tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates recovered from hospitalized patients in Germany

tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates recovered from hospitalized patients in Germany

Accepted Manuscript Title: In-vitro activity of ceftolozane/tazobactam against pseudomonas aeruginosa and enterobacteriaceae isolates recovered from h...

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Accepted Manuscript Title: In-vitro activity of ceftolozane/tazobactam against pseudomonas aeruginosa and enterobacteriaceae isolates recovered from hospitalized patients in germany Author: Harald Seifert, Barbara Körber-Irrgang, Michael Kresken, German Ceftolozane/Tazobactam Study Group PII: DOI: Reference:

S0924-8579(17)30273-X http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.06.024 ANTAGE 5213

To appear in:

International Journal of Antimicrobial Agents

Received date: Accepted date:

25-4-2017 24-6-2017

Please cite this article as: Harald Seifert, Barbara Körber-Irrgang, Michael Kresken, German Ceftolozane/Tazobactam Study Group, In-vitro activity of ceftolozane/tazobactam against pseudomonas aeruginosa and enterobacteriaceae isolates recovered from hospitalized patients in germany, International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi: 10.1016/j.ijantimicag.2017.06.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1

In-vitro activity of ceftolozane/tazobactam against Pseudomonas

2

aeruginosa and Enterobacteriaceae isolates recovered from

3

hospitalized patients in Germany

4 5

Harald Seiferta,b*, Barbara Körber-Irrgangc, and Michael Kreskenc,d, on behalf of the German

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Ceftolozane/Tazobactam Study Group§

7 8

a

9

Cologne, Germany

Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne,

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b

11

c

12

d

University of Applied Sciences, Cologne, Germany;

§

Other members of the Study Group are listed in the acknowledgements

German Center for Infection Research (DZIF), partner site Cologne-Bonn

Antiinfectives Intelligence GmbH, Rheinbach, Germany

13 14 15 16

*Corresponding author. Mailing address: Institute for Medical Microbiology, Immunology,

17

and Hygiene, University of Cologne, Goldenfelsstr. 19-21, 50935 Cologne, Germany. Phone:

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+49-221-47832009. Fax: +49-221-32035. E-mail: [email protected]

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Running title: Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and

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Enterobacteriaceae in Germany

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Highlights

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Ceftolozane/tazobactam is a novel antimicrobial with anti-Gram-negative activity

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Ceftolozane/tazobactam exhibited the best in vitro potency against P. aeruginosa

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Its activity was not impacted by resistance phenotype or MDR phenotype

1 Page 1 of 23

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Abstract

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To evaluate the activity of ceftolozane/tazobactam in comparison with other broad-spectrum

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antimicrobials against Pseudomonas aeruginosa and Enterobacteriaceae, 497 non-duplicate P.

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aeruginosa and 802 Enterobacteriaceae clinical isolates were consecutively collected during

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the period from September 2014 to April 2015 from patients in Germany with bloodstream,

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lower respiratory tract, intraabdominal or urinary tract infections. Antimicrobial susceptibility

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testing was performed by broth microdilution. Results were interpreted according to EUCAST

32

criteria. Ceftolozane/tazobactam showed good activity against Escherichia coli and Klebsiella

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pneumoniae isolates with MIC50/90 values of 0.25/0.5 mg/L and 0.25/1 mg/L, respectively.

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Comparatively, piperacillin/tazobactam, ceftazidime, and meropenem MIC50/90 values were

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2/8 mg/L, 0.25/8 mg/L, and ≤0.03/≤0.03 mg/L for E. coli, and 2/16 mg/L, 0.12/8 mg/L, and

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≤0.03/≤0.03 mg/L for K. pneumoniae isolates. Against P. aeruginosa, the activity of

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ceftolozane/tazobactam was superior compared to other antipseudomonal antimicrobials.

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Based on MIC50/90 values, ceftolozane/tazobactam (0.5/2 mg/L) was more active than

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piperacillin/tazobactam (8/64 mg/L), ceftazidime (2/16 mg/L), cefepime (2/16 mg/L), or

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meropenem (0.5/8 mg/L). In conclusion, ceftolozane/tazobactam exhibited the best in vitro

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potency

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piperacillin/tazobactam, cefepime, ceftazidime, doripenem, meropenem, ciprofloxacin,

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levofloxacin, amikacin, and tobramycin, compared to other compounds. It has the potential to

44

become a useful addition to the limited armamentarium of drugs that can be used to treat this

45

problem pathogen.

against

P.

aeruginosa,

including

isolates

that

were

resistant

to

46 47

Keywords: multi-drug resistance; intraabdominal infection; urinary tract infection; multi-

48

centre study

Page 2 of 23

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1. Introduction

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Gram-negative bacterial organisms including Enterobacteriaceae and Pseudomonas

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aeruginosa are a major cause of community-acquired and healthcare-associated infections. In

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the past two decades, there has been a dramatic increase in resistance rates of these organisms

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against all major antimicrobial drug classes including broad-spectrum penicillins,

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cephalosporins, carbapenems, and fluoroquinolones mediated mainly through the action of β-

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lactamases, efflux pumps, porin loss, and target site modifications [1]. Multidrug-resistance

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(MDR) in Enterobacteriaceae and P. aeruginosa is now considered a serious threat of global

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concern that leaves few therapeutic options [2]. In many cases, colistin and/or polymyxin B

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are the only antimicrobial agents to retain activity, but resistance has developed even with

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these drugs [3].

