Marin H. Kollef
Subjects: 0301 basic medicine, Microbiological culture, 030106 microbiology, Pneumonia ventilator associated, Microbiology, 03 medical and health sciences, medicine, Pneumonia, Bacterial, Humans, Urea, Pharmacology (medical), In patient, Pharmacology, Bacteriological Techniques, medicine.diagnostic_test, business.industry, Bacterial pneumonia, Pneumonia, Ventilator-Associated, medicine.disease, Bacterial Load, Infectious Diseases, Bronchoalveolar lavage, Dilution ratio, Erratum, business, Bronchoalveolar Lavage Fluid
Abstract: Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log
Published: 2018

39. Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects

Author: Elizabeth E. Morgan, David C. Griffith, Sujata M. Bhavnani, Jeffery S. Loutit, Michael N. Dudley, Christopher M. Rubino, and Dan White
Subjects: 0301 basic medicine, Adult, Male, Carbapenem, Adolescent, medicine.drug_class, 030106 microbiology, Antibiotics, Urine, Pharmacology, Clinical Therapeutics, Meropenem, Drug Administration Schedule, 03 medical and health sciences, Young Adult, Pharmacokinetics, Double-Blind Method, medicine, Humans, Pharmacology (medical), Drug Interactions, Adverse effect, business.industry, Drug interaction, Middle Aged, Boronic Acids, Healthy Volunteers, Infectious Diseases, Tolerability, Female, business, medicine.drug
Abstract: Meropenem-vaborbactam is a fixed combination of the novel β-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.)
Published: 2018

40. Correction to: PK-PD Compass: bringing infectious diseases pharmacometrics to the patient's bedside

Author: Li Zhang, Paul G. Ambrose, Scott A. Van Wart, Christopher M. Rubino, Sujata M. Bhavnani, Justin C Bader, Kim L Sweeney, and Catharine C. Bulik
Subjects: Pharmacology, medicine.medical_specialty, business.industry, InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL, Pharmacology toxicology, ComputerApplications_COMPUTERSINOTHERSYSTEMS, Pharmacy, Pharmacometrics, Compass, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMilieux_COMPUTERSANDEDUCATION, Data_FILES, Medicine, Medical physics, business, PK/PD models
Abstract: The original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum.
Published: 2018

41. We can do better: a fresh look at echinocandin dosing

Author: Paul G. Ambrose, Justin C Bader, David R. Andes, and Sujata M. Bhavnani
Subjects: 0301 basic medicine, Microbiology (medical), Antifungal Agents, Echinocandin, Drug-Related Side Effects and Adverse Reactions, 030106 microbiology, Pharmacology, 03 medical and health sciences, chemistry.chemical_compound, Echinocandins, 0302 clinical medicine, polycyclic compounds, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dosing, business.industry, Micafungin, bacterial infections and mycoses, Regimen, Infectious Diseases, chemistry, Pharmacodynamics, Anidulafungin, Caspofungin, business, medicine.drug
Abstract: First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally. This review presents pharmacokinetic/pharmacodynamic (PK/PD) evaluations for approved echinocandins (anidulafungin, caspofungin and micafungin) and rezafungin (previously CD101), an investigational agent. PK/PD-optimized regimens were evaluated to extend the utility of approved echinocandins when treating patients with resistant isolates. Although the benefits of these regimens were apparent, it was also clear that anidulafungin and micafungin, regardless of dosing adjustments, are unlikely to provide therapeutic exposures sufficient to treat highly resistant isolates. Day 1 probabilities of PK/PD target attainment of 5.2% and 85.1%, respectively, were achieved at the C. glabrata MIC90 (0.12 mg/L) and MIC97 (0.06 mg/L) values, respectively, for these agents. However, evaluations of rezafungin demonstrated high probabilities of target attainment over 4 weeks of therapy (100%) after administration of a single-dose regimen at the MIC90 of 0.06 mg/L. This signals that although existing therapies are not optimal to treat resistant organisms, more potent new echinocandins (relative to achievable drug exposures) may be on the horizon.
Published: 2018

