Antibiotic failure in the treatment of urinary tract infections in young women

Ross A. Lawrenson,* and John W. Logie

Postgraduate Medical School, University of Surrey, Stirling House, Surrey Research Park, Guildford GU2 7DJ, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Urinary tract infections (UTIs) are a common problem in young women. The aim of this study was to describe the pattern of antibiotic prescribing to young women presenting with new UTIs and to investigate the proportion who required further treatment if prescribed antibiotics. A secondary aim was to investigate whether the likelihood of treatment failure varied between different antibiotics and, in the case of trimethoprim (the antibiotic most frequently prescribed for UTIs) between prescriptions of different duration. The study included all women aged 15–44 years registered on the UK General Practice Research Database. All diagnoses of UTI or cystitis with an associated prescription for an antibiotic were identified. A further prescription of an antibiotic within 28 days was taken to indicate failure of the initial treatment. Overall, 14% of 75045 newly treated patients with UTI received a second antibiotic within 28 days. Older women, aged 35–44, pregnant patients and those with diabetes were significantly more likely to require further treatment. With trimethoprim as the reference antibiotic, after 28 days patients prescribed amoxicillin were significantly more likely to require a second course of antibiotics. Those prescribed co-trimoxazole were significantly less likely to require further treatment. In each case the difference in failure rate was small and may be of little clinical significance. There was no significant difference between trimethoprim and nitrofurantoin, norfloxacin, ciprofloxacin or the cephalosporins. Three-day prescriptions for trimethoprim appeared as effective as those for 5 or 7 days. This study gives some observational evidence of the effectiveness of antibiotic prescribing in young women with UTIs and shows that between 12% and 16% of patients will return within 28 days for further treatment, irrespective of the antibiotic prescribed initially.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
General practitioners are frequently consulted by young women with urinary frequency and dysuria. Approximately 3% of young women will present with these symptoms in any one year.1 In such cases a decision must be made as to whether the patient has a bacterial infection. This is influenced by age and how well the doctor knows the patient.2 The recommended treatment for severe symptoms is a short course of appropriate empirical antibiotic and up to 95% of general practitioners will prescribe before the results of any bacteriological investigation are available, if any investigations are undertaken at all.1 The antibiotic chosen will reflect the fact that the organism is most likely to be Escherichia coli3–5 and that a number of broad-spectrum antibiotics that have proved effective in clinical trials are recommended by the British National Formulary (BNF).6 There has been an increasing problem with antibiotic resistance to common organisms both in the UK and overseas. There is concern that resistance to the two antibiotics prescribed most frequently, trimethoprim and amoxicillin, is increasing.5,7,8 Although a common cause of treatment failure is antibiotic resistance, one study has shown that the bacteriological cure rate is the same irrespective of the susceptibilities of the infecting organism.4 It therefore seems reasonable to ask ‘Which treatment is most likely to cure a patient with these symptoms and reduce the need for a further course of antibiotics?' This would seem to be a more objective measure of treatment failure than repeat consultation, which can be influenced by the duration of the original prescription.9

The UK Chief Medical Officer has indicated that resistance to commonly used antibiotics is a major threat to public health. The goals set for the National Health Service (NHS) include minimizing morbidity and mortality due to antimicrobial-resistant infection, contributing to the control of antimicrobial-resistant organisms and facilitating more efficient and effective use of NHS resources.10 When considering the management of urinary tract infections (UTIs) in young women, the issues of efficiency and effectiveness probably guide general practitioner prescribing in the UK. Empirical prescribing of antibiotics is cost effective.11 The choice of antibiotic will be influenced by knowledge of the resistance patterns of urinary pathogens locally, although the correlation between in vitro resistance and clinical outcome is far from absolute.7

The aim of this study was to describe the pattern of antibiotic prescribing to young women presenting with signs of new UTI, and to investigate the proportion who will require further treatment if prescribed antibiotic. A secondary aim was to investigate whether the likelihood of treatment failure varied between different antibiotics and, in the case of trimethoprim, the antibiotic most frequently prescribed for UTIs, between prescriptions of different duration.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was carried out using the General Practice Research Database (GPRD), a computerized database of anonymized patient records drawn from a sample of representative general practices throughout the UK. The database contains high quality data on demographic characteristics, consultation details, risk factors, diagnosis, prescribing and outcomes for c. 5.4 million people resident in the UK. Data quality is monitored continuously, and its validity for epidemiological studies has been described elsewhere.12 This study was approved by the Scientific and Ethical Advisory Group of the Department of Health.

