Bacterial and fungal pathogens isolated from patients with bloodstream infection: frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (2012–2017)

Journal Pre-proof Bacterial and fungal pathogens isolated from patients with bloodstream infection: Frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial surveillance Program (2012–2017)

Michael A. Pfaller, Cecilia G. Carvalhaes, Caitlin J. Smith, Daniel J. Diekema, Mariana Castanheira PII:

S0732-8893(19)31093-4

DOI:

https://doi.org/10.1016/j.diagmicrobio.2020.115016

Reference:

DMB 115016

To appear in:

Diagnostic Microbiology & Infectious Disease

Received date:

31 October 2019

Revised date:

4 February 2020

Accepted date:

8 February 2020

Please cite this article as: M.A. Pfaller, C.G. Carvalhaes, C.J. Smith, et al., Bacterial and fungal pathogens isolated from patients with bloodstream infection: Frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial surveillance Program (2012–2017), Diagnostic Microbiology & Infectious Disease(2020), https://doi.org/10.1016/j.diagmicrobio.2020.115016

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© 2020 Published by Elsevier.

Journal Pre-proof Bacterial and fungal pathogens isolated from patients with bloodstream infection: Frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (2012-2017)

Running title: SENTRY bloodstream infections

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Michael A. Pfaller , Cecilia G. Carvalhaes , Caitlin J. Smith , Daniel J. Diekema , Mariana Castanheira b

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JMI Laboratories, North Liberty, Iowa; University of Iowa College of Medicine, Iowa City, Iowa

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#Corresponding author:

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Cecilia G. Carvalhaes, MD, PhD JMI Laboratories

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345 Beaver Kreek Centre, Suite A North Liberty, IA 52317

FAX: (319) 665-3371

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[email protected]

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Phone: (319) 665-3370

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Journal Pre-proof ABSTRACT The SENTRY Antimicrobial Surveillance Program has monitored bloodstream infections (BSI) from patients in medical centers worldwide since 1997. In this report, we examine the frequency of occurrence and antimicrobial susceptibility profiles of 6,741 bacterial and 222 fungal pathogens causing BSI in 16 medical centers from 2012-2017. These results were stratified according to patient age, intensive care unit (ICU) location, and hospital onset (HO) versus community onset (CO) of infection. The leading pathogen isolated from patients in all age groups (range, 20.3-32.5%), except for those >64 years old

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(19.9%), was S. aureus. E. coli was the most common agent in patients over 64 years of age (26.7%). Staphylococcus aureus was frequently recovered from patients with HO or CO BSI (20.9-24.1%).

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However, E. coli was the most commonly isolated species (24.5%) from CO infections. BSI caused by

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vancomycin-resistant enterococci, penicillin-non-susceptible S. pneumoniae, extended spectrum βlactamase-producing Klebsiella spp., carbapenem-resistant Enterobacteriaceae, and multidrug-resistant

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P. aeruginosa were more common among patients in ICUs compared to patients hospitalized in a non-

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ICU setting. The frequency of MRSA was slightly higher in the non-ICU population (37.5%) compared with the ICU group (34.1%). A trend toward a decrease in BSI due to Gram-positive cocci and an

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increase in infections with Gram-negative bacilli were observed. Overall, the frequency of resistant phenotypes was high for S. aureus (MRSA; 37.0%), enterococci (VRE; 24.6%), Klebsiella spp. (ESBL

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phenotype; 21.5%), and Pseudomonas aeruginosa (multidrug-resistant [MDR]; 15.4%) and generally

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declined from 2012 to 2017. Whereas the frequency of penicillin-nonsusceptible (NS) Streptococcus pneumoniae (3.4%) and carbapenem-resistant Enterobacteriaceae (CRE; 1.5%) was low overall and both resistant phenotypes declined over time. Fluconazole-resistant Candida spp. isolates were only detected in years 2013-2015.

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Journal Pre-proof 1 INTRODUCTION Bloodstream infections (BSIs) are among the top seven causes of death in Europe (EUR) and North America (NA) with over 2 million episodes each year and a case fatality rate (CFR) of 13-20%, resulting in 250,000 deaths annually in EUR and NA combined (Goto & Al-Hasan, 2013). In the United States, BSI mortality is comparable to Alzheimer’s disease mortality and greater than the mortality rate due to other major causes of death, including diabetes, heart failure, and many forms of cancer (Goto & Al-Hasan, 2013; Wenzel, 2007). Approximately 30% of patients with BSI receive inappropriate (inactive) or delayed

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antimicrobial therapy (Ibrahim, et al., 2000; Kollef, et al., 1999; Zhang, et al., 2015; Zilberberg & Shorr, 2015), which is an independent predictor of poor outcome and mortality (Kang, et al., 2005) likely due to

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increased antimicrobial resistance and the relatively slow and insensitive nature of blood cultures (BCs)

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(Cosgrove, 2006; Lamy, et al., 2016).

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The lack of timely and sensitive BSI diagnoses coupled with the understanding that delays in administering appropriate (active against BSI pathogens) antimicrobial therapy are directly related to

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increased mortality (Kollef, et al., 1999; Zhang, et al., 2015; Zilberberg & Shorr, 2015) lead to the frequent use of empirical therapy in patients considered to be at risk for BSI (Caliendo, et al., 2013; Cosgrove,

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2006; Dellinger, et al., 2013; She, et al., 2015). The challenge of empirical coverage is daunting: the most

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important BSI pathogens are frequently related to antimicrobial resistance, drug toxicity issues (e.g. colistin), minimizing consumption of more expensive third-line agents, (e.g., ceftaroline, daptomycin,

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tigecycline, ceftazidime-avibactam), or invasive fungal (e.g., Candida) infections. Excessive antimicrobial therapy is widely considered to result in exposing patients to risks of drug toxicity and harmful drug-drug interactions as well as contributing to the growing epidemic of antibacterial and antifungal resistance (Ammerlaan, et al., 2013; Cosgrove, 2006; Edmond, et al., 1999; Fisher, et al., 2018; Weiner, et al., 2016; Wisplinghoff, et al., 2004). Specifically, inappropriate and/or delayed treatment practices are common when dealing with the following pathogens: Acinetobacter, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus, Escherichia coli, Staphylococcus aureus, and Candida species, and, thus, have been shown to represent an independent risk for mortality (Erbay, et al., 2009;Ibrahim, et al., 2000; Kollef, et al., 1999; Lodise, et al., 2003; Micek, et al., 2005; Morrell et al, 2005; Tumbarello, et al., 2007; Zhang, et al., 2015; Zilberberg & Shorr, 2015).

