Published on in Vol 10 (2024)

This is a member publication of Imperial College London (Jisc)

Preprints (earlier versions) of this paper are available at https://preprints.jmir.org/preprint/53828, first published .
Economic Burden of Community-Acquired Antibiotic-Resistant Urinary Tract Infections: Systematic Review and Meta-Analysis

Economic Burden of Community-Acquired Antibiotic-Resistant Urinary Tract Infections: Systematic Review and Meta-Analysis

Economic Burden of Community-Acquired Antibiotic-Resistant Urinary Tract Infections: Systematic Review and Meta-Analysis

1National Institute for Healthcare Research, Health Protection Research Unit in Healthcare-Associated Infection and Antimicrobial Resistance, Imperial College London, , London, , United Kingdom

2Centre for Antimicrobial Optimisation, Imperial College London, , London, , United Kingdom

3Healthcare Associated Infections, Fungal, Antimicrobial Resistance, Antimicrobial Use, and Sepsis Division, UK Health Security Agency, , London, , United Kingdom

4Institute of Systems, Molecular and Integrative Biology, University of Liverpool, , Liverpool, , United Kingdom

5Department of Primary Care and Public Health, School of Public Health, Imperial College London, , London, , United Kingdom

6Patient Safety Translational Research Centre, Institute of Global Health Innovation, Imperial College London, , London, , United KingdomUnited Kingdom

*these authors contributed equally

Corresponding Author:

Nina Jiayue Zhu, MPH, MSc, PhD


Background: Antibiotic resistance (ABR) poses a major burden to global health and economic systems. ABR in community-acquired urinary tract infections (CA-UTIs) has become increasingly prevalent. Accurate estimates of ABR’s clinical and economic burden are needed to support medical resource prioritization and cost-effectiveness evaluations of urinary tract infection (UTI) interventions.

Objective: This study aims to systematically synthesize the evidence on the economic costs associated with ABR in CA-UTIs, using published studies comparing the costs of antibiotic-susceptible and antibiotic-resistant cases.

Methods: We searched the PubMed, Ovid MEDLINE and Embase, Cochrane Review Library, and Scopus databases. Studies published in English from January 1, 2008, to January 31, 2023, reporting the economic costs of ABR in CA-UTI of any microbe were included. Independent screening of titles/abstracts and full texts was performed based on prespecified criteria. A quality assessment was performed using the Integrated Quality Criteria for Review of Multiple Study Designs (ICROMS) tool. Data in UTI diagnosis criteria, patient characteristics, perspectives, resource costs, and patient and health economic outcomes, including mortality, hospital length of stay (LOS), and costs, were extracted and analyzed. Monetary costs were converted into 2023 US dollars.

Results: This review included 15 studies with a total of 57,251 CA-UTI cases. All studies were from high- or upper-middle-income countries. A total of 14 (93%) studies took a health system perspective, 13 (87%) focused on hospitalized patients, and 14 (93%) reported UTI pathogens. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are the most prevalent organisms. A total of 12 (80%) studies reported mortality, of which, 7 reported increased mortality in the ABR group. Random effects meta-analyses estimated an odds ratio of 1.50 (95% CI 1.29-1.74) in the ABR CA-UTI cases. All 13 hospital-based studies reported LOS, of which, 11 reported significantly higher LOS in the ABR group. The meta-analysis of the reported median LOS estimated a pooled excess LOS ranging from 1.50 days (95% CI 0.71-4.00) to 2.00 days (95% CI 0.85-3.15). The meta-analysis of the reported mean LOS estimated a pooled excess LOS of 2.45 days (95% CI 0.51‐4.39). A total of 8 (53%) studies reported costs in monetary terms—none discounted the costs. All 8 studies reported higher medical costs spent treating patients with ABR CA-UTI in hospitals. The highest excess cost was observed in UTIs caused by carbapenem-resistant Enterobacterales. No meta-analysis was performed for monetary costs due to heterogeneity.

Conclusions: ABR was attributed to increased mortality, hospital LOS, and economic costs among patients with CA-UTI. The findings of this review highlighted the scarcity of research in this area, particularly in patient morbidity and chronic sequelae and costs incurred in community health care. Future research calls for a cost-of-illness analysis of infections, standardizing therapy-pathogen combination comparators, medical resources, productivity loss, intangible costs to be captured, and data from community sectors and low-resource settings and countries.

