- Email: [email protected]
The additional costs of antibiotics and re-consultations for antibiotic-resistant Escherichia coli urinary tract infections managed in general practice
International Journal of Antimicrobial Agents 33 (2009) 255–257
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
The additional costs of antibiotics and re-consultations for antibiotic-resistant Escherichia coli urinary tract infections managed in general practice M. Fasihul Alam a,∗ , David Cohen a , Christopher Butler b , Frank Dunstan b , Zoe Roberts b , Sharon Hillier b , Stephen Palmer b a b
Health Economics and Policy Research Unit, Faculty of Health, Sport and Science, University of Glamorgan, Pontypridd, Glamorgan CF37 1DL, UK Department of Primary Care and Public Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4YS, UK
a r t i c l e
i n f o
Article history: Received 3 July 2008 Accepted 21 August 2008 Keywords: Cost Antibiotic resistance General practice
a b s t r a c t The emergence of antibiotic resistance is a major threat to public health. In the UK, most antibiotics are prescribed in general practice but the extra costs to general practice of resistant infections have not previously been well described. We compared the costs of treating patients presenting with resistant Escherichia coli urinary tract infections (UTIs) (resistant to ampicillin, trimethoprim or at least one antibiotic) with the costs of treating patients with UTIs that were sensitive to all six tested antibiotics (ampicillin, trimethoprim, amoxicillin/clavulanic acid, cefalexin, ciprofloxacin and nitrofurantoin) with regard to reconsultations and antibiotics prescribed. There were significantly higher antibiotic costs (mean extra antibiotic cost £1.19/D 1.75), re-consultation costs (£2.42/D 3.55) and total costs (£3.62/D 5.31) for patients whose infections were resistant to at least one antibiotic compared with those with sensitive infections even after accounting for potentially confounding factors. Although these per-patient costs may appear small, they do not take into account the full additional costs of resistant UTIs in the community and, given the high prevalence of UTIs, the overall costs to the health service are substantial. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction The emergence of antibiotic resistance is a major threat to public health. Direct and indirect use of antibiotics are among the main contributors to the development of resistance [1]. In secondary care, antibiotic resistance increases the length of hospital stay [2], mortality [3] and costs [2], but the consequences for general practice are less clear [4]. In the UK, 80% of antibiotic consumption is through prescriptions from general practitioners (GPs) in primary care [5]. The management of antibiotic-resistant infections in primary care is not well described in the literature. GPs often view the problem as a ‘public health issue’, remote from their prescribing decisions for their individual patients [6]. Qualitative studies have identified a number of factors influencing GPs’ decisions to prescribe antibiotics, but concerns about antimicrobial resistance are generally a secondary consideration or are not taken into account at all [7]. Whilst some GPs are concerned about the development of resistance, the associated costs are seldom considered. This may be due to the lack of information on the impact of antibiotic resistance
∗ Corresponding author. Tel.: +44 1443 483 882; fax: +44 1443 483 118. E-mail address: [email protected] (M.F. Alam).
for general practice and, in particular, the excess costs incurred [8]. Urinary tract infections (UTIs) are one of the commonest bacterial infections managed in general practice, accounting for between 1% and 3% of all general practice consultations [9]. We recently found that resistant Escherichia coli UTIs are symptomatic for longer and cause increased workload in general practice [10]. Whilst we did not attempt to quantify the full costs to general practice associated with resistant E. coli UTIs, additional analysis of the data collected allows an estimation of these costs. The aim of this report was therefore to estimate the extra costs to the UK National Health Services (NHS) of additional re-consultations and additional antibiotics owing to treating antibiotic-resistant compared with sensitive E. coli UTIs in general practice. 2. Materials and methods Ten GP practices from the former Bro Taf Health Authority in South East Wales, UK, were recruited. These practices were geographically dispersed and were shown to be representative of all practices in the area in terms of antibiotic-prescribing rates, number of registered patients and indicators of social deprivation. Patients consulting with clinically suspected UTI from 17
0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2008.08.027
256
M.F. Alam et al. / International Journal of Antimicrobial Agents 33 (2009) 255–257
Table 1 Mean (standard deviation in £) costs per patient for antibiotic-resistant and -sensitive groups.
