Cystic fibrosis is a monogenetic disease complicated by recurrent bacterial lung infections that require chronic antibiotics. Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen associated with cystic fibrosis morbidity and mortality. Here, we describe the development of a three-phage cocktail (BX004-A) designed to target a wide range of P. aeruginosa strains. We evaluated BX004-A in Part 1 of a first-in-human double-blind placebo-controlled phase 1b/2a clinical trial, which included nine adult cystic fibrosis patients chronically infected with P. aeruginosa (NCT05010577). BX004-A met the primary endpoints of safety and tolerability. Exploratory endpoints included pharmacokinetics and Pseudomonas aeruginosa sputum density reduction. Efficient phage delivery to the lower respiratory tract was observed, and a potential reduction in P. aeruginosa sputum burden was noted in the phage arm. However, due to the study's small sample size, definitive conclusions regarding efficacy are limited. These data pave the way toward further development of novel phage-based therapeutics in antibiotic-resistant pulmonary bacterial infections.

ABSTRACT Bacillus anthracis is a gram-positive, spore-forming bacterium and the etiological agent of anthrax. As a Tier 1 Select Agent, the pathogen can be isolated from the natural environment, and the endospore is a significant biological threat that can be produced in large quantities, stored, and disseminated by aerosolization. The intentional release of B. anthracis spores has the potential for mass casualties and is a serious threat to public and military health. Fluoroquinolones and tetracyclines are common antibiotics used for post-exposure prophylaxis and treatment in the United States (U.S.), whereas penicillin is the drug of choice throughout the rest of the world. However, these commonly used antibiotics may be contraindicated or suboptimal in a public health crisis. Thus, there is a need for novel medical countermeasures to be developed and tested against B. anthracis . Sulopenem is a broad-spectrum, orally bioavailable penem antibiotic recently approved in the U.S. for the treatment of uncomplicated urinary tract infections in women with limited therapeutic options. Here, we demonstrate that sulopenem has potent in vitro activity against both wild-type virulent B. anthracis strains, as well as biosafety level 2 surrogate strains resistant to current standards of care. Using human-equivalent dosing regimens, we show that sulopenem is highly protective in both the mouse and rabbit inhalational anthrax models. Together, these results support continued evaluation of this oral penem as a countermeasure for inhalational anthrax.

ABSTRACT Sulopenem is an oral and intravenous penem antibiotic in clinical development for treatment of urinary tract and intra-abdominal infections caused by multidrug-resistant pathogens. This study evaluated in vitro antimicrobial activity of sulopenem by post-antibiotic effect (PAE), sub-inhibitory minimal inhibitory concentration PAE effect (PAE-SME), checkerboard testing, and time-kill testing. Testing sulopenem at 1×, 5×, or 10× the baseline MIC resulted in a PAE interval of 0.0–0.7 hours. When exposed to 0.5× the sulopenem MIC following 5× MIC, all isolate/agent combinations had PAE-SME values of >4.8 hours. Checkerboard testing revealed no instances of antagonism between sulopenem and comparator agents—indifference was observed in most sulopenem checkerboard combinations. Sulopenem demonstrated bactericidal activity (≥3 log10 [99.9%] reduction in viable organism counts) in all time-kill assays following 24 hours of incubation at 8× the baseline MIC (6/6), 5/6 displaying this activity within 8 hours. The present antimicrobial parameters seen at concentrations surrounding the MIC support optimization of sulopenem dosing and further development. The oral dosing regimen of sulopenem etzadroxil/probenecid 500 mg/500 mg administered every 12 hours was recently evaluated in two phase 3 clinical trials where sulopenem demonstrated efficacy against amoxicillin-clavulanate in uncomplicated urinary tract infection (uUTI) and against ciprofloxacin in fluoroquinolone-resistant uUTI.IMPORTANCESulopenem is an oral and intravenous penem antibiotic in clinical development for treatment of urinary tract and intra-abdominal infections caused by multidrug-resistant pathogens. This study evaluated sulopenem via broth microdilution susceptibility testing, PAE, sub-inhibitory MIC PAE effect, checkerboard testing, and time-kill testing. The results of this study—interpreted along with recent pharmacodynamic in vitro one-compartment and hollow-fiber infection model work—provide insight into the in vitro activity of sulopenem.

