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Objectives: We sought to define regional variations in fluoroquinolone non-susceptibility (FQ-NS) among bloodstream isolates of Escherichia coli across the Veterans Health Administration (VHA) in the United States. Methods: We analyzed a retrospective cohort of patients managed at 136 VHA hospitals who had a blood culture positive for E.coli between 2003 and 2013. Hospitals were classified based on US Census Divisions, and regional variations in FQ-NS were analyzed. Results: Twenty-four thousand five hundred twenty-three unique E.coli bloodstream infections (BSIs) were identified between 2003 and 2013. 53.9 % of these were community-acquired, 30.7 % were healthcare-associated, and 15.4 % were hospital-onset BSIs. The proportion of E.coli BSIs with FQ-NS significantly varied across US Census Divisions (p < 0.001). During 2003–2013, the proportion of E.coli BSIs with FQ-NS was highest in the West South- Central Division (32.7 %) and lowest in the Mountain Division (20.0 %). Multivariable analysis showed that there were universal secular trends towards higher FQ-NS rates (p < 0.001) with significant variability of slopes across US Census Divisions (p < 0.001). Conclusion: There has been a universal increase in FQ-NS among E.coli BSIs within VHA, but the rate of increase has significantly varied across Census Divisions. The reasons for this variability are unclear. These findings reinforce the importance of using local data to develop and update local antibiograms and antibiotic-prescribing guidelines. Keywords: Fluoroquinolones, Antimicrobial resistance, Epidemiology, Escherichia coli, Introduction Historically, fluoroquinolones have been reliably active Fluoroquinolones are a synthetic class of antibiotics that against Escherichia coli, a common cause of urinary tract have been used in clinical medicine since the 1970s. infections, bloodstream infections, and intra-abdominal Fluoroquinolones have excellent oral bioavailability, infections. National antibiotic-prescribing guidelines still provide a broad-spectrum of antibacterial activity, and recommend the empiric use of fluoroquinolones for are highly efficacious in the treatment of a variety of infections that commonly involve E.coli [4, 5], but given infections. However, the overuse of these agents has led the rising prevalence of FQ-NS, the empiric use of fluor- to rising rates of FQ non-susceptibility (FQ-NS) [1–3]. oquinolones may no longer be appropriate in some geographic regions [1–3]. In this study, we sought to define regional variations in * Correspondence: email@example.com FQ-NS among bloodstream isolates of E.coli in the Iowa City VA Health Care System, Iowa City, IA, USA 2 Veterans Health Administration (VHA) over an 11-year Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, period. Identifying temporal and regional differences in USA Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Livorsi et al. Antimicrobial Resistance and Infection Control (2016) 5:38 Page 2 of 5 resistance patterns may inform development of national Table 1 Number of VHA hospitals and E.coli bloodstream isolates (BSIs) from each census region, 2003–2013 versus regional or local treatment guidelines. Census region Number of hospitals Number of included E. coli BSIs (%) Methods East North Central 18 2799 (11.4 %) We constructed a retrospective cohort of all patients East South Central 11 2146 (8.8 %) within the VHA who had a blood culture positive for Middle Atlantic 18 2544 (10.4 %) E.coli between January 1, 2003 and December 31, 2013. Mountain 13 2010 (8.2 %) Data from 136 acute care hospitals in 48 US states contributed to the cohort. FQ-NS was defined as a non- New England 7 783 (3.2 %) susceptible result to at least one FQ: ciprofloxacin, Pacific Central 13 3253 (13.3 %) levofloxacin, and/or moxifloxacin. In line with guidelines South Atlantic 26 5358 (21.8 %) from the Clinical and Laboratory Standards Institute, West North Central 16 1896 (7.7 %) only the first isolate was included when the patient had West South Central 14 3734 (15.2 %) more than one blood culture positive for E. coli in the same calendar year . Bloodstream infections (BSIs) were defined as associated E.coli-BSIs, and 37.7 % for hospital-onset hospital-onset, healthcare-associated, or community- E.coli-BSIs. acquired. Hospital-onset BSIs were defined as an E.coli- Throughout the VHA, the percentage of E.coli-BSIs positive blood culture that was obtained after the patient with FQ-NS increased from 13.9 % in 2003 to 31.3 % in had been hospitalized for ≥48 h. Healthcare-associated 2008 and 32.6 % in 2013. Among E.coli strains demon- BSIs were defined as an E.coli-positive blood culture strating FQ-NS, the frequency of non-susceptibility to obtained at the time of admission or <48 h of admission other antibiotic classes was as follows: 16.6 % extended- if the patient met established criteria for healthcare spectrum cephalosporins, 34.4 % aminoglycosides, and exposure . Community-acquired BSIs were defined as 0.3 % carbapenems. E.coli-positive blood cultures obtained at the time of The proportion of E.coli-BSIs with FQ-NS signifi- admission or <48 h of admission in patients who did not cantly varied across Census Divisions (range: 20.0– meet criteria for healthcare-associated infections. 