In vitro activity of imipenem-relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples – SMART Surveillance United States 2015-2017

In vitro activity of imipenem-relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples – SMART Surveillance United States 2015-2017

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Journal Pre-proof In vitro activity of imipenem-relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples – SMART Surveillance United States 2015-2017 James A. Karlowsky, Sibylle H. Lob, Krystyna M. Kazmierczak, Katherine Young, Mary R. Motyl, Daniel F. Sahm

PII:

S2213-7165(19)30290-5

DOI:

https://doi.org/10.1016/j.jgar.2019.10.028

Reference:

JGAR 1085

To appear in:

Journal of Global Antimicrobial Resistance

Received Date:

21 May 2019

Revised Date:

17 October 2019

Accepted Date:

27 October 2019

Please cite this article as: Karlowsky JA, Lob SH, Kazmierczak KM, Young K, Motyl MR, Sahm DF, In vitro activity of imipenem-relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples – SMART Surveillance United States 2015-2017, Journal of Global Antimicrobial Resistance (2019), doi: https://doi.org/10.1016/j.jgar.2019.10.028

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier.

JGAR-D-19-00436 R1 Revised Manuscript

In vitro activity of imipenem-relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples – SMART Surveillance United States 2015-2017

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Running title: Imipenem-relebactam US IAI UTI GN bacilli

James A. Karlowsky a,b, Sibylle H. Lob a,*, Krystyna M. Kazmierczak a , Katherine Young c,

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Mary R. Motyl c, and Daniel F. Sahm a

International Health Management Associates, Inc., Schaumburg, IL, 60173, USA

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Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine,

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University of Manitoba, Winnipeg, MB, R3E 0J9, Canada Merck & Co., Inc., Kenilworth, NJ 07033, USA

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c

*Corresponding author: Sibylle H. Lob, [email protected] Mailing address: International Health Management Associates, Inc., 2122 Palmer Drive,

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Schaumburg, IL, 60173, USA. Phone: (847) 303-5003. Fax: (847) 303-5601.

Authors’ email addresses: James A. Karlowsky, [email protected] Sibylle H. Lob, [email protected]

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Krystyna M. Kazmierczak, [email protected] Katherine Young, [email protected] Mary R. Motyl, [email protected] Daniel F. Sahm, [email protected]

Highlights Intraabdominal (IAI) and urinary tract (UTI) infection isolates were tested



96.6% of Pseudomonas aeruginosa were imipenem-relebactam-susceptible (IMR-S)



99.5% of non-Proteeae Enterobacteriaceae (NPE) were IMR-S



85.0% and 77.9% of imipenem-nonsusceptible P. aeruginosa and NPE were IMR-S



MDR NPE (98.7%), KPC-positive NPE (96.3%) and MDR P. aeruginosa (87.3%) were IMR-

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Abstract

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Objectives:

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Antimicrobial resistance including multidrug-resistance (MDR) is increasing especially among Gram-negative bacilli. New agents are needed to treat infections caused by these pathogens. For this report, the activity of imipenem-relebactam was assessed against Gram-negative bacilli from

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intraabdominal infections (IAIs) and urinary tract infections (UTIs) submitted to the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program in the United States from 2015 to 2017. Methods: Broth microdilution MICs for imipenem-relebactam and comparators were determined by a central laboratory against isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas 2

aeruginosa. Imipenem-relebactam MICs were interpreted using United States Food and Drug Administration (FDA) breakpoints. Results: 99.5% of NPE isolates collected from patients with IAIs (n=3,633) and UTIs (n=3,038) were susceptible to imipenem-relebactam, as were 77.9% of imipenem-nonsusceptible, 96.3% of KPC-positive, and 98.7% of MDR isolates from IAIs and UTIs combined. 96.7% of IAI isolates

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(n=486) and 96.4% of UTI isolates (n=360) of P. aeruginosa were susceptible to imipenem-

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relebactam, as were 85.0% of imipenem-nonsusceptible and 87.3% of MDR isolates from IAIs and UTIs combined. Percent susceptibility to imipenem-relebactam for cefepime-, ceftazidime-,

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and piperacillin-tazobactam-nonsusceptible isolates was 98.3-98.8% for NPE and 87.3-90.0% for

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P. aeruginosa. Conclusions:

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Imipenem-relebactam demonstrated potent in vitro activity against NPE and P. aeruginosa isolates from IAIs and UTIs, including against resistant subsets, and will provide important

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coverage for IAIs and UTIs caused by β-lactam-resistant, MDR, and KPC-positive Gramnegative bacilli.