Abstract Background Existing oral antibiotics for treatment of uUTI are not reliably effective due to rising antimicrobial resistant uropathogens. Sulopenem is a broad-spectrum IV/oral penem being developed for treatment of multidrug resistant infections. We conducted a pivotal Phase 3 randomized, double-blind, double-dummy, active controlled trial to evaluate the safety and efficacy of sulopenem/probenecid (SUL) vs amoxicillin/clavulanate (AMC) for treatment of uUTI. Methods Adult women with uUTI were randomized to SUL or AMC, both bid for 5 days. The primary objective was to establish noninferiority of SUL to AMC in the mMITT population (patients with ≥105 CFU/mL Enterobacterales in baseline urine culture). The primary endpoint was overall success (combined clinical and microbiologic success) at the Test of Cure (TOC) visit. Using a pre-specified procedure to control for multiplicity, mMITT patients with baseline pathogens susceptible to AMC (mMITTS) were tested for noninferiority/superiority and those with nonsusceptible pathogens (mMITTR) were tested for superiority. Results Of 2222 women randomized, 990 (44.6%) had ≥105 CFU/mL Enterobacterales in baseline urine cultures and were in the mMITT population (Table 1). Of these, 922 had pathogens susceptible to AMC (mMITTS). The sample size in the mMITTR population (N=67) was lower than anticipated and not sufficiently powered to draw any conclusions. Treatment emergent adverse events (TEAE) occurred more frequently in SUL treated patients (all, 18.9% vs 12.3%; related, 14.0% vs 7.7%) with the most frequent TEAEs being diarrhea, nausea and headache. Premature discontinuation from study drug due to TEAEs was low in both treatment groups (≤1%). No serious adverse events were reported in the SUL group, while 5 (0.5%) occurred in the AMC group. Conclusion Sulopenem/probenecid was non-inferior to AMC for the treatment of adult women with uUTI in the mMITT population. In the mMITTS population, SUL demonstrated non-inferiority and based on an ad hoc analysis, demonstrated superiority to AMC. SUL was well tolerated with a safety profile consistent with other β-lactams and has the potential to fill the substantial unmet medical need for an empiric oral antibiotic option for outpatients with uUTI in this era of rising antimicrobial resistance. Disclosures Sailaja Puttagunta, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Steven I. Aronin, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Jayanti Gupta, PhD, Iterum Therapeutics: Advisor/Consultant Anita F. Das, PhD, Cidara: Advisor/Consultant|Contrafect: Advisor/Consultant|Iterum Therapeutics: Advisor/Consultant|Paratek: Advisor/Consultant|Utility therapeutics: Advisor/Consultant Kalpana Gupta, MD, Iterum Therapeutics: Advisor/Consultant Michael W. Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds (Public Company)

Abstract Background Per FDA Guidance, the primary efficacy endpoint for trials evaluating antimicrobials for treatment of UTI is a combined clinical/microbiologic response. Overall success requires both resolution of UTI symptoms and demonstration that the causative uropathogen is reduced to < 103 CFU/mL at a fixed time point after randomization, regardless of whether the patient is asymptomatic. Previously, we retrospectively evaluated the impact of post treatment asymptomatic bacteriuria (ASB) for Phase 3 clinical trial patients with UTI and found that ASB was not a predictor of subsequent clinical failure. In this study, we prospectively assessed the impact of post treatment ASB on subsequent clinical response for adult women with uUTI. Methods Study IT001-310 was a Phase 3 randomized, double-blind, double-dummy, active controlled trial to evaluate the safety and efficacy of sulopenem/probenecid (SUL) versus amoxicillin/clavulanate (AMC) for the treatment of uncomplicated UTI (uUTI). Adult women were randomized to receive SUL or AMC, both bid for 5 days. The primary efficacy outcome was overall success (combined clinical/microbiologic success) at the Test of Cure (TOC) visit in the mMITT population. ASB at TOC was prespecified as an additional efficacy endpoint to be assessed, and the presence of ASB at the End of Treatment (EOT) and TOC visit was evaluated to see if it impacted clinical response at the following visit. Results 2,222 women were randomized; 990 (44.6%) were in the mMITT population. ASB was the reason for nonresponse in 74 (14.2%) and 93 (19.9%) patients treated with SUL and AMC, respectively. As shown in the table, for both treatment arms, the presence of ASB at the EOT and TOC visit did not lead to clinical failure at the following visit. Conclusion SUL and AMC, both β-lactams, appear to have similar effects on the frequency of post treatment ASB. For patients in both treatment arms, the presence of ASB a week after completing UTI therapy was not a marker of subsequent clinical failure. The inclusion of ASB as part of the primary endpoint for studies of UTI should be reconsidered. Inclusion of microbiologic results from asymptomatic patients after complete resolution of uUTI symptoms is a practice inconsistent with available treatment recommendations. Disclosures Steven I. Aronin, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Michael Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds (Public Company) Sailaja Puttagunta, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company)