The study population included all women aged 15–44 years between 1992 and 1999 with at least 6 months data on the GPRD. Patients were followed from initial registration, and all ‘new' diagnoses of a UTI or cystitis, as indicated by the appropriate symptom code, were identified. A ‘new' diagnosis was defined as a UTI in a patient with no record of these symptoms during the preceding 6 months. Pregnancy or diabetes at the time of the event was identified from the patient records. Data were not generally available on the results of urine analysis. The antibiotic prescribed on the date of the record of cystitis/ UTI was identified, allowing the patterns of prescribing to be described. All patients with a diagnosis plus a prescription were then followed for 28 days and any further prescriptions of an antibiotic were noted. The need for a further antibiotic during this time was taken to indicate failure of the initial treatment. All products classified as ‘antibacterial drugs' by the BNF were included as antibiotics. Antifungals were not considered.

There is no requirement for prescribing data to be linked to a symptom code within the GPRD. To account for the possibility that the initial (or subsequent) antibiotic treatments were not given for the UTI, all antibiotic prescriptions issued between 1992 and 1999 for women aged 15–44 were selected from the database. The symptom codes on the day of the prescription were identified for each patient to create a list of potential antibiotic indications. This list was then checked by hand and all likely indications for antibiotic prescribing were retained. Patients were excluded from the analysis if they had a prescription for an antibiotic at any time in the 6 months before diagnosis or a record of any other indication for antibiotic treatment on the day of the UTI or during the following 28 days.

Cox regression analyses were conducted to examine the time before treatment failure, accounting for age, year of treatment, diabetes and pregnancy. Patients who did not receive a second antibiotic were censored on the 28th day. Failure rates were compared for the 10 antibiotics most frequently prescribed for a UTI during the study period. The percentage of patients failing at 7, 14, 21 and 28 days were calculated for each antibiotic. To maintain statistical independence, only the first new infection, with an accompanying prescription for an antibiotic issued on the same day, is included for each patient. This was termed the ‘first infection'.

Additional analyses were undertaken comparing trimethoprim prescriptions of 3, 5 and 7 days' duration to assess whether the length of prescription influenced the likelihood of treatment failure. The analysis included all ‘first infections' of known duration treated with trimethoprim included in earlier analyses, together with the records for patients who had received another antibiotic for a first infection, but trimethoprim for a subsequent new event. As before, to be included these additional patients had to have no record of UTI/cystitis or antibiotic treatment in the 6 months before the infection treated with trimethoprim; each patient was included in the analysis only once. The prescription duration was ascertained where the number of days of treatment was recorded in the patient's records, or where the prescription quantity and daily dose were both given, allowing duration to be calculated directly.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
From a population of 1 240 000 women aged 15–44 between 1992 and 1999 we identified 171 708 new, treated cases of cystitis/UTI for 123 788 patients. Of these, 65 889 (38.4%) cases were excluded because the patients had received antibiotic treatment in the previous 6 months. A further 1720 cases had a possible alternative indication for antibiotic treatment on the day of the original diagnosis or within the following 28 days. In total, 104 099 new infections from 75 045 patients were included. Of these, 509 patients (0.7%) had a previous record of diabetes and 4316 patients (5.7%) were pregnant at the time of the first treated infection.

The 10 antibiotics most frequently associated with a diagnosis of UTI/cystitis are shown in Table 1Go, with trimethoprim being prescribed most frequently (61%) followed by amoxicillin (14%) and then cefalexin (10%). Prescribing of co-trimoxazole for new UTIs declined from 8.6% in 1992 to <0.1% in 1999 (Table 2Go). Prescribing of cefalexin increased from 8% to 20% of prescriptions over the same period.


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Table 1. The 10 most frequently prescribed antibiotics for UTI/cystitis between 1992 and 1999a
 

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Table 2. Percentage of UTIs treated with each antibiotic (all ‘new' cases included, n = 104 099)
 
Overall, 14% of patients required a further prescription for an antibiotic within 28 days of the initial prescription. Older patients, aged 35–44, were significantly more likely to require a further course than patients aged 15–24 [HR 1.05, 95% confidence interval (CI) 1.01, 1.10]. Patients with a previous record of diabetes or those pregnant at the time of the infection appeared significantly less likely to respond (HR 1.41, 95% CI 1.15, 1.72 for diabetes; HR 1.16, 95% CI 1.07, 1.26 for pregnancy). The rate of treatment failure was not related to the year of prescribing (HRs between 0.96 and 1.03, P >= 0.169, for the years 1992–1999 inclusive, 1995 as reference).

