Impact of Clinical and Laboratory Standards Institute

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Nov 30, 2017 - Watertown Plank Road, Milwaukee, Wisconsin 53226. 2. Amanda Harrington was affiliated with the University of Illinois at Chicago Department.
    Impact of Clinical and Laboratory Standards Institute breakpoint changes on susceptibility rates of cephalosporins in uncomplicated urinary tract infections caused by Enterobacteriaceae Kristen L. Bunnell, Eric Wenzler, Amanda Harrington, Larry H. Danziger PII: DOI: Reference:

S0732-8893(17)30403-0 doi: 10.1016/j.diagmicrobio.2017.12.007 DMB 14487

To appear in:

Diagnostic Microbiology and Infectious Disease

Received date: Revised date: Accepted date:

18 August 2017 30 November 2017 2 December 2017

Please cite this article as: Bunnell Kristen L., Wenzler Eric, Harrington Amanda, Danziger Larry H., Impact of Clinical and Laboratory Standards Institute breakpoint changes on susceptibility rates of cephalosporins in uncomplicated urinary tract infections caused by Enterobacteriaceae, Diagnostic Microbiology and Infectious Disease (2017), doi: 10.1016/j.diagmicrobio.2017.12.007

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ACCEPTED MANUSCRIPT Impact of Clinical and Laboratory Standards Institute breakpoint changes on susceptibility rates

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Running Title: Cephalosporin susceptibility in urinary infections

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of cephalosporins in uncomplicated urinary tract infections caused by Enterobacteriaceae

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Kristen L. Bunnella#1, Eric Wenzlera, Amanda Harringtonb2, Larry H. Danzigera

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a. University of Illinois at Chicago College of Pharmacy, Department of Pharmacy Practice, 833 S. Wood Street Room 164 MC 886, Chicago, Illinois 60612; Eric Wenzler:

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[email protected]; Larry Danziger: [email protected] b. Loyola University Medical Center, Department of Pathology, 2160 S. First Avenue,

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Maywood, Illinois 60153; [email protected]

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# Address correspondence to Kristen L. Bunnell, PharmD, [email protected]

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Medical College of Wisconsin School of Pharmacy

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8701 Watertown Plank Road Milwaukee, WI 53226 Phone: 414-955-2888 Fax: 414-955-6476

1. Present/permanent address: Medical College of Wisconsin School of Pharmacy, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226 2. Amanda Harrington was affiliated with the University of Illinois at Chicago Department of Pathology at the time data was acquired for this study Abstract: 50 Body: 791

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ACCEPTED MANUSCRIPT ABSTRACT Breakpoint changes may impact cephalosporin susceptibility rates in uncomplicated urinary tract

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infections (uUTI). Applying the ≤ 16 mg/L breakpoint to urine cultures from adult women in an academic health system resulted in cefazolin being the most active uUTI antimicrobial, with

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86.9% susceptibility, compared to levofloxacin (80%), nitrofurantoin (76.5%), and

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sulfamethoxazole-trimethoprim (72.6%).

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ACCEPTED MANUSCRIPT In 2014, the Clinical and Laboratory Standards Institute (CLSI M100-S24) defined site-specific cefazolin breakpoints for Enterobacteriaceae, maintaining the systemic susceptibility breakpoint

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at ≤ 2 mg/L and creating a urine breakpoint (≤ 16 mg/L) for uncomplicated urinary tract

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infections (uUTI) caused by Escherichia coli (EC), Klebsiella pneumoniae (KP), and Proteus mirabilis (PM) (1, 2). The urine breakpoint applies not only to cefazolin susceptibility in uUTI,

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but also, in more recent editions, replaces cephalothin as a surrogate to predict susceptibility of

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oral cephalosporins (2, 3). Elevating the breakpoint was necessary to sustain cefazolin as a surrogate, as the systemic breakpoint (≤ 2 mg/L) falls within the wild-type distribution for

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several uropathogens and would overestimate resistance to oral cephalosporins despite their

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ability to achieve adequate concentrations in uUTI (1, 4-6). Implementation of revised breakpoints can be a challenge for clinical microbiology laboratories

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that utilize automated antimicrobial susceptibility testing platforms that have not been FDA-

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approved with the revised breakpoints (7). Susceptibility interpretation in this context also requires that clinicians distinguish uncomplicated cystitis from other types of genitourinary

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infections, a potential source of confusion when evaluating susceptibility reports or making empiric therapy decisions based on antibiograms. A potential consequence of these susceptibility testing and reporting challenges is that cephalosporin prescribing for uUTI may be limited, despite rising resistance among first-line uUTI antibiotics and potential antimicrobial stewardship advantages of narrow-spectrum agents (6, 8-11). The objective of this report is to determine the difference in cefazolin susceptibility with the urine-specific and systemic breakpoints, and to compare cefazolin susceptibility rates to alternative uUTI antibiotics from urine specimens collected at an academic medical center.