Resistant to ampicillin (n = 347) Resistant to trimethoprim (n = 148) Resistant to at least one antibiotic (n = 389) Sensitive to all six antibiotics (n = 476)
Re-consultation cost
Antibiotic cost
Total costs
£11.62/D 17.05 (18.2) £17.35/D 25.45 (22.5) £11.60/D 17.02 (18.4) £9.18/D 13.47 (17.8)
£2.84/D 4.17 (6.5) £4.68/D 6.87 (9.5) £2.84/D 4.17 (6.2) £1.65/D 2.42 (1.5)
£14.46/D 21.21 (19.9) £22.04/D 32.33 (24.7) £14.44/D 21.18 (20.1) £10.82/D 15.87 (18.4)
July 2002 to 31 March 2004 were identified and approached to participate in the study. Those who agreed to participate and had a laboratory-confirmed E. coli infection were followed up by interview and by review of their medical records. Further details of research methods have been published previously [10]. Statistically significant differences between those with antibioticresistant infections (resistant to at least one antibiotic) and sensitive infections (sensitive to six antibiotics, namely ampicillin, trimethoprim, amoxicillin/clavulanic acid, cefalexin, ciprofloxacin and nitrofurantoin) were found across a range of outcomes [10]. For consistency with the original study, the present analyses concentrated on four groups of patients with UTI: those with infections resistant to ampicillin; those with infections resistant to trimethoprim; those with infections resistant to at least one of six antibiotics; and those whose infections were sensitive to all six antibiotics. Data were monitored with regard to the number of reconsultations and prescriptions for up to three antibiotics for the incident UTI. The cost of each patient’s use of antibiotics was determined using prices from the British National Formulary [11] according to product, strength, frequency and duration for each antibiotic prescribed. Re-consultations were monitored and valued (£24/consultation) using the figure from a national source [12]. Because the cost data were not normally distributed, nonparametric bootstrapping [13] was applied to the raw data to determine 95% confidence intervals (CIs) and significance levels (Pvalues) for mean differences in costs between antibiotic-resistant and -sensitive groups. This technique, which is commonly used within economic evaluations to account for skewed cost data, involves repeated random re-sampling from within the original sample. In this study, the CIs and P-values were based on 10 000 bootstrapped samples. A multiple linear regression approach was used to examine the effect on results of taking account of the five potentially confounding variables: age; gender; previous bladder operation; co-morbidity; and previous catheterisation.
3. Results A total of 932 patients with UTIs completed questionnaires in the original study. Of these, 865 had complete data on resistance status and all potential confounders and had their medical records checked. In total, 347 infections were resistant to ampicillin (40.1%), 148 were resistant to trimethoprim (17.1%) and 389 were resistant to at least one antibiotic (45.0%). Table 1 shows the mean (standard deviation) total cost per patient and separately for re-consultations and antibiotics costs. Table 2 compares mean differences between groups (resistant versus sensitive) with 95% CIs and P-values. Antibiotic prescribing costs were significantly higher for patients with UTIs resistant to ampicillin (P < 0.001), trimethoprim (P < 0.001) and to at least one antibiotic (P < 0.001) compared with patients with infections sensitive to all six antibiotics. Reconsultation costs were significantly higher for patients with infections resistant to trimethoprim (P < 0.001) and to at least one antibiotic (P = 0.050), with higher costs approaching statistical significance for patients with infections resistant to ampicillin (P = 0.056). Total costs were statistically