42. 1565. Characterization of Tebipenem (SPR859) Pharmacokinetics–Pharmacodynamics (PK-PD) for Efficacy Against Enterobacteriaceae in a One-Compartment In Vitro Infection Model

Author: Nicole Cotroneo, Thomas R. Parr, Sujata M. Bhavnani, Paul G. Ambrose, Ana I Caranco, Nikolas J Onufrak, Haley Conde, Ian A. Critchley, and Brian VanScoy
Subjects: biology, business.industry, Tebipenem, Pharmacology, biology.organism_classification, Enterobacteriaceae, In vitro, chemistry.chemical_compound, Abstracts, Infectious Diseases, Oncology, chemistry, Pharmacokinetics, Pharmacodynamics, Poster Abstracts, Medicine, Compartment (pharmacokinetics), business, PK/PD models
Abstract: Background SPR859 (tebipenem) is the active form of the orally bioavailable prodrug SPR994. Tebipenem is an oral carbapenem with a broad-spectrum activity against Gram-positive and -negative bacteria. SPR994 is being developed as an oral option for the treatment of complicated urinary tract infections (cUTI). The goal of these studies was to characterize the PK-PD of tebipenem against a diverse panel of Enterobacteriaceae. Methods 24-hour dose-fractionation and dose-ranging studies were carried out utilizing the one-compartment in vitro infection model. Bacteria (1 × 106 CFU/mL) were exposed to tebipenem concentrations that mimicked human healthy volunteer free-drug plasma (f) concentration–time profiles following oral drug administration. For the dose-fractionation studies, 7 total daily dose levels (fAUC range, 0.11 to 19.0 mg hours/L) were fractionated in equal divided doses administered every 4, 8 or 12 hours (q4h, q8h and q12h, respectively). A single challenge isolate, E. coli ATCC 25922 (MIC = 0.015 mg/L), was evaluated in the dose-fractionation studies. In the dose-ranging studies, 13 Enterobacteriaceae clinical isolates (MIC values from 0.008 to 0.25 mg/L) were exposed to doses ranging from 4.69 to 1200 mg administered q8h (fAUC ranging from 0.14 to 37.2 mg hours/L). Relationships between change in log10 CFU from baseline at 24 h and each of fCmax:MIC ratio, f%T>MIC, and fAUC:MIC ratio, with and without adjustment for dosing interval tau for the latter (fAUC:MIC ratio·1/τ), were fit using Hill-type models. Results Dose-fractionation study results demonstrated the activity of tebipenem to be time-dependent, with both f%T>MIC and fAUC:MIC ratio·1/τ similarly describing the PK-PD of tebipenem. The relationship between change in log10 CFU from baseline at 24 hours and fAUC:MIC ratio·1/τ, as assessed using pooled data for 13 Enterobacteriaceae isolates evaluated in the dose-ranging studies, described the PK-PD of tebipenem well (Figure 1). The magnitude of fAUC:MIC ratio·1/τ associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline was 7.23, 13.1, and 32.4, respectively. Conclusion These data will be useful to design other pre-clinical studies and support tebipenem dose selection for clinical studies in patients with cUTI. Disclosures All authors: No reported disclosures.
Published: 2019

43. 733. Pharmacokinetic–Pharmacodynamic (PK–PD) Analyses for Alanine Aminotransferase (ALT) Using Phase 3 Data From Omadacycline (OMC)-Treated Patients