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Journal Pre-proof Surveillance programs help guide clinicians to choose appropriate empirical therapy for patients suspected to have BSI by defining species distribution of pathogens and their resistance patterns. As a result, antimicrobial resistance surveillance programs have proliferated over the past two decades (Adam, et al., 2011; Ammerlaan, et al., 2013; Fuhrmeister & Jones, 2019; Langley, et al., 2015; Nunez-Nunez, et al., 2018; Rello, et al., 2019; Sader, et al., 2019; Sirijatuphat, et al., 2018; Wisplinghoff, et al., 2004). These programs provided useful information regarding pathogen distribution and resistance trends from a wide variety of infection sites (Diekema, et al., 2002; Fuhrmeister & Jones, 2019; Langley, et al., 2015;

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Rello, et al., 2019; Weiner, et al., 2016). Considerable attention has been given to hospitalonset/nosocomial (HO) BSI (Adam, et al., 2011; Ammerlaan, et al., 2013; Biedenbach, et al., 2004;

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Wisplinghoff, et al., 2004). However, few reports have described the species distribution and antimicrobial

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susceptibility of both HO and community-onset (CO) BSI, and fewer still have stratified these data

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according to the age of the patient with BSI (Adam, et al., 2011; Biedenbach, et al., 2004; Diekema, et al., 2002; Sirijatuphat, et al., 2018).

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The SENTRY Antimicrobial Surveillance Program has been active continuously since January 1997 and

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reported antimicrobial susceptibility and pathogen occurrence data for more than 270,000 episodes of BSI in 232 medical centers representing 44 nations (Fuhrmeister & Jones, 2019). In this report, we

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examine the frequency of occurrence and antimicrobial susceptibility profiles of pathogens causing BSI in 16 medical centers contributing isolates in each month from January 2012 through December 2017.

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These results were stratified according to patient age and according to HO versus CO of infection. 2 MATERIALS AND METHODS 2.1 Study design The SENTRY Program was established to monitor the predominant pathogens and antimicrobial resistance patterns of HO and CO infections via a network of sentinel hospitals distributed by geographical location and bed capacity. Participating institutions during 2012-2017 included only those centers contributing BSI isolates and associated demographic data in each of the six study years: 10 medical centers in the United States (located in Georgia, Illinois, Virginia [Charlottesville and Richmond], Michigan, Kansas, New York [New York City and Rochester], Nebraska, and Utah), four in EUR (France,

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Journal Pre-proof Germany, Ireland and Italy), and one each in Mexico and South Korea. Each participating center contributed results (organism identification, date of isolation, and antimicrobial susceptibility profile) for consecutive episodes (up to 20 per month) of bacteremia/fungemia (blood culture isolates from separate patients that were judged by local laboratory criteria to be clinically significant; duplicate patient isolates were not accepted). Among the 16 participating medical centers, all were either academic or tertiary care centers. Bed size ranged from medium (367 beds) to large (2,600 beds). The number of isolates submitted over the six-

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year period averaged 435 per center (range 200-590).

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Each participating center determined whether the isolate was HO or CO based upon standard criteria (patient with bacteremia/fungemia judged to be clinically significant where blood cultures were obtained

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either <48h [CO] or ≥48h [HO] after admission). We were unable to differentiate CO infections that

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occurred in patients with hospital/health care exposure versus those with no such exposure. Importantly, each laboratory was instructed to use its own criteria to determine clinical significance of a positive blood

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culture and to send only isolates felt to be clinically significant, i.e., not contaminants. All isolates were

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saved on agar slants and sent to the monitoring laboratory (JMI Laboratories, North Liberty, Iowa) for storage and further characterization by reference identification and susceptibility testing methods.

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Organisms. A total of 6,741 bacterial and 222 fungal isolates were collected from 16 medical centers in 2012-2017. Species identification was confirmed when necessary by standard phenotypic or biochemical

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tests and using the MALDI Biotyper (Bruker Daltonics, Billerica, Massachusetts, USA) according to the manufacturer’s instructions. Isolates that were not identified by either phenotypic or proteomic methods were identified using sequence-based methods as previously described (Deshpande, et al., 2015; Deshpande, et al., 2007; Jones & Deshpande, 2003; Low, et al., 2001; Mendes, et al., 2016; Mutnick, et al., 2003). 2.2 Antimicrobial susceptibility testing Staphylococci, enterococci and Gram-negative bacilli (GNB) were tested in cation-adjusted MuellerHinton broth and streptococci were tested in that broth supplemented with 2.5-5% lysed horse blood, according to Clinical and Laboratory Standards Institute (CLSI) document M07 (CLSI, 2018). Quality control strains included S. aureus ATCC 29213, Streptococcus pneumoniae ATCC 49619, and E. coli

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Journal Pre-proof ATCC 25922 and 35218. Susceptibility percentages and quality control results validation were based on the CLSI M100 document (CLSI, 2019). Resistant subsets. Staphylococcus aureus strains were classified as methicillin/oxacillin-resistant (MRSA) according to their level of oxacillin resistance (MIC, ≥4 mg/L). Enterococci were classified as vancomycin-susceptible (VSE; MIC, ≤4 mg/L) or vancomycin-resistant (VRE; vancomycin MIC >16 mg/L). Escherichia coli, K. pneumoniae, and Klebsiella oxytoca were grouped as extended-spectrum βlactamase (ESBL) screen-positive (SP) phenotype based on the CLSI screening criteria for potential

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ESBL production (ceftazidime, ceftriaxone, or aztreonam MIC ≥2 mg/L) (CLSI, 2019). Isolates of P. aeruginosa were categorized as multidrug-resistant (MDR) according to criteria published

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by Magiorakos et al. (Magiorakos, et al., 2012), which defines MDR as nonsusceptible to ≥1 agent in ≥3

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antimicrobial classes. Isolates were categorized as nonsusceptible based on the CLSI criteria (CLSI,

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2019), unless noted, and the antimicrobial classes and drug representatives used in the analysis were: broad-spectrum cephalosporins (ceftazidime, and cefepime), carbapenems (imipenem, meropenem, and

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doripenem), broad-spectrum penicillin combined with a β-lactamase-inhibitor (piperacillin-tazobactam), fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (gentamicin, tobramycin, and

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amikacin), glycylcyclines (tigecycline; U.S. FDA criteria), and the polymyxins (colistin; EUCAST criteria). Additionally, carbapenem-resistant Enterobacteriaceae (CRE) was defined as resistant (MIC, ≥4 mg/L

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[CLSI]) to imipenem, meropenem, or doripenem.