Keywords: imipenem-relebactam; Gram-negative bacilli; United States; SMART;

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intraabdominal infection; urinary tract infection

1. Introduction

Intraabdominal infections (IAIs) and urinary tract infections (UTIs) typically arise following the introduction of gastrointestinal tract flora into normally sterile anatomical sites.

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Enterobacteriaceae and other Gram-negative bacilli are important pathogens causing both IAIs and UTIs. Multidrug-resistant (MDR) Gram-negative pathogens, including Enterobacteriaceae isolates that are extended-spectrum β-lactamase (ESBL)-positive or carbapenem-resistant, and Pseudomonas aeruginosa resistant to carbapenems are of increasing concern. One approach to slow the spread of antimicrobial-resistant pathogens is the introduction of new therapeutic agents.

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Relebactam is a non-β-lactam diazabicyclooctane inhibitor of Ambler class A β-

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lactamases, including ESBLs and KPCs [Klebsiella pneumoniae carbapenemases], and class C (AmpC) β-lactamases in Enterobacteriaceae [1]. Imipenem-relebactam is active against isolates

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of P. aeruginosa that are carbapenem-resistant because of a combination of porin loss or

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upregulated drug efflux and elevated production of the intrinsic AmpC [1,2]. Relebactam, in combination with imipenem-cilastatin, was approved by the United States Food and Drug

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Administration (FDA) in July 2019 for the treatment of adults with complicated IAI and complicated UTI, including pyelonephritis caused by susceptible aerobic and anaerobic Gram-

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negative bacilli [3].

The current report summarizes the results of antimicrobial susceptibility testing with imipenem-relebactam and comparator agents for isolates of Gram-negative bacilli submitted to the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance

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program by 26 participating hospital laboratories in 18 states in the United States. This study expands on a report of isolates collected in 2016 by focusing on IAI and UTI isolates and by including data from additional years [4].

2. Materials and methods

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2.1 Bacterial isolates The current study summarizes testing of 3,633 isolates of non-Proteeae Enterobacteriaceae [NPE] and 486 isolates of P. aeruginosa collected from patients with IAIs, and 3,038 NPE and 360 P. aeruginosa from UTIs. Each hospital laboratory collected up to 100 isolates of Gramnegative bacilli from IAIs in 2015 and 2016 and 75 isolates in 2017; and up to 50 isolates from UTIs in 2015 and 2016 and 75 isolates in 2017. Only one clinically significant isolate per

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species per patient was accepted into the study. Patient age distribution and location at the time

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of specimen collection are described in Supplemental Table 1. Species within the tribe Proteeae were excluded from analysis because they are intrinsically less susceptible or resistant to

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imipenem by a mechanism independent of β-lactamase production [5,6], and relebactam would

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not be expected to enhance imipenem’s activity against Proteeae isolates. The current study also excluded isolates of Stenotrophomonas maltophilia, Burkholderia spp., and other non-

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Enterobacteriaceae Gram-negative bacilli known to be intrinsically resistant to imipenem and specific species of Gram-negative bacilli (e.g., Acinetobacter spp.), for which imipenem and

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imipenem-relebactam have previously demonstrated limited activity [7]. All isolates were transported to International Health Management Associates, Inc. (IHMA; Schaumburg, IL, USA) which served as the central testing laboratory for the SMART program. All isolates received by IHMA were re-identified using matrix-assisted laser

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desorption ionization-time of flight (MALDI-TOF) mass spectrometry (Bruker Daltonics, Billerica, MA, USA) prior to antimicrobial susceptibility testing.

2.2 Antimicrobial susceptibility testing

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Antimicrobial susceptibility testing was performed at IHMA following the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method [8], using custommade dehydrated broth microdilution panels manufactured by TREK Diagnostic Systems (Thermo Fisher Scientific, Oakwood Village, OH, USA). Relebactam was tested at a fixed concentration of 4 µg/ml. MICs were interpreted using CLSI breakpoints [5] for all agents, with two exceptions. First, imipenem-relebactam MICs were interpreted using FDA breakpoints for

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Enterobacteriaceae (susceptible, ≤1 µg/ml; intermediate, 2 µg/ml; resistant, ≥4 µg/ml) and P.