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ACCEPTED MANUSCRIPT Enterobacteriaceae cultured from clean-catch urine specimens of inpatient and ambulatory adult women > 18 years of age at the University of Illinois Hospital and Health Sciences System from

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January 2012- December 2015 were identified from microbiology records. Susceptibility testing

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was performed on Vitek 2 (bioMérieux, Durham, NC) with GN67 AST card. Given that the card’s lowest cefazolin MIC dilution was ≤ 4 mg/L, isolates were retrospectively classified as

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susceptible with MIC of ≤ 4 mg/L and ≤ 16 mg/L (as a proxy for the systemic and urine

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breakpoints, respectively). Comparator agents were nitrofurantoin (susceptible MIC ≤ 32 mg/L), sulfamethoxazole-trimethoprim (susceptible MIC ≤ 2/38 mg/L), and levofloxacin (susceptible

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MIC ≤ 2 mg/L). Only the first isolate per patient was included in the annual aggregation; analysis was performed with WHONET software (WHO Collaborating Centre for Surveillance

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of Antimicrobial Resistance, version 5.6, Boston, MA) (12). Susceptibility was compared within

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years with χ2 and post-hoc z-test with Bonferroni correction.

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Susceptibility rates of Enterobacteriaceae from 2012- 2015 are displayed in Figure 1. Cefazolin interpretation at the revised urine breakpoint (≤ 16 mg/L) resulted in significantly higher

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susceptibility each year compared to ≤ 4 mg/L. Cefazolin was the most active of the uUTI antibiotics, with 86.9% mean susceptibility compared to 80%, 76.5%, and 72.6% for levofloxacin, nitrofurantoin, and sulfamethoxazole-trimethoprim, respectively. Levofloxacin susceptibility interpretation at its intermediate breakpoint (≤ 4 mg/L), which may be more comparable for uUTI given its implication of efficacy when high antimicrobial concentrations are expected at the site of infection, had minimal impact on its overall susceptibility and yielded rates that were lower than cefazolin (81.2% versus 86.9%) (13).

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Figure 1: Enterobacteriaceae Antimicrobial Susceptibility of Urinary Isolates from Adult Women

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at University of Illinois Health System, 2012-2015

Figure 1 Key: CEF ≤ 4- cefazolin with MIC breakpoint ≤ 4 mg/L, CEF ≤ 16- cefazolin with MIC breakpoint ≤ 16 mg/L, LEV- levofloxacin, SMX-TMP- trimethoprim-sulfamethoxazole, NITnitrofurantoin *, ^, + - denotes statistically significant difference observed between denoted group and comparators

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ACCEPTED MANUSCRIPT This report is limited by reliance on a commercial AST platform that did not quantify cefazolin MICs < 4 mg/L, preventing comparison to the current systemic breakpoint. In surveillance

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studies, the number of isolates with an MIC = 4 mg/L has ranged from approximately 10% in

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wild-type EC and KP to 20-25% in Enterobacteriaceae identified from clinical specimens (1, 4, 14). In order to best characterize the utility of cefazolin as empiric uUTI therapy, all

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Enterobacteriaceae (75.5% EC, 12.2% KP, 5.1% PM, 7.2% other) were included in this cohort

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as potential uropathogens. It should be noted that the breakpoint established by CLSI is specific to EC, KP, and PM. Finally, isolates were clean-catch specimens from female patients, but we

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did not distinguish cystitis from upper UTI by clinical review.

