Research

Natural history of uncomplicated urinary tract infection without antibiotics: a systematic review

Tammy Hoffmann, Ruwani Peiris, Chris Del Mar, Gina Cleo and Paul Glasziou
British Journal of General Practice 2020; 70 (699): e714-e722. DOI: https://doi.org/10.3399/bjgp20X712781

Abstract

Background Although uncomplicated urinary tract infection (UTI) is commonly treated with antibiotics, the duration of symptoms without their use is not established; this hampers informed decision making about antibiotic use.

Aim To determine the natural history of uncomplicated UTI in adults.

Design and setting Systematic review.

Method PubMed was searched for articles published until November 2019, along with reference lists of articles identified in the search. Eligible studies were those involving adults with UTIs in either the placebo group of randomised trials or in single-group prognostic studies that did not use antibiotics and measured symptom duration. A modified version of a risk of bias assessment for prognostic studies was used. Outcomes were the percentage of patients who, at any time point, were symptom free, had symptom improvement, or had worsening symptoms (failed to improve). Adverse event data were also extracted.

Results Three randomised trials (346 placebo group participants) were identified, all of which specified women only in their inclusion criteria. The risk of bias was generally low, but incomplete reporting of some details limited assessment. Over the first 9 days, the percentage of participants who were symptom free or reported improved symptoms was reported as rising to 42%. At 6 weeks, the percentage of such participants was 36%; up to 39% of participants failed to improve by 6 weeks. The rate of adverse effects was low and, in two trials, progression to pyelonephritis was reported in one placebo participant.

Conclusion Although some uncertainty around the natural history of uncomplicated UTIs remains, some women appear to improve or become symptom free spontaneously, and most improvement occurs in the first 9 days. Other women either failed to improve or became worse over a variable timespan, although the rate of serious complications was low.

INTRODUCTION

Uncomplicated urinary tract infections (UTIs) are very common in general practice, and UTI symptoms can be burdensome and impact a person’s quality of life.1 Antibiotics are usually used to manage UTIs on the assumption that they reduce the duration and severity of symptoms and complications. However, evidence from randomised trials about the efficacy of antibiotics in UTIs shows that the benefit/harm trade-off of antibiotic use must be considered.2 Additionally, it is known that, as well as possible harms to individual patients, antibiotic use promotes antibiotic resistance — a serious threat to modern medicine.3

Clinicians and patients overestimate the benefits and underestimate the harms of treatments;4 for acute respiratory infections, for example, they greatly overestimate the reduction in symptom duration from antibiotic use.5 As well as inaccurate expectations about antibiotic benefits, clinicians and patients may have poor awareness about possible antibiotic harms, including resistance, and the natural course of infections. Without such information, evidence-based decision making — in which the benefits and harms of antibiotic use are carefully considered,4 along with patients’ preferences and values — is not possible.

As far as the authors are aware, there is no known synthesis of the research regarding the resolution of symptoms and complications if antibiotics are not used in the management of uncomplicated UTIs in adults; as such, this review aimed to determine the natural course of symptoms of such patients.

METHOD

Eligibility criteria

The reviewers aimed to identify studies that met the following criteria:

  • included adults who had uncomplicated UTI;

  • reported outcome data on the duration of UTI symptoms; and

  • included a group that received no therapeutic treatment (that is, placebo or ‘no treatment’) — this could be either a comparison group in a randomised trial or a single-group prognosis study (such as a cohort study).

Studies were excluded if the study population had any of the following features:

  • asymptomatic UTIs;

  • asymptomatic bacteriuria;

  • complicated UTI (for example, pyelonephritis and sepsis);

  • recurrent UTI;

  • chronic UTI;

  • emphysematous cystitis;

  • Candida infection;

  • haemorrhagic cystitis;

  • interstitial cystitis; or

  • schistosomiasis.

Uncomplicated urinary tract infections (UTIs) are a very common reason for general practice consultations and one of the most common reasons for the prescription of antibiotics. Informed decision making should consider the benefit/harm trade-off of antibiotic use and the natural course of the illness. The studies reviewed here, which focused solely on women, demonstrated that UTI symptoms resolve spontaneously in approximately a third of women in the first 7–10 days. Current guideline recommendations from the National Institute for Health and Care Excellence are to delay prescribing by 2 days but the findings of this systematic review indicate that this may be too short a timeframe.

How this fits in

Search methods

In May 2019, a search was conducted using PubMed to identify systematic reviews (as a method of identifying potentially eligible randomised trials) and prognosis studies (search strings are detailed in Supplementary Box S1). Potentially relevant articles were also identified from the references of articles identified during the screening process. An updated search was conducted on 20 November 2019, but no further eligible articles were found.