32.7 %; p < 0.001). During 2003–2013, the proportion of Hospitals were regionalized based on US Census Divi- E.coli BSIs with FQ-NS was highest in the West South sions (https://www.census.gov/geo/reference/gtc/gtc_cen Central Division (32.7 %) and lowest in the Mountain sus_divreg.html), and annual averages of FQ-NS were Division (20.0 %, Fig. 1). In 2013 alone, the highest mapped. Monthly and annual counts of isolates with and frequency of FQ-NS among E.coli-BSIs was seen in the without FQ-NS were measured as outcomes. East South Central Division (39.6 %) and the lowest Poisson regression models were used to predict the frequency of FQ-NS was seen in the Pacific Central number of isolates with FQ-NS while incorporating total Division (25.4 %). number of isolates as an offset variable. The generalized Regression analysis showed that there were universal estimating equations (GEE) method was used to account temporal trends towards higher FQ-NS rates (p < 0.001) for grouping effect within Census Divisions. Residual with significant variability of slopes across Census plots were inspected to ensure the appropriateness of all Divisions (p < 0.001, Fig. 2). The annual mean rate of models. An interaction term between time and region increase in FQ-NS was as follows: East North Central was included in the model, and region-specific incidence 0.41 % /month; Mountain 0.86 % /month; South Atlantic rate ratios (IRRs) by month and year were estimated to 0.54 % /month; East South Central 0.51 % /month; New assess variability of slopes across divisions. England 0.44 % /month; West North Central 0.89 % /month; Middle Atlantic 0.45 % /month; Pacific Central Results 0.19 % /month; West South Central 0.40 % /month. Twenty-four thousand five hundred twenty-three unique E.coli (BSIs) were identified between 2003 and 2013 across 136 hospitals and 9 Census Divisions (Table 1). A Discussion majority of these BSIs were classified as community- Our study has demonstrated a sustained increase in the acquired (53.9 %); 30.7 % were healthcare-associated and frequency of FQ-NS among E.coli BSIs across VHA 15.4 % were hospital-onset BSIs. during 2003–2013. The rate of change has significantly The prevalence of FQ-NS increased with healthcare varied across Census Divisions. The high prevalence of exposure. The frequency of FQ-NS was 20.2 % for FQ-NS in some divisions could influence the empiric community-acquired E.coli-BSIs, 37.0 % for healthcare- use of fluoroquinolones for infections thought to involve Livorsi et al. Antimicrobial Resistance and Infection Control (2016) 5:38 Page 3 of 5 Fig. 1 Region-specific changes in FQ-NS among E.coli BSIs in the Veterans Health Administration, 2003–2013 E.coli and suggests that regional or even local guidelines patient-to-patient transmission. Long-term care facilities might be preferred over national guidelines. may serve as reservoirs of this clone [16, 17]. At 2 long- The clonal expansion of sequence type (ST) 131 E.coli term care facilities in Minnesota, 24 % of residents were is likely a major driver of this rising prevalence of fluoro- colonized with ST131, and molecular analysis quinolone resistance [8–11]. ST131 represents one of demonstrated evidence of intra-facility and inter-facility more than 1000 STs of E.coli defined by multilocus transmission . Single-center studies at different acute sequence typing (MLST). The clonal expansion of care hospitals found that 50 % of inpatients are carriers ST131 has been a global phenomenon that has not  and that 13 % of stool samples sent to the microbiol- spared the VHA. In a 2011 analysis of E.coli clinical iso- ogy laboratory grew E.coli ST131 . lates from 24 VHA medical centers, ST131 accounted Antibiotic-prescribing practices are probably also con- for 78 % of fluoroquinolone-resistant isolates and 28 % tributing to the spread of ST131. In a population-based of all isolates . The aminoglycoside and carbapenem cohort study, multivariable analysis showed that ST131 susceptibility profiles of ST131 strains described in this carriage was predicted by older age, healthcare exposure, 2011 study are similar to that of FQ-NS strains in our and prior antibiotic use . Specifically, prior use of report. Studies outside of VHA have also found that fluoroquinolones, macrolides or extended-spectrum ST131 accounts for 70–80 % of fluoroquinolone- cephalosporins was predictive . Other studies have resistant E.coli infections [12–14]. A specific subclone, found that prior fluoroquinolone-exposure is a risk which represents the vast majority of fluoroquinolone- factor for fluoroquinolone-resistant E.coli, but these resistant ST131 isolates, first emerged around 2000 and studies did not describe the sequence type of the infect- has since expanded rapidly around the world . ing strains of E.coli [2, 20, 21]. The global dissemination of ST131 and its subclones It’s unclear why the frequency of FQ-NS significantly is not well understood. Possible microbiologic contribu- varied across Census Divisions within the VHA over tors include the clone’s enhanced transmissibility, its time. These differences may reflect broad ecological increased virulence, its resistance to multiple antibiotics, trends beyond the VHA patient cohort. Alternately, and its success at colonizing the human body . specific infection control and antibiotic-prescribing In certain healthcare settings, there is a high practices within VHA may be influencing the spread of colonization