Antibiotics for asymptomatic bacteriuria (Review)

Transcription

1 Zalmanovici Trestioreanu A, Lador A, Sauerbrun-Cutler MT, Leibovici L This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2015, Issue 4

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 1 Symptomatic UTI Analysis 1.2. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 2 Complications Analysis 1.3. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 3 Death Analysis 1.4. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 4 Any adverse event Analysis 1.5. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 5 Bacteriological cure Analysis 1.6. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 6 Symptomatic UTI: allocation concealment Analysis 1.7. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 7 Death: allocation concealment.. 38 Analysis 1.8. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 8 Death: randomisation process.. 39 Analysis 1.9. Comparison 1 Antibiotics versus placebo or no treatment, Outcome 9 Any adverse event: randomisation process Analysis Comparison 1 Antibiotics versus placebo or no treatment, Outcome 10 Bacteriological cure: allocation concealment Analysis Comparison 1 Antibiotics versus placebo or no treatment, Outcome 11 Bacteriological cure: randomisation process ADDITIONAL TABLES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST i

3 [Intervention Review] Antibiotics for asymptomatic bacteriuria Anca Zalmanovici Trestioreanu 1, Adi Lador 2, May-Tal Sauerbrun-Cutler 3, Leonard Leibovici 2 1 Department of Family Medicine, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. 2 Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. 3 Obstetrics and Gynecology, St Luke s Roosevelt, New York, New York, USA Contact address: Anca Zalmanovici Trestioreanu, Department of Family Medicine, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva, 49100, Israel. anca_z@hotmail.com. Editorial group: Cochrane Renal Group. Publication status and date: New, published in Issue 4, Review content assessed as up-to-date: 24 February Citation: Zalmanovici Trestioreanu A, Lador A, Sauerbrun-Cutler MT, Leibovici L. Antibiotics for asymptomatic bacteriuria. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Asymptomatic bacteriuria is commonly detected in women aged up to 60 years, patients with diabetes, and the elderly. The benefit of antibiotic treatment for this condition is controversial. Objectives To assess the effectiveness and safety of antibiotics treatment for asymptomatic bacteriuria in adults. Specific objectives were to assess 1) the effectiveness of antibiotics for preventing development of symptomatic UTI, UTI-related complications, overall mortality, UTIrelated mortality, and resolution of bacteriuria; 2) the development of resistance to antibiotic treatment by comparing resistance of grown bacteria in urine before and after therapy; and 3) the frequency of adverse events. Search methods We searched the Cochrane Renal Group s Specialised Register up to 24 February 2015 through contact with the Trials Search Coordinator using search terms relevant to this review. Selection criteria Randomised controlled trials (RCTs) and quasi-rcts comparing antibiotics to placebo or no treatment for asymptomatic bacteriuria in adults were included. The outcomes of interest were the development of symptomatic urinary tract infection (UTI), complications, death, any adverse event, development of antibiotic resistance, bacteriological cure, and decline in kidney function. Data collection and analysis Two authors independently extracted the data and assessed study quality. Statistical analyses were performed using the random effects model and the results expressed as risk ratios (RR) with 95% confidence intervals (CI). Main results We included nine studies (1614 participants) in this review. Symptomatic UTI (RR 1.11, 95% CI 0.51 to 2.43), complications (RR 0.78, 95% CI to 1.74), and death (RR 0.99, 95% CI 0.70 to 1.41) were similar between the antibiotic and placebo or no treatment arms. Antibiotics were more effective for bacteriological cure (RR 2.32, 95% CI 1.11 to 4.83) but also more adverse events developed in this group (RR 3.77, 95% CI 1.40 to 10.15). No decline in the kidney function was observed across the studies; minimal data were available on the emergence of resistant strains after antimicrobial treatment. 1

4 The included studies were of medium and high quality, used different treatments for different durations of treatment and follow-up, different populations, but this did not appear to influence the results of review. Authors conclusions No differences were observed between antibiotics versus no treatment of asymptomatic bacteriuria for the development of symptomatic UTI, complications or death. Antibiotics were superior to no treatment for the bacteriological cure but with significantly more adverse events. There was no clinical benefit from treating asymptomatic bacteriuria in the studies included in this review. P L A I N L A N G U A G E S U M M A R Y Antibiotic treatment for asymptomatic bacteriuria Growth of bacteria in the urine without any complaints (asymptomatic bacteriuria) is commonly detected in women up to 60 years, people with diabetes and in the elderly. It is not clear whether antibiotic treatment for this condition is of benefit for non-pregnant adults. Nine studies of medium to high quality, enrolling 1614 institutionalised participants or outpatients, assigned to antibiotics or placebo/ no treatment for treating asymptomatic bacteriuria for different durations of treatment and follow-up were included in this review. The evidence is current to February No clinical benefit was found for antibiotic treatment. Antibiotics eradicated the growth of bacteria in more participants but at the cost of more adverse events than in the no treatment groups. 2