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2.3 Antifungal susceptibility testing

Broth microdilution testing of Candida spp. was performed in accordance with the guidelines in the CLSI document M27 (CLSI, 2017a). MICs were determined visually after 24h incubation for the echinocandins and fluconazole as the lowest concentration of each drug that caused a significant diminution (≥50%) of growth below control levels. We used the most recent CLSI breakpoints to identify strains resistant to the echinocandins and fluconazole (CLSI M60) (CLSI, 2017b). Quality control was performed by testing CLSI-recommended strains C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 (CLSI M60) (CLSI, 2017b). 2.4 Statistical analysis

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Journal Pre-proof Statistical analyses were performed using R version 3.6.1. Trends in resistance rates over time were evaluated using linear regression. Results of linear regression are reported as the regression coefficient (β) and p-value. P-values <0.05 are considered statistically significant.

3 RESULTS The 10 most frequent pathogens that were submitted and their occurrence in BSI during the entire study period and for each year monitored are presented in Table 1. Overall, the 10 listed pathogens accounted

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for 89.4% of all isolates. Linear regression analyses did not reveal any significant trends across the 20122017 time period for any of the pathogens; however, qualitative differences between years were

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observed. Staphylococcus aureus, E. coli, and Enterococcus spp. were the three most frequently isolated

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pathogens in all years (Enterococcus spp. in four of the six years) of the study. Staphylococcus aureus

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was the most frequently isolated pathogen overall and in 2012-2014 and 2017; however, E. coli ranked first in 2015 and 2016. The frequency of S. aureus as a cause of BSI decreased from 23.9% in the first

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three years of the study (2012-2014), declining to 19.9% and 20.8% in 2015 and 2016, respectively, and increased to 24.5% in 2017. In contrast, E. coli frequency increased from 19.5% to 22.1% over the same

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time period. The isolation frequency of Enterococcus spp. ranked third in all years except 2015 and 2016 when it was displaced by coagulase-negative staphylococci (CoNS). The frequency of CoNS was 8.7%

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5.9% in 2017.

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overall and did not significantly change from 2012 to 2017, despite a decrease from 10.5% in 2016 to

The rank order of the remaining seven pathogens listed in Table 1 showed modest variability from year to year. Klebsiella spp. were frequently isolated in each year of the study (ranked fourth or fifth among the 10 listed pathogens) and showed a slight increase in frequency from 8.8% (2012-2014) to 9.4% (20152017), although the frequency did not change significantly from 2012-2017. Pseudomonas aeruginosa (3.1-5.4%) and Enterobacter spp. (2.7-4.8%) were also common Gram-negative isolates and ranked seventh and eighth, respectively, among the 10 listed BSI pathogens. Among streptococci, the βhemolytic (BHS) and viridans group (VGS) accounted for 4.4% and 2.5%, respectively, of the BSI pathogens (ranked sixth and 10th, respectively) with little variation over time. Notably, S. pneumoniae

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Journal Pre-proof th

ranked 11 overall, accounting for only 2.1% of infections with a low of 1.4% in 2017 (data not shown). Finally, Candida spp. accounted for 3.1% of BSI (range 2.1-4.2%). Important differences were observed in pathogen prevalence based upon patient demographic profiles, including age, source of the infection (HO or CO), and intensive care unit (ICU) versus non-ICU hospitalization for some of the 10 recovered species. The leading pathogen isolated from patients in all age groups (range, 20.3-32.5%), except for those >64 years old (19.9%), was S. aureus. E. coli was the most common agent in patients over 64 years of age (26.7%). Other common species also showed

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variability among age groups. BHS isolates were more frequently recovered from pediatric/adolescent patients (<1-18 years old; 6.7%) than other age groups, and this species group accounted for only 3.5-

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4.6% of all BSI isolates. Enterococcus spp. were isolated more frequently from neonates and patients <6

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years (10.0%-10.2%, ranked fourth for both groups) and adults age 50 and older (10.6%, ranked third).

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Pseudomonas aeruginosa was more commonly isolated from patients age 16-18 years (5.0%, ranked fifth) compared to neonates and infants (3.5%, ranked seventh or eighth). Streptococcus pneumoniae

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was an uncommon cause of bacteremia among all age groups (range 1.2-5.1%) with the lowest frequency observed among the elderly (> 64 years of age; 1.2%, ranked 12th). Aside from E. coli, K.

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pneumoniae was a leading agent of BSI due to GNB and ranked third in all age groups (range 6.8-9.5%) except for neonates where it ranked sixth and accounted for 5.6% of infections. Candida spp. was ranked

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as the eighth or ninth most common cause of BSI in all age groups (range, 2.7-3.7%) except for the

the top 10 BSI.

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adolescent age group (6-18 years) in which it accounted for 5.5% of infections and ranked sixth among

Staphylococcus aureus was frequently recovered from patients with HO or CO BSI (20.9-24.1%). However, E. coli was the most commonly isolated species (24.5%) from CO infections, greater than the rate of HO bacteremia (17.8%). Streptococcus pneumoniae, although infrequent overall, was six-fold more common as the cause of CO BSI (3.4%) compared to HO infection (0.6%). Nonetheless, HO BSI was approximately two- to three-fold more likely to be caused by Enterococcus spp. (13.8%), CoNS (10.8%), P. aeruginosa (5.2%), and Candida spp. (5.1%) than CO BSI, for which these species groups were isolated at rates of 7.5%, 5.7%, 3.3%, and 1.5%, respectively.

