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Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against common Enterobacterales pathogens, including extended-spectrum-β-lactamase (ESBL)-producing multidrug-resistant strains. This study evaluated the intrapulmonary pharmacokinetics (PK) and epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations of tebipenem relative to plasma levels in nonsmoking, healthy adult subjects. Thirty subjects received oral TBP-PI-HBr at 600 mg every 8 h for five doses. Serial blood samples were collected following the last dose. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) 1, 2, 4, 6, or 8 h after the fifth dose of TBP-PI-HBr. The tebipenem area under the concentration-time curve for the 8-h dosing interval (AUC(0–8)) values in plasma, ELF, and AMs were calculated using the mean concentration at each BAL sampling time. Ratios of AUC(0–8) values for total ELF and AMs to those for unbound plasma were determined, using a plasma protein binding value of 42%. Mean values ± standard deviations (SD) of tebipenem maximum (C(max)) and minimum (C(min)) total plasma concentrations were 11.37 ± 3.87 mg/L and 0.043 ± 0.039 mg/L, respectively. Peak tebipenem concentrations in plasma, ELF, and AMs occurred at 1 h and then decreased over 8 h. Ratios of tebipenem AUC(0–8) values for ELF and AMs to those for unbound plasma were 0.191 and 0.047, respectively. Four (13.3%) subjects experienced adverse events (diarrhea, fatigue, papule, and coronavirus disease 2019 [COVID-19]); all resolved, and none were severe or serious. Tebipenem is distributed into the lungs of healthy adults, which supports the further evaluation of TBP-PI-HBr for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT04710407.)

Background SPR206 is a novel intravenously (IV)-administered next-generation polymyxin being developed for the treatment of multi-drug resistant (MDR) Gram-negative (GN) infections. A Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206 safety and PK in plasma and pulmonary matrices (ELF and AM) in healthy volunteers. Methods Subjects received 100 mg SPR206 administered intravenously over 1 h q8h for 3 consecutive doses. Blood samples were collected pre-dose (second and third dose) and at 2, 3, 4, 6, and 8 h after the start of the last dose. Each subject underwent one standardized bronchoscopy with BAL at 2, 3, 4, 6 or 8 hours after the start of the third IV infusion. Concentrations of SPR206 in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Plasma, ELF, and AM PK parameters were determined by noncompartmental analysis. SPR206 AUC0–8 in ELF and AM were calculated using the mean concentration values at the BAL sampling times. SPR206 AUC0–8 ratios of ELF and AM to unbound plasma were determined using plasma protein binding value of 8.6%. Results Thirty-four subjects were enrolled and completed the study and 30 of 34 completed bronchoscopy. The mean SPR206 Cmax concentrations in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean AUC0-8 h values in plasma, ELF, and AM concentrations were 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively--leading to a free ELF to plasma concentration ratio of 0.264 and free AM to plasma ratio of 0.328. Importantly, mean concentrations of SPR206 in the ELF achieved lung exposures above its minimum inhibitory concentration for the targeted gram-negative pathogens for the entire 8-hour dosing interval. Figure 1 displays the mean (±SD) SPR206 total and unbound plasma, ELF, and AM concentrations at the BAL sampling times. Overall, SPR206 was well tolerated; 22 subjects (64.7%) experienced at least 1 TEAE, mostly mild with a few moderate. The most frequently reported TEAEs were oral paresthesia [10 subjects (29.4%)] and nausea [2 subjects (5.9%)], which were reversible. Conclusion This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with pneumonia caused by MDR GN infections. Figure 1.Mean (±SD) plasma (total and unbound), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of SPR206 in healthy adult subjects. This study was conducted in collaboration with, and with financial support from, the United States Department of Defense (Award No. W81XWH1910295). Disclosures Keith A. Rodvold, PharmD, Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Honoraria Justin Bader, n/a, Spero Therapeutics: Employee Vipul K. Gupta, Ph.D., Spero Therapeutics: Employee Troy Lister, Ph.D., Spero Therapeutics: Employee Praveen Srivastava, Ph.D., Spero Therapeutics: Employee Jon Bruss, M.D., Spero Therapeutics: Employee.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales . This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg).