5 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Antibiotics versus placebo or no treatment for asymptomatic bacteriuria in adults Patient or population: adults with asymptomatic bacteriuria Settings: outpatients or geriatric centres Intervention: antibiotics Comparison: placebo or no treatment Outcomes Illustrative comparative risks*(95% CI) Relative effect (95% CI) Number of subjects who developed symptomatic UTI (6monthsto1year) Number of subjects who developed complications (10monthsto3years) Assumed risk no treatment Corresponding risk antibiotics No of Participants (studies) Medium risk population RR 1.11(0.51 to 2.43) 1046(5) moderate 200per per1000 (102to486) Medium risk population RR 0.80(0.36 to 1.75) 814(3) moderate 30per per1000 (11to52) Quality of the evidence (GRADE) Comments blinding methods not reported or not adequate blinding methods not reported or not adequate Death (6monthsto8years) Number of subjects who develop any adverse event (42daysto10months) Medium risk population RR 0.99(0.70 to 1.41) 761(6) moderate 140per per1000 (98to197) Medium risk population RR 3.77(1.40 to 10.15) 248(3) moderate included quasi-randomised studies and studies with blinding method not reported or not adequate blinding method not reported or not adequate 3

6 Number of subjects with bacteriological cure (42daysto4years) 40per per1000 (56to406) Medium risk population RR 2.32(1.11 to 4.83) 1154(9) moderate 430per per1000 (477 to 2077) included quasi-randomised studies and studies with blinding method not reported or not adequate *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention(and its 95% CI). CI: Confidence interval; RR: Risk Ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate. Very low quality: We are very uncertain about the estimate. The studies included mostly elderly men and women and one study included only diabetic patients 4

7 B A C K G R O U N D Description of the condition The prevalence of asymptomatic bacteriuria varies according to age, sex, sexual activity and the presence of genitourinary abnormalities. Asymptomatic bacteriuria is commonly detected in women aged up to 60 years at the rate of 3% to 5%. Asymptomatic bacteriuria is more common in patients with diabetes and the elderly (Lin 2008). As many as 25% to 50% of elderly women and 15% to 40% of elderly men in long-term care facilities are bacteriuric. Asymptomatic bacteriuria is rare in healthy young men, but its prevalence increases substantially after the age of 60 years. Men with diabetes do not appear to have an increased prevalence of bacteriuria compared with non-diabetic men (Nicolle 1997; Zhanel 1991). Causes of increased susceptibility to asymptomatic bacteriuria among older people can be attributed to declining cell-mediated immunity, increased bacterial receptivity of uroepithelial cells, neurogenic bladder dysfunction, changed bladder defences from obstructive uropathy, reduced prostatic and vaginal antibacterial factors, urinary and vaginal ph, hormones, and urinary and faecal incontinence that favour bacteriuria (Nicolle 1987a; Nicolle 1988; Reid 1984; Sant 1987). The association of asymptomatic bacteriuria with symptomatic urinary tract infection (UTI) is likely attributable to host factors that promote both symptomatic and asymptomatic urinary infection, rather than symptomatic infection being attributable to asymptomatic bacteriuria. The risk factors for developing symptomatic UTI have not been well defined and the consequences of asymptomatic bacteriuria in diabetic patients are controversial (Ribera 2006). Glucosuria enhances bacterial growth in vitro, but this finding could not be confirmed in vivo in diabetic patients (Geerlings 1999). It is also unknown if asymptomatic bacteriuria precedes symptomatic bacteriuria in these patients (Geerlings 2000). It appears that in patients with diabetes, asymptomatic bacteriuria does not lead to severe complications, and it has therefore been recommended that screening for asymptomatic bacteriuria is unnecessary in diabetic patients (Nicolle 2005). Some studies have reported increased mortality associated with asymptomatic bacteriuria in the elderly (Dontas 1981; Evans 1982), but other studies did not confirm this finding. Clinical studies of older residents in long-term care facilities have shown no benefits from screening or antimicrobial treatment for asymptomatic bacteriuria (Heinamaki 1986; Nicolle 1987a; Nordenstam 1986). Premenopausal, non-pregnant women with asymptomatic bacteriuria experience no adverse effects and usually clear bacteriuria spontaneously. However, these women are more likely to experience subsequent symptomatic UTI than women who do not have asymptomatic bacteriuria (Hooton 2000). Asymptomatic bacteriuria is characterised by the presence of a significant quantity of bacteria in a urine specimen properly collected from a person without symptoms or signs of UTI. Quantitative criteria for identifying significant bacteriuria in an asymptomatic person are at least 100,000 colony-forming units (CFU)/mL of same species bacteria in midstream clean-catch urine specimens in a single specimen for men or in two consecutive specimens for women, and at least 100 CFU/mL of same species from single catheterised urine specimens in men or women (Nicolle 2005). The leukocyte esterase and nitrite tests are often used in primary care settings to evaluate urinary symptoms; however, these tests are not useful in diagnosing asymptomatic bacteriuria because pyuria detection is not specific for UTIs. Urinalysis by microscopic examination for bacteria remains a useful test for the identification of bacteriuria (Colgan 2006). Escherichia coli (E. coli) remains the most common organism isolated from patients with asymptomatic bacteriuria; coagulase-negative staphylococci are common in men, as well as gram-negative bacilli and Enterococcus species (Mims 1990). Patients with abnormalities of the genitourinary tract, including elderly institutionalised people, can have a wide variety of organisms isolated. In uncomplicated UTI, infecting E. coli have a number of virulence factors that assist in their colonisation of the urinary tract, including a variety of adhesions, iron sequestration systems and toxins (Zhang 2003); these strains are less virulent in patients with asymptomatic bacteriuria (Holden 2004; Hull 1999). Recent molecular studies demonstrate that some asymptomatic bacteriuria-causing E. coli strains are non-virulent commensal strains, whereas others were originally virulent strains that have evolved to commensalism (Klemm 2007; Zdziarski 2008). This low prevalence of virulence characteristics is consistent with previous reports among otherwise healthy individuals and in diabetic women with asymptomatic bacteriuria (Geerlings 2001; Vranes 2003). Bacteria that normally inhabit the bowel but do not invade the urinary tract under usual circumstances may be capable of migration in diabetic women; these infections can be persistent (Dalal 2009). The increased adherence of E. coli with type 1 fimbriae to diabetic uroepithelial cells, with lower cytokine secretion and leucocyte number, can partially explain the increased incidence and prevalence of asymptomatic bacteriuria in diabetic patients (Geerlings 2008). Description of the intervention A common dilemma in clinical practice is whether to treat asymptomatic patients who present with bacteria in their urine. Increasing antimicrobial resistance among bacteria is a major concern, and rational use of these agents requires identification of clinical situations in which antimicrobial therapy is not indicated. No consensus exists about treatment of asymptomatic bacteriuria in patients with diabetes (Zhanel 1990). The Infectious Diseases Society of America (IDSA) recommends screening and treatment of asymptomatic bacteriuria in adults for pregnant women, before urological procedures where mucosal bleeding is anticipated, and among women with catheter-acquired bacteriuria that persists 48 hours after removal of an indwelling catheter. No treatment is recommended for other groups of pa- 5