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aeruginosa (susceptible, ≤2 µg/ml; intermediate, 4 µg/ml; resistant, ≥8 µg/ml) [9], and second, EUCAST breakpoints were used for colistin tested against Enterobacteriaceae (susceptible, ≤2

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µg/ml; resistant, ≥4 µg/ml) [10].

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MDR isolates were defined phenotypically as those isolates testing as nonsusceptible (intermediate or resistant) to any three or more of the following eight sentinel antimicrobial

piperacillin-tazobactam.

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agents: amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, colistin, imipenem, and

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All isolates of NPE, with the exception of Serratia spp., and all isolates of P. aeruginosa that were nonsusceptible to imipenem or imipenem-relebactam (MIC ≥2 µg/ml, NPE; MIC ≥4 µg/ml, P. aeruginosa) were screened for β-lactamase genes encoding the metallo-β-lactamases (IMP, VIM, NDM, GIM, and SPM), serine carbapenemases (KPC, GES, and OXA-48-like

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[NPE] or OXA-24-like [P. aeruginosa]), ESBLs (SHV, TEM, CTX-M, VEB, PER, and GES), acquired AmpC β-lactamases (ACC, ACT, CMY, DHA, FOX, MIR, MOX), and the chromosomal AmpC intrinsic to P. aeruginosa (PDC) using published multiplex PCR assays, followed by full-gene DNA sequencing as described previously [11, 12]. For the Serratia spp., only isolates with imipenem MIC ≥4 µg/ml (resistant) or imipenem-relebactam MIC ≥2 µg/ml

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were screened for β-lactamase genes because isolates testing with imipenem MIC = 2 µg/ml were rarely found to carry acquired β-lactamases (data not shown).

3. Results Imipenem-relebactam inhibited 99.5% of NPE (MIC ≤1 µg/ml) collected from patients with IAIs and UTIs and demonstrated MIC50 and MIC90 values of 0.12 µg/ml and 0.25 µg/ml,

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respectively, against IAI isolates and 0.12 µg/ml and 0.5 µg/ml against UTI isolates (Table 1 and

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Supplemental Table 2). Susceptibility to imipenem was 1-2 percentage points lower and

susceptibility to the other comparator β-lactams was 6-14 percentage points lower than to

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imipenem-relebactam.

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Imipenem-relebactam inhibited 99-100% of isolates of E. coli, K. pneumoniae, E. cloacae, K. oxytoca, and C. freundii from both IAI and UTI sources (Table 1). For K. aerogenes,

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100% of UTI isolates were susceptible to imipenem-relebactam compared to 97.6% for IAI isolates. For these individual species of NPE, susceptibility to imipenem was >95% except for

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K. aerogenes isolates collected from IAI (90.4%), whereas percent susceptibilities to the other tested β-lactams were up to 35 percentage points lower than to imipenem-relebactam. S. marcescens, the seventh most common NPE species isolated from both IAIs and UTIs, was the only species of NPE that demonstrated reduced susceptibility to imipenem (IAI, 68.0%

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susceptible; UTI, 61.9%) (Table 1). The percentages of susceptibility of S. marcescens isolates to imipenem-relebactam (IAI, 91.8%; UTI, 76.2%) were 14-24 percentage points higher than to imipenem but were still considerably lower than susceptibilities observed for other species of NPE (97.6-100% susceptible) (Table 1).

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Table 2 and Supplemental Figure 1 document the NPE species distribution and susceptibility rates for β-lactam-nonsusceptible and MDR isolates of all NPE, the three most prevalent species of NPE, and P. aeruginosa. Given that the species distribution and susceptibility rates were similar for NPE isolates from IAI and UTI, we combined the isolates from these two sources in order to increase the sample sizes of the resistant subsets being analysed. The proportion of NPE isolates nonsusceptible to β-lactams ranged from 2.3% for

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imipenem to 12.9% for ceftazidime, MDR isolates represented 12.6% of all NPE, and KPC-

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positive isolates (18 KPC-2-positive and 36 KPC-3-positive) made up 0.8% of isolates (Table 1). The majority of cefepime-nonsusceptible isolates were E. coli (62%), which together with K.

