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A Spanish study published in The Lancet found that a 5-day course of nitrofurantoin was more effective than fosfomycin trometamol or pivmecillinam in treating uncomplicated urinary tract infections (UTIs) in women.

This randomized. open-label study included 768 women and was led by Carl Llor, MD, PhD, of the Institute for Primary Health Care Research Jordi Gol i Gurina in Barcelona, Spain. Researchers found that short-course nitrofurantoin therapy produced significantly better outcomes than a single fosfomycin dose. Nitrofurantoin also performed better than the two fosfomycin doses and a 3-day course of pivmecillinam, although the differences were smaller.

Speaking with Medscape's German edition, Giuseppe Magistro , MD, chief physician in the Department of Urology at Asklepios Westklinikum in Hamburg, Germany, and chair of Working Group on Infectiology and Hygiene of the German Society of Urology in Berlin, said "Despite some shortcomings, such as the lack of blinding and the somewhat small sample size, I consider this study — which examined the efficacy and safety of antibiotic therapy for uncomplicated cystitis — to be very important."

The substances studied — fosfomycin, nitrofurantoin, and pivmecillinam — are also recommended in German and European guidelines. He also considered it sensible that the expanded use of two doses of fosfomycin administered 24 hours apart was examined: "In clinical practice, it is often observed that a single dose leads to treatment failure," he said.

UTIs are among the most common bacterial infections in women. Approximately half of women experience at least one infection during their lifetime, and recurrent infections are common. Nearly 10% of all girls and women ages 12 and older in Germany experience such a bacterial infection every year, often caused by the intestinal bacterium Escherichia coli. 

In outpatient care, UTIs are the second most common reason for antibiotic prescription after respiratory tract infections.

Current guidelines recommend symptomatic treatment alone or short antibiotic courses lasting 1-3 days for uncomplicated infections in women. First-line therapies include fosfomycin, nitrofurantoin, pivmecillinam, and, less commonly, nitroxoline, which was not included in the study.

The authors noted that high use of antibiotics in this field contributes to the growing challenge of antibiotic resistance and highlights the urgency of evidence-based prescribing practices that balance effectiveness with responsible use, highlighting the need for evidence-based prescribing strategies that balance treatment effectiveness with responsible antibiotic use.

In particular, a single 3 g dose of fosfomycin has remained a popular treatment option among both patients and physicians. Earlier studies have suggested that the treatment is easy to administer, safe, and effective. In addition, resistance to fosfomycin among the UTI pathogens was relatively low.

However, a 2018 study published in JAMA had already shown that a 5-day course of nitrofurantoin produced significantly better results than a single fosfomycin dose, findings consistent with Magistro's clinical experience. However, until now, no direct comparison among the three antibiotics has been conducted.

Study Details

Llor and colleagues addressed that gap in a multicenter study involving 768 women aged 34-63 years recruited from 34 Spanish primary care practices between April 2022 and November 2024. The median age of the participants was 48 years.

All participants reported at least one typical UTI symptom, including dysuria, urinary urgency, frequent urination, or suprapubic tenderness, and had a positive urine test for nitrites or leukocyte esterase. However, only 57% of the participants had a positive urine culture.

The participants were randomly assigned to four treatment groups. Women included in the study were randomly assigned to the following four treatment groups:

• Group 1: 191 women received a single 3 g dose of fosfomycin.
• Group 2: 194 women received two 3 g doses of fosfomycin administered 24 hours apart.
• Group 3: 190 women received nitrofurantoin 100 mg three times a day for 5 days.
• Group 4: 193 women received pivmecillinam 400 mg three times a day for 3 days.

Researchers deliberately avoided using broad-spectrum antibiotics.

Primary Endpoint

The primary endpoint was the proportion of patients achieving clinical resolution on day 7, defined as the complete disappearance of UTI symptoms. Secondary endpoints included clinical and microbiological efficacy and treatment safety at 14 and 28 days. Data from 720 of the original 768 participants were available for the primary analysis.

Single-dose fosfomycin showed the lowest efficacy in the direct comparison, with only 59% of patients being symptom-free after 1 week. Nitrofurantoin achieved the highest cure rate at 74%, followed by pivmecillinam at 70%, and two doses of fosfomycin at 67%. Similar findings were observed on days 14 and 28 and among women with positive baseline urine cultures.

Mild Effects

Adverse events occurred in 19.9% of women who received a single fosfomycin dose and 26.3% of those who received two doses. The corresponding rates were 26.8% for nitrofurantoin and 21.2% for pivmecillinam.

Most adverse events were mild, self-limiting gastrointestinal symptoms that resolved spontaneously. Researchers documented four serious adverse events, although only one event, a case of pyelonephritis in the pivmecillinam group, appeared to be related to the study treatment.

Conclusion

The authors of the study noted that the results of the current study support the findings of an earlier randomized clinical trial, which suggested that fosfomycin is less effective as a single dose than nitrofurantoin. Short-course antibiotic regimens should be preferred over a single dose of fosfomycin based on these new findings.

"Overall, however, the study also shows that all approaches are successful — that is, effective and safe — although the highest cure rate was observed with nitrofurantoin," said Magistro. "Unfortunately, the number of participants was probably too small to identify any further interesting differences between the various treatment strategies."

Comparisons Between the 5-day and 3-day Treatment Regimens

Jesús Rodríguez Baño , MD, PhD, and Pilar Retamar Gentil, MD, PhD, from Hospital Universitario Virgen Macarena, Departamento de Medicina, Universidad de Sevilla, Instituto de Biomedicina de Sevilla in Seville, Spain, also called for larger follow-up studies. In a commentary published in The Lancet, they emphasized the need for direct comparisons between 3-day and 5-day nitrofurantoin regimens and noted that evidence supporting equivalent efficacy of shorter treatment courses remains limited.

Despite the study's limitations, Rodríguez Baño and Retamar Gentil praised the researchers for conducting a practical randomized trial in busy primary care settings. They concluded that the findings reinforce evidence showing nitrofurantoin is superior to a single fosfomycin dose for uncomplicated lower UTIs in women.

This story was translated from Medscape's German edition.