8 tients. No recommendations can be made for transplant recipients (Nicolle 2005). Criteria for considering studies for this review How the intervention might work Benefits and harms of treating or not treating asymptomatic bacteriuria are not clear. Screening and treatment of asymptomatic bacteriuria is appropriate if bacteriuria has adverse outcomes that can be prevented by antimicrobial therapy. There are a few scenarios in which antibiotic treatment of asymptomatic bacteriuria has been shown to improve patient outcomes, mainly in pregnancy. It was reported that treatment of asymptomatic bacteriuria neither decreases the frequency of symptomatic infections nor prevents further episodes of asymptomatic bacteriuria (Nicolle 2005). The eradication of microorganisms that cause UTI has been reported to be more difficult in diabetic patients because of an increased frequency of multidrug resistance (Wright 2000). Why it is important to do this review IDSA guidelines recommend further research and evaluation of asymptomatic bacteriuria in appropriately conducted clinical studies; the current guidelines were based on a review of published evidence that included studies of different qualities, with increased heterogeneity and controversial results (Nicolle 2005). No evidence based on a systematic review of randomised controlled trials (RCTs) exists to establish the need for screening and treatment of asymptomatic bacteriuria in adult non-pregnant patients. Issues relating to pregnant women have been included in separate Cochrane reviews (Guinto 2010; Smaill 2007; Widmer 2011). O B J E C T I V E S To assess the effectiveness and safety of antibiotics treatment for asymptomatic bacteriuria in adults. Specific objectives were to assess the following. 1. The effectiveness of antibiotics for preventing development of symptomatic UTI, UTI-related complications, overall mortality, UTI-related mortality, overall and resolution of bacteriuria 2. The development of resistance to antibiotic treatment by comparing resistance of grown bacteria in urine before and after therapy 3. The frequency of adverse events. M E T H O D S Types of studies All RCTs and quasi-rcts in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the use of antibiotics for the treatment of asymptomatic bacteriuria. Types of participants Inclusion criteria Outpatients or institutionalised adults over 18 years of age with asymptomatic bacteriuria (no dysuria, suprapubic pain, frequency or urgency, fever, chills or flank pain) and with bacterial growth defined as at least 100,000 CFU/mL of same species bacteria in midstream clean-catch urine specimens in a single specimen for men, or in two consecutive specimens for women, and at least 100 CFU/mL of same species from single catheterised urine specimens in men or women will be included. Exclusion criteria Pregnant women, catheterised participants (any type of catheter), patients with urinary stents, nephrostomy tubes, kidney or other transplant recipients, bacteriuria related to or close to urological procedures, spinal cord injury and hospitalised patients. Studies were excluded if any of the following present: more than 10% participants were less than 18 years old, hospitalised, symptomatic UTI and no separate data for these groups will be available, a drop-out rate of more than 30%. Types of interventions 1. Antibiotic treatment of any type, dose or duration compared to placebo or no treatment. 2. Studies reporting combined interventions were included only if both treatment arms received the same co-intervention. Types of outcome measures Primary outcomes 1. Proportion of patients who develop symptomatic UTI 2. Proportion of patients with complications: urosepsis, pyelonephritis 3. Death. 6