BACKGROUND:Existing antibiotics for uncomplicated urinary tract infections are becoming less reliably effective owing to increasing antimicrobial resistance. Our objective was to evaluate the safety and efficacy of sulopenem/probenecid for uncomplicated urinary tract infections. METHODS:We conducted a double-blind, randomized, controlled, noninferiority trial of 5 days of sulopenem versus amoxicillin/clavulanate for women with uncomplicated urinary tract infection. The primary end point was overall success, defined as combined clinical cure and microbiologic eradication by day 12, evaluated in the microbiologic-modified intent-to-treat population, which comprised all randomly assigned patients who received any trial medication and had a positive urine culture with 105 colony-forming units (CFU)/ml or more of an Enterobacterales uropathogen (e.g., Escherichia coli, Klebsiella species). RESULTS:A total of 2222 patients were enrolled, and the median age was 51 years (interquartile range, 35-62 years). Ninety-one (9.2%) patients in the primary population (microbiologic-modified intent-to-treat population), the combined population of patients with a positive baseline urine culture and without regard to amoxicillin/clavulanate susceptibility, had a baseline pathogen resistant to three or more classes of antibiotics. Overall success in the microbiologic-modified intent-to-treat population occurred in 318 of 522 (60.9%) participants treated with sulopenem versus 260 of 468 (55.6%) participants treated with amoxicillin/clavulanate (difference, 5.4 percentage points; 95% confidence interval [CI], -0.8 to 11.5), meeting criteria for noninferiority. In the primary population with a baseline uropathogen susceptible to amoxicillin/clavulanate, success occurred in 296 of 480 (61.7%) participants treated with sulopenem versus 243 of 442 (55.0%) participants treated with amoxicillin/clavulanate (difference, 6.7 percentage points; 95% CI, 0.3 to 13.0). In the primary population with a baseline uropathogen not susceptible to amoxicillin/clavulanate, success occurred in 22 of 42 (52.4%) patients treated with sulopenem versus 17 of 25 (68.0%) patients treated with amoxicillin/clavulanate (difference, -15.6 percentage points; 95% CI, -37.5 to 9.1]. Treatment-emergent adverse events occurred more frequently with sulopenem compared with amoxicillin/clavulanate, including diarrhea (8.1% vs. 4.1%), nausea (4.3% vs. 2.9%), and headache (2.2% vs. 1.5%). CONCLUSIONS:Sulopenem was noninferior to amoxicillin/clavulanate for the treatment of adult women with uncomplicated urinary tract infection, but was associated with more frequent mild adverse events. (Funded by Iterum Therapeutics; REASSURE ClinicalTrials.gov number, NCT05584657.).