Study objective Telavancin and vancomycin are both approved for treatment of hospital-acquired and ventilator-associated bacterial pneumonias caused by Staphylococcus aureus, and both agents can cause renal dysfunction. The objective of this study was to assess renal function changes by performing renal shift table analyses of telavancin- and vancomycin-treated patients in phase III trials. Design Retrospective, descriptive analysis of data from the safety population from the Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials. Patients A total of 1503 adults with hospital-acquired or ventilator-associated bacterial pneumonia primarily caused by gram-positive pathogens and who received telavancin (n = 751) or vancomycin (n = 752). Measurements and main results Decline or improvement in creatinine clearance (CrCl) across seven defined categories (≤30, >30-40, >40-50, >50-60, >60-70, >70-80, and >80 ml/min) was classified as negative or positive shifts, respectively. The number of categories crossed (either positive or negative) determined the grade of shift (of a potential grades 1-6, with crossing from one category to the next adjacent category defined as a grade 1 shift) at specific time points compared with baseline: day 4, day 7, and end of therapy (EOT). Approximately 77%-91.6% of patients had either no change or improvement of CrCl across all time points for both treatments. Negative shifts were consistent for telavancin (day 4, 19.3%; day 7, 19.0%; EOT, 23.0%) but increased over time for vancomycin (day 4, 8.4%; day 7, 12.3%; EOT, 19.3%). A significantly lower proportion of patients receiving vancomycin showed renal function decline on day 4 and day 7. At EOT, negative shift rates were similar between treatments (treatment difference 3.6% [95% CI -0.7 to 7.9]). At day 7 and EOT, a higher percentage of vancomycin-treated patients experienced high-grade negative shifts relative to telavancin (day 7, vancomycin 2.8% vs telavancin 1.9%; EOT, vancomycin 4.7% vs telavancin 4.1%), though differences were not statistically significant. Conclusion Use of shift tables revealed differences in timing of renal function changes in patients receiving telavancin and vancomycin. Telavancin-related declines in renal function were similar at day 4 and day 7, with a slight increase by EOT. This differed from vancomycin, which caused a steady increase in the percentage of patients with renal function decline over time. A significant difference in negative renal shifts between treatments occurred at day 4 and day 7 and favored vancomycin; however, the difference was minimal and not significant at EOT.

The in vitro broth microdilution testing method for telavancin, a lipoglycopeptide active against S. aureus, was revised in 2014 to include polysorbate-80 in the test media. This study evaluates the bactericidal activity of telavancin against S. aureus in media containing polysorbate-80 by in vitro time-kill analysis alongside relevant comparators.

Background A significant percentage of patients admitted to the hospital with UTI are infected with ESBL positive and quinolone-resistant (FQ NS) enterobacteriaceae (ENT) that can complicate patient outcomes due to potentially inadequate antibiotic therapy. We used a large national multicenter database to ascertain the demography associated with susceptible and resistant UTI and the underlying comorbidities. Methods We analyzed the first positive ENT urine culture ≤3 days from admission in those with a discharge primary or secondary UTI ICD10 code from 68 US hospitals from October 1, 2015–2017 (BD Insights, Franklin Lakes, NJ). Patient demographics were identified using AHRQ classifications to assess for specific risk factors and categorized by ESBL and FQ resistance status. Healthcare-associated (HCA) episodes were defined as admissions from another care facility, admission in the prior 30 days, and presence of dialysis or cancer comorbidity. The Fisher’s exact test was used to test for significance. Results Of 16,022 adults (mean age 69.5 years; 77.7% female) with culture positive ENT UTI were identified; 11.0% (n = 1,763) were ESBL +, 31.3% (n = 5,017) were FQ NS and 8.9% (n = 1,433) being both ESBL + and FQ NS. Admissions with ESBL + /FQ NS were significantly more likely to be male, admitted with HCA risk factors and with higher important comorbidities. Demographic ESBL − /FQ S FQ NS ESBL + /FQ NS N (%) 10,784 (67.3%) 5,017 (31.3%) 1,433 (8.9%) % Male 2,252 (20.9%) 1,284 (25.6%) ¥ 401 (28.0%)* %HCA 2,716 (25.2%) 1,505 (30.3%) ^¥ 489 (34.1%)* Deficiency anemias 2,840 (26.3%) 1,563 (31.2%) ^¥ 508 (35.5%)* Renal failure 2,196 (20.4%) 1,227 (24.5%) ^¥ 402 (28.1%)* Chronic pulmonary disease 2,009 (18.6%) 1,191 (23.7%) ¥ 345 (24.1%)* Diabetes 1,947 (18.1%) 1,095 (21.8%) ¥ 318 (22.2%)* Diabetes w/ chronic complications 1,872 (17.4%) 979 (19.5%) ¥ 313 (21.8%)* Congestive heart failure 1,648 (15.3%) 1,011 (20.2%) ¥ 292 (20.4%)* * P < 0.0002 vs. ESBL-/FQ S; ^ P < 0.0032 FQ NS vs. ESBL+/FQ NS; ¥ P < 0.0012 FQ NS vs. ESBL-/FQ S. Conclusion About one in 11 admissions with UTI are ESBL + /FQ NS and are more likely to be male, with HCA risk factors and other important comorbidities. Current oral antibiotic therapy is limited in such episodes and oral treatment alternatives are needed. Disclosures J. Bruss, Alarus Development International: Employee, Salary; Spero Therapeutics: Consultant, Consulting fee. D. Melnick, Spero Therapeutics: Employee, Salary. A. Jain, Spero Therapeutics: Employee, Salary. J. Murray, Becton Dickinson and Company: Employee, Salary. I. Critchley, Spero Therapeutics: Employee, Salary. S. Kurtz, Becton Dickinson and Company: Employee, Salary. V. Gupta, Becton Dickinson and Company: Employee, Salary.