9 Secondary outcomes 1. Proportion of patients who develop any adverse event during treatment 2. Proportion of patients who develop resistance (grown bacteria in urine) during the treatment period, by comparing resistance of grown bacteria in urine before and after therapy 3. Proportion of patients with bacteriological cure 4. Proportion of patients with sepsis-related mortality 5. Decline in kidney function as defined in the individual studies. Search methods for identification of studies Data extraction and management Data extraction was performed independently by two authors using standard data extraction forms. There were not studies reported in non-english language journals that had to be translated before assessment. Where more than one publication of one study exists, reports were grouped together and the publication with the most complete data was included. Where relevant outcomes are only published in earlier versions this data was used. Any discrepancy between published versions was highlighted. Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review. Disagreements were resolved by consultation with all authors. Electronic searches We searched the Cochrane Renal Group s Specialised Register up to 24 February 2015 through contact with the Trials Search Coordinator using search terms relevant to this review. The Cochrane Renal Group s Specialised Register contains studies identified from the following sources. 1. Quarterly searches of the Cochrane Central Register of Controlled Trials CENTRAL 2. Weekly searches of MEDLINE OVID SP 3. Handsearching of renal-related journals and the proceedings of major renal conferences 4. Searching of the current year of EMBASE OVID SP 5. Weekly current awareness alerts for selected renal journals 6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. See Appendix 1 for search terms used. Assessment of risk of bias in included studies The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (Appendix 2). Was there adequate sequence generation (selection bias)? Was allocation adequately concealed (selection bias)? Was knowledge of the allocated interventions adequately prevented during the study (detection bias)? Participants and personnel Outcome assessors Were incomplete outcome data adequately addressed (attrition bias)? Are reports of the study free of suggestion of selective outcome reporting (reporting bias)? Was the study apparently free of other problems that could put it at a risk of bias? Searching other resources 1. Reference lists of review articles and relevant studies. 2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies. Data collection and analysis Selection of studies The search strategy described was used to obtain titles and abstracts of studies that may be relevant to the review. Titles and abstracts were screened independently by two authors, who discarded studies that are not applicable; however, studies and reviews that included relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, if necessary the full text, of these studies to determine which satisfy the inclusion criteria. Measures of treatment effect For dichotomous outcomes (all outcomes considered in the review) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment, the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales have been used. Unit of analysis issues For studies with multiple intervention groups, the numbers of participants of similar treatment groups were aggregated and considered as one treatment arm; the control group was considered only once in the analyses. Dealing with missing data We attempted to contact authors of the included studies to obtain missing data or for clarification if required. 7

10 Assessment of heterogeneity Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity. Assessment of reporting biases There were not sufficient data and studies for funnel plots to be constructed to estimate precision of studies (plots of RR for efficacy against the sample size) for potential asymmetry and publication bias. Data synthesis Data were pooled using the random-effects model but the fixedeffect model was also used to ensure robustness of the model chosen and susceptibility to outliers. these subgroups available. Because of the likelihood of differences among the various agents used, adverse effects were tabulated and assessed using descriptive techniques (Table 1). Sensitivity analysis We conducted sensitivity analyses for studies that were found to include adequate concealment to allocation of treatment methodologies. We also compared high versus low risk random sequence generation. R E S U L T S Description of studies Subgroup analysis and investigation of heterogeneity We anticipated heterogeneity between studies for different antibiotics, doses, qualities of studies, duration of treatment and follow-up, random sequence generation and types of participants included: young, elderly, diabetic, those presenting with urinary tract abnormalities, immunosuppressed people, and among patients after removal of urinary catheters. Subgroup analyses were planned for these populations but could not be performed given the small number of studies included in the review and no separate data for Results of the search We identified 340 unique references of which we excluded 321 after inspection of the abstracts for the following reasons: not asymptomatic bacteriuria, not randomised or quasi-randomised, observational studies, no intervention of interest or outcomes for our review, review articles, papers not fulfilling our inclusion criteria. We considered that 19 reports were potentially eligible for inclusion, but after inspection of the full papers, we excluded eight reports of seven studies (Figure 1). Figure 1. Study flow diagram 8