JMIR Public Health Surveill 2024;10:e53828

doi:10.2196/53828

Keywords



Urinary tract infections (UTIs) are infections of the kidneys, bladder, or urethra defined by a combination of clinical features and the presence of bacteria in urine. These are some of the most common conditions managed in primary care, with approximately 75% of women experiencing at least one episode in their lifetime [Urinary tract infection (lower) - women. Clinical knowledge summaries (CKS). National Institute for Health and Care Excellence. URL: https://cks.nice.org.uk/topics/urinary-tract-infection-lower-women/ [Accessed 2023-10-14] 1]. Consequently, UTIs are the second most common reason for primary care antibiotic prescribing in England [Gharbi M, Drysdale JH, Lishman H, et al. Antibiotic management of urinary tract infection in elderly patients in primary care and its association with bloodstream infections and all cause mortality: population based cohort study. BMJ. Feb 27, 2019;364:l525. [CrossRef] [Medline]2,Shallcross L, Rockenschaub P, Blackburn R, Nazareth I, Freemantle N, Hayward A. Antibiotic prescribing for lower UTI in elderly patients in primary care and risk of bloodstream infection: a cohort study using electronic health records in England. PLoS Med. Sep 21, 2020;17(9):e1003336. [CrossRef] [Medline]3]. However, it is estimated that up to 50% of these prescriptions were inadequate [Woodford HJ, George J. Diagnosis and management of urinary tract infection in hospitalized older people. J Am Geriatr Soc. Jan 2009;57(1):107-114. [CrossRef] [Medline]4,Menting SGP, Redican E, Murphy J, Bucholc M. Primary care antibiotic prescribing and infection-related hospitalisation. Antibiotics (Basel). Nov 30, 2023;12(12):1685. [CrossRef] [Medline]5]. If managed inappropriately, in cases such as undertreating, subsequent sequelae include recurrent infections, bacteremia, sepsis, and potential mortality [Gharbi M, Drysdale JH, Lishman H, et al. Antibiotic management of urinary tract infection in elderly patients in primary care and its association with bloodstream infections and all cause mortality: population based cohort study. BMJ. Feb 27, 2019;364:l525. [CrossRef] [Medline]2]. In addition, inappropriate management of UTIs, including overusing antibiotics (ie, using antibiotics when not required or for prolonged durations), accelerates the emergence and transmission of antibiotic resistance (ABR) in the long-term [UK Health Security Agency. English surveillance programme for antimicrobial utilisation and resistance (ESPAUR): report 2021 to 2022. GOV.UK. 2022. URL: https:/​/assets.​publishing.service.gov.uk/​media/​65cf498ee1bdec001132225c/​ESPAUR-report-2022-to-2023.​pdf [Accessed 2024-09-16] 6]. An increasing level of ABR in the community poses challenges to infection due to the higher risk of first-line antibiotic regime failure [Lishman H, Costelloe C, Hopkins S, et al. Exploring the relationship between primary care antibiotic prescribing for urinary tract infections, Escherichia coli bacteraemia incidence and antimicrobial resistance: an ecological study. Int J Antimicrob Agents. Dec 2018;52(6):790-798. [CrossRef] [Medline]7]. In the United Kingdom, the susceptibility of Escherichia coli’s (E coli), the most common cause of UTIs, to first-line treatments of trimethoprim and nitrofurantoin is declining [Kahlmeter G, Åhman J, Matuschek E. Antimicrobial resistance of Escherichia coli causing uncomplicated urinary tract infections: a European update for 2014 and comparison with 2000 and 2008. Infect Dis Ther. Dec 2015;4(4):417-423. [CrossRef] [Medline]8]. This may have resulted in a rise in bacteremia caused by drug-resistant Gram-negative bacteria (GNB), as over 40% of E coli bacteremia had a urinary source [Bou-Antoun S, Davies J, Guy R, Johnson AP, Sheridan EA, Hope RJ. Descriptive epidemiology of Escherichia coli bacteraemia in England, April 2012 to March 2014. Euro Surveill. Sep 1, 2016;21(35):30329. [CrossRef] [Medline]9].

Drug-resistant UTIs impose an economic burden on individuals, health care systems, and society as a whole [Öztürk R, Murt A. Epidemiology of urological infections: a global burden. World J Urol. Nov 2020;38(11):2669-2679. [CrossRef] [Medline]10-Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13]. The reduced effectiveness of UTI antibiotics can lead to repeated and more extensive treatment, hospital admission and prolonged length of stay (LOS), increased medical costs, and mortality [Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14]. The UK government has set new commitments in the National Action Plan to improve the prevention and control of UTIs in the community, particularly for older adults, and to gain a better understanding of the economic impacts of ABR [Department of Health and Social Care. UK 5-year action plan for antimicrobial resistance 2019 to 2024. GOV.UK. Jan 24, 2019. URL: https:/​/www.​gov.uk/​government/​publications/​uk-5-year-action-plan-for-antimicrobial-resistance-2019-to-2024 [Accessed 2024-08-12] 15]. Despite the high prevalence of UTIs in the community, evidence of the financial and human costs associated with drug-resistant UTIs is scarce, particularly due to the difficulties in quantifying costs incurred outside secondary care [Yang X, Chen H, Zheng Y, Qu S, Wang H, Yi F. Disease burden and long-term trends of urinary tract infections: a worldwide report. Front Public Health. Jul 27, 2022;10:888205. [CrossRef] [Medline]11]. An understanding of the clinical and economic burden of antibiotic-resistant UTIs is key to evaluating the cost-effectiveness of stewardship interventions, including those aimed at using point-of-care diagnosis, clinical decision support tools, and reducing prescribing in the community [Turner D, Little P, Raftery J, et al. Cost effectiveness of management strategies for urinary tract infections: results from randomised controlled trial. BMJ. Feb 5, 2010;340:c346. [CrossRef] [Medline]16]. In this research, we sought to systematically synthesize the evidence on the economic burden associated with antibiotic-resistant community-acquired UTIs (CA-UTIs), using published studies comparing the costs of antibiotic-susceptible and antibiotic-resistant cases.


This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance [Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. Jul 21, 2009;6(7):e1000097. [CrossRef] [Medline]17] and was registered at PROSPERO (CRD42023374551).

Search Methods

We searched for studies estimating the economic costs attributable to antibiotic drug-resistant CA-UTIs published from January 1, 2008, to January 31, 2023, using a combination of broad-based (and wildcard) search criteria, including terms for UTI, community-acquired, ABR, and health economic cost. We searched the PubMed, Ovid MEDLINE and Embase, Cochrane Review Library, and Scopus databases using strings developed for each database (Table S2 in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1). The bibliographies of the identified studies were also reviewed.

