Summary of Individual Studies
This systematic review evaluated evidence from four European double-blinded randomized control trials involving 1144 patients with uncomplicated urinary tract infection conducted between 2007 to 2016.
The 2010 pilot study by Bleidorn et. al. analyzed 79 otherwise healthy women presenting with uncomplicated UTI symptoms, who were randomly assigned to either ibuprofen or ciprofloxacin for 3 days. Results supported the assumption that ibuprofen is non-inferior as compared to ciprofloxacin for treatment of uncomplicated UTI regarding symptom resolution and symptom course. However, there were no significant differences between Ibuprofen and ciprofloxacin (58.3% vs 51.5%; p= 0.744) as for symptom resolution on Day 4. Conversely, the proportion of patients requiring secondary antibiotic treatment due to persistent or worsening symptoms was not statistically significant between the Ibuprofen and the Ciprofloxacin group (33.3 % vs 18.2%, p = 0.247) . Even with these trial results, the pilot study was limited by its inadequately powered study design with small number of participants. This triggered a series of pivotal trials with a determination of non-inferiority of NSAIDs compared with antibiotics for symptom control and treatment.
The Immediate versus Conditional treatment of Urinary Tract Infection (ICUTI) double blinded randomized multicenter trial by Gágyor et. al. recruited 494 patients and randomly assigned them to treatment with a single dose of fosfomycin or ibuprofen for 3 days. The study assessed whether the antibiotic prescriptions for UTI can be reduced by symptomatic treatment with ibuprofen, without a significant increase in symptoms, recurrences or complications. Data showed that the ibuprofen group received significantly lower antibiotic courses compared to the fosfomycin group with an incidence rate reduction of 66.5% (95% CIs [58.8%, 78.4%]; p <0.001). However, during the follow-up period, significantly more women in the Ibuprofen group (34%) received antibiotic prescriptions compared to the fosfomycin group (14%) (mean difference 21.1, 95% CIs [13.8, 28,7], p <0.001) due to worsening or persistent symptoms. The findings are similar with the pilot study. Symptom relief of UTI was also less effective. A significantly higher total burden of symptoms and impairment of activity were observed in the Ibuprofen group and more cases of pyelonephritis. Though, nearly two-thirds of women treated symptomatically with Ibuprofen recovered without any antibiotic treatment . A follow-up analysis of the ICUTI trial showed that there is no difference in rates of recurrent UTI between antibiotic and non-antibiotic treatment beyond four weeks after initial treatment .
The next trial by Kronenberg et. al. involved 253 women with uncomplicated lower UTI and they were randomly assigned to receive diclofenac or norfloxacin for 3 days. Results revealed symptom resolution at Day 3 were more common among women who took norfloxacin (80%) versus those assigned to diclofenac (54%) (risk difference 27%, 95% CIs [15%, 38%], p < 0.001). A higher incidence of pyelonephritis (5%) was also observed in the diclofenac group (risk difference 5%, 95% CIs [1%, 8%], p = 0.031). On the beneficial side, similar with the study results by Gagyor et. al., antibiotic use can be lessened as women who received diclofenac were 37% less likely to use any antibiotic until day 30 after the randomization (risk difference 37%, 95% CIs [28%, 46%], p <0.001 .
The 2017 trial conducted by Vik et. al. enrolled 383 women who were randomly allocated to treatment with either ibuprofen or pivmecillinam for 3 days. It concluded that ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. Despite that more than half of women treated with ibuprofen recovered without antibiotics, this came at a cost of higher symptom burden with only 38.7% of the Ibuprofen group felt cured by Day 4 versus 73.6% in pivmecillinam group (risk difference 35%, 90% CIs [27%, 43%]; p >0.99), followed by longer duration of symptoms (6 days vs 3 days), and higher rate of pyelonephritis at 3.9%.
Summary of Evidence
Consolidating all the findings above, this meta-analysis determined that the treatment of uncomplicated UTI with non-steroidal anti-inflammatory drugs does not substantially improve symptom burden and achieve symptomatic cure, compounded further by complication risks as compared to standard antibiotic use. Our sensitivity analyses showed that the effectiveness of symptom resolution is less with NSAID treatment than use of antibiotics (RR: 0.63, 95% CIs [0.53, 0.74], I2=56). Moreover, the pooled number needed to harm is 4.76 for persistence of symptoms on Day 3 or 4 of illness (NNH 4.76, 95% CIs [12.5, 2.94]), with a risk difference of 0.21 (RD 0.21, 95% CIs [0.08, 0.34], I2=78) (Figure 3B).
