Oral Fosfomycin Shows Promise as Effective Alternative to IV Antibiotics for Drug-Resistant UTIs]

Oral Fosfomycin Shows Promise as Effective Alternative to IV Antibiotics for Drug-Resistant UTIs]

Each year in the United States, hundreds of thousands of patients are hospitalized with complicated urinary tract infections caused by bacteria resistant to most oral antibiotics, specifically ESBL-producing Enterobacterales. Current treatment requires intravenous carbapenem antibiotics, typically administered in hospital or infusion centers, due to limited effective oral options.

A recent randomized clinical trial published in Clinical Infectious Diseases and reported by CIDRAP demonstrated that oral fosfomycin is noninferior to IV carbapenem antibiotics for step-down or transition therapy in these drug-resistant infections, potentially reducing hospital stays and healthcare costs for this common and increasingly problematic category of antibiotic-resistant infection.

Clinical Significance

Antimicrobial stewardship efforts have consistently prioritized reducing carbapenem use. These antibiotics are among the last-resort treatments for many resistant infections, and their overuse contributes to the development of carbapenem-resistant Enterobacterales (CRE), severely limiting treatment options for physicians.

From a patient perspective, IV antibiotic treatment necessitates hospitalization or infusion center visits, resulting in associated costs, inconvenience, infection risks from IV catheters, and lifestyle disruption. An effective oral alternative allows patients to complete treatment as outpatients.

Key Findings

ESBL-producing Enterobacterales are bacteria—primarily E. coli and Klebsiella pneumoniae—that produce enzymes (extended-spectrum beta-lactamases) that inactivate most penicillin and cephalosporin antibiotics, leaving few effective treatment options.

The trial was conducted at four tertiary hospitals in South Korea from November 2022 to June 2025, enrolling patients with complicated UTIs caused by ESBL-producing Enterobacterales who had already improved after three to seven days of IV carbapenem treatment—a “step-down” or transition therapy design. Among 299 patients enrolled, 152 received oral fosfomycin, and 147 continued IV carbapenem treatment.

Results showed: clinical cure rates were 92.8% in the oral fosfomycin group and 95.2% in the IV carbapenem group—a risk difference of −2.47 percentage points, well within the prespecified noninferiority margin of 15 percentage points. Microbiologic cure rates and 30-day outcomes were similarly comparable between groups.

Fosfomycin, an older antibiotic used for decades in Europe for UTIs, operates through a distinct mechanism from beta-lactam antibiotics and remains active against ESBL-producing bacteria. As the trial authors from Chosun University and the National Institute of Infectious Diseases noted: “Fosfomycin has favorable oral bioavailability and maintains activity against ESBL-producing Enterobacterales. Although approved only for acute uncomplicated cystitis, it is increasingly used off-label in clinical practice for complicated UTIs because of its preserved susceptibility profile.”

Potential Impact

If confirmed in broader populations and adopted into clinical practice, this finding could:

• Enable patients with ESBL UTI to complete antibiotic courses at home rather than in hospital or infusion centers
• Reduce hospital length of stay and associated risks of hospital-acquired infections and IV catheter complications
• Decrease carbapenem use, supporting stewardship efforts and reducing selection pressure toward carbapenem-resistant organisms
• Lower healthcare costs for a common and expensive hospitalization category

Study Considerations

Evidence Summary

• Study type: Randomized controlled noninferiority trial
• Drug tested: Oral fosfomycin versus IV carbapenem as step-down/transitional therapy
• Patient population: Adults with complicated UTIs caused by ESBL-producing Enterobacterales, conducted at four tertiary hospitals in South Korea, N=299
• Published in: Clinical Infectious Diseases
• Primary finding: Clinical cure 92.8% (fosfomycin) vs. 95.2% (IV carbapenem); noninferior within the 15% margin
• Limitations: Does not establish oral fosfomycin as initial treatment replacement; efficacy may vary across complicated UTI subtypes; performance in immunocompromised patients, those with sepsis, or bacteremia uncertain; geographic limitation to South Korea may affect generalizability; not yet incorporated into major infectious disease society guidelines

Expert Perspective

Infectious disease specialists and antimicrobial stewardship pharmacists have long sought oral options for ESBL UTIs to safely replace IV carbapenems for step-down therapy. CIDRAP notes that fosfomycin’s distinct mechanism of action, activity against ESBL-producing bacteria, and oral availability have made it an attractive candidate for European clinical practice, where it has broader use for complicated UTIs than in the United States. This trial provides the prospective randomized evidence U.S. infectious disease guidelines require before recommending treatment changes.

Clinical Takeaway

Patients diagnosed with ESBL UTI requiring IV antibiotic treatment should discuss oral step-down therapy options, including fosfomycin, with their infectious disease physician or hospitalist.

Patients should not self-medicate or request fosfomycin without proper evaluation—the appropriateness of oral step-down depends on infection specifics, bacterial susceptibility to fosfomycin, and patient clinical status.

For healthcare providers: consult institutional antimicrobial stewardship programs for guidance on incorporating this data into transition therapy decisions pending guideline updates.

Bottom Line

A randomized controlled trial found that oral fosfomycin is noninferior to IV carbapenem as transition therapy for complicated UTIs caused by drug-resistant ESBL-producing bacteria, with clinical cure rates of 92.8% versus 95.2%. If confirmed in broader populations and incorporated into clinical guidelines, this finding could shift a significant portion of inpatient IV treatment for a common, growing category of resistant infection to safer, more convenient outpatient oral therapy. Patients should discuss oral step-down options with their infectious disease physician at their next relevant appointment.

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