Accepted Manuscript

In vitro activity of meropenem-vaborbactam and characterization of

carbapenem resistance mechanisms among carbapenem-resistant
Enterobacteriaceae from the 2015 meropenem-vaborbactam
surveillance program

Michael A. Pfaller , Michael D. Huband , Rodrigo E. Mendes ,

Robert K. Flamm , Mariana Castanheira

PII: S0924-8579(18)30064-5
DOI: 10.1016/j.ijantimicag.2018.02.021
Reference: ANTAGE 5390

To appear in: International Journal of Antimicrobial Agents

Received date: 18 December 2017

Revised date: 16 February 2018
Accepted date: 24 February 2018

Please cite this article as: Michael A. Pfaller , Michael D. Huband , Rodrigo E. Mendes ,
Robert K. Flamm , Mariana Castanheira , In vitro activity of meropenem-vaborbactam and charac-
terization of carbapenem resistance mechanisms among carbapenem-resistant Enterobacteriaceae
from the 2015 meropenem-vaborbactam surveillance program, International Journal of Antimicrobial
Agents (2018), doi: 10.1016/j.ijantimicag.2018.02.021

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 ACCEPTED MANUSCRIPT

Highlights

 The dissemination of carbapenem-resistant Enterobacteriaceae isolates is a matter of great

concern among infectious disease professionals and microbiologists worldwide
 CRE isolates are often multidrug resistant and few, sometimes suboptimal, therapeutic agents
are effective against these isolates
 Meropenem-vaborbactam was recently approved by the US FDA and our data demonstrates the
activity of this combination against contemporary isolates
 Isolates tested include CRE that were characterized for the presence of carbapenemase genes

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 ACCEPTED MANUSCRIPT

In vitro activity of meropenem-vaborbactam and characterization of carbapenem resistance

mechanisms among carbapenem-resistant Enterobacteriaceae from the 2015 meropenem-

vaborbactam surveillance program

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a,b
Michael A. Pfaller

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a
Michael D. Huband

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a
Rodrigo E. Mendes
a
Robert K. Flamm
a*

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Mariana Castanheira
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a
JMI Laboratories, North Liberty, Iowa, USA
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b
University of Iowa, Iowa City, Iowa, USA
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*
Corresponding author: Mariana Castanheira, PhD

JMI Laboratories
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345 Beaver Kreek Center, Suite A

North Liberty, IA, 52317, USA

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Phone: 319-665-3370

Fax: 319-665-3371

mariana.castanheira@jmilabs.com
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Abstract

We evaluated meropenem-vaborbactam activity against 11,559 Enterobacteriaceae isolates, including

330 carbapenem-resistant phenotypes (CRE) and carbapenemase genotypes collected worldwide during

2015. Meropenem-vaborbactam (inhibitor at 8 mg/L) and comparators were susceptibility tested using

reference broth microdilution methods. CRE isolates were screened for the presence of genes encoding

carbapenemases and 292 (88.5%) of the CRE isolates carried these resistance genes. A total of 209

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(63.3% of the CRE; 1.8% of the overall Enterobacteriaceae population) isolates carried blaKPC, including

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genes encoding KPC-2 (90 isolates), KPC-3 (117), and KPC-17 (2). Overall, meropenem-vaborbactam

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(vaborbactam at 8 mg/L) inhibited 99.3% of all Enterobacteriaceae isolates at the FDA susceptibility

breakpoint of ≤4/8 mg/L. Meropenem alone inhibited 96.9% of the isolates at the current CLSI

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susceptibility breakpoint of ≤2 mg/L. Susceptibility rates for comparator antimicrobial agents tested

against Enterobacteriaceae isolates ranged from 82.1% to 98.2% applying the CLSI breakpoints. Against
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CRE isolates, meropenem-vaborbactam displayed MIC50/90 values at 0.5/32 mg/L, whereas meropenem

MIC50/90 values were 16/>32 mg/L. Meropenem-vaborbactam was very active against KPC-producers,

and 99.5% of isolates were inhibited by ≤4/8 mg/L. The single resistant isolate was shown to harbour a
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porin protein alteration. Meropenem-vaborbactam had limited activity against MBL-producing isolates that

included 49 NDM, 1 IMP-64, and 2 VIM-producers) and/or oxacillinases (47 OXA-48/-232) that were
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detected mainly in European countries. Meropenem-vaborbactam was active against contemporary CRE

and wild-type Enterobacteriaceae collected worldwide, and this combination demonstrated enhanced
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activity when compared to meropenem and most comparator agents against CRE and KPC-producers.
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Keywords: meropenem-vaborbactam, CRE, KPC-producers, metallo-beta-lactamases, susceptibility

testing, carbapenemases
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1 Introduction

Carbapenem-resistant Enterobacteriaceae (CRE) isolates have been detected worldwide, and their

elevated prevalence is mainly due to the dissemination of isolates producing carbapenemases, such as

Klebsiella pneumoniae carbapenemase (KPC) and metallo-β-lactamases (MBL), and oxacillinases [1-4].