Abstract Background Sulopenem (SUL) is a penem β-lactam antibiotic in development for the treatment of resistant bacterial infections. It is available as intravenous and oral prodrug formulations, and its activity aligns with the most urgent drug-resistant antimicrobial threats defined by the CDC. SUL possesses potent activity against Enterobacterales species that encode ESBLs or AmpC-type β-lactamases that confer resistance to 3rd generation cephalosporins. SUL has also demonstrated potent in vitro activity against numerous biothreat pathogens, including Bacillus anthracis at concentrations likely to be achieved after oral dosing in humans. B. anthracis is a CDC Tier 1 Select Agent, and remains of considerable concern for biodefense. The potential for mass casualties resulting from a biothreat incident combined with the risk of antibiotic resistance necessitates development of novel medical countermeasures (MCM) for B. anthracis. Orally administered SUL was previously shown to be protective in the murine model of inhalational anthrax and provided proof-of-concept to advance the drug into the well-established rabbit model. Methods Female New Zealand White rabbits were challenged with a lethal dose of B. anthracis Ames spores via the inhalational route. Post-exposure prophylaxis (PEP) was initiated at 24 ±1 h postchallenge with cohorts (N=6) of animals receiving vehicle (saline, SC), ciprofloxacin (CIP) 10 mg/kg, SC or SUL 10 mg/kg, SC. This dosing regimen was informed by pharmacokinetic models to establish a human-equivalent dose. Treatment was continued BID for 14 days. Clinical progression and survival were assessed up to 30 days postchallenge. Results The untreated saline control group demonstrated 100% lethality with a median time to death of 48 h. Both the SUL and CIP groups demonstrated 100% survival through study termination on day 30. Conclusion As a MCM for inhalational anthrax, SUL would provide considerable advantages as an addition to the slate of current standards of care. Combined with positive efficacy results in two preclinical models of inhalational anthrax and advantages offered by an orally available penem antibiotic, SUL remains a promising candidate for advanced development for treating B. anthracis. Disclosures Sailaja Puttagunta, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Steven I. Aronin, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company)

OBJECTIVE:To demonstrate the non-inferiority of intravenous (IV) sulopenem to IV ertapenem, each followed by an oral regimen, in adults with complicated intra-abdominal infections (cIAI). METHODS:Hospitalized adults with cIAI were randomly assigned to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid twice daily or 5 days of IV ertapenem followed by oral ciprofloxacin/metronidazole or amoxicillin-clavulanate depending on baseline pathogen susceptibility. The target treatment duration was 7-10 days. The primary (FDA [Food and Drug Administration]-specified) endpoint was clinical response at day 28 (test-of-cure) in the micro-modified intent-to-treat (micro-MITT) population. RESULTS:A total of 674 patients were randomly assigned. The two treatment arms were well balanced. Escherichia coli (395 patients) and Bacteroides fragilis (111 patients) were the most frequently isolated pathogens. Clinical success rates in the micro-MITT population were 81.9% (204/249) for sulopenem-treated patients and 87.9% (233/265) for ertapenem-treated patients. The lower bound of the CI for the treatment difference of the primary endpoint was below the pre-specified non-inferiority margin of -10.0 (treatment difference -6.0%, 95% CI, [-12.2 to 0.2]). In all other analysis populations, the lower limit of the 95% CI was above -10.0. Treatment-emergent adverse events (all, 26.0% [87/335] vs. 23.4% [78/333]; related, 6.0% [20/335] vs. 5.1% [17/333]) were similar for sulopenem and ertapenem, respectively. Most events were mild to moderate in severity. There were more serious adverse events in the sulopenem arm (7.5% [25/335] vs. 3.6% [12/333]), only two of which were considered possibly drug-related. DISCUSSION:Sulopenem IV followed by oral sulopenem etzadroxil/probenecid was not non-inferior to ertapenem followed by oral step-down in treating cIAI in the micro-MITT population. This finding should be interpreted in the context of country regulations, as endpoint timing, primary analysis population and non-inferiority margin may vary regionally. Both IV and oral sulopenem were well-tolerated; the oral formulation allowed patients with resistant pathogens to step-down from IV therapy.

