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Background Diabetes mellitus and hyperglycemia are associated with increased susceptibility to bacterial infections and poor treatment outcomes. This post hoc evaluation of the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) aimed to evaluate baseline characteristics, efficacy, and safety in patients with and without diabetes treated with ceftolozane/tazobactam and comparators. Ceftolozane/tazobactam is an antibacterial with potent activity against Gram-negative pathogens and is approved for the treatment of cIAI (with metronidazole) and cUTI (including pyelonephritis). Methods Patients from the phase 3 ASPECT studies with ( n  = 245) and without ( n  = 1802) diabetes were compared to evaluate the baseline characteristics, efficacy, and safety of ceftolozane/tazobactam and active comparators. Results Significantly more patients with than without diabetes were 65 years of age or older; patients with diabetes were also more likely to weigh ≥75 kg at baseline (57.1% vs 44.5%), to have renal impairment (48.5% vs 30.2%), or to have APACHE II scores ≥10 (33.8% vs 17.0%). More patients with diabetes had comorbidities and an increased incidence of complicating factors in both cIAI and cUTI. Clinical cIAI and composite cure cUTI rates across study treatments were lower in patients with than without diabetes (cIAI, 75.4% vs 86.1%, P  = 0.0196; cUTI, 62.4% vs 74.7%, P  = 0.1299) but were generally similar between the ceftolozane/tazobactam and active comparator treatment groups. However, significantly higher composite cure rates were reported with ceftolozane/tazobactam than with levofloxacin in patients without diabetes with cUTI (79.5% vs 69.9%; P  = 0.0048). Significantly higher rates of adverse events observed in patients with diabetes were likely due to comorbidities because treatment-related adverse events were similar between groups. Conclusions In this post hoc analysis, patients with diabetes in general were older, heavier, and had a greater number of complicating comorbidities. Patients with diabetes had lower cure rates and a significantly higher frequency of adverse events than patients without diabetes, likely because of the higher rates of medical complications in this subgroup. Ceftolozane/tazobactam was shown to be at least as effective as comparators in treating cUTI and cIAI in this population. Trial registration cIAI, NCT01445665 and NCT01445678 (both trials registered prospectively on September 26, 2011); cUTI, NCT01345929 and NCT01345955 (both trials registered prospectively on April 28, 2011).

Background. Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae. Methods. ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4–14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24–32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated. Results. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, −4.2%; 95% confidence interval [CI], −8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, −1.0%; 95% CI, −4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea. Conclusions. Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens.

Introduction Ceftolozane/tazobactam is an antibacterial agent with potent in vitro activity against Gram-negative pathogens, including many extended-spectrum β-lactamase-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa . Because ceftolozane/tazobactam is primarily excreted renally, appropriate dose adjustments are needed for patients with renal impairment. Monte Carlo simulations were used to determine the probability of pharmacokinetic/pharmacodynamic target attainment for patients with varying degrees of renal function, including augmented renal clearance (ARC) and end-stage renal disease (ESRD) with hemodialysis. Methods Monte Carlo simulations were conducted for 1000 patients with ARC and normal renal function, mild renal impairment, moderate renal impairment, or severe renal impairment, and for 5000 patients with ESRD. Simulated dosing regimens were based on approved doses for each renal function category. Attainment targets for ceftolozane were 24.8% (bacteriostasis), 32.2% (1-log kill; bactericidal), and 40% (2-log kill) f T > minimum inhibitory concentration (MIC). The target for tazobactam was to achieve a 20% f T > minimum effective concentration (MEC) at an MEC of 1 mg/L, which was derived from a neutropenic mouse thigh infection model and was confirmed by efficacy data from clinical studies for complicated intraabdominal infections and complicated urinary tract infections. Results In patients with ARC or normal renal function, ≥91% achieved bactericidal activity (32.2% f T > MIC) up to an MIC of 4 mg/L with a 1000-mg ceftolozane dose. In patients with renal impairment (mild, moderate, severe, ESRD), ≥93% achieved bactericidal activity up to an MIC of 8 mg/L. In patients of all renal function categories, the approved dosing regimens of tazobactam achieved ≥91% target attainment against a target of 20% f T > MEC. Conclusions At the approved dosing regimens for ceftolozane/tazobactam, ≥91% of patients in all renal function categories, including ARC (up to 200 mL/min) and ESRD, reached target attainment for bactericidal activity at MICs that correspond to susceptibility breakpoints for Enterobacteriaceae and P. aeruginosa .