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pneumoniae and E. cloacae accounted for 93% of isolates (Supplemental Figure 1). E. coli was

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also the most common species among ceftazidime-nonsusceptible (48%), MDR (52%), and piperacillin-tazobactam-nonsusceptible NPE (34%). Among the imipenem-nonsusceptible

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subset, S. marcescens and K. pneumoniae each accounted for approximately 30% of isolates. The majority of the 54 KPC-positive isolates (67%) were K. pneumoniae, with the remaining 18

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isolates distributed among 6 other NPE species. Imipenem-relebactam remained active against 98.3-98.8% of all MDR and cefepime-, ceftazidime-, and piperacillin-tazobactam-nonsusceptible NPE isolates, as well as against 96.3% of KPC-positive isolates. Against the imipenemnonsusceptible subset, the activity of imipenem-relebactam decreased to 77.9%, in part due to

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relatively low activity against imipenem-nonsusceptible S. marcescens isolates (29/47, 61.7% susceptible, Supplemental Tables 3 and 4). Nevertheless, in this subset of imipenemnonsusceptible NPE, the modal MIC decreased from 2 to ≤0.5 µg/ml (Supplemental Figure 2). On the other hand, for all NPE combined, the distribution of imipenem MICs was similar with and without relebactam, as resistance to imipenem was rare (Supplemental Figure 2).

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Among the 6,671 NPE isolates in the study, 34 (0.5%) were nonsusceptible to imipenemrelebactam and all but one were molecularly characterized (Table 3). Of these, six isolates carried OXA-48-like, NDM-type, or VIM-type carbapenemases. An additional carbapenemasepositive isolate carried KPC-3 with an SHV-12 (imipenem MIC >32 µg/ml, imipenemrelebactam MIC 2 µg/ml), and in another isolate only KPC-2 was detected (imipenem MIC >32 µg/ml, imipenem-relebactam MIC 4 µg/ml). The nonsusceptibility to imipenem-relebactam

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observed in these two isolates may be the result of one or more undetected β-lactamases or

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another resistance mechanism. In the remaining 25 isolates (imipenem-relebactam MIC 2 µg/ml [n=19], 4 µg/ml [n=4], and 8 µg/ml [n=2]), no acquired β-lactamases were detected, and most of

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these (21/25, 84.0%) were Serratia spp.

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Imipenem-relebactam demonstrated MIC50 and MIC90 values of 0.5 µg/ml and 2 µg/ml, respectively, against P. aeruginosa isolates from both IAIs (n=486) and UTIs (n=360)

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(Supplemental Table 2). The activity of imipenem-relebactam against P. aeruginosa from IAIs and UTIs was >96%, 16 to 22 percentage points higher than imipenem and 12 to 31 percentage

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points higher than the other tested β-lactam comparators (Table 1). Imipenem-relebactam remained active against 85-90% of P. aeruginosa isolates with resistant phenotypes, including 87.3% of MDR isolates, 45-82 percentage points higher than the activity of the other tested βlactams against MDR isolates (Table 2). Against imipenem-nonsusceptible P. aeruginosa

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isolates (most of which had an imipenem MIC of 4, 8, or 16 µg/ml), the modal imipenem MIC decreased from 8 to 2 µg/ml upon addition of relebactam, and susceptibility was restored to 85.0% of isolates (Table 2 and Supplemental Figure 2). Among the 846 P. aeruginosa isolates, 29 were nonsusceptible to imipenem-relebactam and all of these were molecularly characterized (Table 3). Four isolates carried carbapenemases

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(3 VIM-positive isolates and 1 isolate carrying both a GES carbapenemase and a GES-type ESBL), and in the remaining 25 isolates (imipenem-relebactam MIC of 4 µg/ml [n=16], 8 µg/ml [n=7], 16 µg/ml [n=1], and 32 µg/ml [n=1]), no acquired β-lactamases were detected.

