Urinary tract infections (UTIs) are among the most commonly observed bacterial infections, and are more likely to occur in women than in men, with a ratio of 14:1.1 More than half of the women go through at least one UTI during their lifetime,2 and up to 20% experience recurrent UTIs.3 Most uncomplicated lower UTIs are self-limited and rarely progress into an upper UTI.4,5 Nonetheless, antibiotic treatment is recommended by primary care guidelines to relieve symptoms and shorten the clinical course of this disease.6
In recent years, the risk posed by antimicrobial-resistant uropathogens is becoming increasingly high both in China and globally due to the extensive consumption of broad-spectrum antibiotics, which complicates treatment of UTIs.7–9 As development of antibiotic resistance is rapid, while reversal to antibiotic susceptibility is slow,10 it is crucial to reduce the use of unnecessary antibiotics and to introduce new alternative therapeutic and prophylactic solutions in the management of UTIs.11
Earlier trials comparing placebo with antibiotics for the treatment of UTIs showed that patients with uncomplicated lower UTIs can recover without antibiotic treatment, albeit with delayed symptom relief and prolonged time to bacterial clearance, without experiencing serious complications.12–14 Studies have evaluated various nonantibiotic interventions, including cranberry products,15 probiotics,16 D-mannose,17 estrogens,18 vitamins,19 and oral immunotherapy20 as options for prevention, the phytodrug Canephron N for both prevention21 and treatment,22 and nonsteroidal anti-inflammatory drugs (NSAIDs)23–26 for treatment of UTIs. The symptoms of UTIs are likely to be related to the increase of local pro-inflammatory factors such as prostaglandins.27–29 Previously, it was shown that severe acute inflammatory reactions will occur in the early stage of UTIs in mice, which resulted in recurrent cystitis.30 NSAIDs, which can inhibit the biosynthesis of prostaglandins, may be helpful in alleviating early symptoms.31 The efficacy of NSAIDs or antibiotics in the treatment of uncomplicated lower UTIs in women has been compared in several studies,23–26 but the conclusions from these studies are inconsistent. Therefore, the present systematic review and meta-analysis were designed to assess the efficacy of NSAIDs in the treatment of uncomplicated lower UTIs in women.
A total of 689 articles were identified according to the search strategy, 405 of which were selected after duplicates were removed. Then 379 irrelevant studies were excluded preliminary through screening the titles and abstracts. The full texts of the remaining 26 studies were further evaluated, 22 of which were excluded for different reasons (Figure 1). A total of four studies (N = 1144 participants) were finally included in this meta-analysis. Characteristics of each study are provided in Table 1.
Basic information and quality assessment
The four studies meeting inclusion criteria23–26 were all designed as double-blind randomized controlled trials (RCT) with RCT quality scores ≥3. A total of 1114 nonpregnant women aged 18–85 (upper age limit ranged from 60 years to 85 years in the trials) with symptoms of an uncomplicated UTI were randomly assigned to the experimental groups, which received NSAIDs for symptom management (ibuprofen or diclofenac), or control groups, which received antimicrobial treatment (fosfomycin, pimecillin, ciprofloxacin, or norfloxacin). All four trials reported outcomes, including symptom resolution at Day 3–4, symptom resolution at Day 7, secondary antibiotic treatment rate during 28–30 days follow-up period, and adverse effects rate. The results of the bias risk assessment of the trials included in this study showed low risks in most categories, with unclear bias risk only observed in other bias, indicating generally good methodological quality.
The meta-analysis of all four studies showed that there was significant inter-study heterogeneity in symptom resolution at Day 3–4 (P = 0.002, I2 = 79%), symptom resolution at Day 7 (P = 0.001, I2 = 85%), secondary antibiotic treatment rate during 28–30 days follow-up period (P < 0.00001, I2 = 95%), and adverse effects rate (P = 0.02, I2 = 71%). Therefore, a randomized effect model was used for analysis of each outcome.
At Day 3–4, three out of four studies showed more patients with symptom resolution in control group than in the experimental group, with a pooled odds ratio (OR) of 0.41 [95% confidence interval (CI): 0.23–0.74, P < 0.05, Figure 2], indicating that antibiotics were superior over NSAIDs for fast symptom resolution. However, at Day 7, the resolution of symptoms in the antibiotics groups was not significantly higher than that of the NSAIDs group (pooled OR = 0.43, 95% CI: 0.17–1.06, P = 0.07, Figure 3).
