Why Nitrofurantoin and Fosfomycin Maintain Low Resistance Rates in UPEC
Nitrofurantoin and fosfomycin maintain remarkably low resistance rates in uropathogenic E. coli primarily because they have been used selectively for uncomplicated UTIs rather than broadly across all infections, and their unique mechanisms of resistance require specific genetic mutations that carry fitness costs or are suppressed by the high urinary concentrations these drugs achieve.
Mechanisms Preserving Low Resistance Rates
Limited and Selective Use Pattern
Nitrofurantoin and fosfomycin remain highly effective with resistance rates below 10% for nitrofurantoin and approximately 3.6% for fosfomycin in UPEC, contrasting sharply with fluoroquinolones (5.1-85.5% resistance) and trimethoprim-sulfamethoxazole (14.6-60% resistance) 1.
These agents have been reserved predominantly for uncomplicated lower UTIs rather than being used broadly for systemic infections, limiting selection pressure 1, 2.
In a large European surveillance study, nitrofurantoin retained 98.5% susceptibility and fosfomycin 96.4% susceptibility against E. coli, even after more than 30 years of clinical use 2.
Unique Resistance Mechanisms with Fitness Costs
Nitrofurantoin Resistance
Nitrofurantoin resistance requires loss-of-function mutations in nitroreductase genes (nfsA and nfsB) and riboflavin synthesis genes (ribE), which are step-wise mutations that accumulate over time 3, 4.
These mutations include specific amino acid changes (His11Tyr, Ser33Arg, Gln67Leu in NfsA; Gln44His, Phe84Ser in NfsB) or production of truncated proteins 3.
Resistant strains demonstrate a 2-10% slower growth rate (doubling time of 23 ± 0.8 min vs 20.8 ± 0.7 min for susceptible strains), indicating a fitness disadvantage that limits their spread 4.
The high urinary concentrations achieved by nitrofurantoin selectively inhibit first-step mutants at sub-MIC levels (4-8 mg/L), preventing the evolution toward full resistance 4.
Fosfomycin Resistance
Fosfomycin resistance primarily occurs through deletion of transporter genes (uhpT and/or uhpA) that are required for drug uptake, rather than through easily transferable plasmid mechanisms 3.
Among 29 resistant isolates studied, 22 had deletions in uhpT/uhpA genes, and only 2 possessed the plasmid-borne fosA3 gene 3.
Chromosomal mutations affecting transport systems are less readily transmitted between bacteria compared to plasmid-mediated resistance 3.
Maintained Activity Against Multidrug-Resistant Strains
Both fosfomycin and nitrofurantoin retain >90% activity against cephalosporin-resistant E. coli, demonstrating lack of cross-resistance with other antibiotic classes 2.
Against ESBL-producing E. coli, fosfomycin maintains 95.5% susceptibility (including hospital-acquired isolates) and nitrofurantoin remains highly active 5.
Ciprofloxacin resistance in ESBL-producing strains does not correlate with decreased fosfomycin susceptibility, indicating independent resistance pathways 5.
Clinical Implications
Common Pitfall to Avoid
- Do not assume fosfomycin has equivalent activity against all uropathogens: while maintaining 95.5% susceptibility against ESBL-producing E. coli, fosfomycin shows only 57.6% susceptibility against ESBL-producing Klebsiella pneumoniae 5.
Preservation Strategy
The continued effectiveness of these agents depends on maintaining their selective use for uncomplicated lower UTIs rather than expanding indications to complicated infections or systemic use 1, 2.
Surveillance data confirms that guidelines advocating fosfomycin for uncomplicated UTIs in women remain microbiologically valid based on current susceptibility patterns 2.