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Regional Differences in Antibiotic-resistant Enterobacterales Urine Isolates in the United States: 2018-2020

Open AccessPublished:March 29, 2022DOI:https://doi.org/10.1016/j.ijid.2022.03.052

      Highlights

      • We evaluated 1,330,095 Enterobacterales urine isolates from US facilities (2018-2020)
      • Isolates had high rates of resistance to drugs used for urinary tract infections
      • Geographic variations in antibiotic resistance were observed
      • The East South Central region had the highest rates of antibiotic resistance
      • In most regions, drug resistance levels exceeded the thresholds for empiric therapy

      [Abstract]

      Antimicrobial resistance (AMR) can complicate effective management of urinary tract infections. We conducted a retrospective study of AMR in Enterobacterales urine isolates from ambulatory and hospitalized adult patients from 2018-2020 (BD Insights Research Database) to evaluate regional differences in isolates with an extended-spectrum beta-lactamase–producing phenotype and those not susceptible to beta-lactams, fluoroquinolone (FQ), nitrofurantoin (NFT), trimethoprim/sulfamethoxazole (TMP/SMX), or multiple antibiotic classes (≥ 2 or ≥ 3). Our analyses included 349,741 Enterobacterales urine isolates from 321 inpatient facilities and 980,354 isolates from 338 ambulatory care facilities. In multivariable analyses, the highest rate of resistance was to beta-lactams (60.8% and 55.8% for inpatient and ambulatory settings, respectively), followed by FQ (27.5%), NFT (27.0%), and TMP/SMX (25.4%) for inpatients and by TMP/SMX (22.4%), FQ (21.6%), and NFT (21.6%) for ambulatory patients. Isolates with an extended-spectrum beta-lactamase–producing phenotype (13.2% and 8.6% for inpatient and ambulatory settings, respectively) and multidrug resistance (inpatient and ambulatory rates of 23.4% and 17.7% for ≥ 2 drugs; 9.9% and 6.4% for ≥ 3 drugs) were also prevalent. Statistically significant differences by geographic region (P ≤ 0.005) were observed for AMR classes in both inpatient and ambulatory settings, but the rates remained above the thresholds recommended for empiric urinary tract infection therapy across most regions.

      Keywords

      Introduction

      Urinary tract infections (UTIs) are common causes of ambulatory patient visits and hospitalizations in the United States. UTIs are typically treated with initial empiric therapy, but antibiotic-resistant UTIs can result in treatment failure (
      • Anesi J
      • Lautenbach E
      • Nachamkin I
      • Garrigan C
      • Bilker WB
      • Omorogbe J
      • et al.
      Poor clinical outcomes associated with community-onset urinary tract infections due to extended-spectrum cephalosoporin-resistant Enterobacteriaceae.
      ;
      • van Hecke O
      • Wang K
      • Lee JJ
      • Roberts NW
      • Butler CC.
      Implications of antibiotic resistance for patients’ recovery from common infections in the community: a systematic review and meta-analysis.
      ;
      • Dunne MW
      • Puttagunta S
      • Aronin SI
      • Brossette S
      • Murray J
      • Gupta V.
      Impact of empirical antibiotic therapy on outcomes of outpatient urinary tract infection due to non-susceptible Enterobacterales.
      ) and may contribute to increased hospitalizations (
      • Simmering JE
      • Tang F
      • Cavanaugh JE
      • Polgreen LA
      • Polgreen PM.
      The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011.
      ).
      An improved understanding of current nationwide resistance patterns can help inform empiric treatment and antimicrobial stewardship efforts. The goal of this study was to evaluate regional differences in antibiotic susceptibility in US Enterobacterales urine isolates.

