Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013–2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program

Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013–2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program

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Accepted Manuscript Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013–2015) as part of the program to assess Ceftolozane-Tazobactam susceptibility (PACTS) surveillance program

Dee Shortridge, Michael A Pfaller, Mariana Castanheira, Robert K. Flamm PII: DOI: Reference:

S0732-8893(18)30168-8 doi:10.1016/j.diagmicrobio.2018.05.011 DMB 14598

To appear in: Received date: Revised date: Accepted date:

9 November 2017 2 April 2018 12 May 2018

Please cite this article as: Dee Shortridge, Michael A Pfaller, Mariana Castanheira, Robert K. Flamm , Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013–2015) as part of the program to assess Ceftolozane-Tazobactam susceptibility (PACTS) surveillance program. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Dmb(2018), doi:10.1016/j.diagmicrobio.2018.05.011

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ACCEPTED MANUSCRIPT Manuscript Ref No.: DMID 17-963 Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013– 2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance

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program

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Running title: C-T Activity vs. US Blood Isolates 2013–2015

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Key words: ceftolozane-tazobactam, surveillance, P. aeruginosa, ESBL, bloodstream isolates

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Dee Shortridge , Michael A Pfaller , Mariana Castanheira , and Robert K. Flamm

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JMI Laboratories, North Liberty, Iowa

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University of Iowa College of Medicine, Iowa City, Iowa

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Corresponding Author: Dee Shortridge, Ph.D.

345 Beaver Kreek Centre, Suite A

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North Liberty, IA 52317 (319) 665-3370 (phone)

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(319) 665-3371 (fax) [email protected]

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ACCEPTED MANUSCRIPT Abstract This study evaluated the in vitro activity of ceftolozane-tazobactam and comparators against 2,647 Enterobacteriaceae and 355 Pseudomonas aeruginosa non-duplicate isolates collected from hospitalized patients with bloodstream infections in US hospitals from 2013-2015. Ceftolozane-tazobactam (95.5% susceptible), amikacin (99.2% susceptible), and meropenem (98.4%

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susceptible) were the most active against Enterobacteriaceae. For Enterobacteriaceae, 1.4% (n=37)

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were carbapenem-resistant (CRE) and 10.2% (n=271) exhibited an ESBL non-CRE phenotype. The most

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common ESBL enzyme detected was blaCTX-M-15-like (n=159). Whereas ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype Enterobacteriaceae (87.1% susceptible), it lacked useful

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activity against CRE strains. Ceftolozane-tazobactam was the most potent (MIC50/90, 0.5/1 mg/L) β-lactam agent tested against P. aeruginosa isolates, with 97.5% susceptible. Only colistin was more active (98.9%

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susceptible).

Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and

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tested against Enterobacteriaceae.

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demonstrated higher in vitro activity than available cephalosporins and piperacillin-tazobactam when

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1. Introduction Bloodstream infections are a serious healthcare-associated infection in the United States (Bassetti, Righi, & Carnelutti, 2016; Magill, et al., 2014). Appropriate initial antimicrobial therapy has been strongly associated with reduced mortality in patients and is particularly critical for bloodstream infections

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(Seymour, et al., 2017; Zilberberg, Shorr, Micek, Vazquez-Guillamet, & Kollef, 2014). In some US regions,

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multidrug-resistant gram-negative pathogens, such as Pseudomonas aeruginosa, carbapenem-resistant

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(CRE), and extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, are increasingly common (Castanheira, Mendes, Jones, & Sader, 2016; Cerceo, Deitelzweig, Sherman, & Amin, 2016).

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Due to the relative lack of new agents to treat these infections, empiric therapy is often ineffective and requires antibacterial agent combinations to achieve optimal coverage (Tangden & Giske, 2015).

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These findings underscore the continued importance of antibiotic resistance surveillance and the need to assess the potential impact of newly introduced and novel antibacterial agents that target specific

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resistance phenotypes. Systematic and comprehensive antibiotic resistance surveillance is essential to

combat the resistance challenge.