11 Included studies Nine studies (11 reports) enrolling 1614 participants assigned to different antibiotics or placebo/no treatment met the pre-stated inclusion criteria for this review. The studies were conducted in Europe, USA, and Canada. Different inclusion criteria were used in the studies, still the thresholds for considering positive urine culture were similar across the studies; different definitions for the bacteriological cure were used in the studies (Characteristics of included studies). Duration of treatment varied from single-dose to up to six months treatment and follow-up was from six months up to eight years across the studies. One study had two treatment arms and the numbers of participants were aggregated and considered as one treatment arm, the control group was considered only once in the analysis (Giamarellou 1998). Interventions Four studies including 607 subjects compared antibiotics to placebo (Abrutyn 1994; Abrutyn 1996; Asscher 1969; Harding 2002). Eight studies including 1520 subjects compared antibiotics to no treatment (Abrutyn 1994, Abrutyn 1996, Boscia 1987, Cai 2012, Giamarellou 1998, Harding 2002, Nicolle 1983, Nicolle 1987). Three studies used placebo for the first part and no treatment for the second part of the study in the control group (Abrutyn 1994, Abrutyn 1996, Harding 2002). No other concomitant therapies were used in the studies. Outcomes All the studies reported at least one of the outcomes included in the review. Participants Participants included in the studies were men and women outpatient or from geriatric centres, independent or nursing home residents, with a diagnosis of asymptomatic bacteriuria. Four studies included participants younger than 65 years (Asscher 1969; Cai 2012; Harding 2002; Nicolle 1983); two of these studies gave no separate data for this group (Harding 2002; Nicolle 1983). One study included diabetic participants (Harding 2002). Excluded studies Seven studies were excluded after inspecting the full papers as they did not fulfil the inclusion criteria of the review; not randomised (2), wrong population (2); wrong intervention (1); outcomes not relevant to this review (2) (Characteristics of excluded studies). Risk of bias in included studies See Characteristics of included studies, Figure 2 and Figure 3 Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies 9

12 Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included study 10

13 Allocation Seven studies were RCTs and two were quasi-randomised (Abrutyn 1994; Abrutyn 1996); all used a parallel group design. Two studies described the randomisation process and allocation concealment was adequate (Asscher 1969, Boscia 1987), three described the randomisation generation but concealment to allocated treatment was unclear (Cai 2012; Harding 2002; Nicolle 1987). Two studies reported randomisation but the method of randomisation and concealment of allocation were not mentioned (Giamarellou 1998; Nicolle 1983). Two were quasi-randomised studies (Abrutyn 1994; Abrutyn 1996). Complications There was no difference in the number of complications between the antibiotic and placebo or no treatment arms (Analysis 1.2 (3 studies, 814 participants): RR 0.78, 95% CI 0.35 to 1.74; I 2 = 0%). Death There was no difference in the number of deaths between the antibiotic and placebo or no treatment arms (Analysis 1.3 (6 studies, 761 participants): RR 0.99, 95% CI 0.70 to 1.41; I 2 = 0%). Blinding Four studies were double-blind (Abrutyn 1994; Abrutyn 1996; Asscher 1969; Harding 2002), one single-blind (Boscia 1987), and three were open-label studies (Cai 2012; Giamarellou 1998; Nicolle 1987). One study did not mention blinding (Nicolle 1983). Incomplete outcome data One study did not describe loss to follow-up and performed intention to treat analyses (Abrutyn 1994). Loss to follow-up was described in the other studies. Any adverse event during treatment Significantly more adverse events were observed in the antibiotic treatment group compared to the placebo or no treatment group (Analysis 1.4 (3 studies, 248 participants): RR 3.77, 95% CI 1.40 to 10.15; I 2 = 0%). Developed resistance (grown bacteria in urine) during treatment One study reported resistant strains in 16 participants from the treatment arm after treatment compared to one participant in the no treatment arm. The number of evaluated participants for this outcome was not reported (Giamarellou 1998). Selective reporting No selective reporting was observed across the studies. Other potential sources of bias No other possible sources of bias were observed in the included studies, except funding for some studies. Effects of interventions See: Summary of findings for the main comparison Symptomatic urinary tract infection There was no difference in the number of symptomatic UTI between the antibiotic treatment and the placebo or no treatment arms (Analysis 1.1 (5 studies, 1046 participants): RR 1.11, 95% CI 0.51 to 2.43; I 2 = 91%). Heterogeneity is attributed to the Cai 2012 study which included a different population. Bacteriological cure Significantly more participants were cured in the antibiotic treatment arm compared to the placebo or no treatment arm (Analysis 1.5 (9 studies, 1154 participants): RR 2.32, 95% CI 1.11 to 4.83; I 2 = 95%). Heterogeneity could be attributed to the different definitions of bacteriological cure and study design across the studies. Sepsis-related mortality One study reported 3.8% (1/26) and 4.1% (1/24) mortality in the treatment and no treatment arms respectively. Different pathogens were isolated from those causing bacteriuria in the control group; UTI may have contributed to one death due to hyperosmolar coma in the treatment group (Nicolle 1987). Decline in kidney function The mean serum creatinine at the end of the study was similar to the initial value for both groups and the post-study creatinine concentration did not differ between groups in one study (Nicolle 1987a). There were non-statistically significant differences in the 11

