Introduction
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 2 3 4,5 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 10 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 15 16 17 18 19 20 21 22 23–26 27–29 30 31 23–26
Results
Search results
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 .
Figure 1: Flow chart of literature selection.
Table 1: Characteristics of the included studies in this meta-analysis.
Basic information and quality assessment
The four studies meeting inclusion criteria23–26
Meta-analysis results
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, I 2 = 79%), symptom resolution at Day 7 (P = 0.001, I 2 = 85%), secondary antibiotic treatment rate during 28–30 days follow-up period (P < 0.00001, I 2 = 95%), and adverse effects rate (P = 0.02, I 2 = 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 ).
Figure 2: Forest plot of symptom resolution at Day 3–4 . The experimental group was treated with NSAIDs and the control group with antibiotics. Symptom resolution at Day 3–4 in the experimental group was significantly lower than in the control group. NSAIDs: Nonsteroidal anti-inflammatory drugs.
Figure 3: Forest plot of symptom resolution at Day 7 . The experimental group was treated with NSAIDs and the control group with antibiotics. Symptom resolution at Day 7 is not significantly different between the experimental group and the control group. NSAIDs: Nonsteroidal anti-inflammatory drugs.
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).
Figure 4: Forest plot of secondary antibiotic treatment rate during 28–30 days follow-up period . The experimental group was treated with NSAIDs and the control group with antibiotics. The secondary antibiotic treatment rate is not significantly different between the experimental group and the control group. NSAIDs: Nonsteroidal anti-inflammatory drugs.
Figure 5: Forest plot of adverse effects rate . The experimental group was treated with NSAIDs and control group with antibiotics. The adverse effects rate is not significantly different between the experimental group and the control group. NSAIDs: Nonsteroidal anti-inflammatory drugs.
Discussion
UTIs account for about 20% of all outpatient antibiotic prescriptions, second only to respiratory tract infections.32
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 26 25 33,34 24,35
Among various nonantibiotic interventions evaluated as options for prevention and treatment of UTIs,33 23–25 12,14
Of note, treatment with NSAIDs instead of antibiotics could result in prolonged symptoms and higher burden of symptoms.24–26 24–26 36 37 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 24,25 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
Materials and methods
Inclusion criteria
(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.
Exclusion criteria
(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.
Search strategy
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
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.
Statistical analysis
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 I 2 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.
References
[1]. Robinson D, Giarenis I, Cardozo L. The management of urinary tract infections in octogenarian women.
Maturitas 2015;81(3):343–347.
[2]. Colgan R, Williams M. Diagnosis and treatment of acute uncomplicated cystitis.
Am Fam Physician 2011;84(7):771–776.
[3]. Stamm WE, McKevitt M, Roberts PL, White NJ. Natural history of recurrent urinary tract infections in women.
Rev Infect Dis 1991;13(1):77–84.
[4]. Naber KG, Wullt B, Wagenlehner FM. Antibiotic treatment of uncomplicated urinary tract infection in premenopausal women.
Int J Antimicrob Agents 2011;38(Suppl):21–35.
[5]. Czaja CA, Scholes D, Hooton TM, Stamm WE. Population-based epidemiologic analysis of acute pyelonephritis.
Clin Infect Dis 2007;45(3):273–280.
[6]. Hummers-Pradier E, Kochen MM. DEGAM-guideline no. 1 (in German).
Z Allg Med 2000;76:35–48.
[7]. 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 2018;18(3):241–251.
[8]. Li F, Zeng X, Tong X, et al. Distribution and drug resistance of pathogens causing urinary tract infections.
Northwest Pharm J 2016;31(5):528–531.
[9]. Linhares I, Raposo T, Rodrigues A, Almeida A. Incidence and diversity of antimicrobial multidrug resistance profiles of uropathogenic bacteria.
Biomed Res Int 2015;2015:354084.
[10]. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance?
Nat Rev Microbiol 2010;8(4):260–271.
[11]. 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 2014;14(8):742–750.
[12]. 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 2002;52(482):729–734.
[13]. Little P, Moore MV, Turner S, et al. Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial.
BMJ 2010;340:c199.
[14]. 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 2004;36(4):296–301.
[15]. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections.
Cochrane Database Syst Rev 2012;10:CD001321.
[16]. 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 2011;52(10):1212–1217.
[17]. 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 2014;32(1):79–84.
[18]. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women.
Obstet Gynecol 2008;112(3):689–690.
[19]. 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) 2016;48(11–12):823–828.
[20]. Naber KG, Cho YH, Matsumoto T, Schaeffer AJ. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis.
Int J Antimicrob Agents 2009;33(2):111–119.
[21]. Miotla P, Wawrysiuk S, Naber K, et al. Should we always use antibiotics after urodynamic studies in high-risk patients?
Biomed Res Int 2018;2018:1607425.
[22]. 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 2018;101(3):327–336.
[23]. 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 2010;8:30.
https://doi.org/10.1186/1741-7015-8-30 .
[24]. 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 2015;351:h6544.
[25]. 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 2018;15(5):e1002569.
[26]. 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 2017;359:j4784.
[27]. Farkas A, Alajem D, Dekel S, Binderman I. Urinary prostaglandin E2 in acute bacterial cystitis.
J Urol 1980;124(4):455–457.
[28]. 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 2002;167(6):2603–2612.
[29]. 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 2001;59(3):893–904.
[30]. 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 2010;6(8):e1001042.
[31]. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs.
Am J Med 1998;104(3A):2S–8S.
[32]. Petersen I, Hayward AC, Subgroup SS. Antibacterial prescribing in primary care.
J Antimicrob Chemother 2007;60(Suppl 1):i43–i47.
[33]. 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 2019;300(4):821–828.
[34]. Wright J, Paauw DS. Complications of antibiotic therapy.
Med Clin North Am 2013;97(4):667–679.
[35]. 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 2012;55(6):771–777.
[36]. 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 2009;58(2):91–102.
[37]. 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 2009;258(1):18–28.
[38]. 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 2010;340:b5633.