Screening and eligibility assessment

One researcher screened the search results and held discussions with a second researcher about eligibility, as needed. Articles in foreign languages were potentially eligible and translated for screening purposes using Google Translate.

Risk of bias assessment and data extraction

As the reviewers were focused on using prognosis outcome data, a modified version of a risk of bias assessment framework proposed by Altman et al 6 was used to assess the included studies. The following study and methodological quality characteristics were also extracted from each included study:

  • country;

  • study design;

  • sample size;

  • participant age;

  • participant sex;

  • UTI diagnosis criteria;

  • method of randomisation;

  • exclusion criteria;

  • concurrent treatments; and

  • duration of follow-up.

To obtain information regarding the proportion of patients who were symptom free, data were extracted from the studies, either directly from the published text and tables or, where needed, by using WebPlotDigitizer extraction software (https://automeris.io/WebPlotDigitizer) to retrieve values from the figures. Where possible, in those trials in which participants left the placebo group because of worsening symptoms and commenced antibiotics, the percentage outcome data were calculated using as the denominator the total number of participants who were initially randomised to the placebo group.

Outcomes

Data were extracted for the following outcomes from participants in the placebo group:

  • ‘symptom free’ — percentage of participants who were symptom free at any time point;

  • ‘symptoms improved’ — percentage of participants who had improved symptoms at any time point; and

  • ‘failure to improve’ — percentage of participants who had worsening of symptoms at any time point.

Data were also extracted regarding the rate of crossover from placebo to antibiotic groups, reasons for the crossover, and adverse events in both treatment and placebo group participants. In some studies, percentage values were given for a time range (for example, ‘x’% symptom free at 5–7 weeks); in these cases, the median time point was used to present values graphically (for example, ‘x’% symptom free at 6 weeks).

Data analysis

Outcome data were graphed on scatter plots against time to enable visualisation of the rate of symptom resolution. The diameter of the data points on the scatter plots was adjusted to represent each study’s sample size.

RESULTS

The article selection process is outlined in Figure 1. Four articles7–10 met the eligibility criteria and were included. Two of the included articles were from one trial conducted by Ferry et al;9,10 these articles use data taken from the same cohort of patients and, as such, were treated as one dataset. The 2007 article10 reported outcomes from a bacterial culture-positive subset of participants. Data on symptom duration were reported in, and extracted from, the 2004 article;9 adverse effects were reported in, and extracted from, the 2007 article.10

Figure 1.
Figure 1.

Flowchart of study recruitment. RCT = randomised controlled trial. SR = systematic review.

Table 1 details characteristics of the included studies. There were 346 placebo participants in total, with Ferry et al ’s trial providing the majority (83%) of these. All participants were non-pregnant adult women, as this was an inclusion criterion for all three trials. Mean age was not consistently reported and the age criteria across the studies ranged from 15–82 years. There was variation in the diagnostic criteria, with dysuria the only criterion common to all three studies. Follow-up was up to 3 months in one study,7 but, for the outcomes relevant to this review, the longest follow-up time was 6 weeks. Most of the outcome data were collected within 2 weeks.

View this table:
Table 1.

Characteristics of included studies

Randomisation was reported in all studies, although little detail of the randomisation method was provided (Table 2). In one study,7 two trials were conducted from one recruitment process: the trial eligible for this review involved a subset of participants classified as bacteriuria negative (urine <104 organisms/ml) who were randomised to either placebo or an antibiotic; the other trial was in women with a significant bacteriuria count (that is, ≥105 organisms/ml) and compared two antibiotics. Using the selected elements of Altman’s risk assessment framework,6 a low-tomoderate risk of bias was determined for the prognostic outcome data.

View this table:
Table 2.

Risk of bias assessment

Synthesis of results

Interpretation of time points

The time points for the data values were not clearly defined in the studies. In Ferry et al ’s trial, symptoms were measured from inclusion or the first day of treatment, but the number of days patients had symptoms prior to this was not reported. Those trials by Brooks et al and Christiaens et al defined neither the starting point for the time points of measured symptoms nor the duration of symptoms prior to study inclusion.

Symptom free or symptom improvement

Symptom improvement over the first 9 days shows a rise, to a maximum of 42% of participants (Figure 2, Table 3). At 6 weeks there was only one data point at 54%, or 36% of participants after the authors adjusted for crossovers (Table 3).

Figure 2.
Figure 2.

