MADRID – Five days of nitrofurantoin was significantly more effective than was a single large dose of fosfomycin in effecting both clinical and microbiological cure among women with uncomplicated lower urinary tract infections (UTIs), a randomized study has determined.

By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.

The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).

“This was very clearly a superiority trial,” said Dr. Huttner. “We were very surprised at the strength of the findings among patients with E. coli.”

Despite its success, nitrofurantoin did not live up to its purported 96% UTI cure rate – an established number based on study data from the 1950s-1970s.

Such efficacy was probably a false finding, she said. Studies of that era were much less rigorous than they are today, Dr. Huttner pointed out. The primary endpoint in those studies was typically defined not as complete resolution of symptoms – as it was in her study – but as resolution or improvement.

“Also, improvement was often defined microbiologically, often something like a decrease from 10⁵ colony-forming units to 10⁴, which is never something we would use today.”

The study was conducted in Geneva, Poland, and Israel. It randomized 512 women with an uncomplicated lower UTI to either 5 days of thrice-daily nitrofurantoin 100 mg or to a single 3-gram dose of fosfomycin. The women returned for clinical exam and urine culture at 14 and 28 days after they completed their treatment.

The primary outcome was 28-day clinical response. Success was defined as complete resolution of symptoms, a characterization that Dr. Huttner and her colleagues chose carefully. Many UTI studies include “improvement” in the clinical picture as part of a successful response. Dr. Huttner disagreed with that. “Our patients don’t want a partial response. They don’t want just an improvement. They want complete resolution of their symptoms.”

Failure was defined as the need for additional antibiotics or a change in antibiotic treatment. There was also an “indeterminate” category, for the small minority of patients who still felt some mild symptoms but were without microbiological signs of infection.

The mean age of the women was 44 years. All had an uncomplicated UTI characterized by dysuria, urgency, frequency, or suprapubic tenderness; 73% had a positive baseline urine culture. E. coli was the most common infective organism (about 60%) followed by different Klebsiella species, Proteus, and Enterococci. A few women had mixed pathogen infections. Only six patients had infective pathogens that were resistant to either of the study drugs.

After 28 days of treatment, a clinical cure was determined in 70% of those taking nitrofurantoin and 58% of those taking fosfomycin – an absolute difference of 12 points.

“The difference was obvious at 14 days,” Dr. Huttner noted. At that point, 75% of those taking nitrofurantoin and 66% of those taking fosfomycin reported resolution of their symptoms.

Pathology reflected the improving clinical picture: Microbiologic resolution occurred in 74% of the nitrofurantoin group and 63% of the fosfomycin group.

A post hoc analysis looked at results among the 214 women with confirmed E. coli infections.

The difference in clinical response was “even more pronounced” in these patients, Dr. Huttner said. Through day 28, clinical resolution occurred in 78% of those taking nitrofurantoin and 50% of those taking fosfomycin – a significant difference of 28 points.

Patients with E. coli infections were 4.48 times more likely to fail treatment if they received fosfomycin than if they received nitrofurantoin.

Adverse events were few and primarily gastrointestinal. The most common were mild to moderate nausea and diarrhea (less than 4% in each group).

Both of the antibiotics were popular from the 1950s on, but gradually fell out of favor as more powerful therapies were developed. However, as antibiotic resistance began to develop, infectious disease specialists began to support bringing nitrofurantoin and fosfomycin out of mothballs. In 2011, a panel of international experts convened by the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommended both of the medications as first-line therapy for women with acute uncomplicated cystitis and pyelonephritis.

The group recommended fosfomycin in a single 3-gram dose and a nitrofurantoin regimen of 100 mg twice daily for 5 days. The fosfomycin recommendation is clearly inadequate, Dr. Huttner said.

“Fosfomycin is not a bad drug. I just think it’s underdosed in this setting,” she said.

Dr. Huttner had no financial disclosures.

SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.

Nitrofurantoin beats fosfomycin for uncomplicated UTI