ing drug-resistant disease, and we wholeheartedly encourage others to continue explore their use further through clinical practice and research endeavors. Thepoint about the “stickiness”of bedaquiline is valid and important to consider. For additional detail on our CSF collection procedure, we used a prepared lumbar puncture kit; CSF was collected through a 3.5-inch spinal needle and a 3-way stopcock directly into polypropylene specimen vials, pipetted into polypropylene cryovials, and frozen at −80°C until shipment and analysis. While the lack of plastic tubing decreased potential drug loss, it is possible that someof the bedaquiline adsorbed to the polypropylene vials, as has been described previously in a pilot experiment [3]. We applaud the work by Upton and colleagues [4] to test and fine tune collection strategies to more accurately measure CSF bedaquiline concentrations. This provides an invaluable technique for futurebedaquiline CSF pharmacokinetic research and will allow for better comparison of results between studies and patients. Our limit of detection for bedaquiline, delamanid, and clofazamine was validated only to 0.01 μg/mLandnot lower, owing to lack of funding for full low-end validation of these drugs in artificial CSF. In our Supplementary Tables 1–5 [2], we categorized CSF drug concentration results as either below the limit of detection or 0, with these below-limit samples having an amount detected below 0.01 μg/mL. More than 50% of the CSF samples we collected had a detectable amount for bedaquiline, clofazimine, and delamanid; however, we chose not to report these values, given lack of validation and potential for inaccuracy. Following the lead of Upton and colleagues, we agree that a lower limit of detection should be validated and used for CSF detection of these drugs to better illuminate the diffusion of free drug into CSF. We hope that our research stimulates further and innovative research into the clinical pharmacology of TBM. The high mortality rate for drug-resistant TBM shown by our group and others necessitates more investigation aimed at improving treatment options [5, 6]. In a search of clinicaltrials.gov, we found no currently registered TBM trials using bedaquiline, delamanid, or pretomanid. This is stark contrast to the abundance of clinical trial activity in drug-resistant pulmonary tuberculosis [7]. However, innovative translational research in TBM is being done, including work evaluating dynamic positron emission tomography to study drug distribution into brain parenchyma [8, 9]. This work has provided a novel way to evaluate brain concentrations, and results to date have shown promising results for pretomanid and that bedaquiline accumulates at higher concentrations in the brain versus CSF, highlighting that CSF analysis may offer an incomplete picture. We encourage others to use our results as launching pad to further study the clinical pharmacology of TBM.

Abstract Background Sulopenem etzadroxil, the oral (PO) prodrug of the active moiety sulopenem, is a thiopenem in development for the treatment of uncomplicated urinary tract infection (uUTI). Oral sulopenem is a bilayer tablet composed of sulopenem etzadroxil and probenecid, an organic anion transport inhibitor that delays renal excretion of sulopenem. The goal of these studies was to determine whether the chosen clinical PO dosing regimen of 500 mg q12h, based on murine thigh models, would induce resistance amplification in a hollow-fiber in vitro infection model over a clinically relevant time period. Methods Four Escherichia coli clinical isolates (fluoroquinolone-R, ESBL +, Sequence Type 131, sulopenem MIC 0.03 to 0.125 mg/L), at an initial burden of 106 CFU/mL, were subjected to sulopenem concentration-time profiles simulating total-drug urine concentrations following a 500 mg PO q12h regimen in a hollow-fiber in vitro infection model. Each isolate was additionally exposed to negative (levofloxacin 750 mg) and positive (meropenem 2 g) control regimens simulating free-drug plasma concentrations following intravenous (IV) dosing every 24 and 8 hours, respectively. Samples were collected for the enumeration of bacterial burdens and evaluation of the simulated pharmacokinetic profiles over the five-day study period. Each sample for bacterial enumeration was suspended onto agar plates, with and without supplementation of the respective antibiotic, to observe the density of the total and drug-resistant subpopulations over five days. Results The sulopenem 500 mg q12h regimen repeatedly reduced the bacterial density of the total population from the initial burden of 1.0 x 106 CFU/mL to those below 1 log10 CFU/mL, and prevented amplification of drug-resistant subpopulations over the five-day period for each isolate (Figure 1). The activity observed for the sulopenem 500 mg q12h regimen simulating urine concentrations was similar to that of the meropenem positive control regimen, while the levofloxacin negative control failed to provide any antimicrobial activity. Conclusion These data support the selection of sulopenem etzadroxil/probenecid 500 mg/500 mg PO q12h, which minimized the potential for on-therapy drug-resistance amplification. Disclosures Brian D. VanScoy, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Haley Conde, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Catherine E. Vincent, Ph.D., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Steven I. Aronin, MD, Iterum Therapeutics Limited: Stocks/Bonds Sailaja Puttagunta, MD, Iterum Therapeutics Limited: Full time employee|Iterum Therapeutics Limited: Stocks/Bonds Paul G. Ambrose, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Suppor