Comparing the secondary antibiotic treatment rate of the experimental group with the control group, the pooled OR was 1.15, with 95% CI 0.16–7.98 and P-value 0.89 (Figure 4), and thus not significantly different. All four trials reported adverse events, mostly gastrointestinal symptoms (nausea, diarrhea, and abdominal pain). There was no significance in adverse effects rate between the experimental group and the control group (pooled OR = 1.09, 95% CI: 0.61–1.96, P = 0.77, Figure 5). In addition, three of the trials reported a total of 19 cases of pyelonephritis (18 in the NSAIDs group and one in the antibiotics group).
UTIs account for about 20% of all outpatient antibiotic prescriptions, second only to respiratory tract infections.32 Efforts should be made to reduce prescriptions and potentially lower levels of antibiotic resistance. This meta-analysis evaluated the available evidence captured by previous randomized clinical studies that compared the efficacy of NSAIDs with conventional antimicrobial therapies for treatment of female uncomplicated lower UTIs. This is the first meta-analysis to assess whether NSAIDs could effectively replace antibiotics for treatment of uncomplicated lower UTIs in women. Our analysis showed that NSAIDs are inferior to antibiotics for in fast symptom resolution, whereas symptom resolution at Day 7, secondary antibiotic treatment rate and adverse events rate are not significantly different between the NSAIDs and antibiotics groups.
The four trials included in this study drew inconsistent conclusions regarding the efficacy of NSAIDs compared with antibiotics for treatment of UTIs. The pilot study by Bleidorn et al.23 concluded that NSAIDs were noninferior to antibiotics for treatment of symptomatic uncomplicated UTIs, while studies by Kronenberg et al.26 and Vik et al.25 concluded that NSAIDs were inferior to antibiotics and that antibiotics were the best choice for treatment of UTIs. Although the superiority of antibiotics for fast symptom resolution is supported by this meta-analysis, long-term antibiotic treatment can lead to alterations in the normal microbiota of the gastrointestinal tract and the vagina, as well as other unpleasant and potentially severe side effects.33,34 In addition, previous studies suggested that antimicrobial treatment might result in recurrent UTIs.24,35 Therefore, nonantibiotic treatment options of UTIs are of great importance in not only minimize the rising crisis of antibiotic resistance but also improving patient quality of life.
Among various nonantibiotic interventions evaluated as options for prevention and treatment of UTIs,33 NSAIDs have been studied only for treatment, but not for prevention. The trials included in this study revealed that up to two-thirds of the patients administered with NSAID recovered without antibiotic treatment,23–25 while spontaneous resolution of UTI symptoms occurs in less than 50% of the cases according to earlier trials comparing placebo with antibiotics.12,14 However, more research that directly compares NSAIDs with placebos is required to establish efficiency of NSAIDs in symptomatic treatment of UTIs. This meta-analysis concludes that treatment with NSAIDs can extensively reduce the total consumption of antibiotics, as the proportion of patients that required additional treatment with antibiotics in the experimental group is not significantly higher than that in the control group.
