Intravenous Fosfomycin as Adjunctive Therapy for Gram-Negative Bacteria Bloodstream Infections: A Propensity Score Adjusted Retrospective Cohort Study

Int J Antimicrob Agents. 2024 Aug;64(2):107247. doi: 10.1016/j.ijantimicag.2024.107247. Epub 2024 Jun 19.

Abstract

Background: The role of intravenous fosfomycin (iv-FOS) as a part of combination therapy for Gram-negative bacteria bloodstream infections (GNB-BSI) needs to be evaluated in clinical practice, as in vitro data show potential efficacy.

Methods: All consecutive patients with a GNB-BSI from 01 January 2021 to 01 April 2023 were included. Primary outcome was 30-day mortality. A Cox regression analysis was used to identify predictors of mortality; an inverse-probability of treatment-weighting (IPTW) analysis was also performed.

Results: Overall, 363 patients were enrolled: 211 (58%) males, with a median (q1-q3) age of 68 (57-78) years, and a median Charlson comorbidity index of 5 (3-7). At GNB-BSI onset, the median SOFA score was 5 (2-7) and 122 patients (34%) presented with septic shock. Pathogens were principally Klebsiella pneumoniae (42%), Escherichia coli (28%) and Pseudomonas aeruginosa (17%); of them, 36% were carbapenem-resistant. The therapy included carbapenems (40%), cephalosporins (37%) and beta-lactams/beta-lactamases-inhibitors (19%); a combination with iv-FOS was used in 98 (27%) cases at a median dosage of 16 (16-18) g/daily. The use of iv-FOS was not associated with reduced crude mortality (21% vs 29%, P = 0.147). However, on multivariable Cox-regression, combination therapy with iv-FOS resulted in protection for mortality (aHR 0.51, 95% CI 0.28-0.92), but not other combo-therapies (HR 0.69, 95% CI 0.44-1.16). This result was also confirmed with the IPTW-adjusted Cox model (aHR 0.52, 95% CI 0.31-0.91). Subgroup analysis suggested a benefit in severe infections (SOFA > 6, PITT ≥ 4) and when iv-FOS was initiated within 24 hours of GNB-BSI onset.

Conclusions: Fosfomycin in combination therapy for GNB-BSI may have a role in improving survival. These results justify the development of further clinical trials.

Keywords: Antimicrobial resistance; Bloodstream infections; Carbapenem resistance; Fosfomycin; Gram-negative bacteria.

MeSH terms

  • Administration, Intravenous*
  • Aged
  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / therapeutic use
  • Bacteremia* / drug therapy
  • Bacteremia* / microbiology
  • Bacteremia* / mortality
  • Drug Therapy, Combination
  • Female
  • Fosfomycin* / administration & dosage
  • Fosfomycin* / therapeutic use
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacterial Infections* / drug therapy
  • Gram-Negative Bacterial Infections* / microbiology
  • Gram-Negative Bacterial Infections* / mortality
  • Humans
  • Male
  • Middle Aged
  • Propensity Score*
  • Retrospective Studies

Substances

  • Fosfomycin
  • Anti-Bacterial Agents