If trimethoprim is considered the reference antibiotic, after 28 days patients prescribed amoxicillin were significantly more likely to require a second course of antibiotics (HR 1.17, 95% CI 1.11, 1.24, adjusted for age, year, pregnancy and diabetes) whereas those prescribed cotrimoxazole were significantly less likely to require further treatment (HR 0.84, 95% CI 0.75, 0.95). There was no significant difference between trimethoprim and the cephalosporins, nitrofurantoin, norfloxacin or ciprofloxacin (Table 3Go). The results remained unchanged if the analysis was restricted to patients with no record of pregnancy or diabetes (results not shown).


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Table 3. Requirement for a second antibiotic (adjusted for age, year of prescribing, pregnancy and diabetes): ‘first infections' only included in this analysis (n = 75 045)
 
In an analysis including 44 045 additional patients with antibiotic exposure in the previous 6 months but no other indication for treatment at the time of the UTI, the overall failure rate rose from 14% to 16% (HR for previous exposure 1.41, 95% CI 1.37, 1.45). The relative success of individual treatments remain unchanged.

Table 4Go shows the absolute risk of a treatment failure at 7, 14, 21 and 28 days for each of the 10 most commonly prescribed antibiotics. At 28 days if co-trimoxazole had been chosen rather than trimethoprim, there would be a reduction in the failure rate from 13.3% to 11.4% or an absolute risk reduction (ARR) of 1.9%. This translates to a number needed to treat (NNT) of 53, i.e. the number of patients that would need to be prescribed co-trimoxazole rather than trimethoprim before one patient would be prevented from having a second course of antibiotics, is 53 (95% CI 33, 149).13 Similarly, with amoxicillin the difference in failure rate is 2.2% or 45 (95% CI 34, 67) patients needed to be treated with trimethoprim rather than amoxicillin to prevent one extra repeat antibiotic prescription.


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Table 4. Percentage of patients (95% CI) receiving a second prescription of an antibiotic: ‘first infections' only (n = 75 045)
 
There were 45 325 patients with a ‘new' prescription of trimethoprim associated with a diagnosis of UTI where the duration of the prescription was known. On average, between 1992 and 1999, only 7.9% of trimethoprim prescriptions were for 3 days, 59.8% were for 5 days and 32.3% were for 7 days (Table 5Go). The percentage of all prescriptions written in any one year for 3 days increased from 6.3% in 1992 to 26.9% in 1999. The percentage given for 7 days fell from 35.9% to 15.4% over the same period.


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Table 5. Percentage of UTIs treated with trimethoprim 200 mg in relation to duration of treatment (n = 45325)
 
The absolute risk of failure for 3, 5 and 7 days of trimethoprim treatment is shown in Table 6Go. There were no significant differences in the rates of failure between treatment groups (HR 1.06, 95% CI 0.97, 1.16 for 3 days, HR 0.96, 95% CI 0.91, 1.02 for 7 days; 5 days of treatment as reference, adjusted for age, year of treatment, diabetes and pregnancy). The results remain unaffected by estimating the relapse rate in the period following completion of treatment, rather than following the day of prescribing (HR 1.01, 95% CI 0.93, 1.10 for 3 days, HR 1.02, 95% CI 0.97, 1.07 for 7 days; 5 days of treatment as reference adjusted for age, year, diabetes and pregnancy). As in previous analyses, diabetic or pregnant patients (HR 1.41, 95% CI 1.11, 1.79 and HR 1.15, 95% CI 1.02, 1.21, respectively) had significantly increased failure rates. The year of treatment had no significant effect on the rate of treatment failure for trimethoprim (HRs between 0.91 and 1.14, P >= 0.215, for the years 1992–1999 inclusive, 1995 as reference).