Study Selection

The study inclusion/exclusion criteria are presented in Table 1, including the Patient/Population, Intervention, Comparison, and Outcomes (PICO) eligibility. Two authors (NJZ and MW) independently screened the titles and abstracts of the records yielded from the database search and independently screened the full-text articles. The discrepancies during title/abstract screening and full-text screening were resolved by consulting the third author (EC). Any article comparing monetary or health economic costs of antibiotic-resistant versus susceptible CA-UTIs through clinical trials, observational designs (eg, cohort study, case-control study), or modeling approaches was included for full-text review.

Table 1. Study inclusion/exclusion criteria.
CriteriaInclusionExclusion
Article type
  • Clinical trials
  • Observational designs (eg, cohort study, case-control study)
  • Modeling approach (eg, economic evaluation)
  • Abstracts without full text
  • Studies with small samples (eg, case reports)
  • Studies with no primary evidence (eg, reviews, commentaries, editorials, or letters)
Language
  • English
  • Other languages
PICOa eligibility
Population
  • Humans
  • All ages
  • All sexes
  • Patients with community-acquired urinary tract infections
  • Animals
  • Environmental studies
  • Patients with health care–associated urinary tract infections
  • Patients with infections from other locations
Intervention/exposure
  • Infected by antibiotic-susceptible bacteria
  • Infected by antifungal-susceptible fungi
  • Infected by virus
  • Infected parasites
Comparison/control
  • Infected by antibiotic nonsusceptible/resistant bacteria
  • Infected by antifungal nonsusceptible/resistant fungi
  • Infected by virus
  • Infected parasites
Outcomes
  • Mortality
  • Hospital length of stay
  • Direct and indirect medical costs
  • Other outcomes (eg, patient satisfaction)

aPICO: Patient/Population, Intervention, Comparison, and Outcomes.

Data Extraction and Analysis

Data were extracted from the included studies, including study identifier, authors, journal, publication year, study design, data collection period, country/region, health care setting, perspective (patient, health system [representing payer or provider], or societal), patient population, number of patients, UTI diagnosis criteria, pathogen, sensitivity profile, treatment, and outcome. We synthesized the impact of ABR on health outcomes (eg, mortality), health care system (eg, hospital LOS, medication cost), and economic system (eg, productivity), and compared these for infections caused by resistant versus susceptible pathogens. The methods to estimate the cost of illness were categorized using a top-down approach for those studies that reported total costs on a population level irrespective of the specific method used to derive these costs or a bottom-up approach for those studies that reported average costs derived from accumulating measured costs from patient samples.

A meta-analysis was performed to synthesize the reported mortality and hospital LOS using a random effect model [Hedges LV, Vevea JL. Fixed- and random-effects models in meta-analysis. Psychological Methods. 1998;3(4):486-504. [CrossRef]18]. A random effects model assumes that the true effect size of the exposure varies from study to study due to study heterogeneity. Particularly, heterogeneities in this type of analysis occurred in definitions and categories of costs across health systems, settings, and disease types; cost measurement instruments; and unit prices. Thus, a random effects model was chosen to allow aggregating cost data from different studies by circumventing this heterogeneity. In the meta-analysis of mortality, we estimated pooled odds ratios based on the crude mortality rate [Chang BH, Hoaglin DC. Meta-analysis of odds ratios: current good practices. Med Care. Apr 2017;55(4):328-335. [CrossRef]19]. In the meta-analysis of LOS, we applied both the transformation-based methods (ie, estimating the sample mean and SD from the median and sample size) [Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. Jun 2018;27(6):1785-1805. [CrossRef] [Medline]20,Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. Dec 19, 2014;14:135. [CrossRef] [Medline]21] and median-based methods (ie, considering study-specific median differences and data distribution) [McGrath S, Sohn H, Steele R, Benedetti A. Meta-analysis of the difference of medians. Biom J. Jan 2020;62(1):69-98. [CrossRef] [Medline]22], considering mean and variance and median and IQR were commonly used when reporting LOS, and the distribution of LOS was heavily right-tailed (eg, not normally distributed) [Williford E, Haley V, McNutt LA, Lazariu V. Dealing with highly SKEWED hospital length of stay distributions: the use of gamma mixture models to study delivery hospitalizations. PLoS One. Apr 20, 2020;15(4):e0231825. [CrossRef] [Medline]23,S H, Subbiah M, Srinivasan MR. Fitting length of stay in hospitals using transformed distributions. Commun Statistics Case Stud Data Analysis Applications. Jan 2, 2018;4(1):1-8. [CrossRef]24]. We assessed the publication bias for the mortality outcome using a funnel plot and Egger test [Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. Sep 13, 1997;315(7109):629-634. [CrossRef] [Medline]25,Lin L, Chu H. Quantifying publication bias in meta-analysis. Biometrics. Sep 2018;74(3):785-794. [CrossRef] [Medline]26]. No meta-analysis was performed for economic costs due to the large variation in the resource costs and the methods used to determine the cost. To compare the reported monetary costs, the outcomes were converted into 2023 US dollars by inflating the cost to 2023 original currency estimates using annual inflation rates [Inflation calculator. CPI Inflation Calculator. URL: https://www.in2013dollars.com/ [Accessed 2023-10-14] 27], then converting this into US dollars utilizing the 2023 average exchange rates [IMF exchange rates. International Monetary Fund. URL: https://www.imf.org/external/np/fin/ert/GUI/Pages/CountryDataBase.aspx [Accessed 2023-10-14] 28].