4. Discussion ESBL- and KPC-producing Enterobacteriaceae have emerged in the U.S. over the past

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two decades, predominantly among isolates of E. coli and K. pneumoniae, and have become

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endemic in some hospitals [13]. Many isolates of ESBL- and KPC-producing

difficult-to-treat resistance phenotypes [7,11,14,15].

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Enterobacteriaceae as well as carbapenem-resistant P. aeruginosa also demonstrate MDR and/or

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Previous studies describing the in vitro susceptibilities of Gram-negative bacilli cultured from patients with IAIs and UTIs at U.S. hospitals have reported reduced susceptibility to β-

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lactams, as observed in the current study [14,16-18, 19]. Flamm et al., reported on Enterobacteriaceae (n=410) and P. aeruginosa (n=82) cultured from IAI specimens at 73 U.S.

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medical centers in 2012 [16]. They found 86% and 89% of Enterobacteriaceae isolates susceptible to ceftazidime and piperacillin-tazobactam, respectively, very similar to the percentages found in the current study; and 85% and 79% of P. aeruginosa susceptible to ceftazidime and piperacillin-tazobactam, 5-6 percentage points higher than found by the current

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study [16]. Zalacain et al. observed substantial differences in imipenem activity compared to the current study against Enterobacteriaceae isolates collected in 2012-2013 from patients with hospital-associated IAI in 21 U.S. medical centers [18]. Rates of susceptibility to imipenem were 94% for K. pneumoniae, 91% for E. cloacae, 89% for Citrobacter freundii, 74% for K. aerogenes, and 93% for S. marcescens. It should be noted that the sample sizes examined in the

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Zalacain study were smaller, especially for isolates of K. aerogenes (n=27) and S. marcescens (n=28), and those results may not be representative of larger populations of isolates. In a more recent study, Sader et al., reported on Enterobacteriaceae (n=829) and P. aeruginosa (n=122) cultured from IAI specimens at 85 U.S. medical centers in 2015-2016 [14]. These investigators found 85%, 89%, and 90% of Enterobacteriaceae isolates to be susceptible to ceftazidime, cefepime, and piperacillin-tazobactam, respectively, very similar to the percentages found in the

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current study; and 88%, 88%, and 80% of P. aeruginosa susceptible to ceftazidime, cefepime,

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and piperacillin-tazobactam, 6-9 percentage points higher than the results of the current study [14].

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Similarly, for UTI isolates, several studies of isolates collected in the U.S. in 2011 [19],

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2012 [16], 2012-2014 [17], and 2015-2016 [14] reported higher susceptibility to β-lactams than found in the current study. Activity of ceftazidime, cefepime, and piperacillin-tazobactam was

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reported between 90% and 98% against Enterobacteriaceae compared to 88-94% found in the current study, and between 77 and 90% against P. aeruginosa compared to 74-84% in the current

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study.

Imipenem-relebactam is being developed for the treatment of patients with antimicrobialresistant Gram-negative infections and in the current study was active against 99.5% of NPE isolates from both IAI and UTI, >98% of MDR and cefepime-, ceftazidime-, and piperacillin-

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tazobactam-nonsusceptible subsets, 96.3% of KPC-positive isolates, and 77.9% of imipenemnonsusceptible isolates. Imipenem-relebactam maintained activity against 96.6% of P. aeruginosa isolates from IAIs and UTIs combined. It also maintained activity against 85-90% of cefepime-, ceftazidime-, imipenem-, and piperacillin-tazobactam-nonsusceptible isolates, and against 87.3% of MDR isolates, 45 to 82 percentage points higher than the activity of the

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commonly prescribed β-lactams tested. Importantly, neither relebactam nor imipenem are substrates of RND (resistance-nodulation-cell division) efflux pumps that, when upregulated, impact the effectiveness of some other antipseudomonal β-lactams and β-lactam/β-lactamase combinations [2]. Notably, the subset of imipenem-nonsusceptible NPE isolates demonstrated reduced susceptibility to imipenem-relebactam (77.9% susceptible). This subset was composed mainly

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of S. marcescens (~30% of isolates) and K. pneumoniae (~30% of isolates) (Supplemental Figure

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1). When evaluating the activity of imipenem-relebactam against S. marcescens, it should be noted that the upper end of the imipenem MIC distribution against the wild-type population of

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isolates (epidemiological cut-off value, 2 µg/ml) [20] exceeds the imipenem susceptible MIC

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breakpoint (≤1 µg/ml) set by the CLSI [5]. Imipenem MICs for S. marcescens typically decrease by at most 1-2 doubling-dilutions following the addition of relebactam (Supplemental Tables 3

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and 4), and the accepted one doubling-dilution variation associated with MIC determinations, in combination with a small sample size, may also have contributed to the reduced percentage of

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susceptibility observed for this species. The data also potentially suggests the presence of isolates expressing β-lactamases or non-enzymatic resistance mechanisms that are not sensitive to inhibition by relebactam.