Abstract Objectives Physicians must leverage several factors when making antibiotic therapy decisions, including route of administration and duration of therapy. Oral administration provides several potential advantages including increased accessibility, prevention of hospitalizations and earlier discharges. Sulopenem—a broad-spectrum, synthetic penem β-lactam agent—uniquely possesses both oral and IV formulations along with noted stability among antimicrobial-resistant subsets. This study evaluated the in vitro activity of sulopenem and comparator agents against contemporary Enterobacterales and anaerobic clinical isolates predominantly from patients with bloodstream, intra-abdominal and urinary tract infections. Methods A contemporary collection of 1647 Enterobacterales and 559 anaerobic isolates was assembled from medical centres in Europe and the USA. Isolates were susceptibility tested using the CLSI reference methods: broth microdilution for Enterobacterales and agar dilution for anaerobes. Results Sulopenem demonstrated potent in vitro antimicrobial activity (MIC50/90, 0.03/0.25 mg/L) against Enterobacterales isolates regardless of infection type, inhibiting 99.2% of isolates at ≤1 mg/L. This activity was conserved against resistant phenotypes including ESBL-phenotype Escherichia coli (MIC50/90, 0.03/0.06 mg/L) and ESBL-phenotype Klebsiella pneumoniae (MIC50/90, 0.06/1 mg/L). Sulopenem maintained activity against ciprofloxacin-, nitrofurantoin- and trimethoprim/sulfamethoxazole-non-susceptible subsets (MIC50/90, 0.03–0.06/0.12–0.5 mg/L). Against anaerobic isolates, sulopenem (98.9% inhibited at ≤4 mg/L) and meropenem [98.4% susceptible (CLSI)] were the most active compounds tested. Conclusions The potent in vitro activity of sulopenem against this large collection of recent Enterobacterales and anaerobic clinical isolates from multiple infection types supports its further clinical evaluation in the treatment of intra-abdominal and urinary tract infections.

Abstract Background There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. Methods Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. Results In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, −11.8%; 95% CI, −18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, −2.3%; 95% CI, −7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). Conclusions Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. Clinical Trial Registration NCT03354598.

Abstract Background Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. Methods Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). Results Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum β-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, −6.1%; 95% confidence interval, −12.0 to −.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. Conclusions Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. Clinical Trial Registration NCT03357614.

Sulopenem disk masses of 2, 5, 10, and 20 μg were evaluated by susceptibility testing isolates by broth microdilution and disk diffusion. A 2-μg disk was chosen, and error-rate bounding analysis in accordance with Clinical and Laboratory Standards Institute (CLSI) guideline M23 was conducted using a proposed sulopenem susceptible/intermediate/resistant (S/I/R) interpretive criterion of ≤0.5/1/≥2 μg/mL.

Abstract Background The DOOR approach has been proposed as an improved way to evaluate novel anti-infective agents by focusing on benefits and harms and providing an assessment of the patient experience. We conducted a Phase 3 cIAI trial comparing IV ertapenem (stepped down to either oral ciprofloxacin and metronidazole or amoxicillin-clavulanate) to IV sulopenem (stepped down to oral sulopenem etzadroxil/probenecid). Using the FDA’s current definition of a successful response (clinical response at Day 28 / Test-Of-Cure (TOC) in the microbiological intent-to-treat (micro-ITT) population using a non-inferiority margin of 10%, sulopenem’s overall success rate was 85.5% while ertapenem’s was 90.2% (treatment difference -4.7%, 95% CI: -10.3, 1.0). In all other study populations including the intent-to-treat (ITT), modified ITT, clinically evaluable (CE), and microbiologically evaluable (ME) populations the lower limit of confidence interval was above -10.0. To further understand these trial results, an analysis using the DOOR methodology was performed post hoc.Table 1Desirability of Outcome Rankings by Treatment Arm Methods The DOOR analysis strategy, developed by the Antibacterial Resistance Leadership group (ARLG), was retrospectively applied to our registrational drug trial for cIAI (SURE-3) to estimate the probability of a more desirable outcome for sulopenem. Results The DOOR probability of a more desirable outcome is 47.4% [95% CI (44.1%, 50.8%)], indicating no significant difference between the sulopenem and ertapenem treatment arms for patients with cIAI. The probabilities for the analyses prioritizing efficacy and safety were identical to the original outcome ranking, and those for the individual components were very similar. Conclusion Traditional endpoints used in registrational trials for cIAI may be inadequate. They evaluate safety and efficacy separately, and they fail to evaluate the cumulative impact of multiple clinical events. DOOR combines clinical efficacy and safety into a single endpoint that may be more reflective of an individual patient’s overall outcome. Applying DOOR to SURE-3 data showed no significant difference between the sulopenem and ertapenem treatment arms for patients with cIAI. Disclosures Steven I. Aronin, MD, Iterum Therapeutics Limited: Stocks/Bonds Michael W. Dunne, MD, Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds Jayanti Gupta, PhD, Iterum Therapeutics: Advisor/Consultant Sailaja Puttagunta, MD, Iterum Therapeutics Limited: Full time employee|Iterum Therapeutics Limited: Stocks/Bonds