Quality Assessment

The included studies were assessed using the Integrated Quality Criteria for Review of Multiple Study Designs (ICROMS) tool [Zingg W, Castro-Sanchez E, Secci FV, et al. Innovative tools for quality assessment: Integrated Quality Criteria for Review of Multiple Study Designs (ICROMS). Public Health. Apr 2016;133:19-37. [CrossRef] [Medline]29].


Study Characteristics

A total of 380 titles and abstracts were yielded from the database search; 214 duplicates were removed, and 132 abstracts were deemed irrelevant. A full-text review was performed on 34 studies, of which, 11 studies were included. Through reference search, another 4 studies were identified and included in the final study pool. Figure 1 summarizes the screening process in a PRISMA flowchart.

Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart. UTI: urinary tract infection.

The characteristics of the 15 identified studies are presented in Table 2 [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30-Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. The countries that individually produced the highest number of studies were the United States (n=5, 33%) [Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Cardwell SM, Crandon JL, Nicolau DP, McClure MH, Nailor MD. Epidemiology and economics of adult patients hospitalized with urinary tract infections. Hosp Pract (1995). 2016;44(1):33-40. [CrossRef] [Medline]39,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], followed by Spain (n=3, 20%) [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40] and South Korea (n=2, 13%) [Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36]. A total of 13 (87%) studies focused on patients who were hospitalized [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38-Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], and 2 (13%) studies focused on primary care patients [Little P, Turner S, Rumsby K, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess. Mar 2009;13(19):1-73. [CrossRef] [Medline]31,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37]. Additionally, 13 (87%) studies included adult patients of all genders [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], of which, 1 study included patients 65 years and older [Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32]. Chang et al [Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30] and Little et al [Little P, Turner S, Rumsby K, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess. Mar 2009;13(19):1-73. [CrossRef] [Medline]31] (n=2, 13%) investigated adult female patients. All hospital-based studies had UTI diagnosed via the presence of symptoms, infection biomarkers, and microbiology culture confirmation, and differentiated community-acquired cases using the 48-hour cutoff time after admission. Two (13%) studies reported hospital-acquired UTI [Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Cardwell SM, Crandon JL, Nicolau DP, McClure MH, Nailor MD. Epidemiology and economics of adult patients hospitalized with urinary tract infections. Hosp Pract (1995). 2016;44(1):33-40. [CrossRef] [Medline]39]. The community-based study recruited patients with urinary tract symptoms (suspected UTI) or a history of dysuria and frequency [Little P, Turner S, Rumsby K, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess. Mar 2009;13(19):1-73. [CrossRef] [Medline]31,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37]. In total, 57,251 CA-UTI cases were reported, and 47,131 UTI cases were analyzed (Table S3 in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1).