significantly higher in all cases: P = 0.008 for infections resistant to ampicillin; P < 0.001 for infections resistant to trimethoprim; and P = 0.006 for infections resistant to at least one antibiotic. Highest costs were experienced by patients with infections resistant to trimethoprim, who had significantly higher additional antibiotic costs (£3.03/D 4.45), re-consultations cost (£8.17/D 11.99) and total costs (£11.21/D 16.45) than their sensitive counterparts. Controlling for the confounding factors in the regression model had little effect on the extra costs of resistance. For example, the model showed an extra total cost of £3.40 (D 4.99) for patients with an infection resistant to at least one antibiotic compared with the value of £3.62 (D 5.31) shown in Table 2. Similarly, for patients with infections resistant to trimethoprim, the model estimated a higher total cost of £11.12 (D 16.31) compared with the value of £11.21 (D 16.45) shown in Table 2. In all cases, after adjusting for these potentially confounding factors, patients with resistant infections
Table 2 Mean cost differences between antibiotic-resistant and -sensitive groups, with P-values and confidence intervals (CIs) for mean differences. Mean differencea
Bootstrap P-valuea
Bootstrap CIb
Total costs Resistant to ampicillin Resistant to trimethoprim Resistant to at least one antibiotic
£3.64/D 5.34 £11.21/D 16.45 £3.62/D 5.31
0.008 <0.001 0.006
£0.84 to £6.24 £7.27 to £15.97 £0.96 to £6.14
Re-consultation cost Resistant to ampicillin Resistant to trimethoprim Resistant to at least one antibiotic
£2.44/D 3.58 £8.17/D 11.99 £2.42/D 3.55
0.056 <0.001 0.050
−£0.25 to £4.79 £4.46 to £12.45 −£0.08 to £4.38
Antibiotic cost Resistant to ampicillin Resistant to trimethoprim Resistant to at least one antibiotic
£1.19/D 1.75 £3.03/D 4.45 £1.19/D 1.75
<0.001 <0.001 <0.001
£0.67 to £2.15 £1.87 to £5.21 £0.74 to £1.95
a Compared with patients with infections sensitive to all six antibiotics tested (ampicillin, trimethoprim, amoxicillin/clavulanic acid, cefalexin, ciprofloxacin and nitrofurantoin). b Refers to costs in £.
M.F. Alam et al. / International Journal of Antimicrobial Agents 33 (2009) 255–257
still experienced significantly higher costs than patients in the sensitive group. The incidence of UTI in England and Wales for 2005 has been estimated at 2.6% (both genders, all ages) [14]. As the total UK population is 60.6 million [15], this suggests that the number of UTIs per year is ca. 1.6 million. Without further evidence of the representativeness of the study sample it would clearly not be appropriate to extrapolate these as an estimate of national costs of resistance. However, if the proportion of resistant to sensitive infections is the same nationally as in the present study, then for patients with infections that are resistant to at least one antibiotic, the total extra annual cost to general practice would be in the order of £5.8 million (D 8.51 million) (95% CI £1.5 million to £9.8 million/D 2.20 million to D 14.38 million).
257
burden of all antibiotic resistance is high, the costs associated with the specific infections in individual evaluations may be felt to be too small to be included in the analyses. They argue that current difficulties are due to the paucity of evidence on resistance costs and argue that any programme that impacts on levels of resistance should be made with reference to such costs. 5. Conclusion Although on a per-case basis the extra costs to general practice of antibiotic-resistant UTIs were relatively small, the high incidence of this infection suggests that the overall cost of resistance in common infections managed in the community can be substantial. The estimates derived in this study can be used in economic evaluations of alternative strategies for treating UTIs.