The initial hypothesis of the possible use of NSAIDs in symptomatic treatment of uncomplicated urinary tract infections stems from the postulate that inflammation plays a key role in the development of lower urinary tract symptoms, with high sensitivity C-reactive protein as a marker of inflammation. Previous studies reported a significant association between CRP levels and lower urinary tract symptoms in women and men [22,23], and subsequently among urinary tract infection patients . Theoretically, NSAIDs may reduce contraction of the bladder muscle, which is partly responsible for the lower urinary tract symptoms, by inhibiting expression of cyclooxygenase 2, and synthesis of prostaglandins. This pathogenic mechanism was replicated in the study by Takagi-Matsumoto et. al., which revealed dose-dependent suppression of rhythmic contraction induced by distension on normal and cystitis rats with intravenous administration of aspirin, indomethacin or ketoprofen . However, it did not translate well in the clinical setting.In the 2019 ATAFUTI trial, there was no evidence of differences between those who took Ibuprofen vs. placebo in terms of symptom severity after 2-4 days of intervention (LS mean -0.01, 95% CI [-0.27, 0.26], p=0.951) . Also, in a randomized controlled pilot study by Ko et. al., no significant difference was observed in the degree of pain scale reduction between those who took cepodoxime plus aceclofenac versus cepodoxime alone on Day 3 of treatment (p = 0.134) 
The non-steroidal anti-inflammatory drugs are known for its anti-inflammatory, analgesic and anti-pyretic properties. Nevertheless, some studies have demonstrated moderate to strong in vitro antimicrobial activity when tested against different bacterial isolates of Gram-positive and Gram-negative organisms. Aspirin inhibited all of the S. aureus and E. faecalis isolates of UTI at the most effective concentration of 500 ug/ml . Conversely, diclofenac exhibited in vitro inhibition on 67% of clinically isolated strains of E.coli, with MIC values ranging from 5-50 ug/ml . In case of Ibuprofen, zones of inhibition were observed for S. aureus, B.subtilis, C. albicans and A. brasiliensis, hence signifying a broad spectrum of activity for bacterial and fungal strains . However, contrary to the previous studies, a recent investigation revealed that Ibuprofen lacks direct antimicrobial properties for treatment of urinary tract infection isolates without any effect on bacterial growth of E. coli or E. faecalis . In our study, results revealed that the non-steroidal anti-inflammatory group is more likely to have a persistence of a positive microbiologic urine culture compared to use of antibiotics after treatment (RR: 2.77, 95% CIs [1.95, 3.94], I2=36%). Failure to reach a bacteriologic cure can delay or not effectively attain optimal symptom improvement. This was shown in one of the reviewed studies by Vik et. al. as patients in the ibuprofen group who have a positive culture had a higher symptom burden and longer duration of lower urinary tract symptoms than those with a negative culture .
Another key finding in this study showed that while 43.34% of women in the combined trials treated with NSAIDs achieved symptomatic cure, the observed odds of developing upper UTI complications (pyelonephritis, and febrile UTI) was significantly higher in the NSAID group (Peto OR: 6.49, 95% CIs [3.02, 13.92], I2=0%). This was due to the delay in instituting antibiotics. Due to the persistence or worsening of symptoms, patients who were given NSAID initially needed secondary treatment with antibiotics (RR: 3.10, 95% CIs [2.17, 4.43], I2=53%). In the study by Vik et. al., some even required hospitalization for IV antibiotics (2 out of 7 with serious adverse events) . While it is an important outcome that at least 40% of patients were spared of antibiotics, we cannot disregard those who were harmed during the process.
These results suggest that NSAIDS are not comparable to antibiotic treatment for uncomplicated UTI. Giving NSAIDs can reduce the use of antibiotics , but at the expense of high symptom burden, longer duration of symptoms, and more cases of progression to pyelonephritis.
Previous studies have compared the use of placebo and antibiotics in uncomplicated UTI favoring the administration of antibiotics due to the worsening of complications in the other placebo arm . The same conclusion can be made in this study.
Other antibiotic sparing strategies for uncomplicated UTI
Herbal preparations has also been used as part of alternative therapy sparing antibiotic use. In the 2019 ATAFUTI study , it investigated on the use of uva-ursi leaf extract in relieving urinary symptoms and reduction in consumption of antibiotics.There was no difference in symptom severity between uva-ursi and placebo (LS mean -0.06, 95% CIs [-0.33, 0.21], p = 0.661), and likewise, no statistical significance in terms of antibiotic reduction (OR 0.59, 95% CIs [0.22,1.58], p =0.293). Cranberries has also been used traditionally in treating UTI as well as from its recurrence among healthy women. However, a metaanalysis showed that cranberry products did not significantly reduce the occurrence of symptomatic UTI overall (RR 0.86, 95% CI [0.71, 1.04], I² = 55%) .
Strengths and Limitations
This manuscript is the first meta-analysis with systematic review of NSAID vs antibiotics for treatment of uncomplicated UTI. However, this study is limited only to search titles or abstracts of English language articles. Other potential sources of bias in each study remain to be elucidated which may affect the magnitude of effect estimate. There is also a paucity of randomized controlled trials available for this meta-analysis.