Table 2. Study characteristics: data collection period, patient population, and identified pathogens.
StudyCountryPeriodPopulationOrganisms identified
Gram-negativeGram-positiveFungi
Chang et al [Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30], 2016South KoreaJanuary 2001-December 2010Hospitalized female patients with COa-APNb defined by presence of fever (≥38.0 °C), pyuria (5‐10 leukocytes per HPFc upon urine microscopic examination), bacteriuria (≥105/ml clean voided urine or ≥104/ml catheterized urine)
  • Escherichia coli
d
Sozen et al [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12], 2015TurkeyJuly 2012-June 2014Hospitalized patients with positive urine culture <48 hours after admission, without hospitalization or urological surgery during the last month
  • Enterobacter aerogenes
  • Escherichia coli
  • Klebsiella pneumoniae
  • Pseudomonas aeruginosa
Little et al [Little P, Turner S, Rumsby K, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess. Mar 2009;13(19):1-73. [CrossRef] [Medline]31], 2009UKApril 2002-May 2003Female patients aged 17‐70 years recruited from primary care practices with suspected UTIe or a history of dysuria and frequency
  • Not reported
Not reportedNot reported
Tabak et al [Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14], 2018USJanuary 2013-September 2015Hospitalized adult patients with urine culture <3 days after admission, with Gram-negative pathogens isolated and tested for carbapenem susceptibility
  • Acinetobacter baumannii
  • Citrobacter freundii
  • Enterobacter aerogenes
  • Enterobacter cloacae
  • Escherichia coli
  • Klebsiella pneumoniae
  • Morganella morganii
  • Proteus mirabilis
  • Pseudomonas aeruginosa
  • Serratia marcescens
Madrazo et al [Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32], 2021SpainJanuary 2016-December 2019Hospitalized patients aged ≥65 years with CAf-UTI and positive urine culture
  • Acinetobacter baumannii
  • Enterobacter cloacae
  • Escherichia coli
  • Klebsiella oxytoca
  • Klebsiella pneumoniae
  • Proteus mirabilis
  • Pseudomonas aeruginosa
  • Other Enterobacterales
  • Enterococcus faecalis
  • Enterococcus faecium
  • Enterococcus gallinarum
  • Streptococcus agalactiae
Candida spp
Wozniak et al [Wozniak TM, Dyda A, Lee X. The increased length of hospital stay and mortality associated with community-associated infections in Australia. Open Forum Infect Dis. May 17, 2022;9(5):fac133. [CrossRef] [Medline]34], 2022AustraliaJanuary 2012-September 2016Hospitalized patients with positive urine culture <48 hours after admission with >2 species identified (>105 CFUsg/ml, 103/ml for cystitis, 104/ml for pyelonephritis)
  • Escherichia coli
  • Klebsiella pneumoniae
  • Pseudomonas aeruginosa
  • Enterococcus faecium
  • Staphylococcus aureus
Zilberberg et al [Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], 2017US2009-2013Hospitalized adult patients aged ≥18 years with CO-UTI defined by ICD-9h code, positive urine culture, and antibiotic treatment beginning <48 hours after admission and continuing for at least 3 consecutive days or until discharge
  • Citrobacter freundii
  • Escherichia coli
  • Enterobacter aerogenes
  • Enterobacter cloacae
  • Klebsiella oxytoca
  • Klebsiella pneumoniae
  • Morganella morganii
  • Serratia marcescens
  • Proteus mirabilis
  • Proteus spp
  • Providencia spp
Mark et al [Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33], 2021USJanuary 2017-June 2019Hospitalized patients aged ≥18 years with febrile UTI defined by fever, ICD-10i code of UTI, pyelonephritis, or sepsis, urine culture (EKP species >100,000 CFUs/ml)
  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus mirabilis
Kim et al [Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36], 2013South KoreaMarch 2010-February 2011Hospitalized patients admitting emergency department or outpatient clinic from the community with CA-APN defined by pyuria (≥5‐9 WBCj/HPF), fever (≥37.8 °C), and positive urine culture collected at the time of admission
  • Acinetobacter baumannii
  • Citrobacter spp
  • Enterobacter spp
  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus spp
  • Pseudomonas aeruginosa
  • Enterococcus spp
  • Staphylococcus aureus
François et al [François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37], 2016FranceJanuary 2012-February 2013Female patients aged >18 years recruited from GPsk with UTI symptoms and followed up for 8 weeks
  • Escherichia coli
Cheong et al [Cheong T, Ahn J, Kim YS, Pai H, Kim B. Quantitative evaluation of the economic impact of antimicrobial resistance on the treatment of community-acquired acute pyelonephritis in Korea. Infect Chemother. Sep 2022;54(3):456-469. [CrossRef] [Medline]35], 2022KoreaJanuary 2018-December 2019Hospitalized patients aged ≥19 years with ICD-10 code of CA-APN <48 hours after admission, defined by fever (≥37.8 °C), pyuria (≥4‐9 WBC/HPF), positive urine or blood culture, and symptoms or signs relevant to APN
  • Citrobacter spp
  • Enterobacter spp
  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus spp
MacVane et al [MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38], 2013USSeptember 2011-August 2012Hospitalized patients aged ≥18 years with UTI present ≤48 hours after admission defined by positive urine culture (≥10,000 CFUs)
  • Escherichia coli
  • Klebsiella spp
Esteve-Palau et al [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13], 2015SpainAugust 2010-July 2013Hospitalized patients aged ≥18 years with symptomatic CA- or CO-HAl-UTI ≤48 hours after admission including cystitis, pyelonephritis, acute prostatitis, and urosepsis, defined by increases in urinary frequency, urgency, dysuria, or suprapubic tenderness, a positive urine culture of Escherichia coli (>105 CFUs/ml)
  • Escherichia coli
Rozenkiewicz et al [Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40], 2021SpainJanuary 2011-
January 2016
Hospitalized patients aged ≥18 years with symptomatic CA-UTI (identified ≤48 hours after admission and not AHAm) including cystitis, pyelonephritis, acute prostatitis, urinary sepsis, and confusion state associated with UTI, defined by fever (>38 °C), urinary urgency, polyuria, dysuria or suprapubic pain, a positive urine culture (>105 CFUs/ml)
  • Klebsiella pneumoniae
Cardwell et al [Cardwell SM, Crandon JL, Nicolau DP, McClure MH, Nailor MD. Epidemiology and economics of adult patients hospitalized with urinary tract infections. Hosp Pract (1995). 2016;44(1):33-40. [CrossRef] [Medline]39], 2016USJuly 2013-September 2013Hospitalized patients aged ≥18 years with fever, chills, rigors, nausea, or vomiting; hematuria; altered mental status; suprapubic or flank pain; costovertebral angle tenderness; urinary frequency, urgency, or dysuria; and treatment for UTI ≤24 hours after admission
  • Citrobacter spp
  • Enterobacter spp
  • Escherichia coli
  • Klebsiella spp
  • Morganella spp
  • Proteus spp
  • Providencia spp
  • Pseudomonas aeruginosa
  • Serratia spp
  • Enterococcus spp

aCO: community-onset.

bAPN: acute pyelonephritis.

cHPF: high-power field.

dNot applicable.

eUTI: urinary tract infection.

fCA: community-acquired.

gCFU: colony-forming unit.

hICD-9: International Classification of Diseases, Ninth Revision.

iICD-10: International Statistical Classification of Diseases, Tenth Revision.

jWBC: white blood cell.

kGP: general practice.

lHA: hospital-acquired.

mAHA: ambulatory health care associated.