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Journal Pre-proof Three key demographic factors evaluated in this study also detailed the prevalence of BSI caused by MRSA, penicillin-intermediate and -resistant (nonsusceptible [NS]) S. pneumoniae, VRE, ESBL-producing Klebsiella spp., CRE and MDR P. aeruginosa (Table 2). Patients under the age of 50 were less likely to be infected with MRSA (18.8-36.2%) than patients over the age of 50 (40.4-40.8%). Only 11 VRE isolates caused BSI among patients that were ≤18 years old (10.2%). The VRE rate was 20.7-40.6% for the other three age groups. The rate of S. pneumoniae isolates with reduced susceptibility to penicillin was highest in the 6- to 18-year-old group (12.5%) and was less than 6% (range 0-5.6%) for all other age groups.

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Phenotypic ESBL Klebsiella spp. isolates causing BSI were observed at a rate greater than 18% for all age groups (range 18.4-36.7%) and was highest among adolescents (age 6-18 yrs; 36.7%). CRE was

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only detected in Klebsiella spp. isolates and was less than 3% (range 0.0-2.5%) across all age groups.

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MDR P. aeruginosa was absent from patients less than 1 year old and was highest in the adult population

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ages 19-49 (22.2%) and 50-64 (21.2%) years. Considering only isolates with CLSI published breakpoints,

year age groups (data not shown).

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fluconazole-resistant Candida spp. was only detected in isolates from the 19-49 (6.3%) and >64 (10.0%)

In addition, differences in the resistance rates were also observed for patients hospitalized in an ICU

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versus those hospitalized in a non-ICU setting and the origin of the infection (HO or CO; Table 2). BSI caused by VRE (34.3%), penicillin-NS S. pneumoniae (3.8%), ESBL-producing Klebsiella spp. (29.4%),

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CRE (2.5%), and MDR P. aeruginosa (16.3%) were more common among patients in ICUs compared to

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patients hospitalized in a non-ICU setting, where these pathogens were isolated at rates of 18.7%, 2.6%, 18.6%, 1.1% and 13.8%, respectively. The frequency of MRSA was slightly higher in the non-ICU population (37.5%) compared with the ICU group (34.1%). Patients who presented with infection ≥48h after hospital admission (HO) were at a higher risk for BSI by a pathogen with a resistant phenotype compared to patients with CO infections. MRSA strains were more frequently detected among HO isolates (40.4%) compared to strains recovered from CO infections (34.5%). VRE (30.9%) and Klebsiella spp. with ESBL phenotypes (30.3%) were more than twice as frequent among patients with HO bacteremia, whereas those with HO BSI due to CRE were nearly eightfold more common than those with CO infection. MDR P. aeruginosa BSI were slightly more frequent in

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Journal Pre-proof HO infection (16.9%) compared with CO infection (13.2%). The rate of penicillin-NS S. pneumoniae was 0.0% in HO BSI and 3.2% in CO infection. Antimicrobial resistance rates during the study among six common pathogens/pathogen groups isolated from BSI are shown in Table 3. Overall, the frequency of resistant phenotypes was high for S. aureus (MRSA; 37.0%), enterococci (VRE; 24.6%), Klebsiella spp. (ESBL phenotype; 21.5%), and P. aeruginosa (MDR; 15.4%), but MRSA and VRE rates significantly declined from 2012 to 2017. In each instance, the frequency of the resistant phenotype was considerably lower in 2017 compared to that in 2012. Whereas

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the penicillin-NS S. pneumoniae (3.4%) and CRE (1.5%) frequencies were low overall, both resistant phenotypes declined over time and had the lowest rates in 2017. Notably, there were no isolates of

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penicillin-NS S. pneumoniae in 2015-2017. Although not shown in Table 3, fluconazole-resistant Candida

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spp. were only detected in 2013-2015. Fluconazole-resistant isolates were not detected in 2016 and

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2017, except for 3 C. krusei isolates that are considered intrinsically resistant among 83 Candida isolates tested with CLSI breakpoints.

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The low number of study sites make any comparison of resistance by geographic region difficult. Given that most isolates were contributed by NA and EUR, differences in the frequency of selected resistant

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phenotypes in these two regions may be noted. The frequency of MRSA and VRE was greater in NA (39.7% and 33.2%, respectively) than in EUR (30.2% and 9.9%, respectively). Conversely, the

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frequencies of ESBL-producing Klebsiella spp, CRE and MDR P. aeruginosa was greater in EUR (24.1%,

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10.9% and 18.8%, respectively) than in NA (12.5%, 2.3% and 13.1%, respectively). Antimicrobial susceptibilities of commonly prescribed antimicrobials against eight selected bacterial BSI pathogens and five species of Candida are shown in Table 4. The frequency of vancomycin resistance among isolates of Enterococcus faecium was 51.4% overall and significantly declined from 69.4% in 2012 to 40.9% in 2016 and was 48.3% in 2017. In contrast, resistance to vancomycin among isolates of Enterococcus faecalis was only 2.8% overall, ranging from 0.0% in 2012 to 5.5% in 2015, and registering as only 1.4% in 2017. In addition to the low rates of penicillin NS seen in BSI of S. pneumoniae, no strains of this species were resistant to either ceftriaxone or cefepime. Conversely, S. pneumoniae isolates resistant to erythromycin were common (34.2% overall) and ranged from 25.0% to 54.2% with the lowest frequencies of resistance observed in isolates from 2016 (25.9%) and 2017 (25.0%). BSI isolates

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Journal Pre-proof of E. coli showed similar rates of resistance to both ceftazidime (11.6% overall) and cefepime (12.0% overall) with little change over time. Likewise, rates of resistance to ciprofloxacin (30.6% overall) and to gentamicin (13.8% overall) did not change appreciably over the six-year time period. Carbapenemresistant isolates of E. coli were not detected in any year. Carbapenem resistance was detected in 5.0% of Klebsiella spp. overall and decreased from 11.4% in 2012 to 2.3% in 2017. Resistance to ceftazidime and cefepime among Klebsiella spp. declined from 18.6% for each agent in 2012 to 10.7% and 6.1%, respectively, in 2015, but increased for both agents in 2016 (20.5% and 17.8%, respectively) and 2017