      Methods

      We conducted a retrospective study of antimicrobial susceptibility of nonduplicate (first isolate of a species within 30 days), noncontaminant Enterobacterales urine isolates from ambulatory and hospitalized adult patients (≥ 18 years) from 2018-2020. Analyses were based on culture results; patients were not required to have a UTI diagnosis or symptoms. Reporting institutions were US hospitals and affiliated testing centers in the BD Insights Research Database (Becton, Dickinson and Company, Franklin Lakes, NJ) (
      • Gupta V
      • Ye G
      • Olesky M
      • Lawrence K
      • Murray J
      • Yu K.
      National prevalence estimates for resistant Enterobacteriaceae and Acinetobacter species in hospitalized patients in the United States.
      ;
      • Dunne MW
      • Aronin SI
      • Yu KC
      • Watts JA
      • Gupta V.
      A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011-2020.
      ;
      • Kaye KS
      • Gupta V
      • Mulgirigama A
      • Joshi AV
      • Scangarella-Oman NE
      • Yu K
      • et al.
      Antimicrobial resistance trends in urine Escherichia coli isolates from adult and adolescent females in the United States from 2011-2019: rising ESBL strains and impact on patient management.
      ).
      Enterobacterales urine isolates were evaluated for the following antimicrobial resistance (AMR) categories: extended-spectrum beta-lactamase (ESBL)–producing phenotype, beta-lactam not susceptible (NS), trimethoprim/sulfamethoxazole (TMP/SMX) NS, fluoroquinolone (FQ) NS, nitrofurantoin (NFT) NS, and resistance to ≥ 2 and ≥ 3 antibiotic classes (see Table 1 legend). We evaluated the percentage of resistant isolates overall based on the geographic region (based on US census regions and zip code tabulation areas) and inpatient and ambulatory populations.
      Table 1Multivariable analyses of antimicrobial resistance in Enterobacterales isolates from urine cultures by census region for inpatient and ambulatory settings (2018-2020).
      Setting and census region
      States included in the data sample by census regions were: East North Central: Illinois, Indiana, Michigan, Ohio, and Wisconsin East South Central: Alabama, Kentucky, Mississippi, and Tennessee Middle Atlantic: New Jersey, New York, and Pennsylvania Mountain: Arizona, Idaho, Montana, and New Mexico New England: Connecticut and New Hampshire Pacific: California, Oregon, and Washington South Atlantic: Delaware, Georgia, Florida, Maryland, North Carolina, South Carolina, Washington D.C., West Virginia, and Virginia West North Central: Iowa and Missouri West South Central: Louisiana, Oklahoma, and Texas
      Number of facilities (%)Isolates testedAdjusted antimicrobial resistance