4. Discussion Acknowledgments Overall, patients presenting with an antibiotic (ampicillin)resistant E. coli UTI incurred mean general practice costs that were £3.64 (D 5.34) (95% CI £0.84–6.24/D 1.23–9.15) higher than those for patients whose infections were sensitive to all six antibiotics assessed in the study. For patients with infections resistant to trimethoprim, the extra cost was £11.21 (D 16.45) (95% CI £7.27–15.97/D 10.67–23.43). Whilst these extra costs may appear small, these estimates must be regarded as minima for several reasons. First, they do not include any potential general practice costs due to adverse drug reactions or complications. The patients studied had higher, but not statistically significant, rates of complications and adverse drug reactions if infected with a resistant organism. Second, they do not include any additional costs in secondary care. Hospitalisation is a high cost event relative to the other variables in the study. The average cost of an episode of hospitalisation for a kidney infection or UTI without complications or co-morbidities is £783 [16]. However, in our sample the number of patients hospitalised was small and was evenly distributed (three resistant, three sensitive). Third, the estimates only relate to UTIs, which clearly are not the only infections for which resistance will incur excess costs. Moreover, this exercise only considered costs to one part of the NHS, but antibiotic resistance can impose costs on society beyond the health service. For example, the original study also recorded the number of days ‘out of action’ (time unable to undertake usual activities, e.g. work or school). Although the difference in mean number of days out of action did not reach statistical significance, it was higher for patients with resistant infections (4.58 days vs. 3.71 days; P = 0.335). Time off work represents an important cost to industry owing to lost productive output. Resistance can also impose significant non-monetary costs. In the original study, the number of days with at least one symptom was significantly higher for those with a resistant infection compared with those whose infections were sensitive to all antibiotics. The costs of antibiotic resistance are generally ignored in economic evaluations of alternative strategies to manage infectious diseases. For example, Fenwick et al. [17] showed that simply prescribing antibiotics to all patients presenting with symptoms of UTI was more cost effective than five alternative strategies that involved more restricted use of antibiotics. The authors acknowledged that one limitation of their model was its exclusion of any impact of such a strategy on resistance. Coast et al. [8] have argued that one reason why the cost of resistance is not generally included in economic evaluations of management strategies is simply that, despite the fact that the total
The authors thank the patients who gave us their time; the GPs, practice managers and practice staff for maintaining their support throughout the study period; Dr A. Howard and colleagues at the laboratories for undertaking the work in addition to their routine work; and Mrs S. Horan, our research nurse, who conducted the interviews and liaised with practices. Funding: The original study was funded by the Wellcome Trust (grant number GR064010MA). Competing interests: None declared. Ethical approval: Not required for secondary data analysis. References [1] Kummerer K. Significance of antibiotics in the environment. J Antimicrob Chemother 2003;52:5–7. [2] Einarsson S, Kristjansson M, Kristinsson KG, Kjartansson G, Jansson S. Pneumonia caused by penicillin-non-susceptible and penicillin-susceptible pneumococci in adults: a case–control study. Scand J Infect Dis 1998;30:253–8. [3] Feikin DR, Schuchat A, Kolczak M, Barrett NL, Harrison LH, Lefkowitz L, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance 1995–1997. Am J Public Health 2000;90:223–9. [4] Gupta K, Stamm WE. Outcomes associated with trimethoprim/ sulphamethoxazole (TMP/SMX) therapy in TMP/SMX resistant communityacquired UTI. Int J Antimicrob Agents 2002;19:554–6. [5] Wise R, Hart T, Cars O, Streulens M, Helmuth R, Huovinen P, et al. Antimicrobial resistance is a major threat to public health. BMJ 1998;317:609–10. [6] Butler CC, Rollnick S, Pill R, Maggs-Rapport F, Stott N. Understanding the culture of prescribing: a qualitative study of general practitioners’ and patients’ perceptions of antibiotics for sore throats. BMJ 1998;317:637–42. [7] Simpson SA, Wood F, Butler CC. General practitioners’ perceptions of antimicrobial resistance: a qualitative study. J Antimicrob Chemother 2007;59:292–6. [8] Coast J, Smith RD, Millar MR. Superbugs: should antimicrobial resistance be included as a cost in economic evaluation? Health Econ 1996;5:217–26. [9] MeReC. Urinary tract infection. MeReC Bull 1995;6:29–32. [10] Butler CC, Hillier S, Roberts Z, Dunstan F, Howard A, Palmer S. Antibioticresistant infections in primary care are symptomatic for longer and increase workload: outcomes for patients with E. coli UTIs. Br J Gen Pract 2006; 56:686–92. [11] Mehta D, editor. British National Formulary, v. 52. London, UK: Pharmaceutical Press; 2006. [12] Curtis L, Netten A. Unit costs of health and social care. Canterbury, UK: Personal Social Services Research Unit, University of Kent at Canterbury; 2006. [13] Efron B, Tibshirani R. An introduction to the bootstrap. New York, NY: Chapman and Hall; 1993. [14] Weekly Returns Service. Annual report 2005. Birmingham, UK: Royal College of General Practitioners; 2005. [15] News Release, Office for National Statistics, August 2007. [16] Department of Health. NHS reference costs 2006-07. http://www.dh.gov. uk:80/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH 082571 [accessed 23 September 2008]. [17] Fenwick EAL, Briggs AH, Hawke CI. Management of urinary tract infection in general practice: a cost-effectiveness analysis. Br J Gen Pract 2000;50: 635–9.