Of the 15 studies, 14 (93%) reported the pathogens identified, of which, all reported GNB [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30-Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], 4 (29%) reported Gram-positive bacteria [Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32,Wozniak TM, Dyda A, Lee X. The increased length of hospital stay and mortality associated with community-associated infections in Australia. Open Forum Infect Dis. May 17, 2022;9(5):fac133. [CrossRef] [Medline]34,Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36,Cardwell SM, Crandon JL, Nicolau DP, McClure MH, Nailor MD. Epidemiology and economics of adult patients hospitalized with urinary tract infections. Hosp Pract (1995). 2016;44(1):33-40. [CrossRef] [Medline]39], 1 (7%) reported fungi [Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32], 3 (21%) exclusively reported UTI caused by E coli [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37], 1 (7%) reported UTI caused by K pneumoniae [Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40]. E coli, K pneumoniae, and P aeruginosa are the most frequently identified organisms. Among the studies in specific antibiotic-pathogen combinations, 2 studies assessed carbapenem-resistant organisms, specifically GNB and Enterobacterales [Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. Mark et al [Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33] examined E coli, K pneumoniae, and Proteus mirabilis (P mirabilis) resistance to third-generation cephalosporins. Sozen et al [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12] and MacVane et al [MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38] examined extended-spectrum β-lactamases– or inducible β-lactamases–producing GNB.

All the included studies estimated the clinical and economic outcomes of patients recruited from single or multiple health facilities. François et al [François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37] provided a national-level estimate of the infection incidence and costs derived from the study cohort. No study performed sensitivity analysis. The results of the quality assessment are presented in Table S5 in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1. All studies met the minimum required score. Of the 15 studies, 6 (40%) failed to meet the minimum required criteria [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41].

The Burden of ABR UTIs

When quantifying the burden attributable to ABR, the included studies compared patient outcomes, health system outcomes, and economic costs of the CA-UTI cases caused by resistant pathogens against those caused by nonresistant pathogens. The most reported outcomes were mortality, hospital LOS, and economic costs due to antibiotic treatment (Table S4 in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1). A health system perspective was taken by all except 1 study when estimating the costs [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30-Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. François et al [François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37] took a societal perspective and included productivity loss due to absenteeism. When comparing the patients with resistant and nonresistant CA-UTIs, 4 studies matched case and control [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], 2 studies adjusted patient characteristics and other risk factors when reporting outcomes [Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33,Cheong T, Ahn J, Kim YS, Pai H, Kim B. Quantitative evaluation of the economic impact of antimicrobial resistance on the treatment of community-acquired acute pyelonephritis in Korea. Infect Chemother. Sep 2022;54(3):456-469. [CrossRef] [Medline]35], other studies performed no matching or adjusting.

A total of 12 studies reported mortality, including in-hospital all-cause mortality [Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32,Wozniak TM, Dyda A, Lee X. The increased length of hospital stay and mortality associated with community-associated infections in Australia. Open Forum Infect Dis. May 17, 2022;9(5):fac133. [CrossRef] [Medline]34,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], in-hospital infection-related mortality [MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38], 30-day all-cause mortality [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40], and 90-day all-cause mortality [Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33] (Table S4 A in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1). A total of 7 studies reported higher crude mortality among the patients with antibiotic-resistant UTIs [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Wozniak TM, Dyda A, Lee X. The increased length of hospital stay and mortality associated with community-associated infections in Australia. Open Forum Infect Dis. May 17, 2022;9(5):fac133. [CrossRef] [Medline]34,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], of which, 1 study demonstrated the statistical significance [Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. The pooled odds ratios of mortality outcomes for resistant UTIs are presented in Figure 2. Results presented odds ratios of resistant compared to nonresistant infections. The blue squares centered at the point estimate the effect size, with horizontal lines depicting the 95% CIs, and the sizes of the blue squares correspond to the patient group sizes. The overall effect sizes are represented by diamonds centered on their estimated values with the diamond width corresponding to the CI length. The random effects model estimated an overall odds ratio of 1.50 (95% CI 1.29-1.74), suggesting that ABR increased the overall mortality. The subgroup analysis conducted for different mortality outcomes suggested increased odds of in-hospital all-cause mortality (Figure 2). No publication bias was detected for mortality (Figure S1 in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KB
Multimedia Appendix 1
).

Figure 2. Pooled mortality of urinary tract infections [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Wozniak TM, Dyda A, Lee X. The increased length of hospital stay and mortality associated with community-associated infections in Australia. Open Forum Infect Dis. May 17, 2022;9(5):fac133. [CrossRef] [Medline]34,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. 3GC: third-generation cephalosporin-resistant; ESBL: extended-spectrum β-lactamase; GNB: Gram-negative bacteria; MDR: multidrug resistant; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-sensitive Staphylococcus aureus.

All 13 hospital-based studies reported LOS [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38-Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], among which, 11 reported significantly higher LOSs associated with antibiotic-resistant UTIs (Table S4 B in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1) [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. Cardwell et al [Cardwell SM, Crandon JL, Nicolau DP, McClure MH, Nailor MD. Epidemiology and economics of adult patients hospitalized with urinary tract infections. Hosp Pract (1995). 2016;44(1):33-40. [CrossRef] [Medline]39] reported higher LOS among patients with clinical failure due to inappropriate antibiotic therapies for resistant infections. The meta-analysis of studies reported LOS in mean and SD estimates of a pooled excess LOS of 2.45 days (95% CI 0.51‐4.39; Figure 3A). The meta-analysis of studies reported LOS in median and IQR estimates of a pooled excess LOS, ranging from the lowest value of 1.50 days (95% CI 0.71-4.00), estimated by the median of the differences of medians method, to the highest value of 2.00 days (95% CI 0.85-3.15), estimated by the linear quantile mixed models method (Figure 3A).