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Table 6. Percentage of treatment failures (95% CI) in women treated for UTIs with 3, 5 and 7 days of trimethoprim 200 mg (n = 45 325)
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Not everyone diagnosed by a general practitioner with a UTI and treated with an antibiotic will necessarily have a bacterial infection. Fifty per cent of patients consulting with urinary tract symptoms may not have a clinically important infection on culture.14 Our evidence indicates that one in seven patients given an antibiotic for UTI symptoms will return within 28 days for a further prescription of antibiotic. This finding is consistent with those of two recent UK studies involving much smaller numbers of patients.9,15 In the GPRD there is no requirement for the prescribing data to be linked to a symptom code. However, the analyses presented here are based only on patients when the initial treatment and any subsequent antibiotic could be linked to a diagnosis of UTI. We do not know whether the failures are due to antibiotic resistance, or because of poor compliance. Patients prescribed antibiotics in the 6 months before their UTI were significantly more likely to fail treatment than those with no exposure. This supports the assertion that antibiotic resistance may be related to failure rates to some extent. Older patients, aged 35–44, were more likely to require additional antibiotics. This is consistent with the finding of Steinke et al.15 that increasing age is associated with increased risk of bacterial resistance. Whilst pregnancy and diabetes were also associated with an increased risk of treatment failure, the small number of cases involved did not alter the results.

A recent systematic review of randomized controlled trials (RCTs) comparing 7 day treatments of cystitis with trimethoprim and co-trimoxazole suggested that there is little difference in rates of eradication of bacteriuria 7 days after the end of therapy. Suitable data were not available to allow a similar analysis of recurrence rates.16 The results here indicate that if co-trimoxazole rather than trimethoprim was used as a first-line antibiotic, then 53 patients would need to be treated to prevent one further patient returning. The clinical significance of this may be marginal. The reason for switching to trimethoprim from co-trimoxazole was mainly on the basis that there were reports of rare but serious side effects associated with the use of co-trimoxazole, particularly in the elderly. However, the BNF states that the results of post-marketing surveillance have shown no difference in the rate of serious side effects between trimethoprim and co-trimoxazole.6 The BNF also recommends that co-trimoxazole should be reserved for treating HIV-positive patients who are infected with Pneumocystis carinii. Although it has been shown to be the most cost-effective option, its benefit over trimethoprim alone may be small and it is reasonable to follow the BNF recommendation that trimethoprim is more suitable for first-line treatment.

Patients prescribed amoxicillin are significantly more likely to return for a further course of antibiotics than those prescribed trimethoprim. There seems to have been a move away from using amoxicillin as first-line treatment, although it was still the third most frequently prescribed antibiotic for urinary infections (Table 2Go). The difference in failure rates is statistically significant but perhaps with a NNT of 45, this is not clinically significant. It should be remembered that 50% of patients are unlikely to have had a bacterial infection and the difference in failure rates in patients with a proven bacterial infection may be higher.

There is an increasing move towards the use of cephalosporins, particularly cefalexin, for first-line treatment of urinary infections. Failure rates were significantly greater for patients receiving cefalexin compared with those treated with co-trimoxazole, and there was no evidence that cefalexin was any more effective than trimethoprim (Table 3Go). Indeed, results for RCTs indicate that failure rates with cephalosporins may be greater than with either co-trimoxazole or trimethoprim.7 The use of the quinolones norfloxacin and ciprofloxacin accounts for <3% of prescriptions. We have shown no difference in failure rates between these products and trimethoprim. There is no support from these findings for using any of these more expensive antibiotics in the first-line treatment of UTIs. They should be reserved for more appropriate clinical situations.

A number of previous studies have shown that short courses of 3 days of antibiotics are as effective as longer courses in uncomplicated UTI.17–19 This is supported by the findings of this study where there was no evidence that treatment failure rates differed between patients treated with trimethoprim for 3, 5 or 7 days (Table 6Go).

This study was retrospective and patients were not randomized between treatments. It is possible, therefore, that the duration of treatment or the antibiotic prescribed reflected symptom severity rather than the arbitrary preferences of individual GPs. However, the increasing use of 3 day treatments of trimethoprim, and the associated reduction in 7 day prescriptions between 1992 and 1999, show that there has been a change in practice (Table 5Go). It is unlikely that this change is related to a reduction in the severity of the disease over time but is more likely to reflect an evidence-based change in prescribing preferences. Including year of prescribing within the analyses revealed no evidence of changes in failure rates within any duration or antibiotic class during the study period. This finding is inconsistent with the suggestion that preferential prescribing is taking place routinely, and suggests instead that the comparisons between treatment durations or antibiotics are valid.

This study gives doctors some observational evidence of the effectiveness of antibiotic prescribing in young women with UTIs and suggests that whichever antibiotic is prescribed, between 12% and 16% will return within 28 days for a further course of treatment.