The limitations of the current study are similar to those of most other large-scale

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surveillance studies. No identifiable patient-specific information regarding clinical presentation or antimicrobial therapy was available, which in this study would have allowed differentiation between complicated and uncomplicated IAI and UTI and more detailed stratified analyses; generalizability is limited in that the described resistance patterns are based on data from 26 hospitals in 18 US states; and since the majority of hospitals participating in the SMART

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program are tertiary care centers, resistance rates found in this study are likely higher than would be found in smaller hospitals and in the community. In conclusion, despite increasing resistance among Gram-negative pathogens, imipenemrelebactam demonstrated potent in vitro activity against 99.5% of clinical isolates of NPE and >96% of P. aeruginosa isolates from IAIs and UTIs collected by clinical laboratories in U.S. hospitals, including strong activity against resistant subsets. Further development of imipenem-

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relebactam appears warranted as it has the potential to provide a new treatment option for IAIs

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and UTIs caused by β-lactam-resistant, MDR, and KPC-positive Gram-negative bacilli.

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Declarations

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Funding: Funding for this research, which included compensation for services related to preparing this manuscript, was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck

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& Co., Inc., Kenilworth, NJ, USA.

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Competing Interests: JAK is a consultant to IHMA, Inc., and an employee of the University of Manitoba and Shared Health Manitoba. SHL, KMK, and DFS work for IHMA, Inc., which receives funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA for the SMART global surveillance program. KY and MRM are

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employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and own stock and options in the company. JAK and the IHMA authors do not have personal financial interests in the sponsor of this manuscript (Merck Sharp & Dohme Corp.). All authors provided analysis input and have read and approved the final manuscript.

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Ethical Approval: Not required.

Acknowledgements

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The authors thank all SMART participants for their contributions to the program.

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RL. Difficult-to-treat resistance in Gram-negative bacteremia at 173 US hospitals:

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retrospective cohort analysis of prevalence, predictors, and outcome of resistance to all first-line agents. Clin Infect Dis 2018; 67: 1803-14.

Flamm RK, Farrell DJ, Sader HS, Jones RN. Ceftazidime/avibactam activity tested

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against Gram-negative bacteria isolated from bloodstream, pneumonia, intra-abdominal

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and urinary tract infections in US medical centres (2012). J Antimicrob Chemother 2014; 69(6): 1589-1598. doi:10.1093/jac/dku025 [17]

Sader HS, Castanheira M, Flamm RK, Jones RN. Antimicrobial activities of ceftazidimeavibactam and comparator agents against Gram-negative organisms isolated from

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patients with urinary tract infections in U.S. medical centers, 2012 to 2014. Antimicrob Agents Chemother 2016; 60(7): 4355-4360. doi:10.1128/AAC.00405-16

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Zalacain M, Biedenbach DJ, Badal RE, Young K, Motyl M, Sahm DF. Pathogen prevalence and antimicrobial susceptibility among Enterobacteriaceae causing hospital-

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associated intra-abdominal infections in adults in the United States (2012-2013). Clin Ther; 38(6): 1510-1521. doi:10.1016/j.clinthera.2016.04.035 [19]

Flamm RK, Sader HS, Farrell DJ, Jones RN. Ceftazidime-avibactam and comparator agents tested against urinary tract isolates from a global surveillance program (2011). Diagn Microbiol Infect Dis 2014; 80(3): 233-238. doi:10.1016/j.diagmicrobio.2014.07.005 European Committee on Antimicrobial Susceptibility Testing. EUCAST MIC and zone

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[20]

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https://mic.eucast.org. Accessed December 5, 2018.