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document the extent of the resistance problem and to inform local, regional, national, and global efforts to

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Ceftolozane-tazobactam is a combination of a novel cephalosporin and a well-described beta-lactamase inhibitor with activity against P. aeruginosa, including antibiotic-resistant strains, and other common gram-

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negative bacilli (GNB), including most ESBL-producing Enterobacteriaceae strains (Sader, Rhomberg, Farrell, & Jones, 2011). Ceftolozane-tazobactam has limited activity against Acinetobacter spp.;

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Stenotrophomonas maltophilia; gram-positive cocci; organisms producing carbapenemases or metallo-βlactamases; or a minority of AmpC β-lactamases found in Enterobacteriaceae. Ceftolozane-tazobactam was recently approved to treat complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections (ZERBAXA, 2016). A Phase 3 clinical trial of ceftolozane-tazobactam to treat nosocomial pneumonia is ongoing. In this study, we assessed the activity of ceftolozane-tazobactam against 3,176 gram-negative bloodstream infection isolates from the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) collected in the US from 2013-2015. In addition to susceptibility testing for ceftolozane-

ACCEPTED MANUSCRIPT tazobactam and 9 comparator agents, the ESBL genes were characterized using the Checkpoint assay in Klebsiella pneumoniae and Escherichia coli isolates that were ESBL phenotype screen-positive. 2. Materials and Methods 2.1 Bacterial isolates A total of 3,176 non-duplicate gram negative isolates (including 2,647 Enterobacteriaceae, 355 P.

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aeruginosa, and 174 other gram negative species) were collected prospectively from 32 US medical

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centers in all 9 U.S. Census Bureau divisions from 2013–2015. Participant centers submitted clinical

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bacterial isolates (1 isolate per patient per infection episode) that were collected consecutively by infection type according to a common protocol. The common SENTRY Antibacterial Surveillance Program

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protocol established the number of isolates for the target infection types and when the isolates should be collected. Each institution contributed a specified number of isolates per year. Isolates included in this

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study were from hospitalized patients with bloodstream infections. Isolates were identified at each medical center with the laboratory’s standard protocol and confirmed by the central laboratory (JMI

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Laboratories, North Liberty, Iowa) using a matrix-assisted laser desorption ionization time of flight

molecular methods, as needed.

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technology mass spectrometer (MALDI-TOF; Bruker, Billerica, Massachusetts) or other phenotypic or

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2.2 Antimicrobial susceptibility testing

Minimal inhibitory concentrations (MICs) for all antibiotics were determined using broth microdilution

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panels according to Clinical and Laboratory Standards Institute (CLSI) standards (CLSI, 2015) with °

standard incubation temperature (35 C) and time (16-20 hours). Antibiotic powders were obtained from

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manufacturers or Sigma-Aldrich (St. Louis, Missouri), and stock solutions were made according to CLSI or the manufacturer’s instructions. All ceftolozane-tazobactam and piperacillin-tazobactam MIC tests used a fixed tazobactam concentration of 4 mg/L. Other comparators tested were amikacin, cefepime, ceftazidime, colistin (for P. aeruginosa), gentamicin, levofloxacin, meropenem, and tigecycline (for Enterobacteriaceae). Quality control and interpretation of results were performed according to CLSI M100-S27, FDA breakpoints were used for tigecycline (CLSI, 2017; Wyeth Pharmaceuticals, 2010). EUCAST Enterobacteriaceae breakpoints were used for colistin (EUCAST, 2017). All MIC results for CLSI quality control strains were within published ranges.

ACCEPTED MANUSCRIPT 2.3 Resistant subsets Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis were grouped as "ESBL screen-positive (SP) phenotype" based on the CLSI screening criteria for potential ESBL production with MIC values of ≥2 mg/L for ceftazidime, ceftriaxone, or aztreonam. CRE isolates were defined as displaying MIC values ≥4 mg/L for imipenem (P. mirabilis and indole-positive Proteeae were

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not included due to the intrinsically elevated MIC values), meropenem, and/or doripenem. Since

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resistant ESBL-phenotype (ESBL non-CRE) isolates were analyzed.

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carbapenemase-producing isolates may also appear to have an ESBL phenotype, non-carbapenem-

Pseudomonas aeruginosa isolates were considered meropenem-nonsusceptible if their MIC value was ≥4

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mg/L, ceftazidime- or cefepime-nonsusceptible if their MIC was ≥16 mg/L, and piperacillin-tazobactamnonsusceptible if their MIC was 32 mg/L, as described in CLSI M100 (CLSI, 2017).

