Comparing Nitrofurantoin and Fosfomycin in the Treatment of UTIs

Stephan Harbarth, MD, MS

Urinary-tract infections (UTIs) are a common malady, particularly in women. Accounting for 10 million visits to health care professionals each year in the United States, total costs for this condition are approximately $2 billion. Statistics show that at least half of all women will experience at least 1 UTI at some point in their lifetimes. Because UTIs are so pervasive, it’s important that available treatments be maximally effective. With that in mind, a team of scientists working in hospitals and health care centers in Switzerland, Poland, and Israel, created a study designed to compare 2 popular UTI treatments: nitrofurantoin and fosfomycin.

In 2010, the Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases (ESCMID) issued updated guidelines for UTI treatment that recommended taking nitrofurantoin twice a day for 5 days or taking fosfomycin 1 time only.

“Since the introduction and publication of the IDSA/ESCMID guidelines 8 years ago, both agents have been increasingly used,” Stephan Harbarth, MD, MS, an infectious disease specialist at Geneva University Hospitals in Switzerland and the lead author of the study, told Contagion^®. “However, the uptake of fosfomycin has been stronger. Still, these agents do not have monopolies; many [clinicians] still prescribe fluoroquinolones, even for lower UTI and female cystitis.”

The US Food and Drug Administration has warned that fluoroquinolones can have potentially permanent deleterious effects on nerves, muscles, bones, joints, and tendons.

Despite the popularity of both fosfomycin and nitrofurantoin, they had rarely been directly compared in clinical trials. “It was really time to reevaluate single-dose fosfomycin,” Dr. Harbarth said. “Single-dose therapy for UTI has not made a strong showing, and fosfomycin’s efficacy has long been questioned.”

The open-label study enrolled 513 women at 3 sites in Petah-Tikvah, Israel; Lodz, Poland; and Geneva. The women were all at least 18 years old, not pregnant, and had symptoms of lower UTI, including urinary urgency, painful or difficult urination, and pain in the pubic or abdominal region. Almost three-quarters had a confirmed positive urine culture. The subjects were then randomized into 2 groups. One group was assigned to take nitrofurantoin 3 times a day for 5 days and the other group was assigned to take a single dose of fosfomycin. All were evaluated 14 and 28 days later so that clinical symptoms could be assessed, and urine collected.

Out of the initial 513 women enrolled, 475 finished the trial. Seventy percent of the nitrofurantoin group achieved clinical resolution of symptoms by week 28, while 58% of the fosfomycin group did the same. Three-quarters of the nitrofurantoin group saw microbiologic resolution compared with 63% of the fosfomycin cohort. Hardly any participant in either group experienced adverse effects such as gastrointestinal distress. The conclusion? Five days of nitrofurantoin was significantly likelier to result in clinical and microbiologic resolution of UTI than a single dose of fosfomycin.

These results beg the question: Given nitrofurantoin’s superiority, is there ever a reason to consider fosfomycin?

“Fosfomycin could still be prescribed for specific resistant pathogens that are not susceptible to nitrofurantoin,” said Dr. Harbarth. “Furthermore, a few patients may (rarely) have serious side effects due to nitrofurantoin. But in all those cases, it is likely that a second dose of fosfomycin administered after 48 to 72 hours may be needed to increase efficacy. Single-dose administration is appealing, but once patients and physicians have understood that, especially for UTIs [due to Escherichia coli], this treatment has low efficacy and does not cure patients within a 28-day follow-up, the ease of dosing may become a secondary issue.”

Dr. Harbarth allowed that optimal dosing for fosfomycin still needs to be explored: “There is an urgent need to assess in a high-quality clinical trial whether a second dose of fosfomycin given orally after 48 to 72 hours could improve clinical efficacy.”

He also mentioned that urine cultures, which are not necessarily ordered by all providers, could provide crucial information that helps determine the proper course of treatment for UTIs. “For certain patients who do not respond to first-line antibiotic therapy such as nitrofurantoin, microbiologic cultures should be requested to clarify whether the causative bacterial pathogen is antibiotic resistant,” he said.

The study did have some limitations. The fact that patients knew which medication they were taking and how often they were taking it could have influenced their perception of symptoms, with those on the more rigorous schedule of nitrofurantoin reporting more improvement. The fact that earlier double-blind trials comparing nitrofurantoin and fosfomycin found no or little difference in results between the groups would seem to support the open-label bias; however, a JAMA editorial on this latest trial calls into question the validity of this hypothesis: “[T]hese concerns appear to be mitigated by the consistency of effects when confining the analysis to microbiologic response and similar time to early clinical failure between groups (6.3 days vs. 6.5 days),” wrote Rupak Datta, MD, PhD and Manisha Juthani-Mehta, MD, both researchers at Yale School of Medicine in New Haven. Drs. Datta and Juthani-Mehta also noted that the medical community has yet to come to a consensus on whether nitrofurantoin is optimally dispensed twice a day, as per IDSA/ESCMID’s recommendations, or 3 times a day, as was done in the study.

Ms. Saloman is a health writer with more than 20 years of experience working for both consumer- and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.