AIDA-WP2

Published

Huttner 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(17):1781-1789.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In adult women with an uncomplicated urinary tract infection (UTI), how does a 5-day course of nitrofurantoin compare to single-dose fosfomycin for clinical and microbiological resolution?

Bottom Line

In women with uncomplicated UTI, a 5-day course of nitrofurantoin improves clinical and microbiologic resolution compared to single-dose fosfomycin.

Major Points

In at least two prior clinical trials, nitrofurantoin and fosfomycin demonstrated similar efficacy in the treatment of uncomplicated UTI, but this predated widespread use and thus higher antibiotic resistance rates.

Published in 2018, the AIDA-WP2 study compared clinical and bacteriologic efficacy of nitrofurantoin 100 mg three times daily for 5 days to a single dose of fosfomycin 3 g. The study randomized 513 nonpregnant women and analyzed outcomes using intention-to-treat and several sensitivity analyses. In the primary outcome of 28-day clinical response, 70% of patients in the nitrofurantoin group demonstrated success over 58% in the fosfomycin group. Bacteriological response at 28 days was superior for nitrofurantoin (74% vs. 63%). In the subpopulation of E. coli infection there was an even greater difference in outcomes between the two drugs.

There are several potential sources of bias in this trial, the first being the open-label design where reporting of clinical symptoms may have been influenced by patients' perception with 5 days vs. 1 day of treatment. Moreover, approximately a quarter of patients were culture negative, which may have biased results. Overall, the trial demonstrated statistically significant superior clinical resolution with nitrofurantoin in comparison to fosfomycin, however, there may still be a space for fosfomycin which further study will need to clarify.

Guidelines

IDSA Guidelines for UTI Management (2010, adapted)

• First-line agents for uncomplicated lower UTI:
  • Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days
  • Trimethoprim-sulfamethoxazole 160 mg/800 mg (one DS tablet) twice daily for 3 days
  • Fosfomycin trometamol 3 g single dose
  • Pivmecillinam 400 mg twice daily for 5 days

Design

• Multinational open-label, analyst-blinded, randomized clinical trial with allocation concealment
• N=513 nonpregnant women with UTI
  • Nitrofurantoin 100 mg TID for 5 days (n=255)
  • Fosfomycin 3 g single dose (n=258)
• Setting: Ambulatory clinics and hospital units in Geneva, Switzerland; Lodz, Poland, and Israel
• Enrollment: October 2013 to May 2017
• Follow-up: 2 visits at 14 (±2) days and 28 (±7) days after completion of treatment
• Analysis: Intention-to-treat
• Primary outcome: Clinical response in the 28 (±7) days following completion of therapy

Population

Inclusion Criteria

• Women ≥18 years old
• At least 1 symptom of acute lower UTI (dysuria, frequency, suprapubic tenderness)
• Urine dipstick positive for nitrates or leukocyte esterase

Exclusion Criteria

• Pregnancy and lactation
• Suspected upper UTI (symptoms of fever, chills, or flank pain)
• Antibiotic use or symptoms of UTI in the past 4 weeks
• Indwelling urinary catheter or otherwise complicated UTI
• Immunosuppression (untreated HIV infection, chemotherapy, radiation, high dose corticosteroids, other immunosuppressants)
• Renal insufficiency (CrCl <30 mL/min)

Baseline Characteristics

From the nitrofurantoin group.

• Demographics: Age 43 years (median), outpatient 93%
• Physiologic parameters: Median number of inclusion symptoms 3, positive urine culture 80%
• Antimicrobials: Antibiotics in past year 33%, at risk of resistant organisms 65%, previous UTI 16%
• Culture results: E. coli 57%, Klebsiella spp 10%, Proteus spp 4%, Enterococcus spp 7%, Group B Streptococcus 4%, Enterobacter spp 3%, mixed flora 26%

Interventions

• Nitrofurantoin 100 mg PO three times daily for 5 days
• Fosfomycin 3 g single oral dose

Outcomes

Comparisons are nitrofurantoin vs. fosfomycin.

Primary Outcomes

Clinical response in the 28 days following completion of therapy

70% vs. 58% (95% CI 4-21%; P=0.004; NNT=8)

Secondary Outcomes

Clinical resolution at 14 days after therapy completion

75% vs. 66% (95% CI 1-17%; P=0.03; NNT=11)

Bacteriologic response to 28 days after therapy completion

74% vs. 63% (95% CI 1-20%; P=0.04; NNT=9)

Bacteriologic success through to 14 days

82% vs. 73% (95% CI 0.4-18%; P=0.04; NNT=11)

Duration of initial symptoms

4 days [IQR 2-14] vs. 3 days [IQR 2-14] (P=0.30)

Subgroup Analysis

E. coli infections subpopulation, clinical response in the 28 days following completion of therapy

78% vs. 50% (95% CI 15-40%; P<0.001; NNT=4)

E.coli infections sub-population, bacteriologic response to 28 days after therapy completion

72% vs. 58% (95% CI 2-27%; P=0.03; NNT=7)

Adverse Events

Development of pyleonephritis

0.4% vs. 2% (95% CI −0.5% to 4.2%; P=0.22)

At least 1 reported adverse event in the 7 days following randomization

7.8% vs. 5.8%

Criticisms

• Open-label design may have influenced clinical symptom response reporting by participants
  • Secondary microbiological response may help mitigate this bias
• The nitrofurantoin dose used (300 mg per day) is higher than the guideline recommended dose (200 mg per day)
  • Would using a longer course of fosfomycin demonstrated better efficacy?
  • Commonly used dose in some areas of Europe so may be more pragmatic
• Resistance rates to fosfomycin and nitrofurantoin among the study sites varied and may not be comparable to those in locations with differing antibiotic use
  • Fosfomycin is not indicated to treat all gram-negative infections commonly associated with UTIs
  • Local antibiograms and susceptibility patterns must be taken into consideration when applying these results.
• The study did not report how the patients received the medications. Though it is assumed the medication was provided by the study, if the patient was required to obtain the medication on their own, the cost of medications may impair adherence.
• A quarter of enrolled patients were culture negative, potentially affecting the findings of this trial/

Funding

• European Commission under the Life Science Health Priority of the 7th Framework Program
  • The Lodz site received funding from the Polish Ministry of Science and Higher Education