Figure 3. (A) Pooled mean difference in length of stay of urinary tract infections. (B) Pooled median difference in length of stay of urinary tract infections [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. Jun 2018;27(6):1785-1805. [CrossRef] [Medline]20,Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. Dec 19, 2014;14:135. [CrossRef] [Medline]21,Chang UI, Kim HW, Wie SH. Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. Korean J Intern Med. Jan 2016;31(1):145-155. [CrossRef] [Medline]30,Madrazo M, Esparcia A, López-Cruz I, et al. Clinical impact of multidrug-resistant bacteria in older hospitalized patients with community-acquired urinary tract infection. BMC Infect Dis. Dec 7, 2021;21(1):1232. [CrossRef] [Medline]32-Kim B, Kim J, Seo MR, et al. Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea. Infection. Jun 2013;41(3):603-612. [CrossRef] [Medline]36,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. 3GC: third-generation cephalosporin-resistant; ESBL: extended-spectrum β-lactamase; GNB: Gram-negative bacteria; IBL: inducible β-lactamase; LQMM: linear quantile mixed model; MDM: median of the differences of medians; MDR: multidrug resistant; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-sensitive Staphylococcus aureus; QE: test for residual heterogeneity; REML: restricted or residual maximum likelihood.

A total of 8 studies reported costs in monetary terms (Table S4 C in

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1) [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Cheong T, Ahn J, Kim YS, Pai H, Kim B. Quantitative evaluation of the economic impact of antimicrobial resistance on the treatment of community-acquired acute pyelonephritis in Korea. Infect Chemother. Sep 2022;54(3):456-469. [CrossRef] [Medline]35,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41], including 5 that reported costs in US dollars [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12,Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Cheong T, Ahn J, Kim YS, Pai H, Kim B. Quantitative evaluation of the economic impact of antimicrobial resistance on the treatment of community-acquired acute pyelonephritis in Korea. Infect Chemother. Sep 2022;54(3):456-469. [CrossRef] [Medline]35,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41] and 3 that reported costs in euros [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40] (Figure 4). None of the included studies discounted the costs. Considering only 2 studies explicitly stated the year of which the costs were adjusted to [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37], the end year of the data collection period was used to convert the reported costs into 2023 US dollars. A total of 8 studies reported direct medical costs incurred in secondary care, including emergency department costs [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33] and outpatient parenteral antibiotic therapy costs in 1 study [Esteve-Palau E, Solande G, Sánchez F, et al. Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: a matched cohort study. J Infect. Dec 2015;71(6):667-674. [CrossRef] [Medline]13,Mark DG, Hung YY, Salim Z, Tarlton NJ, Torres E, Frazee BW. Third-generation cephalosporin resistance and associated discordant antibiotic treatment in emergency department febrile urinary tract infections. Ann Emerg Med. Sep 2021;78(3):357-369. [CrossRef] [Medline]33]. All 8 studies reported higher medical costs spent treating patients with resistant UTIs in hospitals. The highest excess cost was observed in UTIs caused by carbapenem-resistant Enterobacterales [Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. François et al [François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37] reported costs incurred in primary care, specifically, the costs of GP visits due to UTI symptoms. The primary care costs of single- or multidrug-resistant E coli UTIs were not significantly higher than those caused by susceptible E coli.

Figure 4. Medical cost of antibiotic-resistant urinary tract infections [Sozen H, Caylak S, Cetinkaya M, et al. Clinical and economic outcomes associated with urinary tract infections caused by extended spectrum beta-lactamase producing bacteria in a tertiary care hospital. Stud Ethno Med. Aug 2015;9(9):173-179. [CrossRef]12-Tabak YP, Sung AH, Ye G, Vankeepuram L, Gupta V, McCann E. Attributable clinical and economic burden of carbapenem-non-susceptible gram-negative infections in patients hospitalized with complicated urinary tract infections. J Hosp Infect. May 2019;102(1):37-44. [CrossRef] [Medline]14,Cheong T, Ahn J, Kim YS, Pai H, Kim B. Quantitative evaluation of the economic impact of antimicrobial resistance on the treatment of community-acquired acute pyelonephritis in Korea. Infect Chemother. Sep 2022;54(3):456-469. [CrossRef] [Medline]35,François M, Hanslik T, Dervaux B, et al. The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. BMC Health Serv Res. Aug 9, 2016;16(a):365. [CrossRef] [Medline]37,MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. Apr 2014;9(4):232-238. [CrossRef] [Medline]38,Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40,Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. Apr 17, 2017;17(1):279. [CrossRef] [Medline]41]. ESBL: extended-spectrum β-lactamase; IBL: inducible β-lactamase; UTI: uniary tract infection.

This review concluded that there is an economic burden attributable to ABR in CA-UTIs, including the costs for patients and health systems as well as costs at the societal level. The review included 15 studies, which were overrepresented by research from high-income countries, hospital settings, and infections caused by E coli and K pneumoniae. All studies were cross-sectional with a limited patient sample size. No sensitivity analysis was performed to quantify the level of uncertainty in the results. The meta-analysis provided pooled estimates of the odds ratio of mortality and mean differences in hospital LOS. The reported variation in economic costs was also synthesized.