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2.4 Screening for β-lactamases

A total of 288 E. coli and K. pneumoniae isolates displaying the CLSI ESBL-phenotype screening criteria

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as described in section 2.3 were tested for β-lactamase-encoding genes using the microarray based assay Check-MDR CT101 kit (Check-Points, Wageningen, Netherlands). The assay was performed

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according to the manufacturer’s instructions and has the capability to detect blaCTX-M groups 1 (blaCTX-M-15-

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like), 2 (blaCTX-M-2-like), 8+25, and 9 (blaCTX-M-14-like), blaTEM wild-type (WT) and ESBL, blaSHV WT and ESBL, blaACC, blaACT/MIR, blaCMY-2-like, blaDHA, blaFOX, blaKPC, and blaNDM-1-like. The most common amino

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acid alterations that expand the spectrum of TEM and SHV enzymes are detected by this assay, and these include E104K, R164S/H or G238S for TEM, and G238A/S and E240K for SHV. The assay was

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validated previously against US isolates (Castanheira, Farrell, Deshpande, Mendes, & Jones, 2013). Isolates producing KPC or NDM-1 carbapenemases in addition to ESBL, or transferable AmpC, were not included in the analysis of the susceptibility rates of isolates producing only ESBL or AmpC (ESBL, nonCRE). 3. Results 3.1 Susceptibilities The 3 most commonly isolated gram-negative species from the bloodstream were E. coli (n=1,306; 41.1%), K. pneumoniae (n=574; 18.1%), and P. aeruginosa (n=355; 11.2%). Susceptibility of 2,647

ACCEPTED MANUSCRIPT Enterobacteriaceae to ceftolozane-tazobactam was 95.5%, while susceptibility to piperacillin-tazobactam was 93.2% (Table 1). Amikacin, meropenem, and tigecycline were the most active with 99.2%, 98.4%, and 98.7% susceptible, respectively. A total of 271 Enterobacteriaceae (10.2%) had the ESBL non-CRE phenotype and 87.1% were susceptible to ceftolozane-tazobactam while 77.5% were susceptible to piperacillin-tazobactam. For the 37 (1.4%) CRE, ceftolozane-tazobactam and other tested beta-lactams

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lacked activity, while susceptibilities to amikacin and tigecycline were 59.5% and 100%, respectively. For

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the three year period, overall susceptibility for ceftolozane-tazobactam was stable, with 96.4% susceptible

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in 2013, 94.7% in 2014 and 95.4% in 2015.

Overall susceptibility of E. coli (n=1,306) to ceftolozane-tazobactam was 98.5% and to piperacillin-

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tazobactam was 95.4%. Amikacin, colistin, meropenem, and tigecycline were the most active with susceptibilities >99%. Against all K. pneumoniae (n=574), ceftolozane-tazobactam susceptibility was

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92.0% and piperacillin-tazobactam was 89.7%. For meropenem, colistin, amikacin, and tigecycline, the susceptibilities were 93.9%, 97.7%, 97.0%, and 99.7%, respectively.

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Against 355 P. aeruginosa isolates, ceftolozane-tazobactam susceptibility was 97.5%, second only to

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colistin with 98.9% susceptible. Susceptibility to ceftolozane-tazobactam remained high over the threeyear period, with 97.6% susceptible in 2013, 97.2% in 2014 and 97.5% in 2015. Ceftolozane-tazobactam

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maintained activity against isolates that were nonsusceptible to the other -lactam comparators, including 23 isolates nonsusceptible to ceftazidime, cefepime, meropenem, and piperacillin-tazobactam, with

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60.9% susceptibility to ceftolozane-tazobactam (Table 1). Nine P. aeruginosa isolates were resistant to all -lactams, including ceftolozane-tazobactam, but were susceptible to amikacin (66.7%) and colistin

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(100.0%) as shown in Table 1. These 9 isolates were geographically diverse, coming from the Middle Atlantic (2), West North Central (1), West South Central (3) and Pacific (3) census divisions. Pseudomonas aeruginosa resistance mechanisms were not characterized in this study. Other studies have found that multiple mutations in OprD, AmpC hyperexpression, and acquisition of extendedspectrum -lactamases are required for ceftolozane-tazobactam resistance development in P. aeruginosa (Cabot, et al., 2014; Fraile-Ribot, et al., 2017).

ACCEPTED MANUSCRIPT 3.2 Activity against ESBL-expressing isolates Escherichia coli (n=198) and K. pneumoniae (n=90) that were screen-positive for the ESBL phenotype were characterized for ESBL and carbapenemase determinants by Checkpoint microarray assay (Table 2). For E. coli, 192 were positive for an ESBL by Checkpoint assay. The most common ESBL was blaCTXM-15-like

and 3 were negative for the genes detected by the Checkpoint assay.

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Two isolates had blaNDM-1-like and 4 had blaSHV or blaTEM ESBL. In addition, 3 isolates had WT blaTEM

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with 121 isolates, 36 had blaCTX-M-14-like, and 39 had transferable AmpC, 36 of which were blaCMY-

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Of the 90 ESBL phenotype screen-positive K. pneumoniae, 82 had at least 1 ESBL or carbapenemase determinant (Table 2). The most common was blaCTX-M-15-like (38 isolates); only 2 had blaCTX-M-14-like.