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Ceftolozane/tazobactam is an antibacterial drug combination of ceftolozane (formerly CXA-

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101), a novel antipseudomonal cephalosporin, and tazobactam, a well-known β-lactamase

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inhibitor [4]. Ceftolozane has demonstrated increased stability to AmpC β-lactamases and is

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less affected by changes in porin permeability and efflux pumps due to enhanced binding to

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selected penicillin-binding proteins (PBPs) [5,6]. However, its activity against extended-

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spectrum β-lactamase (ESBL)-producing organisms is limited [5]. The addition of tazobactam

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enhanced the activity of ceftolozane against selected ESBL-producing organisms in a

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concentration-dependent manner [5]. Ceftolozane/tazobactam demonstrated greater in vitro

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activity than piperacillin/tazobactam, antipseudomonal cephalosporins, and carbapenems

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when tested against Pseudomonas aeruginosa isolates and greater activity than

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piperacillin/tazobactam and cephalosporins when tested against most Enterobacteriaceae

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[7,8]. Ceftolozane/tazobactam at a fixed 2:1 ratio has been approved for the treatment of

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complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI)

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[9-11], and is currently being investigated for the treatment of hospital-acquired pneumonia

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(HAP), including ventilator-associated pneumonia (VAP) [12]. Page 3 of 23

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In this study, which was performed prior to the introduction of ceftolozane/tazobactam in

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Germany, we compared the activity of ceftolozane/tazobactam with other antimicrobial

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reference drugs including β-lactams, fluoroquinolones, aminoglycosides and colistin against

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prospectively collected contemporary P. aeruginosa and Enterobacteriaceae clinical isolates

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in Germany from patients with community-acquired and nosocomial infections.

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2. Materials and methods

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2.1. Bacterial isolates. Non-duplicate P. aeruginosa and Enterobacteriaceae clinical isolates

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were prospectively collected from September, 2014 to April, 2015 at 10 German tertiary care

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medical centers. Each centre had agreed to provide 130 bacterial isolates comprising P.

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aeruginosa (n=50), Escherichia coli (n=20), Klebsiella pneumoniae / Klebsiella oxytoca

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(n=30), Enterobacter spp. (n=10), Proteus spp. / Morganella morganii / Providencia spp.

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(n=10), Citrobacter spp. (n=5), and Serratia spp. (n=5) from patients with bloodstream

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infection (BSI), lower respiratory tract infection (LRTI), intraabdominal infection (IAI) or

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complicated urinary tract infection (cUTI). Only one isolate per species per patient was

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permitted. Species identification of all isolates was confirmed by standard laboratory methods

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including matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass

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spectrometry (MALDI Biotyper, Microflex, Bruker Daltonik GmbH, Bremen, Germany) at

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the central laboratory (Antiinfectives Intelligence GmbH, Rheinbach, Germany).

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2.2. Antimicrobial susceptibility testing. The following antibacterial agents were tested

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(respective concentration ranges are given in parenthesis): amikacin (0.125 – 256 mg/L),

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amoxicillin/clavulanic acid (0.06/2 – 128/2 mg/L), cefepime (0.06 – 128 mg/L), ceftazidime

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(0.06 – 128 mg/L), ceftolozane (0.06 – 128 mg/L), ceftolozane/tazobactam (0.06/4 – 128/4

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mg/L), ceftriaxone (0.06 – 128 mg/L), ciprofloxacin (0.015 – 32 mg/L), colistin (0.03 – 64

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mg/L), doripenem (0.03 – 64 mg/L), ertapenem (0.03 – 32 mg/L), fosfomycin (0.03 – 64

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mg/L), levofloxacin (0.015 – 32 mg/L), meropenem (0.03 – 64 mg/L), piperacillin/tazobactam Page 4 of 23

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(0.125/4 – 256/4 mg/L), and tobramycin (0.06 – 64 mg/L). Fosfomycin was tested in the

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presence of a constant concentration of 25 mg/L glucose-6-phosphate.

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Antimicrobial susceptibility testing was performed by standard broth microdilution in cation-

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adjusted Mueller-Hinton broth (CAMHB) according to the international standard ISO 20776-

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1 [13]. Microtitre plates containing dehydrated antibacterial agents (Sensititre® CUBDGN1

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and CUBDGN2) were purchased from TREK Diagnostic Systems (Thermo Fisher Scientific,

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Basingstoke, UK). Plates were incubated at 35 ± 1°C for 18 ± 2 h and read visually. MICs

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were interpreted according to the species-specific clinical breakpoints approved by the

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European Committee on Antimicrobial Susceptibility Testing (EUCAST, Version 6.0,

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January 2016) [14]. E. coli ATCC 25922, E. coli ATCC 35218 and P. aeruginosa ATCC

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27853 were used as quality control strains.

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2.3. Phenotypic classification of P. aeruginosa and Enterobacteriaceae isolates.

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Pseudomonas aeruginosa isolates were classified into two different phenotypic groups, i.e.

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isolates that were resistant and those that were not resistant to ceftazidime. Enterobacteriaceae

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isolates were also classified into two different groups, i.e. isolates that were ESBL producers

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and those that were not. ESBL screening and confirmatory tests were performed according to

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the guideline of the CLSI [15]. Screen positive isolates with MICs of > 1 mg/L for

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ceftazidime and/or ceftriaxone were then tested for susceptibility to ceftazidime and

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cefotaxime alone and in combination with clavulanic acid (4 mg/L fixed) using industrially

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manufactured trays purchased from Merlin Diagnostika GmbH (Bornheim, Germany).

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Isolates were considered ESBL-positive if ≥ 3 twofold decreases in the MIC for either

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antibacterial agent tested in combination with clavulanic acid was observed [15].

123 124 125

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3. Results

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A total of 1,299 clinical isolates were submitted to the central laboratory including 497 P.

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aeruginosa and 802 Enterobacteriaceae isolates (including species listed in Table 3 and 22

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isolates of other Enterobacteriaceae species). Forty-one per cent (n=534) of the isolates were

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derived from patients with hospital-acquired infections and 27% (n=346) from patients with

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community-acquired infections. No information on the source of acquisition was available for

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419 patients (32%). Seven-hundred and sixteen (55.1%), 438 (33.7%) and 126 (9.7%) isolates

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were obtained from patients on general wards, intensive care units and intermediate care

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wards, respectively. Three-hundred and nineteen (24.6%), 292 (22.5%), 243 (18.7%) and 138

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(10.6%) of the isolates were recovered from urine, blood, tracheal secretions, and surgically

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obtained intra-abdominal specimens, respectively. Sixty P. aeruginosa isolates were

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considered ceftazidime-resistant (12.1%). An ESBL phenotype was confirmed for 32/202 E.