We would suggest that 3 days of treatment with trimethoprim appears as effective as 5 or 7 days in everyday practice and we would support this as the preferred option for uncomplicated UTIs in young women.


    Notes
 
* Corresponding author. Tel: +44-1483-302239; Fax: +44-1483-300359; E-mail: r.lawrenson{at}surrey.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Brooks, D. (1990). The management of suspected urinary tract infection in general practice. British Journal of General Practice 40, 399–401.[ISI][Medline]

2 . Nazareth, I. & King, M. (1993). Decision making by general practitioners in diagnosis and management of lower urinary tract symptoms in women. British Medical Journal 306, 1103–6.[ISI][Medline]

3 . Bailey, R. R. (1993). Management of lower urinary tract infections. Drugs 45, Suppl. 3, 139–44.[Medline]

4 . Ferry, S., Burman, L. G. & Holm, S. E. (1988). Clinical and bacteriological effects of therapy of urinary tract infection in primary health care: relation to in vitro sensitivity testing. Scandinavian Journal of Infectious Diseases 20, 535–44[ISI][Medline]

5 . Gupta, K., Scholes, D. & Stamm, W. E. (1999). Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. Journal of the American Medical Association 281, 736–8.[Abstract/Free Full Text]

6 . Anonymous. (1999). British National Formulary. pp. 238–74. British Medical Association and the Royal Pharmaceutical Society of Great Britain. London, UK.

7 . Davey, P., Steinke, D., MacDonald, T., Phillips, G. & Sullivan, F. (2000). Not so simple cystitis: how should prescribers be supported to make informed decisions about the increasing prevalence of infections caused by drug-resistant bacteria? British Journal of General Practice 50, 143–6.[ISI][Medline]

8 . Magee, J. T., Pritchard, E. L., Fitzgerald, K. A., Dunstan, F. D. & Howard, A. J. (1999). Antibiotic prescribing and antibiotic resistance in community practice: retrospective study 1996–8. British Medical Journal 319, 1239–40.[Free Full Text]

9 . Lipman, T. & Price, D. (2000). Decision making, evidence, audit and education: case study of antibiotic prescribing in general practice. British Medical Journal 320, 1114–8.[Abstract/Free Full Text]

10 . Donaldson, L. J. (1999). Health Services Circular 1999/049 NHS Executive.

11 . Fenwick, E. A. L., Briggs, A. H. & Hawke, C. I. (2000). Management of urinary tract infection in general practice: a cost-effectiveness analysis. British Journal of General Practice 50, 635–9.[ISI][Medline]

12 . Lawrenson, R. A., Williams, T. J. & Farmer, R. D. (1999). The use of general practice databases in epidemiological research. Journal of Public Health 21, 299–304.[ISI]

13 . Sackett, D., Richardson, S., Rosenberg, W. & Haynes, B. (1997). Evidence-based Medicine: How to Practice and Teach EBM. Churchill Livingstone, London, UK.

14 . Mond, N. C., Percival, A., Williams, J. D. & Brumfitt, W. (1965). Presentation, diagnosis and treatment of urinary tract infections in general practice. Lancet ii, 514–6.

15 . Steinke, D. T., Seaton, R. A., Phillips, G., MacDonald, T. M. & Davey, P. G. (1999). Factors associated with trimethoprim-resistant bacteria isolated from urine samples. Journal of Antimicrobial Chemotherapy 43, 841–3.[Abstract/Free Full Text]

16 . Warren, J. W., Abrutyn, E., Hebel, R., Johnson, J. R., Schaeffer, A. J. & Stamm, W. E. (1999). Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clinical Infectious Diseases 29, 745–58.[ISI][Medline]

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18 . Charlton, C. A., Crowther, A., Davies, J. G., Dynes, J., Haward, M. W., Mann, P. G. et al. (1976). Three-day and ten-day chemotherapy for urinary tract infections in general practice. British Medical Journal 1, 124–6.[Medline]

19 . Trienekens, T. A., Stobberingh, E. E., Winkens, R. A. & Houber, A. W. (1989). Different lengths of treatment with co-trimoxazole for acute uncomplicated urinary tract infections in women. British Medical Journal 299, 1319–22.[ISI][Medline]

Received 15 January 2001; returned 8 May 2001; revised 6 July 2001; accepted 23 August 2001





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