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There were 28 isolates with blaKPC, 1 with blaNDM-1-like, 7 had transferable AmpC, and 25 with blaSHVESBL. The majority of K. pneumoniae isolates had more than 1 ESBL or AmpC enzyme, including 1

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isolate that had 7 genes, including blaSHV and blaNDM-1-like. In addition, 7 isolates had WT blaSHV and 1 was negative for the genes screened for by the Check-points assay.

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A species-related difference was observed when examining the activities of ceftolozane-tazobactam and

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other comparators against the various β-lactamase-producing E. coli and K. pneumoniae isolates, with the latter showing lower susceptibilities. E. coli and K. pneumoniae (n=151) carrying the most common

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ESBL, blaCTX-M-15-like, were 90.6% and 76.5% susceptible to ceftolozane-tazobactam, 81.2% and 73.5% susceptible to piperacillin-tazobactam, 99.1% and 85.3% susceptible to meropenem, respectively and

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<10% were susceptible to the cephalosporins tested in this study (Table 1). The 37 E. coli and K. pneumoniae isolates with blaCTX-M-14-like were 100% susceptible to ceftolozane-tazobactam and

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meropenem , while for piperacillin-tazobactam, 97.1% of E. coli and 50% of K. pneumoniae, were susceptible. E. coli (n=37) and K. pneumoniae (n=5) isolates with transferable AmpC were 83.8% and 20% susceptible to ceftolozane-tazobactam, 75.7% and 40% susceptible to piperacillin-tazobactam, and 100% and 40% susceptible to meropenem, respectively. 3.3 Regional susceptibility Overall susceptibility of Enterobacteriaceae to ceftolozane-tazobactam was >90% for all US census divisions, ranging from 98.9–91.4% (Table 3). The susceptibility of E. coli to ceftolozane-tazobactam was excellent and varied slightly from 100% (in 5 divisions) to 94.7% in West South Central. For K.

ACCEPTED MANUSCRIPT pneumoniae, susceptibility varied from 100% (in 3 divisions) to 80.0% in West South Central. The susceptibility to ceftolozane-tazobactam for P. aeruginosa by division was excellent, with all divisions >95% except for the Pacific division, which was 90%. The number of ESBL-containing isolates varied across the divisions as well (Table 2). The rate of ESBLenzyme containing E. coli and K. pneumoniae ranged from 8.8% in New England to 25.4% in West South

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Central. The Middle Atlantic division had the highest number of blaKPC containing K. pneumoniae. The

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West South Central division had the highest number of blaCTX-M-15-like and blaSHV-like ESBL.

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4. Discussion

Increasing antibiotic resistance among GNB has been documented by population-based surveys in

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medical centers around the US (Sievert, et al., 2013; Weiner, et al., 2016). Weiner et.al showed increases in central line-associated bloodstream infections caused by gram-negative pathogens, including resistant

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E. coli and P. aeruginosa, which were among the most frequently isolated (Weiner, et al., 2016). Prompt initiation of effective antimicrobial therapy is complicated by the prevalence and types of antimicrobial

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resistance in an institution but has been shown to be critical for the patient with a bloodstream infection

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(Bassetti, et al., 2016; Kumar, et al., 2009; Tumbarello, et al., 2007). The results of this study confirm and extend previous studies regarding the in vitro activity of ceftolozane-

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tazobactam against Enterobacteriaceae, including those with extended-spectrum β-lactamases, and P. aeruginosa causing bloodstream infections (Farrell, Sader, Flamm, & Jones, 2014; Livermore, et al.,

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2017). Ceftolozane-tazobactam was more active than other tested cephalosporins and piperacillintazobactam overall against the Enterobacteriaceae (95.5% susceptibility) and P. aeruginosa (97.5%

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susceptibility) pathogens.

The most common ESBL identified in both E. coli and K. pneumoniae was blaCTX-M-15-like, which confirms reports by others of CTX-M increasing globally, particularly in E. coli (Bevan, Jones, & Hawkey, 2017). Ceftolozone-tazobactam retained very good activity against E. coli isolates containing blaCTX-M-15-like and blaCTX-M-14-like with a susceptibility of 90.6% and 100%, respectively. For blaCTX-M-15-like containing K. pneumoniae, ceftolozane-tazobactam susceptibility was 76.5%. In Phase 3 clinical treatment trials for complicated urinary tract infections and complicated intra-abdominal infections, ceftolozane-tazobactam had a cure rate of 97.4% in 78 patients with ESBL-positive Enterobacteriaceae (Popejoy, et al., 2017).