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coli isolates (15.8%), 40/233 K. pneumoniae isolates (17.2%), 11/68 K. oxytoca isolates

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(16.2%), and 1/56 P. mirabilis isolates (1.8%).

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MIC distribution, MIC50 and MIC90 values and percent susceptibility rates for P. aeruginosa

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isolates are summarised in Table 1. Of note, comparison of MIC values and susceptibility or

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resistance rates provided throughout is based only on a numerical observation rather than

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being of statistical significance. Based on MIC50/90 values, ceftolozane/tazobactam (0.5/2

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mg/L) was more active than piperacillin/tazobactam (8/64 mg/L), ceftazidime (2/16 mg/L),

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cefepime (2/16 mg/L), and meropenem (0.5/8 mg/L) against P. aeruginosa isolates.

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Ceftolozane alone exhibited identical activity as the ceftolozane/tazobactam combination

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indicating that the addition of tazobactam to ceftolozane did not influence the activity of

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ceftolozane against P. aeruginosa. Of the 497 isolates tested, 475 (95.6%) were susceptible

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and 22 (4.4%) were resistant to ceftolozane/tazobactam. Colistin inhibited all but one isolates

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at 4 mg/L, resulting in a susceptibility rate of 99.8%. Susceptibility rates of more than 90%

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were also noted for tobramycin (92.8%) and amikacin (92.4%), while susceptibility to Page 6 of 23

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ciprofloxacin was lower (73.8%). Of note, susceptibility to ceftolozane/tazobactam was also

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seen in 65% of ceftazidime-resistant (n=60; Table 2) and in 50% of meropenem-resistant

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(n=36; data not shown) isolates, respectively. On the other hand, susceptibility to ceftazidime

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or meropenem among the 22 isolates that were resistant to ceftolozane/tazobactam was

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detected in one isolate each only (data not shown).

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MIC50 and MIC90 values and percent susceptibility rates for Enterobacteriaceae isolates are

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summarised in Table 3. Ceftolozane/tazobactam showed good activity against E. coli, with

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MIC50/90 values of 0.25/0.5 mg/L. Of the 202 isolates, 194 (96%) proved susceptible and 8

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resistant to ceftolozane/tazobactam. In comparison, lower susceptibility rates were noted for

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piperacillin/tazobactam (91.6%) and ceftazidime (83.2%). Ceftolozane/tazobactam also

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showed slightly better activity than piperacillin/tazobactam against ESBL-positive isolates

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(81.3% vs 75.0% susceptibility). Higher rates of resistance among E. coli isolates were

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recorded for amoxicillin/clavulanic acid (33.2%) and the fluoroquinolones (29.7%). In

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contrast, resistance to fosfomycin was rare (1%), and resistance to the carbapenems and

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colistin was not detected.

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Ceftolozane/tazobactam also showed good activity against K. pneumoniae (n=233), with

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MIC50/90 values of 0.25/1 mg/L. Two-hundred and seventeen isolates (93.1%) were

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susceptible and 16 (6.9%) were resistant to ceftolozane/tazobactam. Resistance rates to the

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other β-lactams ranged from 9.9% (piperacillin/tazobactam) to 18.5% (amoxicillin/clavulanic

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acid). Two isolates exhibited resistance to ertapenem, but none was resistant to doripenem or

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meropenem. Five isolates were resistant to colistin (2.1%). Of the 40 K. pneumoniae isolates

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with an ESBL phenotype, 25 (62.5%) were susceptible to ceftolozane/tazobactam and 15

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(37.5%) resistant (Table 3).

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Ceftolozane/tazobactam showed only moderate activity also against E. cloacae (n=73), with

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MIC50/90 values of 0.5/16 mg/L with 51 of 73 isolates tested susceptible (69.9%) and 22 tested

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resistant

(30.1%).

Similar

results

were

obtained

with

other

AmpC

producing

Page 7 of 23

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Enterobacteriaceae species such as E. aerogenes (n=14) and C. freundii (n=26) with MIC50/90

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values of 0.5/8 and 0.5/16 mg/L and resistance rates of 42.9% and 30.8%, respectively.

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4. Discussion

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Facing a growing public health threat imposed by increasing resistance to major antimicrobial

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drug classes in Enterobacteriaceae, P. aeruginosa and A. baumannii there is now an ever

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greater need for the development of new drugs that show activity against multi-drug resistant

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(MDR) Gram-negative bacteria. In Enterobacteriaceae, it is the development of resistance to

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extended-spectrum β-lactams, fluoroquinolones, and more recently carbapenems that has left

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clinicians with few viable alternatives [16,17]. In some countries, colistin is often the only

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antimicrobial showing measurable activity, but owing to toxicity and low serum

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concentrations, it is not always effective. In Germany, resistance to carbapenems is still low at

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<1% but resistance to third generation cephalosporins according to the most recent European

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Antimicrobial Resistance Surveillance Network (EARS-Net) data was 10.4% for E. coli and

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10.1% for K. pneumoniae in 2015 [18]. Another surveillance study conducted in Germany by

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the Paul-Ehrlich-Society for Chemotherapy (PEG) showed a decrease in E. coli resistance to

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cefotaxime from 17.4% in 2010 to 15.4% in 2013, while K. pneumoniae resistance to

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cefotaxime slightly increased from 16.9% to 17.8% [19,20]. In P. aeruginosa, it is the

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combined resistance to β-lactams including the carbapenems, fluoroquinolones and

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aminoglycosides that poses the greatest problems in the most vulnerable patient groups such

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as patients in the ICU, in burn centres and those with hematologic malignancies [1].

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Combined resistance to three or more antimicrobial groups among piperacillin/tazobactam,

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ceftazidime, fluoroquinolones, aminoglycosides and carbapenems, was 12.9% in Europe and

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8.2% in Germany in 2015 according to EARS-Net data [18]. The PEG study performed in

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2013 showed combined resistance to piperacillin/tazobactam, ceftazidime, imipenem,

Page 8 of 23

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meropenem, ciprofloxacin, levofloxacin, gentamicin and tobramycin in 19/733 P. aeruginosa

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isolates (2.6%) (M. Kresken, personal communication).

