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. 
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.  The second study from Switzerland that compared diclofenac to norfloxacin is summarized below. 
|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.
· Women ages 18 to 70
· One or more symptoms
· Urine dipstick positive for nitrite and/or leucocytes.
· 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|
|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.  Of note, fluoroquinolones are becoming less frequently prescribed due to resistance in the States, especially if there are alternative options. . 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. 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. 
 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.
 Gupta Kalpana, et al. Guidelines for antimicrobial treatment of acute uncomplicated cystitis and pyelonephritis in women. Clinical Infectious Diseases. 2011;52:e103-e120.
 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.
 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
 Norfloxacin. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexi-Comp, Inc; 2017.Updated November 15, 2017. Accessed November 30, 2017.