ACCEPTED MANUSCRIPT No data are available for ceftolozane-tazobactam treatment of bloodstream infections caused by ESBLproducing organisms. As previously reported, ceftolozane-tazobactam did not have in vitro activity against isolates containing carbapenemases or metallo-beta-lactamases, such as blaKPC or blaNDM-1-like, which were uncommon (1.4%) in the current study. Ceftolozane-tazobactam retained excellent in vitro activity against P. aeruginosa bloodstream isolates

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resistant to other β-lactams, including those resistant to meropenem. Limited case reports in the literature

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have described ceftolozane-tazobactam off-label use in the treatment of P. aeruginosa bacteremia

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(Aitken, et al., 2016; Patel, Nicolau, & Sabzwari, 2016).

These in vitro data suggest that ceftolozane-tazobactam may be an effective initial therapy for infections

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caused by Enterobacteriaceae in institutions with a low rate of carbapenem resistance or for P. aeruginosa-caused infections. However, more clinical studies are required to determine if ceftolozane-

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tazobactam would be an effective treatment for bloodstream infections.

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Acknowledgements The authors would like to thank the US hospitals participating in the Program to Assess Ceftolozanetazobactam Susceptibility (PACTS).

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Author Disclosure Statement

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This study was performed by JMI Laboratories and supported by Merck & Co., which included funding for

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services related to preparing this manuscript.

JMI Laboratories contracted to perform services in 2017 for Achaogen, Allecra Therapeutics, Allergan,

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Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas, Basilea Pharmaceutica, Bayer AG, BD, Becton, Dickinson and Co., Boston, CEM-102 Pharma, Cempra, Cidara Therapeutics,

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Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Entasis Therapeutics, Inc., Geom Therapeutics, Inc., GSK, Iterum Pharma, Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., MicuRx

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Pharmaceuticals, Inc., N8 Medical, Inc., Nabriva Therapeutics, Inc., NAEJA-RGM, Novartis, Paratek

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Pharmaceuticals, Inc., Pfizer, Polyphor, Ra Pharma, Rempex, Riptide Bioscience Inc., Roche, Scynexis, Shionogi, Sinsa Labs Inc., Skyline Antiinfectives, Sonoran Biosciences, Spero Therapeutics, Symbiotica,

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Synlogic, Synthes Biomaterials, TenNor Therapeutics, Tetraphase, The Medicines Company, Theravance Biopharma, VenatoRx Pharmaceuticals, Inc., Wockhardt, Yukon Pharma, Zai Laboratory, Zavante

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Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.

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Tangden, T, & Giske, CG (2015) Global dissemination of extensively drug-resistant carbapenemaseproducing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control.

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Fadda, G, Cauda, R, & Spanu, T (2007) Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae:

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importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother, 51: 19871994.

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ACCEPTED MANUSCRIPT ZERBAXA (2016) ZERBAXA® (ceftolozane/tazobactam). In. Whitehouse Station, NJ: Merck & Co. Inc. Zilberberg, MD, Shorr, AF, Micek, ST, Vazquez-Guillamet, C, & Kollef, MH (2014) Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic

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shock: a retrospective cohort study. Crit Care, 18: 596.

ACCEPTED MANUSCRIPT Table 1 Susceptibilities of ceftolozane-tazobactam and comparators tested against the organisms and organism groups in this study, collected in US medical centers in 2013-2015 % susceptiblea Organism group (no. tested)

Ceftolozanetazobactam 95.5

Ceftazidime

Cefepime

Meropenem

Amikacin

Colistin

Levofloxacin

87.4

90.4

98.4

99.2

85.1

77.6

87.1

21.8

27.7

98.5

98.1

87.1

2.7

0.0

5.4

0.0

59.5

86.1

98.5

87.9

88.1

99.8

99.8

E. coli NDM-1 (2)

0.0

0.0

0.0

0.0

50.0

E. coli ESBL-producers (153)

92.8

24.8

7.8

99.3

E. coli all CTX-M (150)

92.7

24.0

6.7

99.3

E. coli CTX-M-15-like (117)

90.6

8.5

5.1

99.1

E. coli CTX-M 14-like (35)

100.0

77.1

11.4

100.0

E. coli SHV ESBL (2)

100.0

50.0

100.0

E. coli TEM ESBL (1)

100.0

100.0

E. coli transferable AmpC (37)

83.8

2.7

(692)c

93.1

K. pneumoniae (574)

92.0

Enterobacteriaceaeb (2,647) ESBL non-CRE (271) CRE (37) Escherichia coli (1,306)c

Klebsiella spp.