pressure with ST131, and this likely facilitates these strains of E.coli. Future research could examine Livorsi et al. Antimicrobial Resistance and Infection Control (2016) 5:38 Page 4 of 5 Fig. 2 Secular trends in FQ-NS among E.coli BSIs within 9 Census Divisions of VHA, 2003–2013 whether use of specific antibiotic agents varies across is contributing to the changing epidemiology of E.coli,but regions and, if so, whether the variations in antibiotic we did not perform any microbiologic typing. A prior usage help explain the variability in FQ-NS. study, however, has demonstrated that ST 131 is prevalent There are several clinical implications to these changing within VHA . resistance patterns among E.coli. Patients undergoing transrectal prostate biopsy typically receive fluoroquiono- Conclusion lone prophylaxis. In one study, colonization with In conclusion, there has been a universal increase in fluoroquinolone-resistant E.coli was the most important FQ-NS among E.coli BSIs within VHA, and the rate of host characteristic associated with infection after transrectal increase has varied across Census Divisions. These find- prostate biopsy. Nearly two-thirds of these resistant strains ings reinforce the importance of using local data to were ST 131 . A survey of Infectious Disease physicians develop and update local antibiograms and antibiotic- found that there is a perceived increase in the incidence of prescribing guidelines. infections after transrectal prostate biopsies . Further- more, rising rates of fluoroquinolone-resistant E.coli limit Abbreviations options for empiric antibiotic therapy. Among patients with BSI: Bloodstream infection; E.coli: Escherichia coli; FQ-NS: Fluoroquinolone non-susceptibility; GEE: Generalized estimating equations; VHA: Veterans E.coli bacteremia, inappropriate empiricantibiotictherapy Health Administration was associated with worse outcomes in some [24, 25] but not all [26, 27] studies. Acknowledgements Our study has some limitations. First, the cohort Not applicable. included older patients who were predominantly male. As a result, the trends we observed may not be generalizable Funding to other populations. Second, we have argued that ST131 Not applicable. Livorsi et al. Antimicrobial Resistance and Infection Control (2016) 5:38 Page 5 of 5 Availability of data and material 9. Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: a The data that support the findings of this study are available from the VA pandemic, multiresistant, community-associated strain. J Antimicrob Informatics and Computing Infrastructure (VINCI) but restrictions apply to the Chemother. 2011;66(1):1–14. availability of these data, which were used under license for the current 10. Johnson JR, Johnston B, Clabots C, Kuskowski MA, Castanheira M. study, and so are not publicly available. Data are however available from the Escherichia coli sequence type ST131 as the major cause of serious authors upon reasonable request and with permission of VINCI. multidrug-resistant E. coli infections in the United States. ClinInfect Dis. 2010;51(3):286–94. 11. Peirano G, Pitout JD. Molecular epidemiology of Escherichia coli producing Authors’ contributions CTX-M beta-lactamases: the worldwide emergence of clone ST131 O25:H4. Study design: DL. Data collection and analysis: MG, MJ, JM, RN, BA, BB, KR. Int J Antimicrob Agents. 2010;35(4):316–21. Study supervision: EP. Manuscript writing: DL. Manuscript review: All authors. 12. Colpan A, Johnston B, Porter S, Clabots C, Anway R, Thao L, Kuskowski MA, All authors read and approved the final manuscript. Tchesnokova V, Sokurenko EV, Johnson JR, et al. Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant Competing interests pathogen among US veterans. Clin Infect Dis. 2013;57(9):1256–65. The authors declare that they have no competing interests. 13. Banerjee R, Johnston B, Lohse C, Porter SB, Clabots C, Johnson JR. Escherichia coli sequence type 131 is a dominant, antimicrobial-resistant Consent for publication clonal group associated with healthcare and elderly hosts. Infect Control Not applicable. Hosp Epidemiol. 2013;34(4):361–9. 14. Croxall G, Hale J, Weston V, Manning G, Cheetham P, Achtman M, McNally A. Molecular epidemiology of extraintestinal pathogenic Escherichia coli Ethics approval isolates from a regional cohort of elderly patients highlights the prevalence The protocol was approved by the University of Iowa Institutional Review of ST131 strains with increased antimicrobial resistance in both community Board and the local VHA Research and Development Committee. and hospital care settings. J Antimicrob Chemother. 2011;66(11):2501–8. 15. Johnson JR, Tchesnokova V, Johnston B, Clabots C, Roberts PL, Billig M, Riddell Author details 1 2 K, Rogers P, Qin X, Butler-Wu S, et al. Abrupt emergence of a single dominant Iowa City VA Health Care System, Iowa City, IA, USA. Division of Infectious multidrug-resistant strain of Escherichia coli. J Infect Dis. 2013;207(6):919–28. Diseases, Department of Internal Medicine, University of Iowa Carver College 3 16. Maslow JN, Lee B, Lautenbach E. Fluoroquinolone-resistant Escherichia coli of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. 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Antimicrobial Resistance & Infection Control – Springer Journals
Published: Oct 19, 2016
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