Author: Kathryn Liolios, Evan Tzanis, Jeffrey P. Hammel, Paul G. Ambrose, Paul C. McGovern, Sujata M. Bhavnani, Michael Trang, Judith N. Steenbergen, Darryl R George, Lawrence V. Friedrich, and Christopher M. Rubino
Subjects: biology, Pharmacokinetic pharmacodynamic, business.industry, Pharmacology, Abstracts, Infectious Diseases, Oncology, Gamma glutamyl transferase, Alanine transaminase, Pharmacodynamics, Poster Abstracts, biology.protein, Medicine, Alanine aminotransferase, business, Patient simulation, PK/PD models
Abstract: Background OMC, an aminomethylcycline structurally related to tetracycline agents, was recently approved by the US FDA for the treatment of adult patients with ABSSSI (IV-to-PO and PO regimens) and CABP (IV-to-PO regimen). To better understand exposure-related concerns for ALT increase, PK-PD relationships for ALT were evaluated using data from OMC-treated patients enrolled in three Phase 3 studies. Methods Repeated-measures multiple linear regression was used to evaluate factors predictive of ALT, including different OMC total-drug AUC measures prior to each ALT, with interactions and covariates selected stepwise. Using a final AIC-optimized model, predicted percent probabilities of ALT elevation >1, 1.5, 2, 3, 5, and 10 × upper limit of normal (ULN) at any time post-baseline and up to 2 days after the end of therapy were calculated among analysis patients for fixed post-baseline OMC AUC measures, and among simulated patients after IV-to-PO and PO dosing regimens. Results The final model, developed using data from 327 patients with PK, included increased prior cumulative AUC among males, increased baseline gamma-glutamyl transferase, and study (ABSSSI, PO only) as factors predictive of increased ALT (P < 0.0001). However, the model-predicted impact of OMC across fixed average daily AUC values on ALT elevation endpoints of >1, 1.5, 2, 3, 5, and 10 × ULN was minimal (Figure 1), even for males despite the interaction with AUC (Figure 2). Among all patients, the estimated increases in percent probabilities for the 90th percentile of AUC relative to zero AUC were 5.81, 5.20, 1.53, 0.61, 0.31, and 0%, respectively, and ≤11.5, 7.76, 8.33, 1.31, 1.31, and 0%, respectively, across single variable patient subsets. Percent probabilities of ALT elevation endpoints were within 2.84% when comparing simulated and observed patients after administration of OMC IV-to-PO and PO dosing regimens (Figure 3). Conclusion A statistically significant relationship between an increase in ALT and increase in OMC AUC for males in the presence of other factors was found. However, increases in model-predicted ALT elevation endpoints across fixed OMC AUC values, or among simulated patients after administration of OMC IV-to-PO and PO dosing regimens relative to observed patients, were minimal. Disclosures All authors: No reported disclosures.
Published: 2019

44. 1561. Omadacycline Pharmacokinetics: Influence of Mortality Risk Score Among Patients with Community-Acquired Bacterial Pneumonia

Author: Lawrence V. Friedrich, Judith N. Steenbergen, Evan Tzanis, Paul C. McGovern, Sujata M. Bhavnani, Christopher M. Rubino, and Elizabeth A Lakota
Subjects: medicine.medical_specialty, Framingham Risk Score, business.industry, Bacterial pneumonia, medicine.disease, chemistry.chemical_compound, Abstracts, Infectious Diseases, Oncology, Pharmacokinetics, chemistry, Internal medicine, Omadacycline, Poster Abstracts, medicine, business
Abstract: Background Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens. Omadacycline was recently approved in the United States for treatment of adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. Analyses were undertaken to determine whether PORT risk class and CURB-65 score influence the pharmacokinetics of omadacycline in patients with CABP. Methods Omadacycline pharmacokinetic data were available from omadacycline-treated patients with CABP enrolled in the Phase 3 OPTIC Study. Patients received omadacycline 100 mg IV q12h on Day 1 followed by 100 mg IV q24h. After Day 3, patients could be switched to 300 mg PO q24h if predefined clinical stability criteria were met. Four pharmacokinetic samples per patient were collected between Days 2 and 5. These data were previously utilized in the development of a population pharmacokinetic model describing the disposition of omadacycline [Microbe 2018; Abstr SAT-628]. Individual post-hoc parameter estimates for patients enrolled in the OPTIC study were utilized to compute Day 1 total-drug plasma area under the concentration-time curve (AUC) values following administration of omadacycline 100 mg IV q12h. Differences among these AUC values by PORT risk class and CURB-65 score were assessed using a one-way ANOVA. Results A total of 187 pharmacokinetic samples were available from 50 patients. Among the patients classified as PORT risk class II, III, and IV (n = 12, 28, and 10, respectively), mean Day 1 omadacycline AUC values were 10.2, 11.0, and 12.0 mg L/h, respectively. Among patients with CURB-65 scores of 0, 1, and 2 (n = 23, 23, and 4, respectively), mean Day 1 omadacycline AUC values were 10.6, 11.6, and 9.7 mg L/h, respectively. The differences in mean AUC values were not statistically significant among patients by PORT risk class (P = 0.248) and CURB-65 score groups (P = 0.745). Moreover, variability was similar across these groups as displayed in Figure 1. Conclusion Omadacycline exposures were similar across PORT risk class and CURB-65 score groups; thus, omadacycline dose adjustments based on these classifications are likely not warranted. Disclosures All authors: No reported disclosures.
Published: 2019