Piperacillintazobactam 93.2

T P

I R

Tigecycline 98.7

26.9

77.5

98.9

18.9

0.0

100.0

65.3

95.4

100.0

100.0

0.0

0.0

100.0

98.7

C S 99.3

13.1

85.6

100.0

98.7

99.3

11.3

85.3

100.0

98.3

99.1

11.1

81.2

100.0

100.0

100.0

11.4

97.1

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

83.8

100.0

100.0

100.0

35.1

75.7

100.0

89.3

94.8

97.5

97.9

90.3

90.4

99.7

86.1

88.0

93.9

97.0

97.7

88.5

89.7

99.7

D E 0.0

A

U N

M

99.7

3.6

T P 0.0

17.9

7.10

53.6

85.2

17.9

0.0

100.0

0.0

0.0

0.0

0.0

0.0

100.0

0.0

0.0

100.0

87.3

K. pneumoniae ESBL-producers (49)

E C 73.5

10.2

16.3

89.8

91.8

93.8

30.6

67.3

100.0

K. pneumoniae all CTX-M (36)

77.8

8.3

0.0

86.1

94.4

97.1

25.0

72.2

100.0

76.5

2.9

0.0

85.3

94.1

97.0

20.6

73.5

100.0

K. pneumoniae CTX-M 14-like (2)

100.0

100.0

0.0

100.0

100.0

100.0

100.0

50.0

100.0

K. pneumoniae SHV ESBL (13)

61.5

15.4

61.5

100.0

84.6

84.6

46.2

53.8

100.0

K. pneumoniae transferable AmpC (5)

20.0

0.0

40.0

40.0

100.0

100.0

80.0

40.0

100.0

K. oxytoca (114)

98.2

93.9

95.6

99.1

100.0

100.0

99.1

93.8

100.0

Enterobacter spp. (270)

85.9

75.9

95.2

99.6

100.0

77.0

97.4

85.1

99.3

E. cloacae (179)

85.5

77.7

95.5

100.0

100.0

72.7

97.2

85.3

99.4

K. pneumoniae KPC (28) K. pneumoniae NDM-1 (1)

K. pneumoniae CTX-M 15-like (34)

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ACCEPTED MANUSCRIPT % susceptiblea Organism group (no. tested)

Ceftolozanetazobactam 92.7

Ceftazidime

Cefepime

Meropenem

Colistin

Levofloxacin

80.0

96.4

98.2

100.0

98.2

98.2

Other Enterobacter spp. (36)

77.8

61.1

91.7

100.0

100.0

64.7

97.2

Citrobacter spp. (48)

87.5

81.2

95.8

100.0

100.0

97.9

C. koseri (15)

100.0

93.3

93.3

100.0

100.0

93.3

C. freundii (21)

76.2

66.7

95.2

100.0

100.0

100.0

Other Citrobacter spp. (12)

91.7

91.7

100.0

100.0

100.0

100.0

Proteus mirabilis (136)

99.3

99.3

97.1

100.0

100.0

Indole-positive Proteeae (49)

98.0

85.7

98.0

100.0

100.0

Serratia spp. (131)

97.7

97.7

97.7

99.2

Pseudomonas aeruginosa (355)