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diameter distributions and ECOFFs. https://mic.eucast.org. Retrieved from

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Table 1. In vitro susceptibility to imipenem-relebactam and comparator agents of non-Proteeae Enterobacteriaceae (NPE) and P. aeruginosa isolates from intraabdominal and urinary tract infections.a Percentage of isolates susceptible to antimicrobial agentb n

Imipenemrelebactam

Imipenem

Cefepime

Ceftazidime

3,633

99.5

97.3

89.8

86.8

1,812

100

99.5

88.5

89.0

K. pneumoniae

723

99.0

96.5

90.0

E. cloacae

318

99.7

96.9

81.5

K. oxytoca

209

100

100

97.1

C. freundii

139

100

95.7

K. aerogenes

83

97.6

90.4

S. marcescens

97

91.8

68.0

All P. aeruginosa

486

96.7

75.1

3,038

99.5

1,817

99.9

609

99.7

130 109

Aztreonam

Amikacin

Ciprofloxacin

Colistin

89.0

85.9

99.1

80.2

94.6

92.3

87.9

99.0

68.1

99.7

89.5

90.5

89.2

98.3

88.5

99.0

70.1

73.0

70.1

99.4

94.3

90.6

98.6

93.8

100

96.2

99.5

68.4

74.8

68.4

99.3

89.9

100

95.2

62.7

69.9

68.7

100

92.8

98.8

99.0

97.9

95.9

96.9

100

95.9

2.1

80.7

78.6

74.1

66.1

98.6

78.2

100

98.2

88.5

87.5

93.6

85.9

99.5

76.0

97.6

99.6

87.0

88.2

96.5

85.9

99.6

66.4

99.7

96.7

89.2

88.8

91.3

89.0

99.0

87.5

98.7

100

97.7

81.5

70.0

76.9

70.0

99.2

87.7

93.1

100

100

92.7

91.7

90.8

86.2

100

93.6

100

84.5

76.2

All NPE E. coli K. pneumoniae E. cloacae K. oxytoca C. freundii K. aerogenes S. marcescens All P. aeruginosa

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Urinary tract infection

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92.3

90.7

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E. coli

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Intraabdominal infection All NPE

Piperacillintazobactam

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Infection site Pathogen group/species

84

100

98.8

90.5

75.0

100

92.9

100

98

100

96.9

95.9

80.6

83.7

81.6

100

98.0

99.0

42

76.2

61.9

97.6

97.6

97.6

97.6

100

90.5

7.1

360

96.4

80.0

84.4

84.4

74.2

66.1

98.6

73.3

100

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Only species of NPE with ≥100 isolates (combined intraabdominal infection and urinary tract infection isolates) were included in the table. b Percent susceptible values of ≥90% are shown in bold font. a

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Table 2. Susceptibility to imipenem-relebactam and comparators of all non-Proteeae Enterobacteriaceae (NPE) isolates, the three most prevalent NPE species, and P. aeruginosa from intraabdominal and urinary tract infections combined.a

