A Combination Therapy With Ceftazidime and Fosfomycin Will be Compared to Ceftazidime Alone in Hospitalized Adult Patients With Suspected Severe Gram-negative Bacterial Infections

Summary

The goal of this clinical trial is to :

1. Test whether the combination of CAZ±AVI and FOS leads to superior clinical outcomes in patients with severe suspected Gram-negative bacterial infection, as demonstrated by a shorter time to normalization of quick Sequential Organ Failure Assessment (qSOFA) parameters and reduction in C-reactive protein (CRP) compared to standard of care (CAZ±AVI alone)
2. to further characterize the safety profile of this combination therapy

In the presence of such an infection, standard treatment is to start intravenous antibiotic therapy. Ceftazidime (Fortam®), or ceftazidime-avibactam (Zavicefta®), is a standard antibiotic commonly used for this purpose (for very resistant bacteria, the compound avibactam is included to protect ceftazidime from being broken down by bacteria).

Researchers will compare ceftazidime (or ceftazdime-avibactam) plus fosfomycin versus ceftazidime alone with placebo (i.e. a look-alike substance given with no drug) to examine whether the addition of another intravenous antibiotic, fosfomycin, would lead to faster recovery from severe infection and evaluate the tolerability of this combination.

Participants will:

* Be randomly assigned to either the intervention group or the control group.
* The intervention group will receive ceftazidime (with avibactam if multidrug resistant bacteria are suspected, per routine practice) and intravenous fosfomycin, and the control group will receive ceftazidime (with avibactam if multidrug resistant bacteria are suspected) and placebo.
* Either treatment will be given for 3 days, three times daily (or less frequently, depending on renal function).
* Provide a few extra blood samples (for CRP measurement, a protein marker of inflammation) during the first few days of the study.
* Be contacted in the hospital or by phone if discharged on day 28 to be asked a few questions.

Conditions

• Gram Negative Infections
• Sepsis and Septic Shock

Interventions

DRUG

Ceftazidime± avibactam with fosfomycin

The intervention will last 72h (±6h). Ceftazidime will be administered intravenously in 5% glucose serum (per hospital standard), either intermittently (divided into three doses daily) or as continuous infusion; doses will be adapted to renal function. The decision to administer CAZ by continuous infusion and to add AVI will be left to the attending physician. CAZ±AVI will be adjusted for renal insufficiency per internal guidelines of dosing and international recommendations. The use of CAZ with its paired beta-lactamase inhibitor avibactam, i.e., the use of ceftazidime-avibactam (Zavicefta®) instead of CAZ will occur in case of suspicion of infection by either extended-spectrum-beta-lactamase-producing Enterobacterales (ESBL-E), cephalosporinase-carrying Enterobacterales (ampC-E) or carbapenem-resistant Enterobacterales (CRE), as determined by treating physician and/or the infectious diseases consultant.

DRUG

Ceftazidime± avibactam with placebo

Participants randomized to the control arm will receive placebo infusion. Placebo will be 5% glucose serum and will be administered IV with the same frequency as FOS would be for the participant's renal function.

Sponsors & Collaborators

• Joint Programming Initiative on Antimicrobial Resistance (JPIAMR)

  collaborator UNKNOWN

• Swiss National Science Foundation

  collaborator OTHER

• Angela HUTTNER

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-08-25

Primary Completion

2026-12-31

Completion

2026-12-31

Countries

• Switzerland

Study Locations