97.5

85.9

89.3

97.2

P. aeruginosa CAZ-NSd (50)

82.0

0.0

40.0

A 40.0

P. aeruginosa MER-NS (64)

85.9

53.1

51.6

P. aeruginosa FEP-NS (38)

76.3

21.1

P. aeruginosa TZP-NS (61)

85.2

P. aeruginosa BL-NS (23)

60.9

E. aerogenes (55)

P. aeruginosa pan-BL-NS (9)

0.0

Piperacillintazobactam 87.3

Tigecycline 100.0

80.6

97.2

97.9

87.5

100.0

100.0

100.0

100.0

95.2

76.2

100.0

100.0

91.7

100.0

65.4

100.0

80.9

0.0

75.5

98.0

93.9

5.3

96.9

96.9

98.5

98.9

81.4

82.8

n/a

88.0

100.0

48.0

10.0

n/a

0.0

85.9

100.0

37.5

40.6

n/a

0.0

18.4

78.9

100.0

26.3

5.3

n/a

26.2

41.0

37.7

85.2

100.0

41.0

0.0

n/a

0.0

0.0

0.0

82.6

100.0

17.4

0.0

n/a

0.0

0.0

0.0

66.7

100.0

0.0

0.0

n/a

D E

T P

E C

Amikacin

M

81.9

U N 99.2

I R

C S 0.0

T P

According to CLSI (2017), FDA breakpoints used for tigecycline, and EUCAST (2017) colistin breakpoints were used for Enterobacteriaceae. Organisms include: Citrobacter amalonaticus (3), C. braakii (3), C. farmeri (1), C. freundii (21), C. freundii species complex (3), C. koseri (15), C. youngae (2), Enterobacter aerogenes (55), E. asburiae (3), E. cloacae (179), E. cloacae species complex (33), Escherichia coli (1,306), E. hermannii (1), Hafnia alvei (1), Klebsiella oxytoca (114), K. pneumoniae (574), K. variicola (4), Kluyvera ascorbata (1), Kosakonia cowanii (1), Morganella morganii (34), Pantoea agglomerans (3), P. eucrina (1), Pluralibacter gergoviae(2), Proteus mirabilis (136), P. penneri (1), P. vulgaris (3), Providencia rettgeri (6), P. stuartii (6), Raoultella planticola (2), Serratia fonticola (1), S. liquefaciens (4), S. marcescens (126), unspeciated Pantoea (1), unspeciated Raoultella (1). c Isolates producing KPC or NDM-1 carbapenemases in addition to ESBL or transferable AmpC were not included in the susceptibility rates of isolates producing only ESBL or AmpC. d P. aeruginosa isolates that were nonsusceptible to ceftazidime (CAZ-NS), meropenem (MER-NS), cefepime (FEP-NS), piperacillin-tazobactam (TZP-NS), were nonsusceptible to all -lactams (BL-NS) except ceftolozane-tazobactam, or were nonsusceptible to all -lactams that include ceftolozane-tazobactam (pan-BL-NS). a b

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ACCEPTED MANUSCRIPT a

Table 2 Results of Check-Points MDR assay for 288 Enterobacteriaceae ESBL phenotype-screen positive isolates collected during 2013–2015

No. of positive Check-Points (CP) results

Total

No. ESBLscreen pos

All isolates No. of isolates by species

1,880

288

275

1

37

159

38

Escherichia coli Klebsiella pneumoniae

1,306

198

192

1

36

121

36

574

90

82

1

38

U N

No. of isolates by census divisionc 1: New England 2: Middle Atlantic 3: East North Central 4: West North Central 5: South Atlantic 6: East South Central 7: West South Central

No. isolates CP pos

CP_AC T/MIR

CP_C MYII

CP_CTXM_group 1

CP_CTXM_group 9

CP_D HA

CP_F OX

CP_K PC

CP_N DM-1

CP_SHV _ESBL

CP_TEM _ESBL

Total no. CP tests posb

3

5

28

3

28

1

303

2

3

1

202

1

25

101

1

17

12

5

55

3

4

32

194

17

17

284

57

52

236

31

29

159

15

15

229

30

2

28

8

4

14

6

5

10

1

1

16

5

3

11

4

3

2

1

85

83

12

53

7

1

5

4

22

10

8

9: Pacific

231

32

32

11

D E

T P

E C 28

102

a Numbers

5

8

8: Mountain

334

M

A

1

4

C A

111

2

1

I R

C S 2

T P

28

4

5

1 1

2

17 3

1 1

8

3

29 1

12

15

100

1

7

2

indicate all isolates with positive Check-Points assay results for the test listed isolate may be positive for more than 1 test c E. coli and K. pneumoniae combined. States of participating medical centers in each US Census Bureau division were 1, New England: Massachusetts and Vermont; 2, Middle Atlantic: New Jersey and New York; 3, East North Central: Indiana, Michigan, Ohio, and Wisconsin; 4, West North Central: Iowa, Missouri, and Nebraska; 5, South Atlantic: Florida, Georgia, and Virginia; 6, East South Central: Kentucky; 7, West South Central: Arkansas and Texas; 8, Mountain: Colorado and Utah; 9, Pacific: California, Hawaii, and Washington b An

34

ACCEPTED MANUSCRIPT Table 3 Ceftolozane-tazobactam MIC distributions and susceptibility in US Census divisions collected in 2013-2015 Number at MIC mg/L Organism/divisiona