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Over the last decade there have been only a few novel anti-Gram-negative drugs developed.

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Ceftolozane/tazobactam is a novel antibacterial agent that has shown broad-spectrum

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antibacterial activity against Enterobacteriaceae including those resistant to other β-lactams

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and MDR strains. In addition, ceftolozane/tazobactam is active against MDR P. aeruginosa

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strains [7,8].

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In our study, resistance to β-lactams and fluoroquinolones in E. coli and K. pneumoniae was

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consistent with data from the EARS-Net surveillance system and ranged between 6% and

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30%. Resistance to carbapenems as well as to colistin was not observed. Among the

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remaining antimicrobials resistance to ceftolozane/tazobactam was lowest at 4% for E. coli

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and 6.9% for K. pneumoniae. Enhanced activity of ceftolozane/tazobactam compared to

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piperacillin/tazobactam and other cephalosporins was also found in E. coli and in K.

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pneumoniae with ESBL phenotype although resistance in the latter was high at 37.5%.

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Comparatively high resistance rates were also found in some AmpC producing

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Enterobacteriaceae spp. such as E. aerogenes, E. cloacae and C. freundii.

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Against P. aeruginosa, only one of 497 isolates was tested resistant to colistin (0.2%).

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Ceftolozane/tazobactam compared to other agents with antipseudomonal activity including

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the cephalosporins cefepime and ceftazidime, the carbapenems doripenem and meropenem,

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and the fluoroquinolones ciprofloxacin and levofloxacin was the second most active agent

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tested with only 4.4% resistant isolates. Of note, ceftolozane/tazobactam exhibited good

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activity against P. aeruginosa isolates that were resistant to ceftazidime with 65% of these

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isolates being susceptible compared to cefepime (16.7% susceptible), meropenem (31.7%),

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piperacillin/tazobactam

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ceftolozane/tazobactam against ceftazidime-resistant P. aeruginosa with 61.5% of isolates

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tested susceptible and MIC50/90 values of 4/>32 mg/L was also reported by Sader et al. [7].

(6.7%)

and

ciprofloxacin

(28.3%).

Good

activity

of

Page 9 of 23

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In conclusion, ceftolozane/tazobactam, recently approved for the treatment of complicated

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IAI and complicated UTI, is a promising new agent with good activity against most

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Enterobacteriaceae including those with ESBL phenotype and, in particular, against P.

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aeruginosa including isolates with combined resistance to other antipseudomonal drugs. It has

233

the potential to become a useful addition to the limited armamentarium of drugs that can be

234

used to treat this problem pathogen.

235 236

Acknowledgements

237

Other members of the German Ceftolozane/Tazobactam Study Group

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U. Göbel, S. Swidsinski (Berlin); P.-M. Rath, J. Steinmann (Essen); C. MacKenzie

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(Düsseldorf); R. Mutters, (Marburg); G. Peters, K. Becker (Münster); A. Podbielski, M.

240

Weise (Rostock); E. Siegel, B. Glöckle (Mainz); E. Kniehl, A Becker (Karlsruhe); T.-A.

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Wichelhaus (Frankfurt/Main); S. Schubert (Kiel).

242 243

Declaration

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Funding: This work was supported by a research grant from Cubist Pharmaceuticals (now

245

Merck & Co., USA).

246

Competing Interests: H.S. has received grants or research support from the German Centre

247

for Infection Research (DZIF), the German Research Foundation, Accelerate, and Novartis,

248

has been a consultant for Astellas, Basilea, Cubist, Durata, Roche Pharma, and Tetraphase,

249

and has received payments for lectures from Astellas, Cubist, Gilead, MSD, and

250

Infectopharm. M.K. is a partner and CEO of Antiinfectives Intelligence GmbH, a research

251

organization providing services to pharmaceutical companies. B.K.-I. is head of laboratory of

252

Antiinfectives Intelligence GmbH.

253

Ethical Approval: Not required

254

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eakpoint_Tables.xls

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[15] Clinical and Laboratory Standards Institute (CLSI). Performance standards for

302

antimicrobial susceptibility testing; twenty-fifth informational supplement. Document M100-

303

S, 26th edition. CLSI, Wayne, PA, USA, 2016.

for

interpretation

of

MICs

and

zone

diameters.

Page 12 of 23

304

[16] Metan G, Akova M. Reducing the impact of carbapenem-resistant Enterobacteriaceae on

305

vulnerable patient groups: what can be done? Curr Opin Infect Dis 2016;29:555-60.

306

[17] Martirosov DM, Lodise TP. Emerging trends in epidemiology and management of

307

infections caused by carbapenem-resistant Enterobacteriaceae. Diagn Microbiol Infect Dis

308

2016;85:266-75.

309

[18] Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-

310

Net).

311

2015.pdf

312

[19] Kresken M, Hafner D, Körber-Irrgang B für die Studiengruppe. Epidemiologie und

313

Resistenzsituation bei klinisch wichtigen Infektionserregern aus dem Hospitalbereich

314

gegenüber Antibiotika. Bericht über die Ergebnisse einer multizentrischen Studie der Paul-

315

Ehrlich-Gesellschaft für Chemotherapie e.V. aus dem Jahre 2010. Antiinfectives Intelligence,

316

Rheinbach, 2013. http://www.p-e-g.org/econtext/Berichte%20der%20Studien

317

[20] Kresken M, Hafner D, Körber-Irrgang B für die Studiengruppe. Epidemiologie und

318

Resistenzsituation bei klinisch wichtigen Infektionserregern aus dem Hospitalbereich

319

gegenüber Antibiotika. Bericht über die Ergebnisse einer multizentrischen Studie der Paul-

320

Ehrlich-Gesellschaft für Chemotherapie e.V. aus dem Jahre 2013. Antiinfectives Intelligence,

321

Rheinbach, 2016. http://www.p-e-g.org/econtext/Berichte%20der%20Studien.

http://ecdc.europa.eu/en/publications/Publications/antimicrobial-resistance-europe-