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(13.7% and 11.5%, respectively). A similar pattern was seen for Klebsiella isolates tested against ciprofloxacin, gentamicin, and the carbapenems in which resistance generally declined for each agent

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between 2012 and 2015 and then slightly increased in resistance in 2016 and 2017. Resistance to

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ceftazidime among Enterobacter spp. isolates decreased from 35.9% in 2012 to 13.5% in 2014,

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increasing to 38.8% in 2015, and was 22.0% in 2017. Enterobacter spp. isolates resistant to cefepime were few, with minimal change over time. Aside from 2012, Enterobacter spp. isolates resistant to the

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carbapenems were not detected over the last five years of the study (2013-2017). Pseudomonas aeruginosa isolates showed a decline in resistance to all seven agents tested between 2012 and 2016

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but increased by two- to eight-fold between 2016 and 2017 for each agent tested. Resistance to antifungal agents was distinctly uncommon among the five species of Candida shown in Table 4. Aside

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from C. krusei, only six isolates were resistant to fluconazole (one isolate each of C. tropicalis and C.

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parapsilosis and four of C. glabrata) and two were resistant to the echinocandins (one isolate each of C. tropicalis and C. glabrata). The latter strains showed resistance to all three echinocandins and were susceptible to fluconazole. 4 DISCUSSION Although the number of potential bacterial and fungal BSI pathogens is endless, over time relatively few have been shown to reliably indicate a BSI (Biedenbach, et al., 2004; Luzzaro, et al., 2011; Pien, et al., 2010). Greater than 90% of BCs growing S. aureus, S. pneumoniae, BHS, Enterobacteriaceae, P. aeruginosa, and Candida spp. represent true BSI (Pien, et al., 2010). Whereas multiple BC sets must be positive before the positive predictive value is sufficiently high for the diagnosis of BSI due to CoNS, the

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Journal Pre-proof positive predictive value is assumed to be 100% when a single BC set is positive for S. aureus, P. aeruginosa, or Candida spp. (Lamy, et al., 2016; Leyssene, et al., 2011). It is important to note that the mortality directly attributable to the BSI is quite high and underscores the need for prompt diagnosis and treatment and for prevention of these frequent HCA infections (Umscheid, et al., 2011; Zimlichman, et al., 2013). The excess (attributable) mortality due to these key pathogens may be associated with increased antimicrobial resistance, the intrinsic virulence of the pathogen, or delays in diagnosis due to insufficient diagnostic methods (Pien, et al., 2010). Delays in administering

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appropriate antimicrobial therapy (>24-48h) has been found to be almost universal in patients with candidemia (Morrell, et al., 2005; Pfaller & Castanheira, 2016) and also affects BSI due to other

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pathogens with antibacterial-resistant profiles, including S. aureus (MRSA), Enterococcus spp. (VRE),

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ESBL-producing Enterobacteriaceae, CRE, and MDR GNB, such as P. aeruginosa and Acinetobacter

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calcoaceticus-A. baumannii (Acb) species complex (Erbay, et al., 2009; Lodise, et al., 2003; Micek, et al., 2005; Tumbarello, et al., 2007). Approximately 30% or more of BSI due to common Gram-positive cocci

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(GPC), GNB, and Candida spp. are either treated initially with agents that are inactive against the infecting pathogen or fail to receive any treatment for the first 24 to 48h of the infectious process with a

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resultant increase in mortality. In these cases, mortality is not decreased by changing to a more active/appropriate therapy later in the course of infection (Kollef, et al., 1999; Luna, et al., 1997).

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The rank order of occurrence of the top 10 pathogens varied little over the six-year study period. These

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organisms largely represent BSI pathogens that have been shown to be clinically significant and represent independent risks for mortality due to their resistance profiles (Biedenbach, et al., 2004; Kollef, et al., 1999; Luzzaro, et al., 2011; Pien, et al., 2010; Zhang, et al., 2015; Zilberberg & Shorr, 2015). In contrast to earlier studies (Biedenbach, et al., 2004; Diekema, et al., 2002; Pfaller, et al., 1999), a trend toward a decrease in BSI due to GPC and an increase in GNB infections were observed when comparing the first three study years (2012-2014) with the latter three study years (2015-2017). Overall, 50.3% of the 6,963 BSI isolates in this study were GPC and 45.8% were GNB; however, among the top 10 pathogens, the frequency of GPC decreased from 51.5% in 2012-2014 to 49.6% in 2015-2017, and the GNB frequency increased from 44.5% in 2012-2014 to 46.5% in 2015-2017. This trend was largely driven by a decrease in the proportion of BSI due to S. aureus (23.9% [2012-2014] and 21.7% [2015-2017]) and an

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Journal Pre-proof increase in the proportion due to E. coli (19.5% [2012-2014] and 22.1% [2015-2017]) in the two time periods. Staphylococcus aureus, including MRSA, was a leading cause of BSI among all age groups as well as the most frequent agent of HO BSI, whereas E. coli predominated among the elderly (>64 years of age) and patients with CO BSI. Among the resistant phenotypes examined in this study, VRE, penicillinNS S. pneumoniae, ESBL-phenotype Klebsiella spp., CRE, and MDR P. aeruginosa were more frequent in the ICU setting and S. aureus (MRSA) was slightly more common outside the ICU. The resistant phenotypes and Candida spp. were more common causes of HO BSI than CO BSI. HO BSI was not

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caused by penicillin-NS S. pneumoniae. One of the most notable findings of this survey was the significant decrease in proportion of resistant

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isolates among S. aureus (MRSA) and enterococci (VRE). Resistance to penicillin was uncommon among

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S. pneumoniae isolates and was not detected in the last three years of the study. The frequency of

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fluconazole-resistant Candida spp. was low among all age groups and in each study year. Also, no fluconazole-resistant Candida spp. were found in 2016 or 2017. The latter finding is surprising but likely

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stems from the fact that there were fewer isolates of C. glabrata and C. krusei from BSI in those years. In addition to the decline in the key resistant phenotypes noted, resistance rates to other antimicrobial