Pemivibart for Prevention of Covid-19Pemivibart, a monoclonal antibody for preexposure prophylaxis for SARS-CoV-2, was recently authorized for emergency use by the FDA. The immunobridging data on which this EUA is based are presented.

Background Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are frequently caused by G+ cocci; TZD has potent in vitro activity against these pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The VITAL study compared the efficacy and safety of TZD vs. LZD for the treatment of ventilated patients with G+ HAP/VAP. Methods Randomized, double-blind, double-dummy, global, phase 3 study in mechanically ventilated adult patients with presumed G+ HAP/VAP (clinicaltrials.gov NCT02019420). Patients were stratified by region, age, and trauma/nontrauma, then randomized 1:1 to intravenous (IV) TZD 200 mg once daily for 7 days or IV LZD 600 mg every 12 h for 10 d (patients with concurrent G+ bacteremia received 14 d of treatment). The primary efficacy endpoint was day 28 all-cause mortality (ACM) in the intent to treat (ITT) population (all randomized patients; noninferiority [NI] margin, 10%). Secondary endpoints included investigator-assessed clinical response at test of cure (TOC; NI margin, 12.5%). Results In total, 726 patients were randomized (TZD n = 366; LZD n = 360). Baseline characteristics were well balanced between arms. TZD was noninferior to LZD for day 28 ACM in the ITT (table). Noninferiority was not demonstrated for TZD vs. LZD for investigator-assessed clinical success at TOC in the ITT. Stratification factors, analysis population, baseline clinical/laboratory signs of HAP/VAP, G+ only vs. mixed G+/gram-negative (G–) HAP/VAP, adjunctive G– therapy, MRSA vs. methicillin-susceptible S. aureus, and HAP vs. VAP were evaluated, and no single factor accounted for the observed imbalance in clinical response between treatment arms. Greater than 90% of patients experienced treatment-emergent adverse events (TEAEs). Anemia, hypokalemia, and diarrhea were the most frequently reported (TEAEs) in both arms. Types and incidence rates of TEAEs overall, and of drug-related TEAEs specifically, were comparable between TZD and LZD. Conclusion TZD was noninferior to LZD for day 28 ACM in the treatment of ventilated G+ HAP/VAP. However, TZD was not noninferior to LZD based on the investigator-assessed clinical response at TOC. Both drugs were similarly well tolerated and TEAEs were well balanced between groups, with no new safety signals identified. Disclosures All Authors: No reported Disclosures.