0.03

Total N

%Sb

266

98.9

8

414

93.7

2

337

98.2

219

97.7

323

94.7

175

97.1

453

91.4

139

97.1

321

95.6

138

100.0

183

97.8

4

153

100.0

3

127

100.0

0.06

0.12

0.25

0.5

1

2

4

8

16

32

11

89

105

43

10

5

1

1

1

10

119

155

79

17

5

7

5

3

3

17

108

125

64

7

10

1

2

1

0

>32

Enterobacteriaceaec 1, New England 2, Middle Atlantic

3

3, East North Central 4, West North Central

11

87

74

35

4

3

4

0

1

5, South Atlantic

6

115

125

46

9

5

4

8

3

6, East South Central

7

53

59

34

12

5

2

1

2

7, West South Central

7

114

183

82

23

5

3

10

1

6

8, Mountain

2

50

54

21

6

2

1

1

1

1

9, Pacific

3

107

124

48

19

6

2

7

2

10

56

59

10

1

2

6

75

66

25

3

3, East North Central

12

66

50

20

1

4, West North Central

10

62

43

5, South Atlantic

6

67

65

6, East South Central

4

30

26

7, West South Central

5

76

2 3

Escherichia coli 1, New England 2, Middle Atlantic

2

T P

D E

9

2

2

1

1

1

U N

M

A 0

C S

19 3

1

9

1

2

150

100.0

5

1

1

67

100.0

103

39

6

2

244

94.7

24

32

4

63

98.4

84

70

14

7

181

98.9

20

21

9

5

56

98.2

1

22

38

16

8

1

8

101

86.1

3, East North Central

4

22

37

12

1

3

2

83

95.2

4, West North Central

1

13

10

7

1

32

100.0

28

28

14

2

79

92.4

14

17

7

5

44

100.0

C A

8, Mountain 9, Pacific Klebsiella pneumoniae 1, New England 2, Middle Atlantic

1

5, South Atlantic 6, East South Central

E C

1

3

1

5

4

1 1

1

1 1

1

1

1

2

2

1

1

4

1

1

I R

T P

ACCEPTED MANUSCRIPT Number at MIC mg/L Organism/divisiona

0.03

0.06

0.12

0.25

0.5

1

2

4

8

1

16

34

12

6

3

1

3

8, Mountain

16

13

6

3

1

9, Pacific

13

19

10

5

1

12

7

6

35

8

1

2

3, East North Central

7

13

8

1

4

4, West North Central

3

16

4

1

2

5

20

7

1

1

6, East South Central

6

9

8

7, West South Central

10

71

24

5

8, Mountain

2

12

2

2

9, Pacific

1

16

7

2

7, West South Central

16

32

>32

Total N

%Sb

1

13

90

80.0

39

100.0

50

94.0

20

100.0

55

96.4

1

2

Pseudomonas aeruginosa 1, New England 2, Middle Atlantic

1

5, South Atlantic

1

1

1 1

A

1 1

1

D E

2

M 1

1

I R

C S

33

100.0

27

96.3

U N

1

T P

35

100.0

24

100.0

113

97.3

18

100.0

30

90.0

States of participating medical centers present in each US census division are 1, New England: Massachusetts and Vermont; 2, Middle Atlantic: New Jersey and New York; 3, East North Central: Indiana, Michigan, Ohio, and Wisconsin; 4, West North Central: Iowa, Missouri, and Nebraska; 5, South Atlantic: Florida, Georgia, and Virginia; 6, East South Central: Kentucky; 7, West South Central: Arkansas and Texas; 8, Mountain: Colorado and Utah; 9, Pacific: California, Hawaii, and Washington a

b

Criteria as published by CLSI (2017)

E C

T P

Organisms include: Citrobacter amalonaticus (3), C. braakii (3), C. farmeri (1), C. freundii (21), C. freundii species complex (3), C. koseri (15), C. youngae (2), Enterobacter aerogenes (55), E. asburiae (3), E. cloacae (179), E. cloacae species complex (33), Escherichia coli (1,306), E. hermannii (1), Hafnia alvei (1), Klebsiella oxytoca (114), K. pneumoniae (574), K. variicola (4), Kluyvera ascorbata (1), Kosakonia cowanii (1), Morganella morganii (34), Pantoea agglomerans (3), P. eucrina (1), Pluralibacter gergoviae(2), Proteus mirabilis (136), P. penneri (1), P. vulgaris (3), Providencia rettgeri (6), P. stuartii (6), Raoultella planticola (2), Serratia fonticola (1), S. liquefaciens (4), S. marcescens (126), unspeciated Pantoea (1), unspeciated Raoultella (1) c

C A

ACCEPTED MANUSCRIPT

Highlights   

A total of 2,647 Enterobacteriaceae and 355 Pseudomonas aeruginosa from hospitalized patients with bloodstream infections in US hospitals from 2013-2015. Ceftolozane-tazobactam (95.5% susceptible), amikacin (99.2% susceptible), and meropenem (98.4% susceptible) were the most active against Enterobacteriaceae. Ceftolozane-tazobactam was the most potent (MIC50//90, 0.5/1 mg/L) β-lactam agent tested against P. aeruginosa isolates, with 97.5% susceptible.

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