Imipenemrelebactam

Imipenem

Cefepime

All isolates

6671

99.5

97.7

89.2

Cefepime-nonsusceptible

720

98.5

89.6

Ceftazidime-nonsusceptible

862

98.8

90.7

Piperacillin-tazobactam-nonsusceptible

596

98.3

86.6

Imipenem-nonsusceptible

154

77.9

0

MDR

843

98.7

KPC-positiveb

54

96.3

All isolates

3629

>99.9

Cefepime-nonsusceptible

445

99.8

Ceftazidime-nonsusceptible

414

Piperacillin-tazobactam-nonsusceptible

203

Pathogen group/species NPE

Imipenem-nonsusceptible MDR K. pneumoniae All isolates

Amikacin

Ciprofloxacin

Colistin

87.1

91.1

85.9

99.3

78.3

96.0

61.1

8.2

94.9

21.8

98.2

0

52.7

6.5

95.9

39.9

95.5

53.0

31.5

0

30.4

95.0

52.2

93.8

51.3

48.1

48.1

47.4

88.3

59.1

61.0

90.2

21.1

10.6

49.5

3.2

95.4

29.9

94.9

3.7

1.9

0

0

0

81.5

20.4

90.7

99.5

87.7

88.6

94.4

86.9

99.3

67.2

99.7

98.0

0

25.4

80.9

9.7

96.2

10.6

99.8

99.8

97.8

19.8

0

80.0

5.8

96.1

18.4

99.3

99.5

95.6

58.1

59.1

0

59.1

93.6

24.1

99.0

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19.0

17

94.1

0

47.1

47.1

47.1

41.2

88.2

41.2

100

437

99.8

97.9

7.8

16.5

78.3

3.0

95.7

7.1

99.3

1332

99.3

96.6

89.6

89.2

90.8

89.1

98.7

88.1

98.9

138

94.9

69.6

0

9.4

41.3

7.3

87.7

14.5

95.7

Ceftazidime-nonsusceptible

144

95.1

70.8

13.2

0

38.9

8.3

88.9

16.7

96.5

Piperacillin-tazobactam-nonsusceptible

122

94.3

65.6

33.6

27.9

0

32.0

88.5

33.6

95.9

Imipenem-nonsusceptible

45

80.0

0

6.7

6.7

6.7

6.7

71.1

15.6

88.9

MDR

136

94.9

69.1

5.2

3.7

36.0

4.4

88.2

10.3

95.6

36

94.4

0

0

0

0

0

77.8

11.1

91.7

All isolates

448

99.8

97.1

81.5

70.1

74.1

70.1

99.3

92.4

91.3

Cefepime-nonsusceptible

83

98.8

89.2

0

2.4

9.6

1.2

97.6

69.9

97.6

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Cefepime-nonsusceptible

Aztreonam

32.4

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E. coli

0

Piperacillintazobactam

Ceftazidime

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Percentage of isolates susceptible to antimicrobial agentc

b

KPC-positive E. cloacae

20

134

100

92.5

39.6

0

14.9

3.7

98.5

81.3

94.0

Piperacillin-tazobactam-nonsusceptible

116

100

92.2

35.3

1.7

0

2.6

98.3

81.0

94.0

Imipenem-nonsusceptible

13

92.3

0

30.8

23.1

30.8

23.1

84.6

53.9

100

MDR

123

99.2

91.9

32.5

1.6

7.3

1.6

97.6

78.1

92.7

All isolates

846

96.6

77.2

82.3

Cefepime-nonsusceptible

150

87.3

42.7

0

Ceftazidime-nonsusceptible

160

90.0

48.8

26.3

Piperacillin-tazobactam-nonsusceptible

219

89.5

50.2

Imipenem-nonsusceptible

193

85.0

0

MDR

204

87.3

42.2

74.1

66.1

98.6

76.1

100

21.3

12.0

10.0

94.7

42.7

100

0

7.5

10.0

95.6

48.1

100

39.7

32.4

0

10.1

95.9

51.1

100

55.4

57.5

43.5

37.3

94.8

50.3

100

31.4

27.0

8.3

5.4

94.6

40.7

100

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81.1

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P. aeruginosa

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Ceftazidime-nonsusceptible

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Only data for the three most prevalent species of Enterobacteriaceae are shown because of small numbers of resistant isolates for other species of NPE. b The KPC-positive subset of isolates is only shown for species with ≥10 KPC-positive isolates. c Percent susceptible values of ≥90% are shown in bold font.

21

Table 3. Acquired β-lactamases detected in imipenem-relebactam-nonsusceptible NPE and P. aeruginosa isolates from intraabdominal and urinary tract infections combined.a

All NPE (33)b

2

OXA232+ESBL 4

E. coli (1)

0

K. aerogenes (2)

Species (n)

KPC±ESBL

NDM-5+AmpC VIM-1+ESBL GES-19+GES-20

None detected

1

0

25

0

1

0

0

0

0

0

0

0

0

2

K. pneumoniae (9)

2

4

0

1

0

2

S. liquefaciens (2)

0

0

0

0

0

2

S. marcescens (18)

0

0

0

0

0

18

S. ureilytica (1)

0

0

0

0

0

1

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1

P. aeruginosa (29) 0 0 0 3 1 25 Original spectrum β-lactamases (e.g., TEM-1, SHV-1) and intrinsic AmpC β-lactamases common to K. aerogenes, Serratia spp., and P. aeruginosa are not shown. b One additional imipenem-relebactam-nonsusceptible E. cloacae isolate was not molecularly characterized.

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a

22