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agents declined for certain pathogens. Specifically, S. pneumoniae isolates showed no resistance to ceftriaxone, E. coli and Enterobacter spp. isolates had little to no resistance to the carbapenems, and only

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two Candida isolates were resistant to the echinocandins. Escherichia coli resistance to ceftazidime,

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cefepime, ciprofloxacin, and gentamicin remained relatively stable over the six-year period. Although resistance rates to the cephalosporins, fluoroquinolones, and aminoglycosides trended downward for Klebsiella spp., Enterobacter spp., and P. aeruginosa between 2012 and 2015, they tended to increase in 2016 and 2017. This study is limited by the relatively small number of institutions providing isolates and the fact that most of these institutions were located in only 8 states within the United States. In addition, the SENTRY Program does not provide population-based information regarding incidence of BSI in a given region, does not compile antimicrobial usage data, and does not detail the underlying conditions of patients (transplant, immunocompromised, post-operative status or nursing home transfer) or outcomes of infection. As such, it is difficult to assess why the observed trends may have emerged at the sites

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Journal Pre-proof contributing isolates to the study. The study provides a level of consistency with each participating institution having contributed isolates using the same protocol each study year. The reported results provide a more optimistic view than many surveys addressing antimicrobial resistance. Trends of declining MRSA and VRE rates have been noted, often in the setting of increasing resistance among GNB (Chatterjee & Otto, 2013; Chiang, et al., 2017; Gagliotti, et al., 2011; McDanel, et al., 2017; Perencevich & Diekema, 2010; Slayton, et al., 2015; Weiner, et al., 2016). Our results support the decline in MRSA and VRE but also show a decrease in key GNB resistant phenotypes. The low levels

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of CRE, penicillin-NS S. pneumoniae, and fluconazole and echinocandin resistance in Candida spp. are very encouraging. The reason for this rather “rosy” picture is not readily apparent, but could reflect the

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more recent efforts in antimicrobial stewardship, increased PVC13 immunization efforts, and enhanced IP

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efforts (Magill, et al., 2018; Perencevich & Diekema, 2010; Pfaller & Castanheira, 2016; Rosen, et al.,

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2011; Slayton, et al., 2015).

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Journal Pre-proof ACKNOWLEDGMENTS The authors would like to thank Jennifer M. Streit, Lori Flanigan, and Amy Chen for their assistance in, respectively, coordinating the SENTRY Program and editorial review of this manuscript.

FUNDING INFORMATION This study was performed by JMI Laboratories and supported by Pfizer, which included funding for

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services related to preparing this manuscript.

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JMI Laboratories contracted to perform services in 2018 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amplyx, Antabio,

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American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas,

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Basilea Pharmaceutica Ltd., Bayer AG, Becton, Dickinson and Company, bioMerieux SA, Boston Pharmaceuticals, Bugworks Research Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics,

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Inc., CorMedix Inc., DePuy Synthes, Destiny Pharma, Discuva Ltd., Dr. Falk Pharma GmbH, Emery

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Pharma, Entasis Therapeutics, Eurofarma Laboratorios SA, US Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc., Gateway Pharmaceutical LLC, GenePOC Inc., Geom

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Therapeutics, Inc., GlaxoSmithKline plc, Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum Therapeutics plc, Laboratory

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Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc, NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics Inc., Qpex Biopharma, Inc., Ra Pharmaceuticals, Inc., Roivant Sciences, Ltd., Safeguard Biosystems, Scynexis, Inc.,SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, The Medicines Company, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Vyome Therapeutics

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Journal Pre-proof Inc., Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc. There are no

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speakers’ bureaus or stock options to declare.

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Journal Pre-proof Zilberberg, M.D., & Shorr, A.F. (2015) Appropriate antibiotic treatment in severe sepsis and septic shock: Timing is everything. Crit Care Med, 43: 2258-2259. Zimlichman, E., Henderson, D., Tamir, O., Franz, C., Song, P., Yamin, C.K., Keohane, C., Denham, C.R., & Bates, D.W. (2013) Health care-associated infections: a meta-analysis of costs and financial

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Journal Pre-proof Table 1. Rank order and frequency of occurrence rates for pathogens associated with bloodstream infection from 16 medical centers during the 2012-2017 SENTRY Antimicrobial Surveillance Program

Rank 1

Organism

Total (%)

2012

2013

2014

2015

2016

2017

S. aureus

307 (20.8)

341 (24.5)

167 (18.6)

327 (21.9)

313 (21.2)

3

Enterococcus spp.

89 (9.9)

145 (9.7)

4

Klebsiella spp.

636 (9.1)

70 (8.6)

206 (23.3) 163 (18.5) 103 (11.7) 72 (8.2)

297 (19.9)

E. coli

200 (24.4) 177 (21.6) 70 (8.6)

216 (24)

2

1567 (22.5) 1473 (21.2) 695 (10)

86 (9.6)

5

CoNS

604 (8.7)

58 (7.1)

78 (8.8)

6

BHS

309 (4.4)

37 (4.5)

7

P. aeruginosa

293 (4.2)

8

Enterobacter spp.

9 10

f o

p-value

0.563

326 (23.5)

0.240

153 (10.4)

0.890

131 (8.8)

146 (9.9)

131 (9.4)

0.137

81 (9)

150 (10)

155 (10.5)

82 (5.9)

0.995

30 (3.4)

39 (4.3)

73 (4.9)

o r p

135 (9.7)

67 (4.5)

63 (4.5)

0.416

44 (5.4)

43 (4.9)

29 (3.2)

70 (4.7)

46 (3.1)

61 (4.4)

0.304

261 (3.7)

39 (4.8)

24 (2.7)

37 (4.1)

49 (3.3)

62 (4.2)

50 (3.6)

0.754

Candida spp.

216 (3.1)

17 (2.1)

37 (4.2)

24 (2.7)

46 (3.1)

52 (3.5)

40 (2.9)

0.735

VGS

173 (2.5)

14 (1.7)

27 (1.8)

44 (3)

34 (2.4)

0.749

6,963

818

n r u

27 (3)

Total

899

1,495

1,478

1,390

27 (3.1) 883

l a

e

r P

CoNS, coagulase-negative staphylococci; BHS, β-hemolytic streptococci; VGS, viridans group streptococci.