Symptom progression. Participants reporting being ‘symptom free’ (outlined circle) or having ‘symptom improvement’ (solid circle).a,b

a Diameter of circles represents weighting by study sample size. Crossover refers to participants in the placebo group who had worsening symptoms and had commenced antibiotic treatment by the time of follow-up.

bThe first 7 days of data from the Ferry 2004 study9 come from the participant daily symptom diary and are not shown inTable 3.

View this table:
Table 3.

Symptom progression results

Individual symptoms

Data for individual symptoms were only available from Ferry et al ’s (2004) article and resolution in 100% of participants was not seen for any symptom, even at 6 weeks. Throughout the follow-up period, a larger percentage of participants were free of suprapubic pain and loin pain compared with dysuria and urgency, for example, at 9 days, 82% of participants were free of suprapubic pain and 85% free of loin pain, compared with 65% for dysuria and 62% for urgency (Figure 3).

Figure 3.
Figure 3.

Symptom progression. Participants reporting being symptom free, by individual symptoms and all symptoms.

aResults all from Ferry SA, Holm SE, Stenlund H, et al . The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis 2004.9 Reprinted by permission of Informa UK Limited, trading as Taylor & Francis Group, www.tandfonline.com.

Failure to improve, and crossover to antibiotic treatment

The percentage of participants who failed to improve over 6 weeks ranged from 16% to 39%, with a large proportion of participants in the placebo group in Ferry et al ’s trial commencing antibiotics because of worsening symptoms (Figure 4, Table 3). Only Brooks et al ’s study did not measure failure to improve explicitly, but rather recorded the number of participants with persisting symptoms. In the studies by Ferry et al and Christiaens et al, rates of leaving the trial because of persistent or worsening symptoms were also interpreted as ‘failure to improve’ and, as such, were included in the review analysis (Figure 4, Table 3). Christiaens et al reported numbers and reasons for placebo participants commencing antibiotics.

Figure 4.
Figure 4.

Symptom progression. Participants with clinical failure to improve.a

aDiameter of circles represents weighting by study sample size. Crossover refers to participants in the placebo group who had worsening symptoms and had commenced antibiotic treatment by the time of follow-up.

In Ferry et al ’s trial, a large proportion of the placebo cohort dropped out prior to the 6-week follow up, because of non-resolving or worsening symptoms, and commenced antibiotics; these participants were also considered as having failed to improve. These ‘crossover’ numbers are not represented in the symptom-free data reported by the authors in the articles. The authors reported that, if these crossovers were accounted for at 6 weeks, the percentage of patients who were symptom free would be 36% rather than 54% (Figure 2). The crossover numbers are not reported for the other time points in Ferry et al ’s study — it is likely that the true values at these time points would also be lower. The reviewers were unable to reconcile a discrepancy in the data in Ferry et al ’s 2004 article: the value of 42% at 9 days is from extracted data derived from a figure included in the article, whereas the reported value in a table in the same article suggested the value was 28%.

Adverse effects and serious complications

The incidence of generalised adverse effects in the placebo groups did not appear to be markedly higher than those in the treatment groups (Table 4). The progression to pyelonephritis or other serious complications was uncommon (Table 4).

View this table:
Table 4.

Incidence rates of adverse events and serious complicationsa

DISCUSSION

Summary

This review of studies that reported on the natural course of UTI symptoms in adults who were managed without antibiotic treatment identified placebo groups from three randomised trials. All three studies included women only; one trial9 predominated with the most data and the largest number of participants. The reviewers found that some women appear to improve or become symptom free without the use of antibiotics, with most improvement in the first 9 days. However, some women who did not receive antibiotic treatment either failed to improve or became worse, over a variable timespan, although the rates of serious complications (for example, pyelonephritis) were low.

Strengths and limitations

This review adopted a novel approach to providing prognostic information that is important for clinical decision making regarding this condition by examining the natural history data that were available from placebo-controlled trials. A possible limitation is that systematic reviews were searched for as a method of identifying relevant randomised trials, as new trials may have been published since the most recently published systematic review conducted its search. However, this pragmatic approach was taken as a number of systematic reviews of trials involving the use of antibiotics for UTIs have been conducted and would have already identified potentially eligible trials. Heterogeneity (such as in UTI definition, symptom definition, and timing of outcome measurement) precluded a meta-analysis being conducted.

Other limitations with the available data include:

  • unclear duration of symptoms prior to study inclusion;

  • loss of follow-up data from some participants who left the placebo groups to commence antibiotics;

  • most of the findings derived from one study;

  • variation in the studies’ inclusion and exclusion criteria — for example, Brooks et al ’s study comprised women with symptoms who had negative or non-significant bacteriuria; and

  • unclear reporting on details of randomisation methods.