      Antimicrobial resistance was defined as: ESBL-producing phenotype: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, and Proteus mirabilis urine isolates confirmed as ESBL-positive on commercial panels or with a result of intermediate (I) or resistant (R) to extended-spectrum cephalosporins (ESC4; cefepime, cefotaxime, ceftazidime, or ceftriaxone). Beta-lactam NS: all ESBL-positive urine isolates per above and Enterobacterales isolates (Citrobacter freundii, E. coli, Enterobacter cloacae, Klebsiella aerogenes, K. oxytoca, K. pneumoniae, Morganella morganii, P. mirabilis, Providencia stuartii, and Serratia marcescens) testing R or I to aminopenicillins (including ampicillin/sulbactam), 1st/2nd/3rd/4th-generation cephalosporins, piperacillin/tazobactam, or carbapenems. TMP/SMX NS: Enterobacterales urine isolates I or R to TMP/SMX. FQ NS: Enterobacterales urine isolates testing I or R to ciprofloxacin, levofloxacin, or moxifloxacin. NFT NS: Enterobacterales urine isolates testing R or I to NFT.
      Estimated % (95% CI)
      Beta-lactamESBLFQNFTTMP/SMX≥ 2 antibiotic classes≥ 3 antibiotic classes
      Inpatient
      All321349,47160.8(59.8-61.9)13.2(12.7-13.9)27.5(26.4-28.1)27.0(25.3-27.8)25.4(23.9-26.5)23.4(22.5-24.3)9.9(9.4-10.4)
      East North Central44 (13.7)55,61961.4(59.4-63.3)10.5(9.9-11.2)24.3(23.2-24.8)27.5(25.8-29.3)22.3(20.8-23.4)20.3(19.4-21.2)8.4(7.9-8.9)
      East South Central48 (15.0)51,95065.4(63.4-67.5)14.6(14.3-15.0)31.4(30.3-31.9)26.2(24.5-27.8)29.2(27.7-30.2)26.6(25.7-27.4)11.4(10.9-11.9)
      Middle Atlantic57 (17.8)55,96263.8(61.8-65.8)13.0(12.6-13.5)26.2(25.2-26.8)28.5(27.0-29.9)23.9(22.5-25.1)22.5(21.6-23.4)10.2(9.6-10.7)
      Mountain12 (3.7)7,73659.6(57.7-61.6)9.1(8.7-9.5)19.8(18.9-20.4)21.7(20.0-23.3)20.6(19.4-21.7)15.7(14.8-16.6)5.7(5.2-6.1)
      New England5 (1.6)8,37567.2(65.2-68.9)9.3(8.9-9.7)15.6(14.7-16.1)26.0(24.4-27.7)17.1(15.7-18.1)14.0(13.0-14.8)5.8(5.3-6.2)
      Pacific34 (10.6)44,43362.0(60.0-63.8)17.1(16.7-17.6)30.2(29.3-30.7)24.8(23.2-26.4)27.7(26.4-28.8)26.1(25.2-26.9)11.3(10.9-11.7)
      South Atlantic49 (15.3)63,75856.7(54.6-58.8)13.3(12.9-13.7)28.5(27.6-29.0)31.0(29.5-32.7)24.4(23.1-25.5)23.7(22.9-24.6)9.6(9.1-10.1)
      West North Central13 (4.0)7,02157.4(55.5-59.5)12.3(11.9-12.7)26.1(25.2-26.5)25.2(23.7-26.9)22.9(21.6-23.9)21.9(21.1-22.8)9.2(8.7-9.6)
      West South Central59 (18.4)54,88756.8(54.7-58.9)14.1(13.7-14.5)28.7(27.7-29.3)25.7(24.2-27.5)28.1(26.8-29.3)25.0(24.1-26.0)10.3(9.8-10.7)
      Ambulatory
      All338980,35455.8(54.1-57.5)8.6(7.8-9.2)21.6(20.1-22.3)21.6(19.7-23.7)22.4(19.8-24.4)17.7(16.9-18.4)6.4(6.3-6.5)
      East North Central47 (13.9)215,89755.9(54.3-57.4)6.2(5.5-6.7)17.2(16.2-18.0)20.4(18.5-22.3)19.6(19.0-21.3)13.6(12.8-14.3)4.9(4.8-5.0)
      East South Central50 (14.8)106,89862.4(60.8-64.1)10.7(9.9-11.2)25.9(25.0-26.6)23.3(21.5-25.4)27.1(26.1-28.4)22.3(21.5-23.0)8.3(8.2-8.5)
      Middle Atlantic57 (16.9)183,47858.0(56.3-59.5)9.0(8.3-9.6)22.1(21.1-22.8)21.8(19.9-23.8)20.9(20.1-22.4)18.3(17.5-19.0)7.5(7.4-7.6)
      Mountain13 (3.8)28,26255.6(54.0-57.2)6.0(5.3-6.6)17.8(16.9-18.5)17.1(15.4-18.9)21.7(21.3-22.8)13.6(12.9-14.4)4.0(3.8-4.1)
      New England6 (1.8)23,72762.9(61.2-64.2)4.5(3.8-5.1)12.3(11.4-13.0)20.3(18.5-22.3)16.8(15.8-18.2)10.0(9.3-10.7)3.1(3.0-3.2)
      Pacific34 (10.1)110,84653.5(51.8-54.9)8.7(8.0-9.2)21.1(20.2-21.8)18.0(16.3-19.8)24.7(23.9-26.2)17.0(16.3-17.7)5.8(5.7-5.9)
      South Atlantic51 (15.1)144,74152.2(50.6-53.7)8.0(7.3-8.5)22.6(21.7-23.3)23.6(21.7-25.4)22.8(21.8-24.2)17.4(16.7-18.1)5.6(5.5-5.7)
      West North Central16 (4.7)27,75752.4(50.8-53.9)9.0(8.4-9.6)24.4(23.5-25.1)23.1(21.3-24.8)19.6(19.1-21.1)20.7(19.9-21.4)8.3(8.2-8.4)