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Journal Pre-proof Table 2. Patient risk factor assessment for rates of resistant phenotypes among bloodstream infection pathogens from 16 medical centers during the 2012-2017 SENTRY Antimicrobial Surveillance Program (number resistant/total number of isolates in each category) ICUb

Age group (years) Organism a (% resistant) S. aureus (%MRSA) Enterococcus spp c (%VRE)

<1 18.8% (19/101) 10.0% (5/50)

1-5 32.5% (26/80) 5.6% (2/36)

6-18 29.5% (38/129) 18.2% (4/22)

19-49 36.2% (110/304) 40.6% (43/106)

50-64 40.4% (146/361) 30.7% (50/163)

>64 40.8% (230/564) 20.7% (63/305)

ICU 34.1% (129/378) 34.3% (74/216)

Source of infectionb Non-ICU 37.5% (423/1,128) 18.7% (85/455)

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HO 40.4% (239/592) 30.9% (121/392)

CO 34.5% (308/893) 14.7% (41/279)

S. pneumoniae 0.0% 5.6% 12.5% 2.6% 0.0% 2.9% 3.8% 2.6% (%Penicillin-NS)d (0/11) (1/18) (1/8) (1/38) (0/37) (1/34) (1/26) (3/117) 0.0% (0/16) 3.2% (4/125) Klebsiella spp. 18.4% 24.3% 36.7% 21.9% 18.9% 22.2% 29.4% 18.6% 30.3% 14.0% (%ESBL) (7/38) (9/37) (11/30) (21/96) (32/169) (57/257) (47/160) (83/447) (81/267) (45/322) Klebsiella spp. and 0% 1.5% 0% 2.5% 1.7% 1.5% 2.5% 1.1% 3.1% 0.4% E. coli (%CRE) (0/114) (1/67) (0/83) (8/319) (8/483) (15/1012) (10/401) (18/1623) (24/772) (5/1227) P. aeruginosa 0.0% 7.7% 10.0% 22.2% 21.2% 12.9% 16.3% 13.8% 16.9% 13.2% (%MDR) (0/17) (1/13) (2/20) (10/45) (14/66) (16/124) (15/92) (25/181) (25/148) (16/121) MRSA, methicillin-resistant S. aureus; VRE, vancomycin-resistant enterococci; penicillin-NS, penicillin-nonsusceptible, ESBL, extended-

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a

Resistance criteria are based upon CLSI M100 recommendations. (CLSI, 2019)

b

Values were not reported for all isolates. Does not represent true prevalence.

c

Vancomycin MIC, >16 mg/L.

d

Includes intermediate and resistant isolates per 2019 CLSI criteria for parenteral, non-meningitis.(CLSI, 2019)

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Journal Pre-proof Table 3. Rates of resistant phenotypes by year for pathogens associated with bloodstream infection from 16 medical centers during the 2012-2017 SENTRY Antimicrobial Surveillance Program

a

p-value

Organism (% resistant )

Total

2012

2013

2014

2015

2016

2017

S. aureus (% MRSA)

1,567 (37.0)

200 (40.0)

206 (39.8)

216 (36.6)

297 (37.0)

307 (35.8)

341 (34.9)

0.0048*

Enterococcus spp. (% VREb)

695 (24.6)

70 (35.7)

103 (28.2)

89 (23.6)

145 (25.5)

153 (19.6)

135 (21.5)

0.020*

S. pneumoniae (% PEN-NSc)

149 (3.4)

18 (5.6)

25 (4.0)

17 (17.6)

42 (0.0)

27 (0.0)

20 (0.0)

0.37

Klebsiella spp. (% ESBL)

636 (21.5)

70 (27.1)

72 (19.4)

86 (19.8)

131 (15.3)

146 (27.4)

131 (20.6)

0.78

E. coli and Klebsiella spp. (% CRE)

2,109 (1.5)

247 (3.2)

235 (2.6)

458 (0.7)

459 (2.0)

457 (0.7)

0.078

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P. aeruginosa (% MDR) 293 (15.4) 44 (31.8) 43 (11.6) 29 (20.7) 70 (10.0) 46 (4.3) 61 (18.0) 0.25 MRSA, methicillin-resistant S. aureus; VRE, vancomycin-resistant enterococci; PEN-NS, penicillin-nonsusceptible; ESBL, extended-spectrum

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a

Resistance criteria are based upon CLSI M100 recommendations. (CLSI, 2019)

b

Vancomycin MIC, >16 mg/L.

c

Includes intermediate and resistant isolates per 2019 CLSI criteria for parenteral, non-meningitis.(CLSI, 2019)

*Statistically significant at p<0.05

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Journal Pre-proof Table 4. Antimicrobial resistance rates by year among BSI isolates from the SENTRY Antimicrobial Surveillance Program (2012-2017)

Year/% resistanta (number tested) Organism S. aureus

Agent Oxacillin

Total 37.0 (1,567)

2012 40.0 (200)

2013 39.8 (206)

2014 36.6 (216)

2015 37.0 (297)

E. faecium

Vancomycin

51.4 (313)

69.4 (36)

66.7 (42)

47.6 (42)

47.8 (69)

E. faecalis

Vancomycin

2.8 (355)

0.0 (32)

1.8 (57)

2.6 (39)

5.5 (73)

Penicillin

3.4 (147)

5.6 (18)

4.0 (25)

20.0 (15)

0.0 (42)

Erythromycin

34.2

33.3

54.2

40.0

31.0

Ceftriaxone

0.0

0.0

0.0

0.0

Cefepime

0.0

0.0

0.0

Ceftazidime

11.6 (1,473)

13.6 (177)

8.0 (163)

Cefepime

12.0

13.6

Ciprofloxacin

30.6

32.2

Gentamicin

13.8

15.8

Imipenem

0.0

0.0

Meropenem

0.0

Ceftazidime

14.9 (636)

Cefepime

12.9

Ciprofloxacin

15.4

Gentamicin

S. pneumoniae

E. coli

Klebsiella spp.