MBL-encoding genes include those of the IMP, NDM, and VIM gene families. Infections due to

carbapenemase-producing Enterobacteriaceae (CPE) have become a serious concern among infectious

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disease and clinical microbiology professionals worldwide because these infections are difficult to

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manage [2, 5-9]. CPE isolates are resistant to all or almost all β-lactam agents, and these organisms are

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usually resistant to other antimicrobial classes, limiting the therapeutic options [2, 5-9].

Combining β-lactamase inhibitors with a broad-spectrum β-lactam agent has been a successful strategy

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for overcoming β-lactamase-mediated resistance; however, older-generation inhibitors such as

tazobactam, sulbactam, and clavulanate are generally not active against various contemporary β-
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lactamases, including KPC serine-carbapenemases [7-10]. The increasing prevalence of multidrug-

resistant (MDR) organisms producing KPC enzymes and other β-lactamases that are poorly inhibited by

clinically available inhibitors suggests the need for new treatment alternatives [6, 7].
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Vaborbactam (formerly RPX7009) is a cyclic boronic acid β-lactamase inhibitor that has activity against

Ambler class A and C enzymes, including KPC [11]. This inhibitor has been paired with meropenem, and
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the combination (meropenem plus vaborbactam at a fixed 8 mg/L) was recently approved (August 2017)

by the US Food and Drug Administration (FDA) for the treatment of adults with complicated urinary tract
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infections (cUTI), including pyelonephritis (The Medicines Company, 2017).

Vaborbactam has been shown to possess pharmacokinetics (PK) similar to that of meropenem. The
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PK/PD (pharmacodynamic) parameters that correlate with efficacy include time above the MIC for

meropenem and overall exposure (measured by the area under the curve [AUC]) for vaborbactam.
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Meropenem-vaborbactam has shown activity in an in vitro hollow-fiber model that simulated human

exposure [12]. The data generated support the use of meropenem-vaborbactam (4 g [2 g meropenem/2 g

vaborbactam] every 8 hours with a 3-hour infusion time) for the treatment of infections caused by KPC-

positive CRE isolates with meropenem MIC values as high as 8 mg/L [12]. These findings are supported

by data from 2 phase 3 clinical trials for cUTI in which a high level of target attainment for meropenem
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was achieved for all patients with a regimen of 2 g meropenem and 2 g vaborbactam given every 8 hours

[13].

In the present study, we evaluated the in vitro activity of the meropenem-vaborbactam combination and

comparator antimicrobial agents against a worldwide collection of 11,559 clinical Enterobacteriaceae

isolates from the 2015 meropenem-vaborbactam surveillance program. We also characterized

carbapenem resistance mechanisms for 330 CRE isolates from this global surveillance program and

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assessed the in vitro activity of meropenem-vaborbactam and comparators according to the resistance

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phenotypes and carbapenemase genotypes.

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2 Materials and Methods

2.1 Bacterial isolates

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A total of 11,559 clinical Enterobacteriaceae isolates were collected during 2015 from 86 medical

institutions located in 30 countries on 5 continents and grouped into 4 geographic regions: Asia-Pacific (681
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isolates; 5.9% overall), Europe (5,278; 45.7%), Latin America (561; 4.9%), and North America (5,039;

43.6%). Limited data suggests that the addition of vaborbactam does not improve the activity of meropenem

against Acinetobacter baumannii, Pseudomonas aeruginosa, or Stenotrophomonas maltophilia and these

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species are not included in this analysis. Isolates were consecutively collected in a prevalence design from

the following infection sources: bloodstream infection (BSI; 3,678; 31.8%), pneumonia in hospitalized
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patients (2,501; 21.6%), skin and skin structure infection (SSSI; 2,016; 17.5%), UTI (2,368; 20.5%), intra-

abdominal infection (IAI; 918; 7.9%), and other less prevalent or undetermined clinical specimen types (78;
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0.7%). Species identification was confirmed, when necessary, by matrix-assisted laser desorption

ionization-time of flight mass spectrometry using the Bruker Daltonics MALDI Biotyper (Billerica,
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Massachusetts, USA), per manufacturer instructions.

2.2 Antimicrobial susceptibility testing

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All isolates were susceptibility tested using the reference broth microdilution method as described by the

Clinical and Laboratory Standards Institute (CLSI) [14] . Meropenem was combined with vaborbactam

and tested at a fixed concentration of 8 mg/L. The susceptibility interpretive criteria for meropenem-

vaborbactam was the criteria proposed by the FDA (The Medicines Company, 2017): susceptible (S),

≤4/8 (meropenem/vaborbactam) mg/L; intermediate (I), 8/8 mg/L; resistant (R), >16/8 mg/L. Categorical
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interpretations for all comparator agents were those found in CLSI document M100-S26 [15], the

European Committee on Antimicrobial Susceptibility Testing (EUCAST) website [16], or FDA package

inserts. Quality control (QC) was performed using Escherichia coli ATCC 25922 and 35218, Klebsiella

pneumoniae ATCC 700603 and BAA-1705, and Pseudomonas aeruginosa ATCC 27853 reference

strains. All QC MIC results were within acceptable ranges as published in CLSI documents [15].