      West South Central64 (18.9)138,74852.7(50.9-54.3)9.7(9.0-10.3)21.8(20.8-22.5)22.0(20.1-23.9)24.8(23.8-26.1)18.2(17.5-19.0)6.5(6.4-6.6)
      ESBL, extended-spectrum beta-lactamase; FQ, fluoroquinolone; NFT, nitrofurantoin; NS, not susceptible; TMP/SMX, trimethoprim/sulfamethoxazole.
      a States included in the data sample by census regions were:East North Central: Illinois, Indiana, Michigan, Ohio, and WisconsinEast South Central: Alabama, Kentucky, Mississippi, and TennesseeMiddle Atlantic: New Jersey, New York, and PennsylvaniaMountain: Arizona, Idaho, Montana, and New MexicoNew England: Connecticut and New HampshirePacific: California, Oregon, and WashingtonSouth Atlantic: Delaware, Georgia, Florida, Maryland, North Carolina, South Carolina, Washington D.C., West Virginia, and VirginiaWest North Central: Iowa and MissouriWest South Central: Louisiana, Oklahoma, and Texas
      b Antimicrobial resistance was defined as:ESBL-producing phenotype: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, and Proteus mirabilis urine isolates confirmed as ESBL-positive on commercial panels or with a result of intermediate (I) or resistant (R) to extended-spectrum cephalosporins (ESC4; cefepime, cefotaxime, ceftazidime, or ceftriaxone).Beta-lactam NS: all ESBL-positive urine isolates per above and Enterobacterales isolates (Citrobacter freundii, E. coli, Enterobacter cloacae, Klebsiella aerogenes, K. oxytoca, K. pneumoniae, Morganella morganii, P. mirabilis, Providencia stuartii, and Serratia marcescens) testing R or I to aminopenicillins (including ampicillin/sulbactam), 1st/2nd/3rd/4th-generation cephalosporins, piperacillin/tazobactam, or carbapenems.TMP/SMX NS: Enterobacterales urine isolates I or R to TMP/SMX.FQ NS: Enterobacterales urine isolates testing I or R to ciprofloxacin, levofloxacin, or moxifloxacin.NFT NS: Enterobacterales urine isolates testing R or I to NFT.
      Figure 1
      Figure 1Geographic distribution of Enterobacterales resistance in ambulatory settings by zip code in the US, 2018-2020. (A) ESBL-producing phenotype; (B) FQ-NS; (C) TMP/SMX-NS; (D) NFT-NS; (E) ≥ 2 antibiotic classes (ambulatory patient isolates); (F) ≥ 3 antibiotic classes.
      Ambulatory data represent 970,219 isolates (913,343 for ESBL-producing phenotype analyses). Facilities with fewer than five isolates were not included, which resulted in slight differences between these numbers and the numbers shown in . For a county that did not have any isolates tested, the susceptibility results of the nearest county either within or across state lines were populated. Counties with insufficient isolates tested (< 1% and < 30 isolates tested) or states with no isolate results are marked in gray. The database does not include facilities in Hawaii or Alaska.
      ESBL, extended-spectrum beta-lactamase; FQ, fluoroquinolone; NFT, nitrofurantoin; NS, not susceptible; TMP/SMX, trimethoprim/sulfamethoxazole.
      Covariates in the multivariable modeling analysis included hospital bed size (< 100, 100-300, and > 300), urban/rural status, teaching status, and geographic region. Statistical analyses were conducted using R version 4.0.3 (R Core Team 2020) and the R geepack package.