Enterobacter spp.

p-value

2016 35.8 (307) 40.9 (66)

2017 34.9 (341) 48.3 (58)

0.0375*

3.8 (80)

1.4 (74)

0.382

0.0 (27)

0.0 (20)

0.537

25.9

25.0

0.151

0.0

0.0

0.0

N/A

NT

NT

NT

N/A

13.2 (167)

11.9 (327)

11.7 (326)

0.952

13.8

11.6

11.2 (313) 12.5

12.0

0.936

38.3

30.1

29.4

29.1

0.670

9.2

13.8

12.5

13.7

16.6

0.523

0.0

0.0

0.0

0.0

0.0

N/A

0.0

0.0

0.0

0.0

0.0

N/A

18.6 (70)

12.5 (72)

12.8 (86)

10.7 (131)

13.7 (131)

0.946

18.6

12.5

12.8

6.1

20.5 (146) 17.8

11.5

0.553

20.0

15.3

17.4

11.5

17.1

13.7

0.238

9.6

10.0

4.2

11.6

5.3

17.1

6.9

0.720

Imipenem

4.9

11.4

8.3

3.5

1.5

6.2

2.3

0.0855

Meropenem

5.0

11.4

8.3

3.5

2.3

6.2

2.3

0.0725

Ceftazidime

26.1 (261)

35.9 (39)

25.0 (24)

13.5 (37)

38.8 (49)

21.0 (62)

22.0 (50)

0.952

Cefepime

3.1

5.1

4.2

0.0

4.2

1.6

4.0

0.936

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27.0

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0.00479*

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Journal Pre-proof a

Year/% resistant (number tested) Organism

P. aeruginosa

Candida spp.c

C. albicans

C. tropicalis

C. parapsilosis

p-value

Agent Imipenem

Total 0.8

2012 5.1

2013 0.0

2014 0.0

2015 0.0

2016 0.0

2017 0.0

Meropenem

0.4

2.6

0.0

0.0

0.0

0.0

0.0

N/A

Tobramycin

7.8 (293)

11.4 (44)

7.0 (43)

17.2 (29)

4.3 (70)

2.2 (46)

9.8 (61)

0.496

Ciprofloxacin

19.8

22.7

18.6

27.6

21.4

10.9

0.395

Ceftazidime

13.3

22.7

14.0

20.7

8.6

2.2

16.4

0.258

Cefepime

7.5

13.6

2.4

17.2

5.7

2.2

8.2

0.506

Piperacillintazobactam Imipenem

10.3

18.6

16.3

6.9

4.3

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19.7

4.3

13.1

0.243

12.3

18.6

20.9

17.2

5.7

6.5

11.5

0.0879

Meropenem

10.6

18.2

9.3

7.1

4.3

11.5

0.242

Fluconazole

6.3 (191)

0.0 (16)

8.8 (34)

9.5 (21)

10.5 (38)

4.2 (48)d

2.9 (35)d

0.968

Caspofungin

1.0

0.0

0.0

2.6

2.1

0.0

Micafungin

1.0

0.0

0.0

2.6

2.1

0.0

Anidulafungin

1.0

0.0

0.0

0.0

2.6

2.1

0.0

Fluconazole

0.0 (91)

0.0 (8)

0.0 (18)

0.0 (8)

0.0 (12)

0.0 (25)

0.0 (20)

Caspofungin

0.0

0.0

0.0

0.0

0.0

0.0

Micafungin

0.0

0.0

0.0

0.0

0.0

0.0

0.0

Anidulafungin

0.0

0.0

0.0

0.0

0.0

0.0

0.0

Fluconazole

3.7 (27)

0.0 (2)

14.3 (7)

0.0 (3)

0.0 (4)

0.0 (7)

0.0 (4)

Caspofungin

3.7

0.0

0.0

0.0)

0.0

14.3

0.0

Micafungin

3.7

0.0

0.0

0.0

0.0

14.3

0.0

Anidulafungin

3.7

0.0

0.0

0.0

0.0

14.3

0.0

Fluconazole

3.4 (29)

0.0 (2)

0.0 (2)

0.0 (3)

12.5 (8)

0.0 (8)

0.0 (6)

Caspofungin

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

rn

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N/A

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Journal Pre-proof a

Year/% resistant (number tested) Organism

C. glabrata

C krusei

Agent Micafungin

Total 0.0

2012 0.0

2013 0.0

2014 0.0

2015 0.0

2016 0.0

2017 0.0

Anidulafungin

0.0

0.0

0.0

0.0

0.0

0.0

0.0

Fluconazole

10.5 (38)

0.0 (3)

28.6 (7)

16.7 (6)

8.3 (12)

0.0 (6)

0.0 (4)

Caspofungin

2.6

0.0

0.0

0.0

8.3

0.0

Micafungin

2.6

0.0

0.0

0.0

8.3

0.0

0.0

Anidulafungin

2.6

0.0

0.0

0.0

8.3

0.0

0.0

Caspofungin

0.0 (6)

NI

NI

0.0 (1)

0.0 (2)

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0.0

0.0 (2)

0.0 (1)

Micafungin

0.0

NI

NI

0.0

0.0

0.0

0.0

Anidulafungin

0.0

NI

NI

0.0

0.0

0.0

NI, species not isolated; N/A, not applicable

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p-value

a

Resistance criteria are based upon CLSI M100 (CLSI, 2019) and CLSI M60 (CLSI, 2017b) recommendations.

b

Includes intermediate and resistant isolates per 2019 CLSI criteria for parenteral, non-meningitis.(CLSI, 2019)

c

Includes only the following Candida spp. isolates with fluconazole breakpoints (C. albicans, C. tropicalis, C. parapsilosis, and C. glabrata) or

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intrinsic resistant (C. krusei isolates) per 2019 CLSI criteria.(CLSI, 2017b) d

Fluconazole resistance in 2016 and 2017 was seen with C. krusei only (2 and 1 isolate, respectively).

*Statistically significant at p<0.05

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Journal Pre-proof DMID_2019_920 Authors Statement

Michael A. Pfaller: Writing- Original draft preparation; Cecilia G. Carvalhaes: Supervision, oversight and leadership responsibility for the research; Caitlin J. Smith: statistics and data analysis and curation; Daniel J. Diekema: review scientific data and text; Mariana Castanheira: project administration and scientific review

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