The unclear reporting of randomisation methods limited the ability to identify biases, but, in the two trials that reported baseline characteristics, these were similar; this suggests the randomisation was adequate.

In the three trials included in the review, outcome definitions differed, for example, ‘improvement’ (symptom severity versus number of symptoms) and ‘relapse/failure’ (defined by bacteriuria versus symptoms versus both). No studies reported on the use of over-the-counter medications — although their use may influence symptom scores, this is also reflective of what many women with UTI are likely to do.11 Most treatments for symptoms have not been evaluated in placebo-controlled trials (for example, urinary alkalisers12), which also precludes their inclusion in this review as an additional source of natural history data.

Comparison with existing literature

The body of evidence to inform the natural history of uncomplicated UTI does not appear to be expanding. A systematic review and meta-analysis published in 20092 on the effectiveness of antibiotics for UTIs identified the three placebo-controlled trials included in this current review, as well as another two that did not meet the inclusion criteria because it was unclear whether, and how, they measured symptom resolution.13,14 An observational study, conducted between 2002 and 2005, of women with suspected uncomplicated UTI reported a mean symptom duration of 3.83 days in the 511 women who saw a clinician for their symptoms and rated the problem as moderately bad or worse;15 however, in that sample, only 17 participants (approximately 3%) did not take antibiotics and their mean symptom duration was 4.94 days.

It was noted that loin pain, usually associated with renal involvement of a UTI, appeared to be present at study inclusion in 40% of participants in Ferry et al ’s trial. This seems unusually high; Ferry et al (2004)9 suggested the symptom diary method of data collection used may have contributed to this and, therefore, documented an incidence rate that was, likely, more accurate but higher than those reported in other studies.

Implications for practice and research

There are insufficient data to be certain about the natural history, including the duration of symptoms and rate of recovery, of uncomplicated UTI that is not managed with antibiotics. The available evidence shows that some UTIs resolve spontaneously over a few weeks. The reviewers found that, at 6 weeks, up to a third of women, approximately, who did not receive antibiotics were symptom free, with approximately another third requiring antibiotics for worsening symptoms between 1 and 6 weeks.

There is inconsistency and a lack of evidence in guideline recommendations about the use of antibiotics for uncomplicated UTI. As an example, guidelines from the Infectious Disease Society of America do not mention using a delayed prescribing approach and consider withholding antibiotics as unjustified,16 whereas guidelines for the UK published by the National Institute for Health and Care Excellence (NICE) recommend a delayed prescribing approach by commencing antibiotic use if there is no symptom improvement in 2 days.17 Therapeutic Guidelines (Australia) state that most women aged <65 years become symptom free within 1 week without the use of antibiotics.18 The NICE guideline recommendation of waiting for 2 days does not appear to be informed by research, and it is also unclear whether the 2-day timeframe is from the start of symptoms or from first consultation.17 The findings from the review presented here suggest this timeframe may be too short, with few participants likely to have improved within 2 days, although approximately a third will have improved by 7–10 days. The low rate of serious complications supports the practice of delayed prescribing to see whether symptoms self-resolve, before treatment is commenced, if required. These findings may assist clinicians to engage in collaborative decision making with their patients and discuss the possible course of the illness, with and without antibiotics, and to consider the benefits and harms of antibiotics. Information about the expected course of untreated UTI may also help patients to frame their expectations about recovery timeframes.

Certainty about the natural history of uncomplicated UTIs would be increased by additional primary research that, ideally, would involve rigorous studies with appropriate sample sizes, follow-up beyond the first few weeks of symptoms, use of standardised outcome measure descriptions and timing, and studies that include men. Further primary research is also needed for promising non-antibiotic treatments for UTIs, for example, non-steroidal anti-inflammatory drugs or increased oral fluids.19,20

Acknowledgments

The authors would like to thank Justin Clark for his assistance in conducting the searches.

Notes

Funding

This review was conducted as part of the work of the Centre for Research Excellence in Minimising Antibiotic Resistance in the Community (CRE-MARC), funded by the National Health and Medical Research Council (NHMRC), Australia (reference number: 1153299). The funder had no involvement in this systematic review.

Ethical approval

Not required.

Provenance

Freely submitted; externally peer reviewed.

Competing interests

The authors have declared no competing interests.

Discuss this article

Contribute and read comments about this article: bjgp.org/letters

  • Received January 24, 2020.
  • Revision requested February 16, 2020.
  • Accepted March 11, 2020.