Abstract Background Sulopenem etzadroxil, the oral (PO) prodrug of the active moiety sulopenem is a thiopenem with activity against drug-resistant pathogens known to cause uncomplicated urinary tract infection (uUTI). Oral sulopenem is a bilayer tablet composed of sulopenem etzadroxil and probenecid, an organic anion transport inhibitor that delays renal excretion of sulopenem. The goal of the studies described herein was to characterize the pharmacokinetics-pharmacodynamics of sulopenem against a diverse panel of Enterobacterales using a dynamic in vitro model. Methods A series of 24-hour dose-fractionation and dose-ranging studies were completed using the one-compartment in vitro infection model. Bacteria (1 x 106 CFU/mL) were exposed to sulopenem concentrations that mimicked human free-drug plasma concentration-time profiles (protein binding of 10.7%, Tmax = 2 hr and a t1/2 of 1.18 hr) following oral drug administration. For the dose-fractionation studies, a single challenge isolate (Escherichia coli NCTC 13441 MIC = 0.125 mg/L) was exposed to five different total daily exposures, fractionated equally into doses administered every 4, 8, or 12 hours (q4h, q8h, or q12h). In the dose-ranging studies, 10 Enterobacterales clinical isolates (MIC values from 0.03 to 0.5 mg/L) were exposed to a range of sulopenem q8h doses representing free-drug (f) %T >MIC values ranging from 0 to 98.8%. Relationships between change in log10 CFU/mL from baseline at 24 hr and each of fCmax:MIC ratio, f%T > MIC, and fAUC:MIC ratio were fit using Hill-type models. Results As evidenced by the highest r2 of 0.90 measuring the tightness of data around the fitted function, the relationship between sulopenem f%T > MIC and change in bacterial burden best described the activity of sulopenem using the dose-fractionation study data (Figure 1). The median sulopenem f%T > MIC values associated with achieving net bacterial stasis, and 1- and 2-log10 CFU/mL reductions from baseline were 40.9, 50.2, and 62.6% based on the data from the dose-ranging studies (Figure 2 and Table 1). Conclusion The results of these analyses demonstrated that f%T > MIC was the PK-PD index that best described sulopenem activity. The f%T > MIC targets for efficacy based on these data will be useful to support sulopenem dose selection for patients with uUTI. Disclosures Brian D. VanScoy, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Sean Jones, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Haley Conde, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Catherine E. Vincent, Ph.D., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: 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|BioFire Diagnostics LLC: Grant/Research Support|Boston Pharmaceuticals: 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|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: 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|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|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Bio

References 1. Pai Mangalore R, Ashok A, Lee SJ, et al. Beta-lactam antibiotic therapeutic drugmonitoring in critically ill patients: a systematic review and meta-analysis. Clin Infect Dis 2022; 75:1848–60. 2. Ewoldt TMJ, Abdulla A, Rietdijk WJR, et al. Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial. Intensive Care Med 2022; 48:1760–71. 3. Dilworth TJ, Schulz LT, Micek ST, Kollef MH, Rose WE. β-lactam therapeutic drugmonitoring in critically ill patients: weighing the challenges and opportunities to assess clinical value. Crit Care Explor 2022; 4:e0726. 4. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 2014; 58:1072–83. 5. Hagel S, Bach F, Brenner T, et al. Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial. Intensive CareMed 2022; 48:311–21.

