Is fosfomycin effective against gram-negative rod-lactose fermenters, such as E. coli (Escherichia coli), in urinary tract infections?

Fosfomycin Coverage of Gram-Negative Lactose-Fermenting Rods

Yes, fosfomycin provides excellent coverage against the most common gram-negative lactose-fermenting rod, Escherichia coli, and is FDA-approved for treating uncomplicated UTIs caused by this organism, but its activity against Klebsiella species (another lactose fermenter) is significantly inferior and unreliable. 1

FDA-Approved Indications and Spectrum

• Fosfomycin is FDA-approved specifically for uncomplicated urinary tract infections (acute cystitis) in women caused by susceptible strains of Escherichia coli and Enterococcus faecalis 1
• The drug demonstrates broad in vitro activity against gram-positive and gram-negative aerobic microorganisms associated with uncomplicated UTIs 1
• Fosfomycin is NOT indicated for pyelonephritis or perinephric abscess 1

E. coli (Primary Lactose Fermenter)

• Fosfomycin shows excellent activity against E. coli with MIC90 ≤ 16 μg/ml 2
• Clinical studies demonstrate 94.4% susceptibility among E. coli isolates, including both ESBL-producing and non-ESBL-producing strains 3
• A single 3-gram oral dose achieves therapeutic urinary concentrations of 706 mcg/mL within 2-4 hours, maintained above 100 mcg/mL for 26 hours 1
• The cumulative fraction of response (CFR) against E. coli is 99% when urine pH is acidic (6.0) 2

ESBL-Producing E. coli

• Fosfomycin maintains good activity against ESBL-producing E. coli strains 3, 4
• Clinical and microbiological success rates of 94.3% and 78.5%, respectively, have been demonstrated in ESBL-producing E. coli lower UTIs 4
• However, fosfomycin resistance is increasing among ESBL-producers (14.3% in 2013 to 20% in 2021) and is significantly associated with CTX-M-type ESBLs 5

Klebsiella Species (Secondary Lactose Fermenter)

• Fosfomycin has poor activity against Klebsiella pneumoniae with MIC90 > 512 μg/ml 2
• The CFR against Klebsiella spp. is only 55%, even under optimal acidic urine conditions 2
• For uncomplicated lower UTIs caused by ESBL-producing Klebsiella, fosfomycin can be considered when other oral agents are unavailable, but clinical data are limited 6
• Fosfomycin monotherapy is insufficient for complicated UTIs or pyelonephritis caused by Klebsiella 7, 6

Other Lactose-Fermenting Organisms

The FDA label indicates in vitro activity (MIC ≤ 64 mcg/mL) against additional lactose fermenters, though clinical efficacy is not established in adequate trials 1:

• Citrobacter species (C. diversus, C. freundii)
• Enterobacter aerogenes
• Klebsiella oxytoca
• Serratia marcescens

Critical Clinical Considerations

• Urine acidification significantly improves fosfomycin activity: decreasing pH from 7.0 to 6.0 increases susceptibility in 71% of isolates 2
• Fosfomycin can be taken without regard to food, though high-fat meals delay peak urinary concentrations from 2-4 hours to 6-8 hours 1
• Metoclopramide should be avoided as it lowers serum concentrations and urinary excretion of fosfomycin 1
• Susceptibility testing for fosfomycin is not routinely performed in many laboratories, which may limit appropriate use 6
• If bacteriuria persists or reappears after treatment, alternative agents should be selected 1

Practical Algorithm

For uncomplicated cystitis in women:

• E. coli suspected or confirmed: Fosfomycin 3g single dose is appropriate first-line therapy 8, 1
• Klebsiella suspected: Consider alternative agents (nitrofurantoin, trimethoprim-sulfamethoxazole, or fluoroquinolones based on local susceptibility) 7
• ESBL-producing E. coli: Fosfomycin remains a reasonable option, though resistance is increasing 6, 5

For complicated UTIs or pyelonephritis:

• Do not use fosfomycin monotherapy regardless of the lactose-fermenting organism 7, 6, 1
• Consider carbapenems or aminoglycosides based on susceptibility testing 6