REFERENCES

  1. 1.↵
    1. Ellis AK,
    2. Verma S
    Quality of life in women with urinary tract infections: is benign disease a misnomer?J Am Board Fam Pract2000136392397
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Falagas ME,
    2. Kotsantis IK,
    3. Vouloumanou EK,
    4. Rafailidis PI
    Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trialsJ Infect200958291102
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Bakhit M,
    2. Hoffmann T,
    3. Scott AM,
    4. et al.
    Resistance decay in individuals after antibiotic exposure in primary care: a systematic review and meta-analysisBMC Med2018161126
    OpenUrl
  4. 4.↵
    1. Hoffmann TC,
    2. Del Mar C
    Clinicians’ expectations of the benefits and harms of treatments, screening, and tests: a systematic reviewJAMA Intern Med20171773407419
    OpenUrl
  5. 5.↵
    1. Coxeter PD,
    2. Del Mar C,
    3. Hoffmann TC
    Parents’ expectations and experiences of antibiotics for acute respiratory infections in primary careAnn Fam Med2017152149154
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Altman DG
    Systematic reviews of evaluations of prognostic variablesBMJ20013237306224228
    OpenUrlFREE Full Text
  7. 7.↵
    1. Brooks D,
    2. Garrett G,
    3. Hollihead R
    Sulphadimidine, co-trimoxazole, and a placebo in the management of symptomatic urinary tract infection in general practiceJ R Coll Gen Pract197222123695703
    OpenUrlPubMed
  8. 8.
    1. Christiaens TCM,
    2. De Meyere M,
    3. Verschraegen G,
    4. et al.
    Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult womenBr J Gen Pract200252482729734
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Ferry SA,
    2. Holm SE,
    3. Stenlund H,
    4. et al.
    The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled studyScand J Infect Dis2004364296301
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Ferry SA,
    2. Holm SE,
    3. Stenlund H,
    4. et al.
    Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW projectScand J Prim Health Care20072514957
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Continence Foundation of Australia
    Your guide to UTIsCFAhttps://continence.org.au/news/your-guide-utis (accessed 6 September 2020).
  12. 12.↵
    1. O’Kane DB,
    2. Dave SK,
    3. Gore N,
    4. et al.
    Urinary alkalisation for symptomatic uncomplicated urinary tract infection in womenCochrane Database Syst Rev201644CD010745
    OpenUrl
  13. 13.↵
    1. Asbach HW
    Single dose oral administration of cefixime 400mg in the treatment of acute uncomplicated cystitis and gonorrhoeaDrugs199142Suppl 41013
    OpenUrl
  14. 14.↵
    1. Dubi J,
    2. Chappuis P,
    3. Darioli R
    [Treatment of urinary infection with a single dose of co-trimoxazole compared with a single dose of amoxicillin and a placebo]Schweiz Med Wochenschr198211239092
    OpenUrlPubMed
  15. 15.↵
    1. Little P,
    2. Merriman R,
    3. Turner S,
    4. 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 studyBMJ2010340b5633
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Gupta K,
    2. Hooton TM,
    3. Naber KG,
    4. et al.
    International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious DiseasesClin Infect Dis2011525e103e120
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. National Institute for Health and Care Excellence
    Urinary tract infection (lower): antimicrobial prescribingLondonNICE2018https://www.nice.org.uk/guidance/ng109 (accessed 17 Apr 2020).
  18. 18.↵
    1. Therapeutic Guidelines Limited
    Treatment of acute cystitis in adultsMelbourneTherapeutic Guidelines Limited(eTG December 2019 edition).
  19. 19.↵
    1. Kronenberg A,
    2. Bütikofer L,
    3. Odutayo A,
    4. et al.
    Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trialBMJ2017359j4784
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Scott AM,
    2. Clark J,
    3. Del Mar C,
    4. Glasziou P
    Increased fluid intake to prevent urinary tract infections: systematic review and meta-analysisBr J Gen Pract2020DOI:https://doi.org/10.3399/bjgp20X708125
View Abstract
Back to top

In this issue

British Journal of General Practice: 70 (699)
British Journal of General Practice
Vol. 70, Issue 699
October 2020
Download PDF
Download PowerPoint
Article Alerts
Email Article
Citation Tools

Natural history of uncomplicated urinary tract infection without antibiotics: a systematic review
Tammy Hoffmann, Ruwani Peiris, Chris Del Mar, Gina Cleo, Paul Glasziou
British Journal of General Practice 2020; 70 (699): e714-e722. DOI: 10.3399/bjgp20X712781
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords

Advertisement

 
 

British Journal of General Practice