Page 13 of 23

Table 1: MIC distributions, MIC50 and MIC90 values and antimicrobial susceptibilities of 497 P. aeruginosa isolates Antimicrobial Agent

<0.06 0.125 0.25 0.5 2a

1

2

4

8

16

32

64 >128 MIC50 MIC90 MIC Range %S

%I %R

1

11

38 164 178 65b

13

9

1

15

4

8

0.125 - ≥128 92.4

4

6

52 195 103 79b

34

12

5

7

2

16

0.25 - ≥128 88.3

-

11.7

Ceftazidime

6

b

11

31

10

8

2

16

0.5 - ≥128 87.9

-

12.1

Ceftolozane

15 280 133

36

11

3

3

3

13

0.5

2

0.25 - ≥128

-c

-

-

Ceftolozane/tazobactam

22 291 123

34

5b

4

2

3

1

12

0.5

2

0.25 - ≥128 95.6

-

4.4

65 54b

23

20

14

11

22

9d

0.25

8

≤0.06 - ≥64 73.8

6.2 19.9

1

1

2

≤0.06 - ≥128 99.8

-

3

0.5

4

≤0.06 - ≥128 73.8 10.5 15.7

0.5

16

Amikacin Cefepime

Ciprofloxacin

42

Colistin

206

1

Doripenem

56

98

Levofloxacin

4

8

Meropenem

44

75

Piperacillin/tazobactam Tobramycin a

≤0.125 mg/L;

b

1a

98 231

31

73 29

4

57 365

58 11b

94

72 47b

52

b

45 200 75 75

87

38

22

6

7

2 d

≤0.06 - ≥64 66.8

5.0

0.2

47

27

33

21

19

55 36b

48

41

19

7

5

5

0.5

8

24 188 144 53b 27

19

35

8

64

≤0.12 - ≥128 83.7

-

16.3

5

22

0.5

1

0.125 - ≥128 92.8

-

7.2

2

4

7 101 267

79

5

2b

3

2

4

18

2.6

9.5 23.7

≤0.06 - ≥128 74.8 17.9

7.2

susceptible breakpoint values are indicated in boldface; c no EUCAST breakpoint available; d ≥ 64 mg/L

Page 14 of 23

Table 2: MIC distributions, MIC50 and MIC90 values and antimicrobial susceptibilities of 60 P. aeruginosa isolates resistant to ceftazidime Antimicrobial Agent

<0.06 0.125 0.25 0.5

1

2

4

8

16

32

2

4

7

12

17a

1

5

2

8a

26

12

11

31

Amikacin Cefepime Ceftazidime

64 >128 MIC50 MIC90 MIC Range %S 8

128

0.5 - ≥128 70.0

5

7

16

128

4 - ≥128 16.7

10

8

32

128

16 - ≥128

13

4

128

0.5 - ≥128

12

2

128

4

32

1

1

2

≤0.06 - ≥128 98.3

-

3

8

32

≤0.06 - ≥128 26.7

3.3 70.0

8

≥64

0.25 - ≥64 25.0

5.0 70.0

8

64

1

8

19

11

3

3

2

Ceftolozane/tazobactam

2

7

25

5a

4

2

2

1

3a

7

4

4

7

5

10

6c

4

47

7

0a

4

7a

2

9

1

10

a

3

8

7

1

7

3

5a

2

1

Colistin

1

Doripenem

1

7

1

Levofloxacin Meropenem

3

6

3

4

Piperacillin/tazobactam Tobramycin a

7

17

13

15

6

%R

12

Ceftolozane

Ciprofloxacin

%I

7

2

8

8

11

c

15

7

7

5

5

1

2

1a

6

15

35

128 ≥128

1a

1

2

1

4

14

1 ≥128

1.7 28.3 -

83.3

0.0

-

100

-b

-

-

0.5 - ≥128 65.0

-

35.0

≤0.06 - ≥64 28.3 11.7 60.0 1.7

0.12 - ≥128 31.7 28.3 40.0 4 - ≥128

6.7

-

93.3

0.25 - ≥128 63.3

-

36.7

susceptible breakpoint values are indicated in boldface; b no EUCAST breakpoint available; c ≥ 64 mg/L

Page 15 of 23

Table 3: Antimicrobial activity of ceftolozane/tazobactam and comparator agents against 780 Enterobacteriaceae isolates including resistant phenotypes Organism (no. tested)/

MIC50 MIC90

MIC Range

%S

%I

%R

antimicrobial All Escherichia coli (202) Amikacin

2

4

1 -

16

98.0

2.0

0.0

Amoxicillin/clavulanic acid a

4

64

≤0.06 -

≥128

66.8

-

33.2

≤0.06

16

≤0.06 -

≥128

83.7

2.5

13.9

Ceftazidime

0.25

8

≤0.06 -

≥128

83.2

6.4

10.4

Ceftolozane

0.25

16

≤0.06 -

≥128

-b

-

-

Ceftolozane/tazobactam

0.25

0.5

≤0.06 -

32

96.0

-

4.0

Ceftriaxone

≤0.06

≥128

≤0.06 -

≥128

84.2

0.0

15.8

Ciprofloxacin

≤0.06

≥64

≤0.06 -

≥64

68.3

2.0

29.7

0.5

0.5

0.12 -

1

100.0

-

0.0

Doripenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 -

0.12

100.0

0.0

0.0

2

8

0.25 -

≥128

99.0

-

1.0

Levofloxacin

0.06

16

≤0.06 -

≥64

69.8

0.5

29.7

Meropenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Piperacillin/tazobactam