45. 1591. Updated Fluoroquinolone MIC Breakpoints: Impact on Susceptibility Rates in the United States

Author: Robert K. Flamm, Michael A. Pfaller, Ronald N. Jones, Paul G. Ambrose, John S. Bradley, David R. Andes, and Sujata M. Bhavnani
Subjects: Abstracts, Infectious Diseases, Oncology, business.industry, Breakpoint, Poster Abstracts, Medicine, Computational biology, business
Abstract: Background In 2015 USCAST, the National Advisory Committee for the United States (US) to EUCAST, produced a report (Version 1.0) on their website (www.uscast.org) re-evaluating fluoroquinolone (FQ) breakpoint interpretive criteria (IC) based on analysis of current microbiology and pharmacokinetic/pharmacodynamic (PK/PD) data. EUCAST initiated a consultative process using USCAST analyses in an effort to update FQ IC, released in 2017. CLSI formed an ad-hoc working group in late 2015 to review the USCAST FQ document and formulate questions about content. In 2018, USCAST released V1.3 of the FQ document and CLSI subsequently published updated FQ MIC IC in the M100-S29 (2019) document. This study evaluated the impact on susceptibility (S) rates for US surveillance data that these IC changes created. Methods Clinical isolates (reference broth microdilution MIC) from 2016–2018 US SENTRY Program were analyzed for S based on current and previous IC. FQ results for ciprofloxacin (CIP), levofloxacin (LEV), and moxifloxacin (MOX) were evaluated. Benchmark S comparison data for meropenem, cefepime, piperacillin–tazobactam and delafloxacin (new FQ) were also included. Results S rates for Enterobacteriaceae (ENT;Figure) were reduced by 3.8/3.7% for CIP/LEV (CLSI) and 2.3/2.5% (EUCAST). MOX-S rate vs. ENT declined 5.7% (EUCAST). Although reductions in S occurred for most organism groups, K. pneumoniae (6.0/5.5% for CIP/LEV [CLSI] and 4.0/4.2% [EUCAST]) and S. marcescens (7.4/4.1% for CIP/LEV [CLSI] and 4.1/5.0% [EUCAST]) reductions were among the largest changes. For Pseudomonas aeruginosa (PSA), CIP-S decreased 6.8% and LEV-S 10.1% (CLSI); but potential for false-S results remain using CLSI IC (5 pathogens). Conclusion USCAST’s comprehensive analyses of FQ IC in 2015 led to revised breakpoints for most organism/drug combinations among ENT and PSA compared with those being used before. USCAST analysis was most influenced by PK/PD in vivo data as current clinical outcomes data by MIC was limited. Awareness and interactions (both formal and informal) among breakpoint setting organizations has modified FQ ICs which are lower than previously recommended, and although not perfectly harmonized in time and detail, this represents a successful model. Disclosures All authors: No reported disclosures.
Published: 2019

46. Dilution Factor of Quantitative Bacterial Cultures Obtained by Bronchoalveolar Lavage in Patients with Ventilator-Associated Bacterial Pneumonia