      Results

      A total of 321 inpatient and 338 ambulatory care facilities provided data from 2018-2020 on antimicrobial susceptibility in Enterobacterales urine culture isolates (349,741 and 980,354 isolates for inpatient and ambulatory settings, respectively). High rates of resistance to UTI therapies were observed, including resistance to FQ (27.5% and 21.6% for inpatient and ambulatory settings, respectively), TMP/SMX (25.4% and 22.4%), and NFT (27.0% and 21.6%) (Table 1). Isolates with an ESBL-producing phenotype (13.2% and 8.6%) or multidrug resistance were also common.
      Statistically significant differences by geographic region (P ≤ 0.005) were observed for all AMR classes in both the inpatient and ambulatory settings (Table 1 and Figure 1). The highest AMR rates were generally observed in the East South Central region. Analyses of geographic distribution by zip code identified subregional and within-state AMR differences for inpatient (data not shown) and ambulatory populations (Figure 1).

      Discussion

      The high AMR rates in Enterobacterales urine isolates in this nationwide study of > 300 US facilities are a cause for concern. Although there were clear geographic variations, all regions showed AMR levels sufficiently high to negate the use of common empiric UTI therapies according to the Infectious Diseases Society of America–recommended thresholds (> 20% for TMP/SMX [uncomplicated cystitis] and > 10% for FQs [acute pyelonephritis]) (
      • Gupta K
      • Hooton TM
      • Naber KG
      • Wullt B
      • Colgan R
      • Miller LG
      • et al.
      International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
      ). Only the New England region had a TMP/SMX resistance rate below 20% in the inpatient (17.1%) and ambulatory (16.8%) settings. All regions and settings had FQ resistance rates substantially above the recommended 10% threshold. Although the Infectious Diseases Society of America does not specify an NFT empiric therapy threshold, NFT resistance rates exceeded 25% in inpatient settings and were higher than 20% in ambulatory settings for most regions.
      Our data are consistent with a recent analysis of AMR in outpatient urine Escherichia coli isolates (
      • Kaye KS
      • Gupta V
      • Mulgirigama A
      • Joshi AV
      • Scangarella-Oman NE
      • Yu K
      • et al.
      Antimicrobial resistance trends in urine Escherichia coli isolates from adult and adolescent females in the United States from 2011-2019: rising ESBL strains and impact on patient management.
      ). However, outpatient E. coli NFT resistance was much lower (4.0%) compared with the larger group of Enterobacterales pathogens evaluated in this study (21.6% for ambulatory patients). We previously reported that the Enterobacterales species with the greatest contribution to NFT resistance in ambulatory patients were Klebsiella pneumoniae, which had a resistance rate of 57.8% and accounted for 39% of NFT-resistant isolates, and Proteus mirabilis, which is intrinsically resistant to NFT; this pathogen had a resistance rate of 89.3% and accounted for 27.5% of NFT-resistant isolates. After E. coli, these two species are the most common causes of UTIs in ambulatory patients (
      • Dunne MW
      • Aronin SI
      • Yu KC
      • Watts JA
      • Gupta V.
      A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011-2020.
      ). Species-specific differences in NFT resistance suggest that pathogen identification may be useful in ambulatory patients who do not respond to initial therapy.
      Other studies have observed high rates of UTI isolates with ESBL-producing phenotypes or co-resistance to multiple agents (
      • Critchley IA
      • Cotroneo N
      • Pucci MJ
      • Mendes R
      • et al.
      The burden of antimicrobial resistance among urinary tract isolates of Escherichia coli in the United States in 2017.
      ;
      • Talan DA
      • Takhar SS
      • Krishnadasan A
      • Mower WR
      • Pallin DJ
      • Garg M
      • et al.
      Emergence of extended-spectrum β-lactamase urinary tract infections among hospitalized emergency department patients in the United States.
      ). Although rates were slightly lower in ambulatory patients compared with inpatients, they were still sufficiently high to be of clinical concern (8.6% for ESBL-producing phenotype and 17.7% for resistance to ≥ 2 antibiotics). Our findings highlight the challenge of prescribing empiric antibiotics for UTIs, especially in the ambulatory setting where multidrug resistance may impact the effectiveness of all commonly available antibiotic classes.
      The limitations of our study include low geographic representation in some regions and the lack of confirmed clinical infections; although Enterobacterales are typically considered pathogens when found in urine, it is possible that some isolates were contaminants, despite the methodology designed to exclude them. Selection bias related to a higher likelihood of obtaining cultures from more severely ill patients may have resulted in increased AMR estimates. AMR results relied on local microbiology practices and were not standardized across facilities.
      The elevated levels of resistance to commonly used empiric UTI therapies highlight the need for new oral antibiotics effective against resistant uropathogens. Until such therapies are available, appropriate UTI management may require judicial use of pathogen diagnostic tests and antimicrobial susceptibility panels along with antimicrobial stewardship programs designed to reduce resistance in uropathogens (
      • Choi PW
      • Benzer JA
      • Coon J
      • Egwuatu N
      • Dumkow LE.
      Impact of pharmacist-led selective audit and feedback on outpatient antibiotic prescribing for UTIs and SSTIs.
      ).