Of note, treatment with NSAIDs instead of antibiotics could result in prolonged symptoms and higher burden of symptoms.24–26 Although the adverse events rate is not significantly different between NSAIDs and antibiotics, with gastrointestinal discomfort as the main adverse reaction by both treatments, the risk of pyelonephritis in the NSAIDs group (both ibuprofen and diclofenac) was significantly higher than that in the antibiotics group during the follow-up period,24–26 and also higher than that in the placebo group in previous RCTs comparing placebo with antibiotics (0.4%–2.6%).36 Further research on this particular outcome is needed to determine whether this is due to the lack of antibiotic treatment or possibly due to a local immune-compromising effect of ibuprofen and other NSAIDs.37 Previously, it was shown that that baseline C-reactive protein values >10 mg/L were positively correlated with subsequent diagnosis of pyelonephritis, which might; therefore, be used as an indication of higher risk for future complications.26
Urine cultures were collected as baseline data in all studies and were repeated in three studies during follow-up, but at different time-points after treatment (1 week, 10 days, and 2 weeks). Therefore, comprehensive bacterial elimination rates could not be determined. One study used fosfomycin trometamolium in the control group, which showed high antibacterial activity but low clinical efficiency in comparison to other studies.24 This discrepancy may be correlated to the highest positive rate of urine culture in that study. Two of the RCTs found that in patients with negative urine culture results, symptom burden did not differ significantly between the experimental group and the control group.24,25 Therefore, it was suggested that women with positive urine culture results might benefit more from antibiotics than those with negative results.24
In this study, we conclude that antibiotics are more efficient in fast symptom resolution. However, for women with mild to moderate symptoms of UTIs, particularly those with negative urine culture results, symptomatic treatment with NSAIDs may be considered as an alternative to antibiotics. However, alternative treatment strategies should be applied with caution in women with positive urine cultures or with C-reactive protein values higher than 10 mg/L. It is suggested that alternative approaches of combining symptomatic treatment with deferred, selective antibiotic use should be developed and tested in future trials.
Four clinical trials included in this study were all double-blind and RTCs with high methodological quality (6 points for one study and 7 points for three studies). The treatment schedules were similar among different studies, with experimental drugs taken for three days, as the mean duration of symptoms in women with uncomplicated UTIs treated with antibiotics is three days in the absence of antimicrobial resistance.38 However, this meta-analysis has some limits. For instance, the antibiotics used in the control group were different and may have different curative effects, which may impact the overall evaluation. In addition, the clinical treatment efficacy was determined subjectively by the patients, which may not be as accurate as the objectively proved microbiological treatment success. Furthermore, due to the low number of clinical trials on the efficacy of NSAIDs for treatment of female uncomplicated lower UTIs and the limited number of subjects, the sample size of this meta-analysis is relatively small, and a publication bias may exist. The generalizability of the results of this meta-analysis may be limited since all four studies included were conducted in Europe. Therefore, more research is needed to verify efficacy NSAIDs efficacy for treatment of uncomplicated UTIs.
Materials and methods
(1) The studies were RCTs. (2) Patients were nonpregnant women with clinically confirmed uncomplicated lower UTIs (dysuria and/or frequency/urgency of micturition, with or without lower abdominal pain, except any signs of upper UTIs). (3) Interventions included NSAIDs versus other antibiotics. (4) Outcomes included symptom resolution at Day 3–4 and at Day 7, secondary antibiotic treatment rate during 28–30 days follow-up period and adverse effects rate.
(1) Experimental trials on animals and non-RCTs were excluded. (2) Abstracts, letters, reviews, expert opinions, case reports, and editorials were excluded. (3) Studies without sufficient data or that did not meet our inclusion criteria were excluded.
Pubmed, Embase, and Cochrane Library were systematically searched from inception to September 10, 2018. Searching terms were as follows: (“cystitis” OR “urinary tract infection” OR “UTI”) AND “random.” Two investigators independently screened the titles and abstracts of each study. Once studies were determined relevant, the full texts were obtained for further evaluation.
Data extraction was performed by two investigators independently according to the inclusion and exclusion criteria of the study, and disagreements were identified and resolved through discussion. The third author was involved whenever required to resolve disagreements. The following information was extracted: (1) author, title, journal, publication date; (2) study design, especially the randomized, controlled, and blind design; (3) sample size, detailed interventions, efficacy and safety outcomes.
Risk of bias assessment
The Cochrane Collaboration's risk of bias tool was used to assess the risk of bias of the included studies, which was also independently performed by the two investigators.
RevMan 5.3 software provided by the Cochrane corporate website was used for the statistical analyses. Heterogeneity was assessed with Chi-square statistics, and quantitative analysis of heterogeneity was assessed with the I2 statistic. When the experimental results showed no significant heterogeneity (P ≥ 0.05), a meta-analysis was performed based on the choice of a fixed-effect model. On the contrary, if the experimental results showed heterogeneity (P < 0.05), a randomized effect model was used. The OR was calculated, and the 95% 95% CI was calculated for both categories. P < 0.05 was considered significantly different.