14 serum creatinine levels between the treatment and no treatment arms in one study by the end of the study (P = 0.23) (Harding 2002). No decline in the kidney function was found in one study from mean laboratory values for serum creatinine (Giamarellou 1998). No data were available for performing a meta-analysis for this outcome. Sensitivity analyses Sensitivity analyses that were performed by allocation concealment or randomisation process did not change the results (Analysis 1.6; Analysis 1.7; Analysis 1.8; Analysis 1.9; Analysis 1.10), except for bacteriological cure. When all studies were included there was a statistically significant difference was obtained between the treatment arms. The results of the study that included only diabetic participants did not differ from the results of the other studies that included non-diabetic participants for the same outcomes by inspecting the graphs (Harding 2002). D I S C U S S I O N Summary of main results Asymptomatic bacteriuria is common and screening for this condition in pregnant women is a well-established, evidence-based standard of current medical practice. Screening other groups of adults has not been shown to improve outcomes (Lin 2008). Nine studies with 1614 participants were included in this review. Overall there was no evidence of any clinical benefit from treating asymptomatic bacteriuria for the categories of participants included. No differences between antibiotic treatment versus no treatment were observed for the development of symptomatic UTI, complications, mortality, decline in kidney function. More participants who received antibiotics were bacteriologically cured, but more adverse events were reported in this group mostly minor; six participants from two studies discontinued treatment because of adverse events (Table 1). Only one study reported sepsis related mortality in 3.8% (1/26) and 4.1% (1/24) in the treatment and no treatment groups, respectively; different pathogens from those causing bacteriuria were isolated in the control group and urinary infection may have contributed to one death due to hyperosmolar coma in the treatment group (Nicolle 1987). Mortality was not related to the asymptomatic bacteriuria in the other studies. Development of resistant urinary strains after treatment was reported in one study (Giamarellou 1998). Overall completeness and applicability of evidence The studies included young and elderly women and men outpatients or from geriatric centres. Overall, by inspecting the graphs, there were no significant differences between the results of the studies that included different populations, except for one study which included younger, sexually active women with recurrent UTI from a sexually transmitted disease centre; also, a definition for the bacteriological cure was not mentioned in this study (Cai 2012). Quality of the evidence The included studies were of medium and high quality (Risk of bias in included studies), used different treatments for different durations of treatment and follow-up, different populations, but this did not seem to influence the results of the individual studies. Heterogeneity between the results of the studies was observed for the bacteriological cure, different populations, different definitions of the bacteriological cure, different durations of treatment and follow-up across the studies and different methodology may have contributed to this finding. Less heterogeneity was observed when considering studies only by concealment. In one study participants developed more symptomatic UTI and had less bacteriological cure in the antibiotic treatment arm than in the no treatment arm as opposed to the results in the other studies included in the review; this could be attributed to the specific population included in this study (Cai 2012). Excluding this study from the meta-analysis did not change the result. Potential biases in the review process Meta-analyses were performed by using the random-effects model and, for testing the robustness of the results the fixed-effects model was used; no different results were obtained by using the two methods. Sensitivity analyses by allocation concealment and by randomisation process did not change the results. Agreements and disagreements with other studies or reviews Controversial results were found across different studies regarding the need for treatment of asymptomatic bacteriuria (Boscia 1986; Marketos 1969; Sourander 1972). The findings of our review are supported by current recommendations. Guidelines published by the IDSA in 2006 state that there is no measurable benefit to screen for or provide antibiotic treatment of asymptomatic bacteriuria in the following patients: premenopausal women who are not pregnant; patients with diabetes elderly patients living in the community and in long-term care facilities; and in patients with 12