      Ethical review

      The study was performed in accordance with all relevant guidelines and regulations, including the Declaration of Helsinki. Outcome studies using this retrospective, deidentified dataset were approved, and informed consent was waived by the New England Institutional Review Board (Wellesley, Massachusetts; No. 120180023).

      Conflicts of interest

      SIA and MWD are employees of and own stock in Iterum Therapeutics. VG, JAW, and KCY are employees of Becton, Dickinson and Company, which was contracted by Iterum Therapeutics to conduct the study. KCY and VG also own stock in Becton, Dickinson and Company.

      Funding

      This work was supported by a grant from Iterum Therapeutics, Old Saybrook, CT, US to Becton, Dickinson and Company, Franklin Lakes, NJ, US. Medical writing was supported by Becton, Dickinson and Company.

      Acknowledgments

      The authors wish to thank Prashant Parikh, Becton, Dickinson and Company, for his dedicated contribution to the database management of this study and for the development of Figure 1. We thank Sharon L. Cross, PhD, Fusion MD Medical Science Network, Inc., Montreal, Canada, for providing manuscript support with funding from Becton, Dickinson and Company.

      References

        • Anesi J
        • Lautenbach E
        • Nachamkin I
        • Garrigan C
        • Bilker WB
        • Omorogbe J
        • et al.
        Poor clinical outcomes associated with community-onset urinary tract infections due to extended-spectrum cephalosoporin-resistant Enterobacteriaceae.
        Infect Control Hosp Epidemiol. 2018; 39: 1431-1435
        • Choi PW
        • Benzer JA
        • Coon J
        • Egwuatu N
        • Dumkow LE.
        Impact of pharmacist-led selective audit and feedback on outpatient antibiotic prescribing for UTIs and SSTIs.
        Am J Health Syst Pharm. 2021; 78: S62-S69
        • Critchley IA
        • Cotroneo N
        • Pucci MJ
        • Mendes R
        • et al.
        The burden of antimicrobial resistance among urinary tract isolates of Escherichia coli in the United States in 2017.
        PLoS One. 2019; 14e0220265
        • Dunne MW
        • Puttagunta S
        • Aronin SI
        • Brossette S
        • Murray J
        • Gupta V.
        Impact of empirical antibiotic therapy on outcomes of outpatient urinary tract infection due to non-susceptible Enterobacterales.
        Microbiol Spectr. 2022; 10e0235921
        • Dunne MW
        • Aronin SI
        • Yu KC
        • Watts JA
        • Gupta V.
        A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011-2020.
        BMC Infect Dis. 2022; 22: 194
        • Gupta K
        • Hooton TM
        • Naber KG
        • Wullt B
        • Colgan R
        • Miller LG
        • et al.
        International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
        Clin Infect Dis. 2011; 52: e103-e120
        • Gupta V
        • Ye G
        • Olesky M
        • Lawrence K
        • Murray J
        • Yu K.
        National prevalence estimates for resistant Enterobacteriaceae and Acinetobacter species in hospitalized patients in the United States.
        Int J Infect Dis. 2019; 85: 203-211
        • Kaye KS
        • Gupta V
        • Mulgirigama A
        • Joshi AV
        • Scangarella-Oman NE
        • Yu K
        • et al.
        Antimicrobial resistance trends in urine Escherichia coli isolates from adult and adolescent females in the United States from 2011-2019: rising ESBL strains and impact on patient management.
        Clin Infect Dis. 2021; 73: 1992-1999
        • Simmering JE
        • Tang F
        • Cavanaugh JE
        • Polgreen LA
        • Polgreen PM.
        The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011.
        Open Forum Infect Dis. 2017; 4: ofw281
        • Talan DA
        • Takhar SS
        • Krishnadasan A
        • Mower WR
        • Pallin DJ
        • Garg M
        • et al.
        Emergence of extended-spectrum β-lactamase urinary tract infections among hospitalized emergency department patients in the United States.
        Ann Emerg Med. 2021; 77: 32-43
        • van Hecke O
        • Wang K
        • Lee JJ
        • Roberts NW
        • Butler CC.
        Implications of antibiotic resistance for patients’ recovery from common infections in the community: a systematic review and meta-analysis.
        Clin Infect Dis. 2017; 65: 371-382