Symptomatic Treatment of Uncomplicated Lower Urinary Tract Infections in the Ambulatory Setting: Randomized, Double Blind Trial

Shawn Yee, Mercer University College of Pharmacy

Antibiotic resistance with urinary pathogens such as E. coli is becoming a global concern, which may be largely attributed to inappropriate and overuse of antibiotics. Finding ways to minimize antibiotic use while still effectively treating infections is an important responsibility tasked not only to physicians but also to pharmacists to reduce antibiotic resistance. [1]

Uncomplicated lower urinary tract infections (UTI) are common in women, and about 50%  will have at least one infection in their lifetime. This infection is also commonly seen in the outpatient or ambulatory (~20%) setting, and antibiotics are the mainstay of therapy. [1,2] It is suggested symptoms of UTI may be associated with increase in proinflammatory factors such as prostaglandins, which may be alleviated with non-steroidal anti-inflammatory drugs (NSAIDs), and a previous trial showed that compared ibuprofen (NSAID) was noninferior to ciprofloxacin for symptomatic treatment in uncomplicated UTI. [1,3]

To further confirm the aforementioned trial, two larger trials were conducted. The first study compared from Germany compared fosfomycin to ibuprofen in the treatment of uncomplicated lower UTIs in women. The results showed that about two-thirds of the patients receiving ibuprofen recovered without the use of an antibiotic, and ibuprofen was somewhat effective for symptom treatment. [4] The second study from Switzerland that compared diclofenac to norfloxacin is summarized below. [1]

Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomized, double blind trial
Design Randomized, double blind, non-inferiority trial; N= 253

 

Objective Evaluate if non-steroidal anti-inflammatory drugs (NSAIDs) are non-inferior to antibiotics in the symptomatic treatment of lower urinary tract infections (UTIs)
Study Groups Diclofenac 75 mg twice daily (n= 133) vs. norfloxacin 400 mg twice daily (n= 120)
Methods Women from 14 clinical sites were randomized into two treatment groups. Diclofenac group received diclofenac 75 mg capsules for three days, and norfloxacin group received norfloxacin 400 mg capsules for three days. Both treatment groups had same regimen of one capsule in the morning and one capsule in the evening. All patients were given a single open-label package of fosfomycin 3 g to be taken after completion of the study at their discretion, if symptoms persisted.

Inclusion Criteria:

·      Women ages 18 to 70

·      One or more symptoms

·      Urine dipstick positive for nitrite and/or leucocytes.

Exclusion Criteria:

·      Pregnant

·      Recurrent or recent UTI

·      Bladder catheter within last 30 days

·      Urinary tract abnormalities

·      Glomerular filtration rate < 60 mL/min

·      Recent immunosuppression

·      Hypersensitivity or allergies to any drugs in the study

Duration February 7, 2012 to December 3, 2014
Primary Outcome Measure Resolution of UTI symptoms after 72 hours
Baseline Characteristics
Values are means (standard deviation), unless stated otherwise
Characteristics Diclofenac group (n= 133) Norfloxacin group (n= 120)
Age 37.8 (14.2) 35.6 (14.0)
Number of patients ≤ 45 years old, n (%) 94 (71) 89 (74)
Symptom duration: days since UTI onset 3.6 (3.1) 3.2 (2.0)
Number of patients w/symptom duration ≤ 3 days, n (%) 80 (60) 83 (69)
Number of UTI symptoms in past 12 months 0.6 (1.1) 0.6 (0.9)
Urinary dipstick:
Number of patients positive for nitrites, n (%) 17 (13) 18 (15)
Number of patients with leukocyte result > ++ 101 (76) 90 (75)
Urinary culture:
Negative, n (%) 36 (27) 31 (26)
Positive, n (%) 96 (72) 89 (74)
Susceptibility to norfloxacin, n (%) 92 (69) 87 (73)
Susceptibility to fosfomycin, n (%) 84 (63) 71 (59)
Results
Values are numbers (percentages) unless stated otherwise
Outcomes Diclofenac group (n= 133) Norfloxacin group (n= 120) Risk or mean difference (95% confidence interval) p-value*  of risk difference in favor of norfloxacin
Resolution of symptoms:
Day 3 72 (54) 96 (80) 27 (15 to 38) < 0.001
Day 7 111 (83) 115 (96) 12 (4 to 19) 0.003
Day 10 126 (95) 116 (97) 2 (-3 to 7) 0.45
Day 30 127 (95) 111 (93) -3 (-9 to 3) 0.32
Complete absence of symptoms:
Day 3 10 (8) 20 (17) 9 (0 to 17) 0.038
Day 7 44 (33) 65 (54) 21 (9 to 34) 0.001
Day 10 70 (53) 77 (64) 12 (-1 to 24) 0.07
Day 30 101 (76) 99 (83) 6 (-4 to 17) 0.22
Change of symptom score, mean (SD):
Day 3 -7.3 (4.7) -10.3 (4.1) 3.0 (1.9 to 4.1) < 0.001
Day 7 -11.0 (4.8) -12.6 (4.2) 1.6 (0.5 to 2.7) 0.005
Day 10 -12.2 (4.3) -12.9 (4.1) 0.7 (-0.4 to 1.7) 0.20
Day 30 -13.0 (4.4) -13.1 (4.3) 0.1 (-1.0 to 1.1) 0.88
Use of any antibiotic:
≤ day 3 58 (44) 116 (97) -54 (-63 to -44) < 0.001
< day 30 82 (62) 118 (98) -37 (-46 to -28) < 0.001
Use of rescue antibiotic:
≤ day 3 55 (41) 9 (8) 34 (24 to 43) < 0.001
< day 30 73 (55) 18 (15) 40 (29 to 51) < 0.001
Negative urinary culture at day 10 96 (72) 112 (93) 21 (11 to 30) < 0.001
Range 0-10, quality of life, mean (SD): EuroQol = European quality of life instrument
EuroQol health state at day 3 8.8 (2.2) 9.4 (1.5) 0.6 (0.2 to 1.0) 0.005
Patient satisfaction with UTI management 5.7 (3.0 8.2 (2.1) 2.5 (1.9 to 3.2) < 0.001
Number of working days lost due to UTI 0.6 (0.8) 0.5 (0.8) 0.2 (-0.1 to 0.5) 0.18
* = Two sided Fisher’s exact test
Adverse Events
Adverse Events: Diclofenac group, n (%) (n=133) Norfloxacin group, n (%) (n=120) Risk difference (95% CI) p-value* of risk difference in favor of norfloxacin
Related to UTI 26 (20) 10 (8) 11 (3 to 20) 0.012
Persistent   symptoms 16 (12) 4 (3) 9 (2 to 15) 0.011
Additional symptoms 6 (5) 2 (2) 3 (−1 to 7) 0.29
Recurrent UTI† 5 (4) 4 (3) 0 (−4 to 5) 1.00
Pyelonephritis‡ 6 (5) 0 (0) 5 (1 to 8) 0.031
Other adverse event 17 (13) 12 (10) 3 (−5 to 11) 0.56
Exanthema 1 (1) 2 (2) −1 (−4 to 2) 0.61
Vaginitis 3 (2) 0 (0) 2 (0 to 5) 0.25
Gastrointestinal symptoms§ 3 (2) 3 (3) −0 (−4 to 4) 1.00
Low back pain¶ 5 (4) 2 (2) 2 (−2 to 6) 0.45
Viral infection 1 (1) 3 (3) −2 (−5 to 1) 0.35
Trauma 3 (2) 1 (1) 1 (−2 to 4) 0.62
Miscellaneous** 3 (2) 1 (1) 1 (−2 to 4) 0.62
* = Two sided Fisher’s exact test