Abstract Background Per FDA Guidance, the primary efficacy endpoint for trials evaluating antimicrobials for treatment of uncomplicated urinary tract infection (uUTI) and complicated urinary tract infection (cUTI) is a combined clinical/microbiologic outcome response. Overall success requires both resolution of UTI symptoms and demonstration that the causative uropathogen is reduced to < 103 CFU/mL at a fixed time point after randomization, regardless of whether the patient is symptomatic. In clinical practice, it is not standard of care to routinely screen for or treat asymptomatic bacteriuria (ASB), nor to obtain ‘proof of cure’ cultures. In the clinical trial setting, the impact of post-treatment asymptomatic bladder recolonization on the rates of microbiologic response, re-infection, or emergence of resistance is unknown. Methods Study IT001-301 and -302 are double blind, double-dummy, Phase 3 randomized trials comparing sulopenem to comparator for patients with pyuria, bacteriuria, and clinical signs/symptoms of uUTI and cUTI, respectively. In Study 301, 1671 ambulatory female adults with uUTI were randomized to oral sulopenem bid x 5d or oral ciprofloxacin bid x 3d. In Study 302, 1395 hospitalized adults with cUTI were randomized to sulopenem IV once daily x 5d followed by oral sulopenem bid or ertapenem IV once daily x 5d followed by either oral ciprofloxacin or amoxicillin-clavulanate bid, depending on baseline uropathogen susceptibility. The primary endpoint was overall (clinical + microbiologic) response in micro-MITT population at TOC visit (D12 in uUTI study and D21 in cUTI study). Results Figure 1 Conclusion Different classes of antibiotics appear to have a differential effect on the frequency of post-treatment ASB with quinolones having a lower rate relative to beta-lactams. The presence of ASB a week or more after completing UTI therapy was not associated with a higher rate of clinical relapse for UTI patients; treatment with ciprofloxacin was associated with the selection of resistant pathogens in the post-treatment flora. Inclusion of ASB in the primary endpoint for studies of UTI should be reconsidered as it implies that a post-treatment culture should be obtained to document resolution of infection, a practice inconsistent with available treatment recommendations. Disclosures Steven I. Aronin, MD, Iterum Therapeutics: Stocks/Bonds Michael Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds Sailaja Puttagunta, MD, Iterum Therapeutics: Stocks/Bonds.

Resistance to oral antibiotics commonly used to treat outpatient urinary tract infections (UTIs) is increasing, but the implications of empirical treatment of resistant pathogens are not well described. Using an electronic records database, we reviewed the outcomes of patients >18 years of age who developed an outpatient UTI and had an outpatient urine culture result showing a member of the order Enterobacterales along with prescription data for an oral antibiotic filled on the day before, day of, or day after the culture was collected. Linear probability models were used to estimate partial effects of select clinical and demographic variables on the composite outcome. In all, 4,792 patients had 5,587 oral antibiotic prescriptions. Of 5,395 evaluable episodes, 22% of patients received an antibiotic to which the pathogen was resistant in vitro, and those patients were almost twice as likely to require a second prescription (34% versus 19%) or be hospitalized (15% versus 8%) within 28 days of the initial prescription fill compared to patients who received an antibiotic to which the pathogen was susceptible. Approximately 1% of Enterobacterales isolates were resistant to all commonly available classes of oral antibiotics. A greater risk of treatment failure was seen in patients over 60 years of age, patients with diabetes mellitus, men, and those treated with an antibiotic when prior culture identified an organism resistant to that class. The increasing resistance among members of Enterobacterales responsible for outpatient UTIs is limiting the effectiveness of empirical treatment with existing antibiotics, and consequently, outpatients with UTI are more likely to require additional courses of therapy or be hospitalized. IMPORTANCE Resistance rates for bacteria that cause urinary tract infections (UTIs) have increased dramatically. Regional rates of resistance to commonly prescribed antibiotics now exceed 20%, which is the threshold at which the Infectious Diseases Society of America recommends therapy be guided by culture. Our goals were to describe outcomes for outpatients with UTIs caused by bacteria resistant to empirically chosen antibiotics and to create a simple stratification schema for clinicians to identify UTI patients at increased risk of treatment failure due to antibiotic mismatch. These data are relevant to clinicians, given how common uncomplicated UTIs are, and highlight the need for clinicians to understand local resistance rates and the importance of culture-guided treatment, especially in vulnerable patients. These findings also showed that 1% of bacteria were resistant to all major classes of oral antibiotics, underscoring the need for new antibiotics to treat patients with UTIs due to resistant bacteria.

Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.