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Narrow-spectrum beta-lactams have the potential to be a cost-effective and fluoroquinolonesparing treatment option for uUTI (6, 11, 15). However, clinicians’ perception of cephalosporin

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efficacy in uUTI may be influenced by reporting and interpretation challenges with revised

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breakpoints in the absence of urine-specific antibiograms (16). Cefazolin had the highest in vitro susceptibility by CLSI interpretive criteria of uUTI treatment options in our cohort, and

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breakpoint revisions increased susceptibility rates above the 80% empiric therapy threshold recommended in practice guidelines (11). In other studies, cefazolin susceptibility among Enterobacteriaceae from urine specimens exceeded 90% when determined by broth microdilution with the ≤ 16 mg/L breakpoint (4). We thus encourage collaboration of clinicians and microbiology specialists to examine the institution-specific effects of breakpoint revisions and potential role of cephalosporins in empiric uUTI treatment.

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ACCEPTED MANUSCRIPT References 1.

Schuetz AN, Brasso WB, Crandon JL, Hardy DJ, Jenkins SG, Jones RN, Knapp CC, Reller LB.

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2013. Cefazolin as a class representative for oral cephalosporins and uncomplicated urinary tract

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Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial

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susceptibility testing. M100-S24. ([Wayne, PA]); 2014.

Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial

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3.

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infections caused by indicated Enterobacteriaceae. Diagn Microbiol Infect Dis 77:381-2.

susceptibility testing. M100-S26. ([Wayne, PA]); 2016. López IA, Montes JC, Álvarez MJ, Mazarrasa CF, Martínez-Martínez L. 2016. Cephalothin is not

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a reliable surrogate marker for oral cephalosporins in susceptibility testing of Enterobacteriaceae

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causing urinary tract infection. Diagn Microbiol Infect Dis 86:412-416. Turnidge JD, Institute SoASTotCaLS. 2011. Cefazolin and enterobacteriaceae: rationale for

Nguyen HM, Labreche MJ, Graber CJ. 2014. Making sense of cephalosporin and

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revised susceptibility testing breakpoints. Clin Infect Dis 52:917-24.

amoxicillin/clavulanate susceptibility testing for uropathogens. Clin Infect Dis 59:1349-50. Heil EL, Johnson JK. 2016. Impact of CLSI Breakpoint Changes on Microbiology Laboratories

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and Antimicrobial Stewardship Programs. J Clin Microbiol 54:840-4. 8.

FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur. May 12, 2016. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed June 5, 2017.

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Kahlmeter G, Åhman J, Matuschek E. 2015. Antimicrobial Resistance of Escherichia coli Causing Uncomplicated Urinary Tract Infections: A European Update for 2014 and Comparison with 2000 and 2008. Infect Dis Ther 4:417-23.

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Khawcharoenporn T, Vasoo S, Ward E, Singh K. 2012. High rates of quinolone resistance among urinary tract infections in the ED. Am J Emerg Med 30:68-74.

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ACCEPTED MANUSCRIPT 11.

Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE, America IDSo, Diseases ESfMaI. 2011. International clinical practice

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guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010

and Infectious Diseases. Clin Infect Dis 52:e103-20.

Clinical and Laboratory Standards Institute (CLSI). Analysis and presentation of cumulative

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update by the Infectious Diseases Society of America and the European Society for Microbiology

antimicrobial susceptibility test data, 4th ed. M39-A4. ([Wayne, PA]). 2014. Turnidge J, Paterson DL. 2007. Setting and revising antibacterial susceptibility breakpoints. Clin

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Microbiol Rev 20:391-408, table of contents.

European Committee on Antimicrobial Susceptibility Testing. Data from the EUCAST MIC distribution website. Accessed 17 November 2017. Available at: http://www.eucast.org. Tamma PD, Sklansky DJ, Palazzi DL, Swami SK, Milstone AM. 2014. Reply to Nguyen et al.

Humphries RM, Hindler JA. 2016. Emerging Resistance, New Antimicrobial Agents  …  but No

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Tests! The Challenge of Antimicrobial Susceptibility Testing in the Current US Regulatory Landscape. Clin Infect Dis 63:83-8.

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16.

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Clin Infect Dis 59:1351.

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ACCEPTED MANUSCRIPT Impact of Clinical and Laboratory Standards Institute breakpoint changes on susceptibility rates of cephalosporins in uncomplicated urinary tract infections caused by Enterobacteriaceae

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Cefazolin susceptibility against urinary Enterobacteriaceae is higher at ≤ 16 mg/L than ≤ 4 mg/L Cefazolin is the most active antimicrobial (> 85%) for urinary Enterobacteriaceae at a single center Cephalosporins may be an appropriate empiric therapy for uncomplicated UTI

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Highlights

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