2

8

≤0.12 -

≥128

91.6

2.0

6.4

Tobramycin

1

8

≤0.06 -

≥128

87.6

1.0

11.4

4

8

1 -

16

90.6

9.4

0.0

Amoxicillin/clavulanic acid a

32

128

0.12 -

≥128

31.3

-

68.7

Cefepime

16

128

0.5 -

≥128

6.3

9.4

84.3

8

32

2 -

64

0.0

37.5

62.5

b

-

-

Cefepime

Colistin

Fosfomycin

Escherichia coli, ESBL+ (32) Amikacin

Ceftazidime Ceftolozane

32

64

1 -

≥128

Ceftolozane/tazobactam

0.5

2

0.25 -

16

81.3

-

18.8

≥128

≥128

0.25 -

≥128

3.1

0.0

96.9

Ciprofloxacin

32

≥64

≤0.06 -

≥64

28.1

6.3

65.6

Colistin

0.5

0.5

0.25 -

0.5

100.0

-

0.0

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Ceftriaxone

Doripenem

-

Page 16 of 23

≤0.06

≤0.06

Fosfomycin

2

8

0.25 -

Levofloxacin

16

32

≤0.06 -

≤0.06

≤0.06

Piperacillin/tazobactam

4

32

Tobramycin

1

Amikacin Amoxicillin/clavulanic acid a

Ertapenem

≤0.06 - ≤0.06

100.0

0.0

0.0

16

100.0

-

0.0

32

31.3

3.1

65.6

≤0.06 - ≤0.06

100.0

0.0

0.0

1 -

≥128

75.0

9.4

15.6

64

0.5 -

≥128

59.4

3.1

37.5

1

2

0.12 -

16

99.1

0.9

0.0

1

64

≤0.06 -

≥128

81.6

0.0

18.4

≤0.06

16

≤0.06 -

≥128

85.0

1.3

13.7

Ceftazidime

0.12

8

≤0.06 -

≥128

82.8

2.6

14.6

Ceftolozane

0.25

32

≤0.06 -

≥128

-b

-

-

Ceftolozane/tazobactam

0.25

1

0.12 -

≥128

93.1

-

6.9

Ceftriaxone

≤0.06

≥128

≤0.06 -

≥128

84.5

0.0

15.5

Ciprofloxacin

≤0.06

32

≤0.06 -

≥64

79.8

4.3

15.9

0.5

0.5

0.25 -

64

97.9

-

2.1

Doripenem

≤0.06

≤0.06

≤0.06 -

2

99.6

0.4

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 -

16

98.3

0.9

0.9

32

≥128

4 -

≥128

57.1

-

42.9

Levofloxacin

≤0.06

8

≤0.06 -

≥64

84.5

2.1

13.3

Meropenem

≤0.06

≤0.06

≤0.06 -

2

100.0

0.0

0.0

2

16

≤0.12 -

≥128

83.3

6.9

9.9

0.5

8

≤0.06 -

≥128

87.6

0.4

12.0

2

8

0.5 -

16

95.0

5.0

0.0

64

≥128

2 -

≥128

0.0

15.0

85.0

Cefepime

16

≥128

0.12 -

≥128

15.0

5.0

80.0

Ceftazidime

16

≥128

1 -

≥128

2.5

15.0

82.5

Ceftolozane

32

≥128

1 -

≥128

-b

-

-

1

4

0.25 -

≥128

62.5

-

37.5

≥128

≥128

0.12 -

≥128

10.0

0.0

90.0

32

≥64

≤0.06 -

≥64

17.5

7.5

75.0

Meropenem

All Klebsiella pneumoniae (233)

Cefepime

Colistin

Fosfomycin

Piperacillin/tazobactam Tobramycin

Klebsiella pneumoniae, ESBL+ (40) Amikacin Amoxicillin/clavulanic acid

Ceftolozane/tazobactam Ceftriaxone Ciprofloxacin

a

Page 17 of 23

Colistin

0.5

0.5

0.25 -

64

92.5

-

7.5

Doripenem

≤0.06

0.12

≤0.06 -

2

97.5

2.5

0.0

Ertapenem

≤0.06

0.25

≤0.06 -

16

92.5

5.0

2.5

Fosfomycin

32

≥128

4

-

≥128

50.0

-

50.0

Levofloxacin

4

≥64

≤0.06 -

≥64

32.5

2.5

65.0

≤0.06

0.12

≤0.06 -

2

100.0

0.0

0.0

16

≥128

2 -

≥128

37.5

17.5

45.0

8

32

0.5 -

≥128

35.0

2.5

62.5

Amikacin

2

2

1 -

8

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

1

≥128

≤0.06 -

≥128

73.5

-

26.5

≤0.06

4

≤0.06 -

16

82.4

10.3

7.4

Ceftazidime

0.12

1

≤0.06 -

4

91.2

8.8

0.0

Ceftolozane

0.25

2

0.12 -

8

-b

-

-

Ceftolozane/tazobactam

0.25

2

0.12 -

8

86.8

-

13.2

Ceftriaxone

0.12

16

≤0.06 -

≥128

73.5

4.4

22.1

≤0.06

0.12

≤0.06 -

≥64

91.2

2.9

5.9

0.5

0.5

0.25 -

1

100.0

-

0.0

Doripenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 -

0.12

100.0

0.0

0.0

32

≥128

2 -

≥128

72.1

-

27.9

Levofloxacin

≤0.06

0.25

≤0.06 -

≥64

94.1

0.0

5.9

Meropenem

≤0.06

≤0.06

≤0.06 -

0.12

100.0

0.0

0.0

2

≥128

≤0.12 -

≥128

73.5

1.5

25.0

0.5

1

≤0.06 -

16

95.6

2.9

1.5

2

2

1 -

2

100.0

0.0

0.0

≥128

≥128

64 -

≥128

0.0

0.0

100.0

2

8

1 -

16

18.2

54.5

27.3

Ceftazidime

0.5

2

0.25 -

4

63.6

36.4

0.0

Ceftolozane

1

8

0.5 -

8

-b

-

-

Ceftolozane/tazobactam

2

4

0.5 -

4

45.5

-

54.5

Meropenem Piperacillin/tazobactam Tobramycin

All Klebsiella oxytoca (68)

Cefepime

Ciprofloxacin Colistin

Fosfomycin

Piperacillin/tazobactam Tobramycin

Klebsiella oxytoca, ESBL+ (11) Amikacin Amoxicillin/clavulanic acid a Cefepime

Page 18 of 23

16

≥128

8 -

≥128

0.0

0.0

100.0

≤0.06

0.12

≤0.06 -

32

90.9

0.0

9.1

0.5

1

0.25 -

1

100.0

-

0.0

Doripenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

32

≥128

8 -

≥128

54.5

-

45.5

Levofloxacin

≤0.06

0.25

≤0.06 -

16

90.9

0.0

9.1

Meropenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Piperacillin/tazobactam