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
The additional costs of antibiotics and re-consultations for antibiotic-resistant Escherichia coli urinary tract infections managed in general practice M. Fasihul Alam a,∗ , David Cohen a , Christopher Butler b , Frank Dunstan b , Zoe Roberts b , Sharon Hillier b , Stephen Palmer b a b
Health Economics and Policy Research Unit, Faculty of Health, Sport and Science, University of Glamorgan, Pontypridd, Glamorgan CF37 1DL, UK Department of Primary Care and Public Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4YS, UK
a r t i c l e
i n f o
Article history: Received 3 July 2008 Accepted 21 August 2008 Keywords: Cost Antibiotic resistance General practice
a b s t r a c t The emergence of antibiotic resistance is a major threat to public health. In the UK, most antibiotics are prescribed in general practice but the extra costs to general practice of resistant infections have not previously been well described. We compared the costs of treating patients presenting with resistant Escherichia coli urinary tract infections (UTIs) (resistant to ampicillin, trimethoprim or at least one antibiotic) with the costs of treating patients with UTIs that were sensitive to all six tested antibiotics (ampicillin, trimethoprim, amoxicillin/clavulanic acid, cefalexin, ciprofloxacin and nitrofurantoin) with regard to reconsultations and antibiotics prescribed. There were significantly higher antibiotic costs (mean extra antibiotic cost £1.19/D 1.75), re-consultation costs (£2.42/D 3.55) and total costs (£3.62/D 5.31) for patients whose infections were resistant to at least one antibiotic compared with those with sensitive infections even after accounting for potentially confounding factors. Although these per-patient costs may appear small, they do not take into account the full additional costs of resistant UTIs in the community and, given the high prevalence of UTIs, the overall costs to the health service are substantial. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction The emergence of antibiotic resistance is a major threat to public health. Direct and indirect use of antibiotics are among the main contributors to the development of resistance [1]. In secondary care, antibiotic resistance increases the length of hospital stay [2], mortality [3] and costs [2], but the consequences for general practice are less clear [4]. In the UK, 80% of antibiotic consumption is through prescriptions from general practitioners (GPs) in primary care [5]. The management of antibiotic-resistant infections in primary care is not well described in the literature. GPs often view the problem as a ‘public health issue’, remote from their prescribing decisions for their individual patients [6]. Qualitative studies have identified a number of factors influencing GPs’ decisions to prescribe antibiotics, but concerns about antimicrobial resistance are generally a secondary consideration or are not taken into account at all [7]. Whilst some GPs are concerned about the development of resistance, the associated costs are seldom considered. This may be due to the lack of information on the impact of antibiotic resistance
∗ Corresponding author. Tel.: +44 1443 483 882; fax: +44 1443 483 118. E-mail address: [email protected] (M.F. Alam).
for general practice and, in particular, the excess costs incurred [8]. Urinary tract infections (UTIs) are one of the commonest bacterial infections managed in general practice, accounting for between 1% and 3% of all general practice consultations [9]. We recently found that resistant Escherichia coli UTIs are symptomatic for longer and cause increased workload in general practice [10]. Whilst we did not attempt to quantify the full costs to general practice associated with resistant E. coli UTIs, additional analysis of the data collected allows an estimation of these costs. The aim of this report was therefore to estimate the extra costs to the UK National Health Services (NHS) of additional re-consultations and additional antibiotics owing to treating antibiotic-resistant compared with sensitive E. coli UTIs in general practice. 2. Materials and methods Ten GP practices from the former Bro Taf Health Authority in South East Wales, UK, were recruited. These practices were geographically dispersed and were shown to be representative of all practices in the area in terms of antibiotic-prescribing rates, number of registered patients and indicators of social deprivation. Patients consulting with clinically suspected UTI from 17
0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2008.08.027
256
M.F. Alam et al. / International Journal of Antimicrobial Agents 33 (2009) 255–257
Table 1 Mean (standard deviation in £) costs per patient for antibiotic-resistant and -sensitive groups.
