P-1170. Impact of Increased Severity of Illness on Outcomes in Complicated Urinary Tract Infections (cUTI) from ZEUS, a Randomized Controlled Trial (RCT) Evaluating IV Fosfomycin (IV-FOS)

TL;DR

A clinical trial compared IV fosfomycin to piperacillin-tazobactam in treating complicated urinary tract infections, finding similar outcomes in patients with severe illness or chronic conditions.

Contribution

The study provides evidence that IV fosfomycin performs comparably to piperacillin-tazobactam in high-risk cUTI subgroups.

Findings

IV fosfomycin showed noninferiority to piperacillin-tazobactam in overall favorable response rates.

Subgroup analyses found similar clinical response rates in patients with high chronic illness burden or severe acute disease.

Composite outcomes were comparable between IV fosfomycin and piperacillin-tazobactam in both subgroups.

Abstract

cUTIs remain a significant cause of hospital admissions and are an economic burden. IV-FOS is a first-in-class injectable epoxide antibiotic under development. A randomized trial (RCT) comparing IV-FOS to piperacillin-tazobactam (PIP-TAZ) in patients suffering from cUTIs demonstrated noninferiority with 64.7% of IV-FOS vs 54.5% of PIP-TAZ groups achieving a favorable response. We sought to compare outcomes within two subgroups: 1) patients with a high burden of chronic illness, and 2) patients with severe acute disease.Table 1.Clinical, Microbiological and Overall Response for Patients meeting SIRs Criteria or a CCI of ≥ 3 (m-MITT population)

Clinical, Microbiological and Overall Response for Patients meeting SIRs Criteria or a CCI of ≥ 3 (m-MITT population)

Two subgroup analyses of the phase 2/3 RCT of IV-FOS vs PIP-TAZ were conducted. A composite of clinical response, defined as both clinical success and microbiologic eradication, within the microbiologic-modified intention to treat (m-MITT) population, served as the primary endpoint. High chronic illness burden was defined as a Charlson co-morbidity index (CCI) > 3, while severe acute disease was based on meeting criteria for the systemic inflammatory response syndrome (SIRS).

Of 465 patients randomized, 362 (77.8%; 184 IV-FOS and 178 PIP-TAZ) constituted the m-MITT population. Within this group, 140 (38.7%; 37.5% IV-FOS vs 39.9% PIP-TAZ) had a CCI ≥ 3 and 114 (31.5%; 33.7% IV-FOS vs 29.2% PIP-TAZ) met the SIRS criteria. In unadjusted analyses, clinical response rates were similar between IV-FOS and PIP-TAZ in the two treatment groups among both patients with CCI ≥ 3 (49.3% IV-FOS vs 40.8% PIP-TAZ, p=NS) and those with SIRS (66.1% IV-FOS vs 75% PIP-TAZ, p=NS). For both subgroups, the individual components of the composites of clinical response as a function of study drug behaved similarly (Table 1).

In this Phase 2/3 RCT in cUTI, subgroup analyses in patients with SIRS and those with high burdens of chronic illness demonstrated comparable composite outcomes between IV-FOS and PIP-TAZ treatments.

Andrew Shorr, MD, MPH, MBA, Bioversys: Advisor/Consultant Keith S. Kaye, MD, MPH, AbbVie: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant Marya D. Zilberberg, MD, MPH, Basilea Pharmaceutica: Grant/Research Support|Eagle Pharmaceuticals: Advisor/Consultant|Eagle Pharmaceuticals: Grant/Research Support|Shionogi: Advisor/Consultant Judith N. Steenbergen, PhD, AcurX: Advisor/Consultant|Basilea: Advisor/Consultant|Bioversys: Advisor/Consultant|Clarametyx: Advisor/Consultant|Eagle Pharmaceuticals: Advisor/Consultant|F2G: Advisor/Consultant|Genentech: Advisor/Consultant|Innoviva: Advisor/Consultant|Meitheal: Advisor/Consultant|Melinta: Advisor/Consultant|Neuraptive: Advisor/Consultant|Neuraptive: Advisor/Consultant|Roche: Advisor/Consultant|Wockhardt: Advisor/Consultant Lauren Bjork, PharmD, Meitheal: employee Mauricio Rodriguez, PharmD, MS-HEOR, BCCCP, BCIDP, Meitheal Pharmaceuticals: employee

Figures