15 spinal cord injury or indwelling bladder catheter. Exceptions occur when the patient is pregnant or when the urinary tract will be surgically manipulated (Nicolle 2005). The US Preventive Services Task Force has published recommendations similar to those of the IDSA (Lin 2008), based on evidence from systematic reviews, meta-analyses, RCTs, cohort and case-control studies and case series of large multi-site databases. The incorrect management of asymptomatic bacteriuria is a worldwide problem. The Scottish Intercollegiate Guidelines Network, among others, has evaluated the issue thoroughly and has concluded that asymptomatic bacteriuria is a benign disorder for which treatment is not indicated (SIGN 2012). Reduction of indiscriminate use of antimicrobial therapy and of the appearance of multidrug-resistant organisms is therefore recommended (Gross 2007). A U T H O R S C O N C L U S I O N S Implications for practice Treating asymptomatic bacteriuria with antibiotics did not show any clinical benefit in our review. More eradication of urinary pathogens was obtained but at the cost of significant more adverse events. Current recommendations for treating asymptomatic bacteriuria should be followed until proved otherwise. Implications for research It is unlikely that more studies in the general population would change the results we show here. Studies on treatment of asymptomatic bacteriuria are needed in persons with diabetes. A C K N O W L E D G E M E N T S We would like to thank the referees for their comments and feedback during the preparation of this review, Ruth Mitchell (Trials Search Coordinator) and Narelle Willis (Managing Editor) from the Renal Group for their support, Dr Lindsay Nicolle for her reply and information on missing data and peer referees Hashim U. Ahmed, David Mehr and Herney Andres Garcia-Perdomo. R E F E R E N C E S References to studies included in this review Abrutyn 1994 {published data only} Abrutyn E, Mossey J, Berlin JA, Boscia J, Levison M, Pitsakis P, et al. Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?. Annals of Internal Medicine 1994;120(10): [MEDLINE: ] Abrutyn 1996 {published data only} Abrutyn E, Berlin J, Mossey J, Pitsakis P, Levison M, Kaye D. Does treatment of asymptomatic bacteriuria in older ambulatory women reduce subsequent symptoms of urinary tract infection?. Journal of the American Geriatrics Society 1996;44(3): [MEDLINE: ] Asscher 1969 {published data only} Asscher AW, Sussman M, Waters WE, Evans JA, Campbell H, Evans KT, et al. Asymptomatic significant bacteriuria in the non-pregnant woman. II. Response to treatment and follow-up. British Medical Journal 1969;1(5647): [MEDLINE: ] Sussman M, Asscher AW, Waters WE, Evans JA, Campbell H, Evans KT, et al. Asymptomatic significant bacteriuria in the non-pregnant woman. I. Description of a population. British Medical Journal 1969;1(5647): [MEDLINE: ] Boscia 1987 {published data only} Boscia JA, Kobasa WD, Knight RA, Abrutyn E, Levison ME, Kaye D. Therapy vs no therapy for bacteriuria in elderly ambulatory nonhospitalized women. JAMA 1987; 257(8): [MEDLINE: ] Cai 2012 {published data only} Cai T, Mazzoli S, Mondaini N, Meacci F, Nesi G, D Elia C, et al. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat?. Clinical Infectious Diseases 2012;55(6): [MEDLINE: ] Cai T, Mazzoli S, Mondaini N, Meacci F, Nesi G, Luciani LG, et al. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: To treat or not to treat [abstract]. European Urology, Supplements 2012; 11(1):e188 e188a. [EMBASE: ] Giamarellou 1998 {published data only} Giamarellou H, Dontas AS, Zorbas P, Staszewska-Pistoni M, Xirouchaki E, Petrikkos G. Asymptomatic bacteriuria in freely voiding elderly subjects. Long-term continuous vs pulse treatment with ofloxacin. Clinical Drug Investigation 1998;15(3): [EMBASE: ] Harding 2002 {published data only} Harding GK, Zhanel GG, Nicolle LE, Cheang M, Manitoba Diabetes Urinary Tract Infection Study Group. Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. New England Journal of Medicine 2002;347(20): [MEDLINE: ] Nicolle 1983 {published data only} Nicolle LE, Bjornson J, Harding GK, MacDonell JA. Bacteriuria in elderly institutionalized men. New England 13