Author: Paul G. Ambrose, Jordi Rello, Catharine C. Bulik, Michael Vicchiarelli, Lisa Mayfield, Leah N. Woosley, Robert Duncan Hite, Ronald N. Jones, Christopher M. Rubino, Krisztina Dorizas, Thomas J. Walsh, Hassan Alnuaimat, Robert K. Flamm, Danijela Djureinovic, Brooks Edward Morgan, Marin H. Kollef, Sujata M. Bhavnani, George L. Drusano, Michelle Ferrari, Ann Doyle, Cristopher Alan Mazo Torre, Alain Combes, Kenneth V. Leeper, Jean Chastre, Richard G. Wunderink, Michael L. Corrado, Evelyn J. Ellis-Grosse, Colleen Berman, Tasnova Malek, Arnold Louie, Mona Brown, Gino Girardi, and Helen K. Donnelly
Subjects: 0301 basic medicine, Pharmacology, Chemotherapy, Microbiological culture, Lung, medicine.diagnostic_test, business.industry, medicine.drug_class, medicine.medical_treatment, 030106 microbiology, Antibiotics, Bacterial pneumonia, Clinical Therapeutics, medicine.disease, 03 medical and health sciences, Infectious Diseases, Bronchoalveolar lavage, medicine.anatomical_structure, Interquartile range, Immunology, Medicine, Pharmacology (medical), business, Pathogen
Abstract: Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log 10 (CFU/ml) [IQR, 5.43 to 6.46 log 10 (CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.)
Published: 2017

47. Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane, or Meropenem: the Pharmacological Basis for a Stand-Alone β-Lactamase Inhibitor

Author: Paul G. Ambrose, Lawrence V. Friedrich, Michael Trang, Brian VanScoy, Sujata M. Bhavnani, Dylan C. Alexander, Haley Conde, and Jennifer McCauley-Miller
Subjects: 0301 basic medicine, Klebsiella pneumoniae, Cefepime, 030106 microbiology, Ceftazidime, Microbial Sensitivity Tests, Pharmacology, Meropenem, beta-Lactamases, 03 medical and health sciences, Pharmacokinetics, Enterobacter cloacae, polycyclic compounds, Escherichia coli, medicine, Humans, Experimental Therapeutics, Computer Simulation, Pharmacology (medical), biology, Chemistry, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Anti-Bacterial Agents, Cephalosporins, 030104 developmental biology, Infectious Diseases, Pharmacodynamics, Thienamycins, Ceftolozane, beta-Lactamase Inhibitors, medicine.drug
Abstract: A major challenge in treating patients is the selection of the “right” antibiotic regimen. Given that the optimal β-lactam/β-lactamase inhibitor pair is dependent upon the spectrum of β-lactamase enzymes produced and the frequency of resistance to the β-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the “right” β-lactam rather than only in a fixed combination. We describe herein a one-compartment in vitro infection model studies conducted to identify the magnitudes of the pharmacokinetic-pharmacodynamic (PK-PD) index for a β-lactamase inhibitor, CB-618, that would restore the activity of four β-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with various doses (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae ( n = 5), Escherichia coli ( n = 2), and Enterobacter cloacae ( n = 1) strains, which produced a wide variety of β-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, and TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each β-lactam partner. The magnitudes of the CB-618 ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (i.e., the AUC/MIC ratio) associated with net bacterial stasis and 1- and 2-log 10 CFU/ml reductions from baseline at 24 h were 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone β-lactamase inhibitor.
Published: 2017

48. Pharmacokinetic-Pharmacodynamic Analysis for Efficacy of Ceftaroline Fosamil in Patients with Acute Bacterial Skin and Skin Structure Infections