Resistant to ampicillin (n = 347) Resistant to trimethoprim (n = 148) Resistant to at least one antibiotic (n = 389) Sensitive to all six antibiotics (n = 476)
Re-consultation cost
Antibiotic cost
Total costs
£11.62/D 17.05 (18.2) £17.35/D 25.45 (22.5) £11.60/D 17.02 (18.4) £9.18/D 13.47 (17.8)
£2.84/D 4.17 (6.5) £4.68/D 6.87 (9.5) £2.84/D 4.17 (6.2) £1.65/D 2.42 (1.5)
£14.46/D 21.21 (19.9) £22.04/D 32.33 (24.7) £14.44/D 21.18 (20.1) £10.82/D 15.87 (18.4)
July 2002 to 31 March 2004 were identified and approached to participate in the study. Those who agreed to participate and had a laboratory-confirmed E. coli infection were followed up by interview and by review of their medical records. Further details of research methods have been published previously [10]. Statistically significant differences between those with antibioticresistant infections (resistant to at least one antibiotic) and sensitive infections (sensitive to six antibiotics, namely ampicillin, trimethoprim, amoxicillin/clavulanic acid, cefalexin, ciprofloxacin and nitrofurantoin) were found across a range of outcomes [10]. For consistency with the original study, the present analyses concentrated on four groups of patients with UTI: those with infections resistant to ampicillin; those with infections resistant to trimethoprim; those with infections resistant to at least one of six antibiotics; and those whose infections were sensitive to all six antibiotics. Data were monitored with regard to the number of reconsultations and prescriptions for up to three antibiotics for the incident UTI. The cost of each patient’s use of antibiotics was determined using prices from the British National Formulary [11] according to product, strength, frequency and duration for each antibiotic prescribed. Re-consultations were monitored and valued (£24/consultation) using the figure from a national source [12]. Because the cost data were not normally distributed, nonparametric bootstrapping [13] was applied to the raw data to determine 95% confidence intervals (CIs) and significance levels (Pvalues) for mean differences in costs between antibiotic-resistant and -sensitive groups. This technique, which is commonly used within economic evaluations to account for skewed cost data, involves repeated random re-sampling from within the original sample. In this study, the CIs and P-values were based on 10 000 bootstrapped samples. A multiple linear regression approach was used to examine the effect on results of taking account of the five potentially confounding variables: age; gender; previous bladder operation; co-morbidity; and previous catheterisation.
3. Results A total of 932 patients with UTIs completed questionnaires in the original study. Of these, 865 had complete data on resistance status and all potential confounders and had their medical records checked. In total, 347 infections were resistant to ampicillin (40.1%), 148 were resistant to trimethoprim (17.1%) and 389 were resistant to at least one antibiotic (45.0%). Table 1 shows the mean (standard deviation) total cost per patient and separately for re-consultations and antibiotics costs. Table 2 compares mean differences between groups (resistant versus sensitive) with 95% CIs and P-values. Antibiotic prescribing costs were significantly higher for patients with UTIs resistant to ampicillin (P < 0.001), trimethoprim (P < 0.001) and to at least one antibiotic (P < 0.001) compared with patients with infections sensitive to all six antibiotics. Reconsultation costs were significantly higher for patients with infections resistant to trimethoprim (P < 0.001) and to at least one antibiotic (P = 0.050), with higher costs approaching statistical significance for patients with infections resistant to ampicillin (P = 0.056). Total costs were statistically significantly higher in all cases: P = 0.008 for infections resistant to ampicillin; P < 0.001 for infections resistant to trimethoprim; and P = 0.006 for infections resistant to at least one antibiotic. Highest costs were experienced by patients with infections resistant to trimethoprim, who had significantly higher additional antibiotic costs (£3.03/D 4.45), re-consultations cost (£8.17/D 11.99) and total costs (£11.21/D 16.45) than their sensitive counterparts. Controlling for the confounding factors in the regression model had little effect on the extra costs of resistance. For example, the model showed an extra total cost of £3.40 (D 4.99) for patients with an infection resistant to at least one antibiotic compared with the value of £3.62 (D 5.31) shown in Table 2. Similarly, for patients with infections resistant to trimethoprim, the model estimated a higher total cost of £11.12 (D 16.31) compared with the value of £11.21 (D 16.45) shown in Table 2. In all cases, after adjusting for these potentially confounding factors, patients with resistant infections