16 Journal of Medicine 1983;309(23): [MEDLINE: ] Nicolle 1987 {published data only} Nicolle LE, Mayhew WJ, Bryan L. Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women. American Journal of Medicine 1987;83(1): [MEDLINE: ] References to studies excluded from this review Butler 1995 {published data only} Butler P, Hamilton-Miller JM, McIntyre N, Burroughs AK. Natural history of bacteriuria in women with primary biliary cirrhosis and the effect of antimicrobial therapy in symptomatic and asymptomatic groups. Gut 1995;36(6): [MEDLINE: ] Dalal 2009 {published data only} Dalal S, Nicolle L, Marrs CF, Zhang L, Harding G, Foxman B. Long-term Escherichia coli asymptomatic bacteriuria among women with diabetes mellitus. Clinical Infectious Diseases 2009;49(4): [MEDLINE: ] Freeman 1968 {published data only} Freeman RB, Bromer L, Brancato F, Cohen SI, Garfield CF, Griep RJ, et al. Prevention of recurrent bacteriuria with continuous chemotherapy. Annals of Internal Medicine 1968;69(4): [MEDLINE: ] Freeman RB, Smith WM, Richardson JA, Hennelly PJ, Thurm RH, Urner C, et al. Long-term therapy for chronic bacteriuria in men. U.S. Public Health Service cooperative study. Annals of Internal Medicine 1975;83(2): [MEDLINE: ] Giamarellou 2007 {published data only} Giamarellou H, Dontas AS, Petrikkos G, Gnardellis C, Zorbas P, Philippou P. Survival of elderly bacteriuric subjects following long-term quinolone therapy. Journal of Chemotherapy 2007;19(2): [MEDLINE: ] Harding 1973 {published data only} Harding GK, Ronald AR. Clinical experiences: genitourinary infections. A. Infections of the urinary tract. Efficacy of trimethoprim-sulfamethoxazole in bacteriuria. Journal of Infectious Diseases 1973;128(Suppl): [MEDLINE: ] Nicolle 2006 {published data only} Nicolle LE, Zhanel GG, Harding GK. Microbiological outcomes in women with diabetes and untreated asymptomatic bacteriuria. World Journal of Urology 2006; 24(1):61 5. [MEDLINE: ] Renneberg 1984 {published data only} Renneberg J, Paerregaard A. Single-day treatment with trimethoprim for asymptomatic bacteriuria in the elderly patient. Journal of Urology 1984;132(5): [MEDLINE: ] Additional references Boscia 1986 Boscia JA, Kobasa WD, Abrutyn E, Levison ME, Kaplan AM, Kaye D. Lack of association between bacteriuria and symptoms in the elderly. American Journal of Medicine 1986;81(6): [MEDLINE: ] Colgan 2006 Colgan R, Nicolle LE, McGlone A, Hooton TM. Asymptomatic bacteriuria in adults. American Family Physician 2006;74(6): [MEDLINE: ] Dontas 1981 Dontas AS, Kasviki-Charvati P, Papanaylotou PC, Mareketos SG. Bacteriuria and survival in old age. New England Journal of Medicine 1981;304(16): [MEDLINE: ] Evans 1982 Evans DA, Kass EH, Hennekens CH, Rosner B, Miao L, Kendrick MI, et al. Bacteriuria and subsequent mortality in women. Lancet 1982;1(8264): [MEDLINE: ] Geerlings 1999 Geerlings SE, Brouwer EC, Gaastra W, Verhoel J, Hoepelman AI. Effect of glucose and ph on uropathogenic and non-uropathogenic Escherichia coli: studies with urine from diabetic and non-diabetic individuals. Journal of Medical Microbiology 1999;48(6): [MEDLINE: ] Geerlings 2000 Geerlings SE, Stolk RP, Camps MJ, Netten PM, Collet TJ, Hoepelman AI, et al. Risk factors for symptomatic urinary tract infection in women with diabetes. Diabetes Care 2000; 23(12): [MEDLINE: ] Geerlings 2001 Geerlings SE, Stolk RP, Camps MJ, Netten PM, Collet JT, Schneeberger PM, et al. Consequences of asymptomatic bacteriuria in women with diabetes mellitus. Archives of Internal Medicine 2001;161(11): [MEDLINE: ] Geerlings 2008 Geerlings SE. Urinary tract infections in patients with diabetes mellitus: epidemiology, pathogenesis and treatment. International Journal of Antimicrobial Agents 2008;31 Suppl 1:S54 7. [MEDLINE: ] Gross 2007 Gross PA, Patel B. Reducing antibiotic overuse: a call for a national performance measure for not treating asymptomatic bacteriuria. Clinical Infectious Diseases 2007; 45(10): [MEDLINE: ] Guinto 2010 Guinto VT, De Guia B, Festin MR, Dowswell T. Different antibiotic regimens for treating asymptomatic bacteriuria in pregnancy. Cochrane Database of Systematic Reviews 2010, Issue 9. [DOI: / CD pub2] Heinamaki 1986 Heinamaki P, Haavisto M, Hakulinen T, Mattila K, Rajala S. Mortality in relation to urinary characteristics in the 14

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