Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—A double-blind, randomized non-inferiority trial

Clinical Question

Among non-pregnant women with uncomplicated UTIs, is administration of ibuprofen vs. pivmecillinam more effective in achieving symptomatic resolution by day 4?

Bottom Line

Among non-pregnant women with symptoms of an uncomplicated UTI, administration of ibuprofen was inferior to pivmecillinam and cannot be recommended alone as an initial treatment option.

Major Points

Uncomplicated UTIs are common in women, pregnant and non-pregnant, with no urinary tract obstructions. First line treatment for this bacterial induced infection is typically antibiotics, but due to the prevalence of antibiotic resistance the authors of this study compared the use of NSAIDs in treating the symptoms of uncomplicated UTIs with hopes of reducing antibiotic use and development of resistance.

The study enrolled 383 women aged 18-60 years, with symptoms of uncomplicated cystitis, utilizing a double-blinded and randomized design. Patients received either ibuprofen or pivmecillinam for a duration of 3 days. The assessment criteria was based on the percentage of patients experiencing a clinical cure by day 4. The results of the study showed that by day 4 only 37.8% of patients who received ibuprofen felt cured, compared to 73.6% of patients who received pivmecillinam. The results of the study suggest that initial treatment with antibiotics is more effective than Ibuprofen in treating uncomplicated UTIs, which corresponds to the study by Kronenberg et al and Gagyor et al referenced in this trial.

Guidelines

As of April 2019, no guidelines have been published that reflect the results of this trial. The Acute Uncomplicated Cystitis and Pyelonephritis 2010 Guidelines are available which is relevant to the disease state of the trial.

• Women diagnosed with acute uncomplicated cystitis can use antimicrobials considering availability, allergy history and tolerance
  • Nitrofurantoin monohydrate/macrocrystals 100 mg BID for 5 days
  • Trimethoprim-sulfamethoxazole 160/800 mg BID for 3 days
  • Fosfomycin trometamol 3 gm single dose
  • Pivmecillinam 400 mg BID for 5 days
  • Low efficacy compared to other recommended agents and avoid if early pyelonephritis
• Note: Guidelines did not mention NSAIDs

Design

• Double-blind, randomized, placebo-controlled non-inferiority trial
• N= 383
• Ibuprofen (n= 194)
• Pivmecillinam (n= 189)
• Setting: 16 general practice sites in Norway, Sweden and Denmark
• Enrollment: April 2013- June 2016
• Mean follow-up: After 14 and 28 days
• Analysis: Intention-to-treat
• Primary Outcome: Symptomatic cure of uncomplicated UTI day by 4

Population

Inclusion Criteria

• Non-pregnant female
• 18-60 years of age
• Symptoms of uncomplicated UTI
  • Dysuria combined with increased urinary frequency or combined with urinary urgency or both, with or without visible hematuria

Exclusion Criteria

• Duration of symptoms for more than 7 days
• Allergies/Adverse reactions to penicillin or ibuprofen
• Breastfeed a child under 1 month of age
• Any sign of upper UTI (fever, upper back pain, reduced general condition)
• Vaginal irritation/discharge, severe abdominal pain; diabetes; kidney disease; genetic aciduria; severe gastritis; ulcerative colitis; Crohn’s disease; low platelets
• Use of probenecid, steroids, immunosuppressant drugs or blood-thinning drugs; previous pyelonephritis
• Use of urinary catheter or symptoms of a UTI within the last 4 weeks or use of antibiotics within the last 2 weeks

Baseline Characteristics

Comparisons are Ibuprofen vs. Pivmecillinam"

• Mean age: 28 (28.1 vs. 28.5)
• UTIs in last 12 months
  • 0-2 UTI: 92% (141 vs. 146)
  • 3 or more UTI: 8% (15 vs. 11)
• Signs and Symptoms:
  • Dysuria: 96% (152 vs. 152)
  • Urinary Urgency: 98% (15 vs. 154)
  • Urinary Frequency: 98% (15 vs. 156)
  • Visible Hematuria: 42% (71 vs. 53)
• Symptom Duration
  • <1 day: 5% (10 vs. 9)
  • 1-2 Days: 48% (89 vs. 84)
  • >2 to 7 days: 46% (80 vs. 84)
  • >7 days: 1% (2 vs. 1)
• Urine Culture Result:
  • Negative/ no significant growth: 35% (59 vs. 64)
  • Positive: 66% (121 vs. 113)
  • Susceptible to pivmecillinam (all pathogens): 75% (93 vs. 83)
  • Susceptible to pivmecillinam (E. coli): 91% (90 vs. 81)

Interventions

• Ibuprofen - 600mg Ibuprofen capsules administered 3 times daily for 3 days
• Pivmecillinam - 200mg Pivmecillinam capsules administered 3 times daily for 3 days
• Follow-up: 14 days and 28 days after administration

Outcomes

Comparisons are Ibuprofen vs. Pivmecillinam

Primary Outcomes

• Patient without symptoms by day 4: 39% vs. 74% (95% CI 27% to 43%)

Secondary Outcomes

• Patient without symptoms by day 7: 63% vs. 91% (95% CI 20% to 36%)
• Patient without symptoms by day 14: 78% vs. 94% (95% CI 9% to 23%)
• Median symptom duration after randomization (days): 6 vs. 3

Subgroup Analysis

The effect of pivmecillinam between the subgroups shows a significant difference on patients that felt a cure by day 4. In the culture negative subgroup, 52% felt cured in the Ibuprofen group compared to 71% in the pivermecillinam group. In patients with a positive urine culture, the symptom burden between the pivmecillinam non-susceptible subgroup vs. the pivmecillinam susceptible group showed a difference but was not significant based on the P-value (P=0.22). Symptom burden when treated with ibuprofen in the recurrent UTI subgroup (3 or more) in the past 12 months had a bigger difference when compared to subgroup with 0-2 UTIs in the past 12 months, however the result was still significant in both groups. Lastly the symptom burden in significant E.coli growth in urine culture vs. other significant uropathogen growth in urine cultures was smaller in the E.coli group but both still were significant.

Adverse Events

• None: 70.2% vs. 68.5% (P=0.68)
• Commonly Seen:
  • Digestive System Events: 11% vs. 15%
  • Cognitive and Behavior Events: 8% vs. 9%

Criticisms

• Extensive exclusion criteria eliminating nearly half of the recruited patients
• 2942 patients were screened for eligibility but only 383 were randomized
• 79 patients were lost to follow-up, dropped out or discontinued the intervention
  • Ibuprofen = 44
  • Pivmecillinam = 35
• 181 patients were randomized with Ibuprofen with 7 developing pyelonephritis, 5 of whom required hospitalization, demonstrating high rates than prior trials
• A placebo group was not included for ethical reasons because of existing data suggesting antibiotics as superior to placebo. Including a placebo arm could have helped characterize potential harms of Ibuprofen
• Nurses had not received proper training to enroll patients
• Symptom burden was not included on the questionnaire resulting in unknown degrees of symptoms among patients

Funding

• Mainly funded by the Research Council of Norway
• Norwegian Medical Association
• Norwegian Committee on Research in General Practice (AFU) and Norwegian Research Fund for General Practice (AMFF)