Although intravenous fosfomycin has not yet proven to be noninferior to ceftriaxone or meropenem for drug-resistant urinary tract infections (UTIs) due to Escherichia coli, it may be an option, according to investigators.

In the FOREST (Fosfomycin vs Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E. Coli) trial, researchers randomly assigned 141 Spanish patients to receive fosfomycin disodium (4 g every 6 hours intravenously, in 60 minutes) or ceftriaxone (1 g every 24 hours intravenously in 2-4 minutes). In the case of ceftriaxone resistance, patients received meropenem (1 g every 8 hours intravenously in 15-30 minutes). After 4 days of intravenous treatment, switching to an active oral drug was allowed. Dose adjustments were specified for patients with kidney dysfunction.

In modified intent-to-treat analyses, the primary end point of clinical and microbiological cure at 5 to 7 days after treatment occurred in 68.6% of the fosfomycin group and 78.1% of the ceftriaxone or meropenem group, which did not meet the noninferiority criterion, Jesús Rodríguez-Baño, MD, PhD, of the Hospital Universitario Virgen Macarena, in Sevilla, Spain, and colleagues reported in JAMA Network Open. When analyses were limited to treated patients, however, the noninferiority margin of less than 7% was met (14.3% vs 19.7%), the investigators pointed out.

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The primary finding was influenced by the higher rate of discontinuations in the fosfomycin than ceftriaxone or meropenem group (8.5% vs 0%), according to the team. In the fosfomycin group, 6 patients older than 80 years with heart failure or kidney insufficiency discontinued the antibiotic due to adverse events. Heart insufficiency may be caused by the sodium content (14.4 mEq/g) of the intravenous formulation. Hypokalemia is also a known adverse event associated with fosfomycin.

The investigators performed a rectal colonization study in a subset of 38 patients. Significantly fewer patients treated with fosfomycin acquired a new gram-negative bacteria resistant to ceftriaxone or meropenem: 0 of 21 patients taking fosfomycin vs 4 of 17 patients taking the comparator drugs.

“Fosfomycin did not demonstrate noninferiority in the treatment of [bacteremic] UTI caused by [multi-drug resistant] E coli,” Dr Rodríguez-Baño’s team concluded. “However, the data suggest that the drug is effective and may be considered among selected patients, particularly those without previous heart disease and with low risk of sodium overload-related problems.”

In an accompanying editorial, Robert A. Bonomo, MD, of the Center for Antimicrobial Resistance and Epidemiology at Case Western Reserve University-Cleveland VA Medical Center in Ohio, and colleagues commented that “teasing apart the clinical outcomes data from the safety data, this study indicates that IV fosfomycin may be a reasonable treatment option for patients with E coli bacteremia from a urinary source.”

They cautioned that although this study provides important insights into the potential roles for intravenous fosfomycin, it does not provide sufficient support for the use of oral fosfomycin to treat invasive infections.


Sojo-Dorado J, López-Hernández I, Rosso-Fernandez C, et al. Effectiveness of fosfomycin for the treatment of multidrug-resistant Escherichia coli bacteremic urinary tract infections. JAMA Netw Open. Published online January 13, 2022. doi:10.1001/jamanetworkopen.2021.37277

Tamma PD, Bonomo RA, Stiefel U, et al. The role of intravenous fosfomycin: finding our way out of Dante’s forest dark. JAMA Netw Open. Published online January 13, 2022. doi:10.1001/jamanetworkopen.2021.38691