A new multicenter randomized clinical trial published in the journal Trials on October 4, 2023 aims to evaluate the efficacy and safety of fosfomycin compared to ciprofloxacin for preventing febrile neutropenia in high-risk hematology patients. The FOVOCIP study is a phase III non-inferiority trial taking place across 11 hospitals in Spain.
The study is funded by a national health research grant and is being conducted by investigators from multiple Spanish institutions. Its purpose is to determine if fosfomycin could serve as an alternative to fluoroquinolones like ciprofloxacin for infection prophylaxis in patients with acute leukemia receiving intensive chemotherapy or hematopoietic stem cell transplant recipients.
The researchers plan to enroll 156 adult patients over a 2-year period. Key inclusion criteria are a diagnosis of acute leukemia about to receive first-line intensive chemotherapy, or being a candidate for first allogeneic or autologous stem cell transplant. Patients must have adequate organ function and a life expectancy of at least 3 months. Those with recent antibiotic use, documented infections, or prior intensive chemotherapy/transplant are excluded.
Participants are randomized 1:1 to receive either oral fosfomycin 500 mg every 8 hours or oral ciprofloxacin 500 mg every 12 hours as prophylaxis during their neutropenic period. The primary endpoint is the occurrence of febrile neutropenia requiring antibacterial treatment. Secondary endpoints include documented infections, antibiotic utilization, overall survival, and safety.
A key aspect of the trial is the extensive microbiological monitoring planned. Weekly surveillance cultures will be performed to detect gut colonization with multidrug-resistant gram-negative bacteria. Changes in the fecal microbiome will also be analyzed at the start and end of prophylaxis using metagenomic sequencing techniques.
The non-inferiority margin is set at 5%. The researchers hypothesize that fosfomycin will be non-inferior to ciprofloxacin for preventing febrile neutropenia, while potentially offering a better safety profile and lower risk of selecting for resistant bacteria. An interim analysis is planned after 50 patients have been enrolled.
As of the publication date, 106 patients had already been recruited. The study is expected to complete enrollment by March 2024. Demographic data is not yet available as the trial is ongoing.
The authors note some limitations of the study design. As an open-label trial, there is potential for bias in early discontinuation of prophylaxis, particularly in the fosfomycin arm. However, they have specified strict definitions for febrile neutropenia to mitigate this. Additionally, as a non-inferiority trial rather than a superiority design, it will not be able to demonstrate if fosfomycin is more effective than ciprofloxacin.
In their discussion, the investigators highlight the ongoing debate around fluoroquinolone prophylaxis in the era of increasing antimicrobial resistance. While effective at preventing infections, fluoroquinolones have been associated with selection of multidrug-resistant organisms. There are also concerns about adverse effects like musculoskeletal toxicity.
The researchers argue there is an urgent need to evaluate alternative prophylactic strategies. Fosfomycin was selected due to its broad-spectrum activity, including against many resistant gram-negative bacteria, and its potentially favorable impact on the gut microbiome compared to fluoroquinolones.
If fosfomycin proves non-inferior to ciprofloxacin with an improved safety profile, it could provide clinicians with an important alternative option for infection prophylaxis in high-risk hematology patients. The extensive microbiological monitoring planned will also generate valuable data on how these prophylactic strategies impact the gut microbiome and selection of resistant organisms over time.
The potential clinical impact of this study is significant. Febrile neutropenia remains a major cause of morbidity and mortality in patients undergoing intensive chemotherapy or stem cell transplantation. An effective prophylactic strategy that minimizes collateral damage to the microbiome and reduces selection of resistant pathogens would be an important advance in supportive care for these vulnerable patients.
Additionally, the prospective evaluation of changes in gut colonization and the microbiome may provide insights to guide future infection prevention approaches. Understanding how different antibiotics affect the complex microbial ecosystems in neutropenic patients could inform more targeted, individualized prophylaxis strategies.
In conclusion, the FOVOCIP trial addresses an important clinical question with potential to impact infection prevention practices in high-risk hematology patients. By rigorously comparing fosfomycin to the current standard of ciprofloxacin, while also deeply characterizing microbiological effects, this study may help optimize antimicrobial prophylaxis approaches in the era of increasing resistance. The results will be eagerly anticipated by hematologists, infectious disease specialists, and microbiologists alike.
References
Moreno AF, Lavín-Alconero L, de Ugarriza PL, et al. FOVOCIP study: a multicenter randomized trial of fosfomycin versus ciprofloxacin for febrile neutropenia in hematologic patients-efficacy and microbiologic safety. Trials. 2023;24(1):694. Published 2023 Oct 27. doi:10.1186/s13063-023-07702-5