We found that no systematic review on the economic burden of ABR in CA-UTIs had been conducted. The increased mortality among the patients with ABR CA-UTIs in this review was less profound, as opposed to the existing research in other types of infections, such as bacteremia [Rozenkiewicz D, Esteve-Palau E, Arenas-Miras M, et al. Clinical and economic impact of community-onset urinary tract infections caused by ESBL-producing Klebsiella pneumoniae requiring hospitalization in Spain: an observational cohort study. Antibiotics (Basel). May 15, 2021;10(5):585. [CrossRef] [Medline]40-McLeod M, Ahmad R, Shebl NA, Micallef C, Sim F, Holmes A. A whole-health-economy approach to antimicrobial stewardship: analysis of current models and future direction. PLoS Med. Mar 29, 2019;16(3):e1002774. [CrossRef] [Medline]42] or health care–associated UTIs [Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. Feb 12, 2022;399(10325):629-655. [CrossRef] [Medline]43]. Overall, ABR is attributed to an increased mortality odds ratio of 1.50. The increased odds of mortality can be explained by the higher risk of treatment failure and UTI complications such as bacteremia and sepsis. The varied types of mortality outcomes reported reduced the comparability across studies. Most of the hospital-based studies reported a longer LOS experienced by the patients in the ABR group. We used multiple modeling methods for the hospital LOS meta-analysis and estimated that the excess duration of hospitalization ranged from 1.50 to 2.45 days. All the studies that captured the costs in monetary terms reported excess medical costs in the ABR group, with the highest excess medical costs being US $11,884.32 per case of CA-UTI caused by carbapenem-resistant Enterobacterales [McLeod M, Ahmad R, Shebl NA, Micallef C, Sim F, Holmes A. A whole-health-economy approach to antimicrobial stewardship: analysis of current models and future direction. PLoS Med. Mar 29, 2019;16(3):e1002774. [CrossRef] [Medline]42,Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. Feb 12, 2022;399(10325):629-655. [CrossRef] [Medline]43]. The findings of this review highlighted the scarcity of research in quantifying the economic burden of ABR, particularly in four areas. First, besides mortality, evidence of other types of patient burden associated with ABR is lacking, such as morbidity (clinical failure, time to clinical stability, secondary infections) and chronic sequelae (recurrent infections). Second, existing research has been restricted to those cases present in the hospitals; the cases managed and the costs incurred in primary care settings were not captured. However, the pathogen distributions and treatment options varied substantially for hospital-acquired and CA-UTIs, and for CA-UTIs managed in the community and in hospitals; community-based investigation is urgently needed to generate a comprehensive understanding across the whole health economy [McLeod M, Ahmad R, Shebl NA, Micallef C, Sim F, Holmes A. A whole-health-economy approach to antimicrobial stewardship: analysis of current models and future direction. PLoS Med. Mar 29, 2019;16(3):e1002774. [CrossRef] [Medline]42,Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. Feb 12, 2022;399(10325):629-655. [CrossRef] [Medline]43]. Third, the types of medical resource costs remained largely inconsistent, which further reduced the validity of the excess costs estimated. Last, all the identified studies were limited in patient cohort size and follow-up duration and lacked analysis to address uncertainty, which led to concerns about the results’ generalizability.

This review has two limitations. First, we only searched for studies published in English. Second, we did not include those studies where the primary focus was to perform an economic evaluation of CA-UTI treatment or prevention measures and the included estimated costs of drug-resistant cases. These limitations provide scope for further research.

There is a pressing need to build an understanding of the economics of AMR. The evidence to provide a full economic case for interventions tackling AMR is lacking. In this review, we identified knowledge and methodological gaps in existing research particularly relevant to quantifying costs associated with ABR that occurred in the community. Future research calls for cost-of-illness analysis of infections standardizing therapy-pathogen combination comparators, medical resources, productivity loss, and intangible costs to be captured, as well as data from community sectors and low-resource settings and countries.

Acknowledgments

This research was funded by the National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London in partnership with the UK Health Security Agency (previously Public Health England), in collaboration with Imperial College Health Partner, University of Cambridge, University of Warwick, and the Department of Health and Social Care, who funded Centre for Antimicrobial Optimisation at Imperial College London. AH is an NIHR senior investigator. PA is supported by the NIHR Applied Research Collaboration Northwest London. This report is independent research funded by the NIHR.

The authors want to thank Hossam W Almadhoon for his help with the assessment of publication bias.

The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

Disclaimer

The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, the Department of Health and Social Care, or the UK Health Security Agency.

Data Availability

All data generated or analyzed during this study are included in this published article and

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KBMultimedia Appendix 1. Additional information about this review can be found on PROSPERO (CRD42023374551).

Authors' Contributions

NJZ and PA developed the concept and methodology for this research. NJZ and MW undertook the literature search, screening, and data extraction. NJZ conducted the meta-analysis. NJZ, MW, and EC performed the quality assessment. NJZ drafted the initial manuscript. NJZ, EC, MW, CB, AH, and PA contributed toward the data interpretation, revision of the manuscript, and finalization for submission. PA is the guarantor of the study. The corresponding author attests that all listed authors meet the International Committee of Medical Journal Editors criteria for authorship and that no others who meet the criteria have been omitted.

Conflicts of Interest

None declared.

Multimedia Appendix 1

Supplementary data tables.

DOCX File, 548 KB

Checklist 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist.

DOCX File, 25 KB

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ABR: antibiotic resistance
CA-UTI: community-acquired urinary tract infection
GNB: Gram-negative bacteria
ICROMS: Integrated Quality Criteria for Review of Multiple Study Designs
LOS: length of stay
PICO: Patient/Population, Intervention, Comparison, and Outcomes
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
UTI: urinary tract infection


Edited by Amaryllis Mavragani; submitted 21.10.23; peer-reviewed by Heinzpeter Schwermer, Mehul Jani; final revised version received 01.07.24; accepted 02.07.24; published 09.10.24.

Copyright

© Nina Jiayue Zhu, Misghina Weldegiorgis, Emma Carter, Colin Brown, Alison Holmes, Paul Aylin. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 9.10.2024.

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