Table 2 Mean cost differences between antibiotic-resistant and -sensitive groups, with P-values and confidence intervals (CIs) for mean differences. Mean differencea
Bootstrap P-valuea
Bootstrap CIb
Total costs Resistant to ampicillin Resistant to trimethoprim Resistant to at least one antibiotic
£3.64/D 5.34 £11.21/D 16.45 £3.62/D 5.31
0.008 <0.001 0.006
£0.84 to £6.24 £7.27 to £15.97 £0.96 to £6.14
Re-consultation cost Resistant to ampicillin Resistant to trimethoprim Resistant to at least one antibiotic
£2.44/D 3.58 £8.17/D 11.99 £2.42/D 3.55
0.056 <0.001 0.050
−£0.25 to £4.79 £4.46 to £12.45 −£0.08 to £4.38
Antibiotic cost Resistant to ampicillin Resistant to trimethoprim Resistant to at least one antibiotic
£1.19/D 1.75 £3.03/D 4.45 £1.19/D 1.75
<0.001 <0.001 <0.001
£0.67 to £2.15 £1.87 to £5.21 £0.74 to £1.95
a Compared with patients with infections sensitive to all six antibiotics tested (ampicillin, trimethoprim, amoxicillin/clavulanic acid, cefalexin, ciprofloxacin and nitrofurantoin). b Refers to costs in £.
M.F. Alam et al. / International Journal of Antimicrobial Agents 33 (2009) 255–257
still experienced significantly higher costs than patients in the sensitive group. The incidence of UTI in England and Wales for 2005 has been estimated at 2.6% (both genders, all ages) [14]. As the total UK population is 60.6 million [15], this suggests that the number of UTIs per year is ca. 1.6 million. Without further evidence of the representativeness of the study sample it would clearly not be appropriate to extrapolate these as an estimate of national costs of resistance. However, if the proportion of resistant to sensitive infections is the same nationally as in the present study, then for patients with infections that are resistant to at least one antibiotic, the total extra annual cost to general practice would be in the order of £5.8 million (D 8.51 million) (95% CI £1.5 million to £9.8 million/D 2.20 million to D 14.38 million).
257
burden of all antibiotic resistance is high, the costs associated with the specific infections in individual evaluations may be felt to be too small to be included in the analyses. They argue that current difficulties are due to the paucity of evidence on resistance costs and argue that any programme that impacts on levels of resistance should be made with reference to such costs. 5. Conclusion Although on a per-case basis the extra costs to general practice of antibiotic-resistant UTIs were relatively small, the high incidence of this infection suggests that the overall cost of resistance in common infections managed in the community can be substantial. The estimates derived in this study can be used in economic evaluations of alternative strategies for treating UTIs.
4. Discussion Acknowledgments Overall, patients presenting with an antibiotic (ampicillin)resistant E. coli UTI incurred mean general practice costs that were £3.64 (D 5.34) (95% CI £0.84–6.24/D 1.23–9.15) higher than those for patients whose infections were sensitive to all six antibiotics assessed in the study. For patients with infections resistant to trimethoprim, the extra cost was £11.21 (D 16.45) (95% CI £7.27–15.97/D 10.67–23.43). Whilst these extra costs may appear small, these estimates must be regarded as minima for several reasons. First, they do not include any potential general practice costs due to adverse drug reactions or complications. The patients studied had higher, but not statistically significant, rates of complications and adverse drug reactions if infected with a resistant organism. Second, they do not include any additional costs in secondary care. Hospitalisation is a high cost event relative to the other variables in the study. The average cost of an episode of hospitalisation for a kidney infection or UTI without complications or co-morbidities is £783 [16]. However, in our sample the number of patients hospitalised was small and was evenly distributed (three resistant, three sensitive). Third, the estimates only relate to UTIs, which clearly are not the only infections for which resistance will incur excess costs. Moreover, this exercise only considered costs to one part of the NHS, but