By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: A single dose of fosfomycin was found to be less effective than five days of thrice-daily dosing of nitrofurantoin in the treatment of symptomatic lower urinary tract infection in women.

SOURCE: Huttner A, Kowalczyk A, Turjeman A, et al. Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women: A randomized clinical trial. JAMA 2018;319:1781-1789.

Huttner and colleagues performed an open-label, randomized clinical trial comparing single-dose (3,000 mg) fosfomycin (FOS) to thrice-daily dosing (100 mg per dose) of nitrofurantoin (NTF) for five days in the treatment of uncomplicated symptomatic lower urinary tract infection in women 18 years of age and older. Patients had at least one symptom and positive leukocyte esterase or nitrite test on urinalysis.

Clinical response 28 days after completion of therapy (the primary outcome) was observed in 171 (70%) of the 244 NTF recipients and in only 139 (58%) of the patients assigned FOS; the 95% confidence interval (CI) for the difference was 4.1% to 21% with a P value of 0.004. A statistically significant difference also was observed at 14 days. The median duration of symptoms, however, was one day longer in NTF recipients (four days vs. three days), but this was not statistically significant.

A midstream urine specimen was obtained at study entry from 487 patients, and 377 (77%) were culture positive, defined as the presence of 103 colony-forming units/mL of at least one organism. Of the positive cultures, 230 (61%) yielded Escherichia coli, while Klebsiella spp. and Enterococcus spp. each accounted for 7%, Proteus spp. for 5%, and Enterobacter spp. for 3%. The culture yielded mixed flora in 91 (18%).

The apparent superiority of NTF treatment at 28 days was even more pronounced among patients from whom E. coli was recovered, with 80 (78%) of 103 having a favorable clinical response compared to only 55 (50%) of 111 FOS recipients. The 95% CI for the 28% difference in response rates was 15% to 40% (P < 0.001). The overall microbiological response rate also favored NTF at both 14 days and 28 days, although the P value for the difference at each time point was only 0.04.

COMMENTARY

The results of this study appear to provide reasonable evidence that a single 3-gram dose of FOS is inferior to 100 mg thrice daily of NTF given for five days in uncomplicated cystitis in women. Consistent with this, as the authors noted, is recent evidence of significant inter-patient variability in achievable urine concentrations of FOS as well as evidence in an in vitro model of rapid regrowth of organisms after exposure to this antibiotic. However, several factors also must be considered, including at least two previous randomized trials that found no difference in outcome when comparing treatment with these two agents.

Furthermore, the open-label design used in this trial provides a potential for significant reporting bias in a study in which the primary outcome was subjective clinical response (although the seemingly paradoxically shorter duration of symptoms in FOS recipients, while not statistically significant, argues against this). Nonetheless, the microbiological response also favored the NTF regimen, particularly in the treatment of E. coli infections.

As the authors also pointed out, the response rates in both treatment arms in this study were markedly lower than the 90% expected based on previous studies. One of the reasons for this could be that many of the patients included in the analysis did not, in fact, have bacterial urinary tract infections. Not all patients actually had a urine culture performed, and among those who did, approximately one in five yielded mixed flora and approximately two in five yielded an organism other than E. coli — both findings suggesting contamination of the specimen. Thus, a study comparing culture of midstream to catheterized urine specimens of premenopausal women with symptoms of cystitis found that the detection of E. coli in voided specimens was highly predictive of bladder bacteriuria, while detection of other organisms (enterococci and/or group B streptococci) was not.1

My conclusion is that a single dose of fosfomycin is, nonetheless, likely inferior to multiple daily doses of nitrofurantoin (and it should be noted that the Infectious Diseases Society of America recommendations for nitrofurantoin include only twice-daily dosing compared to the three times daily used in this study). It also is likely that FOS may be just as effective as NTF but that we have not yet determined the optimal way of dosing this drug, which is increasingly important as antibiotic resistance progresses.

REFERENCE

  1. Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal women. N Engl J Med 2013;369:1883-1891.