BackgroundVilastobart is a tumor-activated, Fc-enhanced high-affinity anti-CTLA-4 designed to focus activity toward tumors while minimizing systemic exposure. We previously reported vilastobart combined with atezolizumab (Tecentriq®) had a 26% overall response rate (ORR) in heavily pretreated patients with MSS mCRC without liver metastases (NLM), and a favorable safety profile consistent with tumor-activated design.1 High tumor mutational burden (TMB) is a biomarker predictive of response to immune checkpoint inhibitors (ICI) and is an approved tissue-based companion diagnostic for pembrolizumab in advanced solid tumors. In MSS mCRC, TMB from tumor tissue (tTMB) provided no predictive utility to ICI; however, a plasma-based assay showed high TMB improved survival with ICI (N=163), and pTMB was significantly higher than tTMB with a majority of patients with pTMB ≥10mut/Mb.2 We explored whether plasma TMB (pTMB) could serve as a predictive biomarker in NLM patients with MSS mCRC and enrich for response to treatment with vilastobart in combination with atezolizumab.MethodsThis Phase 2 study (NCT04896697) evaluated vilastobart (100mg IV-Q6W) in combination with atezolizumab (1200mg IV-Q3W) in patients with MSS mCRC who had ≥1 prior chemotherapy regimen in the metastatic setting. Baseline pTMB was assessed retrospectively using the Guardant-Infinity Liquid Assay. We evaluated the relationship between pTMB status (pTMB-High[H]≥10mut/Mb; pTMB-Low[L]<10mut/Mb) and best overall response using 2-sided Fisher’s Exact Test.ResultsAs of 12 May 2025, 44 heavily pretreated patients with MSS mCRC were treated with vilastobart in combination with atezolizumab, including 27 NLM. Twenty-four NLM patients had sufficient ctDNA to determine pTMB status. A TMB threshold of ≥10mut/Mb was selected as this captured all responders with known pTMB status. Overall, 63% (n=15) of TMB-evaluable patients were pTMB-H. In this pTMB-H population, the ORR was 40% (95% CI:16%, 68%), with 5 of 6 responses confirmed, while the ORR in TMB-L patients (n=9) was 0% (figure 1, p=0.05). One additional confirmed responder was non-evaluable for pTMB status. Responses were deep and durable (figure 2). Consistent with the tumor-activated design of vilastobart, treatment was generally well-tolerated: overall (n=44), 11 patients (25%) required immunosuppression for immune-related adverse events; 3 (7%) experienced colitis; 2 (5%) discontinued treatment due to a related event.ConclusionsUsing pTMB status as a predictive biomarker, heavily pretreated patients with MSS mCRC who were pTMB-H had a 40% ORR following treatment with vilastobart in combination with atezolizumab. These encouraging data suggest pTMB is a promising biomarker approach that may enrich for response in a disease setting with a significant unmet need.Trial RegistrationNCT04896697ReferencesDavar D, Fakih M, Bekaii-Saab TS, DeVito NC, Knecht JG, Vandross AL, Perez CA, Bessudo A, Gupta A, Patel E, Fantini D, Paramasivan S, Crowe D, Duncan M, McConnell S, Luptakova K, Parikh AR. Phase 1/2 study of XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with advanced solid tumors and in MSS CRC. Journal of Clinical Oncology 2025;43(4_suppl):206–206. https://ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.206Loree JM, et al. Plasma versus tissue tumor mutational burden as biomarkers of durvalumab plus tremelimumab response in patients with metastatic colorectal cancer in the CO.26 trial. Clin Cancer Res. 2024;30(15):3189–3199. https://pubmed.ncbi.nlm.nih.gov/38727700/Ethics ApprovalThis study was approved by Advarra Institutional Review Board, approval number Pro00054400. All study participants gave informed consent before taking part in the study.Abstract 1315 Figure 1pTMB correlated with response following treatment with vilastobart in combination with atezolizumab: All NLM patients. (A) Waterfall plot showing pTMB status for all NLM patients who had target lesion measurements available (24/27). Note: Of 2 patients with 0% best change, one patient was TMB-Low, and the other was non-evaluable for TMB status. (B) Boxplot showing pTMB scores at baseline with respect to best overall response. TMB status was available for 24/27 NLM patients; 3 were non-evaluable for TMB status. pTMB=plasma tumor mutational burden; NLM=non liver metastases; PR=partial response.[Image Omitted. See PDF.]Abstract 1315 Figure 2Deep tumor reductions and durable responses observed in pTMB-H patients treated with vilastobart in combination with atezolizumab. Figures showing all pTMB-high (≥10 mut/Mb) NLM patients who had target lesion measurements available (12/15). pTMB=Plasma Tumor Mutation Burden; NLM=non liver metastases; PR=partial response[Image Omitted. See PDF.]