antibiotic resistance can impose costs on society beyond the health service. For example, the original study also recorded the number of days ‘out of action’ (time unable to undertake usual activities, e.g. work or school). Although the difference in mean number of days out of action did not reach statistical significance, it was higher for patients with resistant infections (4.58 days vs. 3.71 days; P = 0.335). Time off work represents an important cost to industry owing to lost productive output. Resistance can also impose significant non-monetary costs. In the original study, the number of days with at least one symptom was significantly higher for those with a resistant infection compared with those whose infections were sensitive to all antibiotics. The costs of antibiotic resistance are generally ignored in economic evaluations of alternative strategies to manage infectious diseases. For example, Fenwick et al. [17] showed that simply prescribing antibiotics to all patients presenting with symptoms of UTI was more cost effective than five alternative strategies that involved more restricted use of antibiotics. The authors acknowledged that one limitation of their model was its exclusion of any impact of such a strategy on resistance. Coast et al. [8] have argued that one reason why the cost of resistance is not generally included in economic evaluations of management strategies is simply that, despite the fact that the total
The authors thank the patients who gave us their time; the GPs, practice managers and practice staff for maintaining their support throughout the study period; Dr A. Howard and colleagues at the laboratories for undertaking the work in addition to their routine work; and Mrs S. Horan, our research nurse, who conducted the interviews and liaised with practices. Funding: The original study was funded by the Wellcome Trust (grant number GR064010MA). Competing interests: None declared. Ethical approval: Not required for secondary data analysis. References [1] Kummerer K. Significance of antibiotics in the environment. J Antimicrob Chemother 2003;52:5–7. [2] Einarsson S, Kristjansson M, Kristinsson KG, Kjartansson G, Jansson S. Pneumonia caused by penicillin-non-susceptible and penicillin-susceptible pneumococci in adults: a case–control study. Scand J Infect Dis 1998;30:253–8. [3] Feikin DR, Schuchat A, Kolczak M, Barrett NL, Harrison LH, Lefkowitz L, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance 1995–1997. Am J Public Health 2000;90:223–9. [4] Gupta K, Stamm WE. Outcomes associated with trimethoprim/ sulphamethoxazole (TMP/SMX) therapy in TMP/SMX resistant communityacquired UTI. Int J Antimicrob Agents 2002;19:554–6. [5] Wise R, Hart T, Cars O, Streulens M, Helmuth R, Huovinen P, et al. Antimicrobial resistance is a major threat to public health. BMJ 1998;317:609–10. [6] Butler CC, Rollnick S, Pill R, Maggs-Rapport F, Stott N. Understanding the culture of prescribing: a qualitative study of general practitioners’ and patients’ perceptions of antibiotics for sore throats. BMJ 1998;317:637–42. [7] Simpson SA, Wood F, Butler CC. General practitioners’ perceptions of antimicrobial resistance: a qualitative study. J Antimicrob Chemother 2007;59:292–6. [8] Coast J, Smith RD, Millar MR. Superbugs: should antimicrobial resistance be included as a cost in economic evaluation? Health Econ 1996;5:217–26. [9] MeReC. Urinary tract infection. MeReC Bull 1995;6:29–32. [10] Butler CC, Hillier S, Roberts Z, Dunstan F, Howard A, Palmer S. Antibioticresistant infections in primary care are symptomatic for longer and increase workload: outcomes for patients with E. coli UTIs. Br J Gen Pract 2006; 56:686–92. [11] Mehta D, editor. British National Formulary, v. 52. London, UK: Pharmaceutical Press; 2006. [12] Curtis L, Netten A. Unit costs of health and social care. Canterbury, UK: Personal Social Services Research Unit, University of Kent at Canterbury; 2006. [13] Efron B, Tibshirani R. An introduction to the bootstrap. New York, NY: Chapman and Hall; 1993. [14] Weekly Returns Service. Annual report 2005. Birmingham, UK: Royal College of General Practitioners; 2005. [15] News Release, Office for National Statistics, August 2007. [16] Department of Health. NHS reference costs 2006-07. http://www.dh.gov. uk:80/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH 082571 [accessed 23 September 2008]. [17] Fenwick EAL, Briggs AH, Hawke CI. Management of urinary tract infection in general practice: a cost-effectiveness analysis. Br J Gen Pract 2000;50: 635–9.