† = Recurrent UTI was defined as additional visits after day 14 because of recurrent UTI symptoms after symptoms had resolved by day 10, and the physician decided to treat with antibiotics.

‡ = One patient in the diclofenac group was admitted to hospital on day 4 because of pyelonephritis.

§ = Includes one case of diverticulitis in the norfloxacin group.

¶ = Considered to be of musculoskeletal origin by treating doctor.

** = Includes one case of external otitis and two cases of tonsillitis in the diclofenac group and one case of hair loss in the norfloxacin group.

Serious Adverse Events: Hospitalization w/pyelonephritis (n= 1 from diclofenac group)
Percentage that Discontinued due to Adverse Events: Hospitalization w/pyelonephritis (n= 1 from diclofenac group)
Study Author Conclusions In regards to symptom relief of uncomplicated lower UTI, diclofenac is inferior to norfloxacin, and diclofenac is associated with an increased risk of pyelonephritis.

The treatment with norfloxacin is not common in the States, but it is indicated for use in UTI with a dosage regimen of 400 mg twice a day for three days. [5] Of note, fluoroquinolones are becoming less frequently prescribed due to resistance in the States, especially if there are alternative options. [2]. Although the results indicate that the antibiotic treatment was more effective in reducing UTI symptoms, it is interesting to note that over half of the patients in the diclofenac group had no symptoms after three days. This appears to be similar to that of a previous trial showing approximately 60% symptom control with ibuprofen. [4]The study overall had a robust design that increases internal validity of the results. However, because of the choice of antibiotics and the absence of MIC, pathogen, or antibiogram information, applicability of the information may be limited in the United States.

Based on the results, due to safety concerns such as pyelonephritis, NSAIDs alone should not be recommended for use in UTI relief. However, a combination of both short term NSAID and an appropriate antibiotic may be appropriate treatment recommendation. Future studies with this combination regimen versus antibiotic monotherapy would be interesting, and may provide more substantial evidence to healthcare professionals for weighing the risks versus benefits of add-on NSAIDs. Also, studies comparing nitrofurantoin and NSAIDs may be more clinically relevant, since it is the recommended first-line therapy over fluoroquinolones in the States. [2]

 

References

[1] Kronenberg A, Bütikofer L, Odutayo A, et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ. 2017;359:j4784.

[2] Gupta Kalpana, et al. Guidelines for antimicrobial treatment of acute uncomplicated cystitis and pyelonephritis in women. Clinical Infectious Diseases. 2011;52:e103-e120.

[3] Bleidorn J, Gágyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?–results of a randomized controlled pilot trial. BMC Med. 2010;359:30.

[4] Gágyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ 2015;351:h6544a

[5] Norfloxacin. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexi-Comp, Inc; 2017.Updated November 15, 2017. Accessed November 30, 2017.

 

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