≥128

≥128

≥128 -

≥128

0.0

0.0

100.0

0.5

0.5

0.25 -

2

100.0

0.0

0.0

Amikacin

4

4

0.5 -

8

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

1

8

0.25 -

≥128

91.1

-

8.9

Cefepime

≤0.06

0.12

≤0.06 -

16

98.2

0.0

1.8

Ceftazidime

≤0.06

0.12

≤0.06 -

0.25

100.0

0.0

0.0

b

-

-

Ceftriaxone Ciprofloxacin Colistin

Fosfomycin

Tobramycin

Proteus mirabilis (56)

Ceftolozane

0.5

0.5

0.25 -

4

Ceftolozane/tazobactam

0.5

0.5

0.25 -

1

100.0

-

0.0

Ceftriaxone

≤0.06

≤0.06

≤0.06 -

8

98.2

0.0

1.8

Ciprofloxacin

≤0.06

2

≤0.06 -

32

73.2

3.6

23.2

Colistin

≥128

≥128

8 -

≥128

0.0c

-

100.0

Doripenem

≤0.06

0.12

≤0.06 -

0.25

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

4

≥128

≤0.06 -

≥128

82.1

-

17.9

Levofloxacin

≤0.06

2

≤0.06 -

16

83.9

8.9

7.1

Meropenem

≤0.06

≤0.06

≤0.06 -

0.12

100.0

0.0

0.0

0.25

0.5

≤0.12 -

2

100.0

0.0

0.0

1

4

≤0.06 -

16

83.9

7.1

8.9

Amikacin

4

8

1 -

8

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

4

16

2 -

32

81.3

-

18.7

Cefepime

0.12

1

≤0.06 -

4

93.8

6.3

0.0

Ceftazidime

0.12

2

≤0.06 -

2

81.3

18.8

0.0

Fosfomycin

Piperacillin/tazobactam Tobramycin

-

Proteus vulgaris (16)