. Robinson D, Giarenis I, Cardozo L. The management of urinary tract infections in octogenarian women. Maturitas
. Colgan R, Williams M. Diagnosis and treatment of acute uncomplicated cystitis. Am Fam Physician
. Stamm WE, McKevitt M, Roberts PL, White NJ. Natural history of recurrent urinary tract infections in women. Rev Infect Dis
. Naber KG, Wullt B, Wagenlehner FM. Antibiotic treatment of uncomplicated urinary tract infection in premenopausal women. Int J Antimicrob Agents
. Czaja CA, Scholes D, Hooton TM, Stamm WE. Population-based epidemiologic analysis of acute pyelonephritis. Clin Infect Dis
. Hummers-Pradier E, Kochen MM. DEGAM-guideline no. 1 (in German). Z Allg Med
. Hu F, Guo Y, Zhu D, et al. Antimicrobial resistance profile of clinical isolates in hospitals across China: report from the CHINET surveillance program, 2017. Chin J Infect Chemother
. Li F, Zeng X, Tong X, et al. Distribution and drug resistance of pathogens causing urinary tract infections. Northwest Pharm J
. Linhares I, Raposo T, Rodrigues A, Almeida A. Incidence and diversity of antimicrobial multidrug resistance profiles of uropathogenic bacteria. Biomed Res Int
. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol
. Van Boeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis
. Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract
. Little P, Moore MV, Turner S, et al. Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial. BMJ
. Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis
. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev
. Stapleton AE, Au-Yeung M, Hooton TM, et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus
probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis
. Kranjcec B, Papes D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol
. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Obstet Gynecol
. Jorde R, Sollid ST, Svartberg J, Joakimsen RM, Grimnes G, Hutchinson MY. Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects. Infect Dis (Lond)
. Naber KG, Cho YH, Matsumoto T, Schaeffer AJ. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. Int J Antimicrob Agents
. Miotla P, Wawrysiuk S, Naber K, et al. Should we always use antibiotics after urodynamic studies in high-risk patients? Biomed Res Int
. Wagenlehner FM, Abramov-Sommariva D, Holler M, Steindl H, Naber KG. Non-antibiotic herbal therapy (BNO 1045) versus antibiotic therapy (fosfomycin trometamol) for the treatment of acute lower uncomplicated urinary tract infections in women: a double-blind, parallel-group, randomized, multicentre, non-inferiority phase III trial. Urol Int
. Bleidorn J, Gagyor 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
. Gagyor 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
. Vik I, Bollestad M, Grude N, et al. Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-a double-blind, randomized non-inferiority trial. PLoS Med
. Kronenberg A, Butikofer L, Odutayo A, et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ
. Farkas A, Alajem D, Dekel S, Binderman I. Urinary prostaglandin E2 in acute bacterial cystitis. J Urol
. Schwarz NT, Jung SY, Kalff JC, Chancellor M, Bauer AJ. Bacterial toxin N-formyl-methionyl-leucyl-phenylalanine acutely contracts human and rabbit detrusor through the release of eicosanoids. J Urol
. Poljakovic M, Svensson ML, Svanborg C, Johansson K, Larsson B, Persson K. Escherichia coli
-induced inducible nitric oxide synthase and cyclooxygenase expression in the mouse bladder and kidney. Kidney Int
. Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren SJ. Early severe inflammatory responses to uropathogenic E. coli
predispose to chronic and recurrent urinary tract infection. PLoS Pathog
. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med
. Petersen I, Hayward AC, Subgroup SS. Antibacterial prescribing in primary care. J Antimicrob Chemother
. Wawrysiuk S, Naber K, Rechberger T, Miotla P. Prevention and treatment of uncomplicated lower urinary tract infections in the era of increasing antimicrobial resistance-non-antibiotic approaches: a systemic review. Arch Gynecol Obstet
. Wright J, Paauw DS. Complications of antibiotic therapy. Med Clin North Am
. Cai T, Mazzoli S, Mondaini N, et al. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? Clin Infect Dis
. Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials. J Infect
. Bancos S, Bernard MP, Topham DJ, Phipps RP. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol
. Little P, Merriman R, Turner S, et al. Presentation, pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic resistance among patients presenting with suspected uncomplicated urinary tract infection in primary care: observational study. BMJ