Author: Todd Riccobene, Sujata M. Bhavnani, Christopher M. Rubino, H. David Friedland, Alan Forrest, Scott A. Van Wart, Paul G. Ambrose, Daniel K. Reynolds, Tatiana Khariton, Jeffrey P. Hammel, and George L. Drusano
Subjects: Male, Methicillin-Resistant Staphylococcus aureus, medicine.medical_specialty, medicine.drug_class, Cephalosporin, Population, Microbial Sensitivity Tests, medicine.disease_cause, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Humans, Ceftaroline fosamil, Pharmacology (medical), education, Skin, Pharmacology, education.field_of_study, business.industry, Middle Aged, Methicillin-resistant Staphylococcus aureus, Anti-Bacterial Agents, Cephalosporins, Clinical trial, Treatment Outcome, Infectious Diseases, Staphylococcus aureus, Immunology, Female, Staphylococcal Skin Infections, business, medicine.drug
Abstract: Ceftaroline is a cephalosporin with broad-spectrum in vitro activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus . Ceftaroline fosamil, the prodrug of ceftaroline, is approved for the treatment of patients with ABSSSI. Using data from the microbiologically evaluable population from two phase 2 and two phase 3 randomized, multicenter, double-blind studies of patients with ABSSSI, an analysis examining the relationship between drug exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remain above the MIC ( f % T >MIC), and clinical and microbiological responses was undertaken. The analysis population included 526 patients, of whom 423 had infections associated with S. aureus . Clinical and microbiological success percentages were 94.7 and 94.5%, respectively, among all of the patients and 95.3 and 95.7%, respectively, among those with S. aureus infections. Univariable analysis based on data from all of the patients and those with S. aureus infections demonstrated significant relationships between f % T >MIC and microbiological response ( P < 0.001 and P = 0.026, respectively). Multivariable logistic regression analyses demonstrated other patient factors in addition to f % T >MIC to be significant predictors of microbiological response, including age and infection type for all of the patients evaluated and age, infection type, and the presence of diabetes mellitus for patients with S. aureus infections. Results of these analyses confirm that a ceftaroline fosamil dosing regimen of 600 mg every 12 h provides exposures associated with the upper plateau of the pharmacokinetic-pharmacodynamic relationship for efficacy.
Published: 2015

49. Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

Author: Ken Bartizal, Lynn Miesel, Justin C Bader, Paul G. Ambrose, Christopher M. Rubino, Voon Ong, Elizabeth A Lakota, Sujata M. Bhavnani, David R. Andes, and Alexander J. Lepak
Subjects: 0301 basic medicine, Antifungal Agents, Echinocandin, 030106 microbiology, Microbial Sensitivity Tests, Pharmacology, Drug Administration Schedule, exposure shape, Echinocandins, Mice, 03 medical and health sciences, 0302 clinical medicine, Candida albicans, Animals, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, PK/PD models, Mice, Inbred ICR, biology, business.industry, Candidiasis, PK/PD, biology.organism_classification, Disseminated Candidiasis, Disease Models, Animal, echinocandin, Infectious Diseases, single dose, Time course, pharmacokinetics/pharmacodynamics, business, Icr mice, medicine.drug
Abstract: CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC 0–168 ) was administered as a single dose, a >2 log 10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log 10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.
Published: 2017

50. Single-Dose Pharmacokinetics and Safety of Meropenem-Vaborbactam in Subjects with Chronic Renal Impairment

Author: Christopher M. Rubino, David C. Griffith, Sujata M. Bhavnani, Michael N. Dudley, Brooke Lohse, and Jeffery S. Loutit
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Klebsiella pneumoniae, medicine.medical_treatment, 030106 microbiology, Urology, Renal function, Clinical Therapeutics, Meropenem, Drug Administration Schedule, 03 medical and health sciences, Pharmacokinetics, Renal Dialysis, medicine, Humans, Pharmacology (medical), Renal Insufficiency, Chronic, Chronic renal impairment, Dialysis, Aged, Pharmacology, biology, business.industry, Washout, Middle Aged, biology.organism_classification, Boronic Acids, Anti-Bacterial Agents, Drug Combinations, Infectious Diseases, Area Under Curve, Creatinine, Injections, Intravenous, Kidney Failure, Chronic, Female, Hemodialysis, business, medicine.drug, Glomerular Filtration Rate, Half-Life
Abstract: Vaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., Klebsiella pneumoniae carbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1.73 m 2 ), moderate (eGFR of 30 to P < 0.001) and vaborbactam (mean of 5.11-fold increase, P = 0.0235) relative to drug administration off dialysis, consistent with dose recovery rates of 38.3% and 52.9% for meropenem and vaborbactam, respectively, in dialysate. Plasma clearance of meropenem and vaborbactam is reduced with renal impairment, requiring dose adjustment. Hemodialysis removes both drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT02020434.)
Published: 2017

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