Page 19 of 23

Ceftolozane

1

4

0.5 -

4

-b

-

-

Ceftolozane/tazobactam

1

2

0.5 -

2

81.3

-

18.8

Ceftriaxone

4

16

≤0.06 -

32

25.0

6.3

68.8

Ciprofloxacin

≤0.06

2

≤0.06 -

4

81.3

0.0

18.8

Colistin

≥128

≥128

64 -

≥128

0.0c

-

100.0

Doripenem

0.12

0.5

≤0.06 -

0.5

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 -

0.25

100.0

0.0

0.0

16

≥128

4 -

≥128

75.0

-

25.0

Levofloxacin

≤0.06

2

≤0.06 -

2

87.5

12.5

0.0

Meropenem

≤0.06

0.12

≤0.06 -

0.25

100.0

0.0

0.0

0.25

1

≤0.12 -

2

100.0

0.0

0.0

0.5

1

0.25 -

4

93.8

6.3

0.0

2

8

1 -

16

95.9

4.1

0.0

Amoxicillin/clavulanic acid a

≥128

≥128

8 -

≥128

-c

-

-

Cefepime

0.12

0.5

≤0.06 -

≥128

93.9

2.0

4.1

Ceftazidime

0.25

1

≤0.06 -

≥128

95.9

0.0

4.1

Ceftolozane

0.5

2

0.25 -

≥128

-b

-

-

Ceftolozane/tazobactam

0.5

2

0.25 -

≥128

89.8

-

10.2

Ceftriaxone

0.25

4

≤0.06 -

≥128

79.6

8.2

12.2

Ciprofloxacin

0.12

1

≤0.06 -

≥64

87.8

4.1

8.2

c

-

100.0

Fosfomycin

Piperacillin/tazobactam Tobramycin

Serratia marcescens (49) Amikacin

Colistin

≥128

≥128

32 -

≥128

0.0

Doripenem

≤0.06

0.12

≤0.06 -

≥128

95.9

0.0

4.1

Ertapenem

≤0.06

0.12

≤0.06 -

≥64

95.9

0.0

4.1

16

64

0.5 -

≥128

77.6

-

22.4

Levofloxacin

0.12

1

≤0.06 -

32

93.9

0.0

6.1

Meropenem

≤0.06

≤0.06

≤0.06 -

≥128

95.9

0.0

4.1

Piperacillin/tazobactam

2

32

0.5 -

≥128

75.5

4.1

20.4

Tobramycin

2

8

0.12 -

16

69.4

18.4

12.2

2

8

1 -

16

96.0

4.0

0.0

≥128

c

-

-

Fosfomycin

Morganella morganii (25) Amikacin Amoxicillin/clavulanic acid

a

≥128

≥128

8 -

-

Page 20 of 23

≤0.06

8

≤0.06 -

≥128

88.0

0.0

12.0

Ceftazidime

1

32

≤0.06 -

≥128

52.0

20.0

28.0

Ceftolozane

1

32

0.25 -

≥128

-b

-

-

Ceftolozane/tazobactam

0.5

1

0.25 -

64

92.0

-

8.0

Ceftriaxone

0.5

32

≤0.06 -

≥128

64.0

4.0

32.0

Ciprofloxacin

≤0.06

2

≤0.06 -

≥64

84.0

0.0

16.0

Colistin

≥128

≥128

32 -

≥128

0.0c

-

100.0

Doripenem

0.25

0.5

≤0.06 -

0.5

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Fosfomycin

≥128

≥128

16 -

≥128

8.0

-

92.0

Levofloxacin

≤0.06

4

≤0.06 -

16

84.0

4.0

12.0

Meropenem

≤0.06

0.12

≤0.06 -

0.25

100.0

0.0

0.0

Piperacillin/tazobactam

0.5

2

≤0.12 -

2

100.0

0.0

0.0

Tobramycin

0.5

2

≤0.06 -

64

92.0

0.0

8.0

1

2

1 -

2

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

≥128

≥128

8 -

≥128

-c

-

-

Cefepime

0.25

32

≤0.06 -

32

78.6

0.0

21.4

Ceftazidime

2

64

0.12 -

≥128

42.9

7.1

50.0

Ceftolozane

1

32

0.25 -

32

-b

-

-

0.5

8

0.25 -

16

57.1

-

42.9

2

≥128

≤0.06 -

≥128

42.9

7.1

50.0

≤0.06

2

≤0.06 -

8

85.7

0.0

14.3

0.5

0.5

0.5 -

0.5

100.0

-

0.0

Doripenem

≤0.06

0.12

≤0.06 -

4

92.9

0.0

7.1

Ertapenem

0.12

0.5

≤0.06 -

32

92.9

0.0

7.1

32

≥128

2 -

≥128

64.3

-

35.7

Levofloxacin

0.12

4

≤0.06 -

8

85.7

0.0

14.3

Meropenem

≤0.06

0.12

≤0.06 -

8

92.9

7.1

0.0

8

≥128

2 -

≥128

50.0

0.0

50.0

0.5

0.5

0.25 -

1

100.0

0.0

0.0

Cefepime

Enterobacter aerogenes (14) Amikacin

Ceftolozane/tazobactam Ceftriaxone Ciprofloxacin Colistin

Fosfomycin

Piperacillin/tazobactam Tobramycin

Page 21 of 23

Enterobacter cloacae (73) Amikacin

1

2

0.5 -

4

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

≥128

≥128

16 -

≥128

-c

-

-

Cefepime

0.25

4

≤0.06 -

≥128

72.6

23.3

4.1

1

64

0.12 -

≥128

54.8

5.5

39.7

b

-

-

Ceftazidime

1

32

≤0.06 -

≥128

0.5

16

0.12 -

≥128

69.9

-

30.1

1

≥128

≤0.06 -

≥128

54.8

0.0

45.2

≤0.06

2

≤0.06 -

≥64

86.3

2.7

11.0

0.5

0.5

≤0.06 -

≥128

95.9

-

4.1

Doripenem

≤0.06

0.12

≤0.06 -

8

98.6

0.0

1.4

Ertapenem

≤0.06

0.5

≤0.06 -

≥64

90.4

2.7

6.8

32

≥128

1 -

≥128

54.8

-

45.2

Levofloxacin

≤0.06

2

≤0.06 -

16

87.7

5.5

6.8

Meropenem

≤0.06

0.12

≤0.06 -

16

98.6

0.0

1.4

4

≥128

1 -

≥128

60.3

9.6

30.1

0.5

1

0.12 -

64

95.9

1.4

2.7

2

2

1 -

4

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

≥128

≥128

≤0.06 -

≥128

-c

-

-

Cefepime

≤0.06

4

≤0.06 -

8

73.1

23.1

3.8

Ceftazidime

0.5

≥128

0.25 -

≥128

61.5

3.8

34.6

Ceftolozane

0.5

32

0.25 -

64

-b

-

-

Ceftolozane/tazobactam

0.5

16

0.12 -

32

69.2

-

30.8

0.25

≥128

≤0.06 -

≥128

61.5

0.0

38.5

≤0.06

16

≤0.06 -

16

84.6

0.0

15.4

0.5

0.5

≤0.06 -

1

100.0

-

0.0

Doripenem

≤0.06

≤0.06

≤0.06 -

0.25

100.0

0.0

0.0

Ertapenem

≤0.06

0.25

≤0.06 -

0.5

100.0

0.0

0.0

2

8

≤0.06 -

8

100.0

-

0.0

Levofloxacin

0.12

8

≤0.06 -

32

84.6

0.0

15.4

Meropenem

≤0.06

≤0.06

≤0.06 -

0.25

100.0

0.0

0.0

2

≥128

≤0.12 -

≥128

65.4

0.0

34.6

Ceftolozane Ceftolozane/tazobactam Ceftriaxone Ciprofloxacin Colistin

Fosfomycin

Piperacillin/tazobactam Tobramycin

-

Citrobacter freundii (26) Amikacin

Ceftriaxone Ciprofloxacin Colistin

Fosfomycin

Piperacillin/tazobactam

Page 22 of 23

0.5

2

≤0.06 -

8

92.3

3.8

3.8

Amikacin

2

2

1 -

2

100.0

0.0

0.0

Amoxicillin/clavulanic acid a

1

2

0.5 -

≥128

94.4

-

5.6

≤0.06

0.12

≤0.06 -

0.25

100.0

0.0

0.0

Ceftazidime

0.12

0.5

0.12 -

1

94.4

0.0

5.6

Ceftolozane

0.25

0.5

≤0.06 -

2

-b

-

-

Ceftolozane/tazobactam

0.25

0.5

0.12 -

2

94.4

-

5.6

Ceftriaxone

≤0.06

0.25

≤0.06 -

4

94.4

0.0

5.6

Ciprofloxacin

≤0.06

0.12

≤0.06 -

0.25

100.0

0.0

0.0

0.5

0.5

≤0.06 -

0.5

100.0

-

0.0

Doripenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

Ertapenem

≤0.06

≤0.06

≤0.06 -

0.12

100.0

0.0

0.0

4

16

≤0.06 -

32

100.0

-

0.0

Levofloxacin

≤0.06

0.25

≤0.06 -

0.5

100.0

0.0

0.0

Meropenem

≤0.06

≤0.06

≤0.06 - ≤0.06

100.0

0.0

0.0

2

4

≤0.12 -

16

94.4

5.6

0.0

0.5

0.5

≤0.06 -

0.5

100.0

0.0

0.0

Tobramycin

Citrobacter koseri (18)

Cefepime

Colistin

Fosfomycin

Piperacillin/tazobactam Tobramycin a

The EUCAST breakpoint of ≤8/>8 mg/l was applied although the National EUCAST Study

Group (German NAC) has set the susceptible breakpoint for Enterobacteriaceae at 0.5 mg/l. b

No EUCAST breakpoint available

c

Species considered intrinsically resistant according to EUCAST expert rules (v. 3.1)

Page 23 of 23