2.3 Definitions of resistance phenotypes and MIC-based screening criteria

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Carbapenem-resistant Enterobacteriaceae isolates were defined as isolates exhibiting an imipenem

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and/or meropenem MIC value at ≥4 mg/L.

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Extended-spectrum β-lactamase screen-positive phenotype (ESBL SP) was defined as an MIC of ≥2

mg/L for ceftriaxone, ceftazidime, and/or aztreonam (CLSI, 2016) for E. coli, Klebsiella spp., and P.

mirabilis. This group also included CRE isolates.

2.4 Carbapenemase screening US

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Among the 11,559 Enterobacteriaceae isolates tested, 330 were CREs and were screened for the

presence of carbapenemase-encoding genes by PCR followed by DNA sequencing of blaKPC, blaIMP,

blaVIM, blaNDM, blaOXA-48, blaGES (blaGES-2, -4, -5, -6 and -8), blaNMC-A, blaSME, and blaIMI amplicons as previously
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described [1]. Isolates were categorized as MBL based on positive screening for any of the following

genes: IMP-64, NDM-1, NDM-9, VIM-1, and VIM-5. Isolates were categorized as KPC based on a positive
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screening for any KPC genes. A third type of carbapenamases, oxacillinases, were identified by a positive

screening for OXA48 and OXA232.

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Isolates yielding negative results for these genes were tested for less common carbapenemases,

including genes encoding FRI-1, BKC-1, GIM-1/-2, SIM-1, SPM-1, KHM-1, AIM-1, BIC-1, and DIM-1.
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3 Results

3.1 Activity of meropenem-vaborbactam and comparators tested against overall isolates

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Overall, meropenem-vaborbactam (Table 1) inhibited 99.3% of all Enterobacteriaceae isolates at the FDA

susceptible breakpoint of ≤4/8 mg/L. Meropenem alone inhibited 96.9% of the isolates at the current CLSI

susceptibility breakpoint of ≤2 mg/L. Susceptibility rates for comparator antimicrobial agents tested against

Enterobacteriaceae isolates ranged from 82.1% to 98.2% applying the CLSI breakpoints (Table 1). The

lowest susceptibility rates were noted for colistin and the highest rates were for tigecycline.
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Meropenem-vaborbactam inhibited all but 8 E. coli isolates (4,913/4,921; 99.8%) at ≤4/8 mg/L (Table 1).

These 8 isolates displayed meropenem-vaborbactam MIC values of 8/8 mg/L to >32/8 mg/L and

originated from Houston, Texas (2 isolates from the same site); Ankara, Turkey (1 isolate); Smolensk,

Russia (4 isolates from the same site); and Bangkok, Thailand (1 isolate). All 8 isolates expressed a CRE

phenotype that carried blaNDM and/or blaOXA-48: 2 isolates (both from Texas) also harboured an altered

outer membrane porin protein. Selected comparator agents displayed activity against E. coli isolates, and

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meropenem (99.8% susceptible), amikacin (99.6%), colistin (99.7%), and tigecycline (>99.9%) inhibited

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>90% of the isolates per their respective breakpoints (Table 1).

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Against 976 ESBL SP phenotype E. coli isolates (Table 1), meropenem-vaborbactam inhibited 99.2% and

meropenem alone inhibited 98.8% of isolates at ≤4/8 and ≤1 mg/L, respectively. The most active

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comparators tested against ESBL SP phenotype E. coli isolates, according to their respective breakpoint

criteria, were amikacin (98.2% susceptible), colistin (99.4% susceptible), and tigecycline (99.9%
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susceptible) (Table 1).

A total of 97.0% of the K. pneumoniae isolates (n=2,458) were inhibited by meropenem-vaborbactam at

≤4/8 mg/L. Meropenem inhibited 88.3% of these isolates at the CLSI breakpoint. Other comparator
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agents inhibiting >90.0% of isolates at current breakpoints were limited to amikacin (93.4% susceptible

[CLSI]), tigecycline (99.1% [FDA]), and colistin (94.1% [EUCAST]; Table 1).
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A total of 843 ESBL SP phenotype K. pneumoniae were tested. Of these, 65.8% were susceptible to

meropenem (Table 1), whereas 91.2% were susceptible to the combination of meropenem-vaborbactam.
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Other comparator agents inhibiting >90.0% of isolates at current breakpoints were limited to tigecycline

(98.6% susceptible [FDA])

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The activity of meropenem-vaborbactam was elevated against other Enterobacteriaceae species, and this

combination at ≤4/8 mg/L inhibited 100.0% of Klebsiella oxytoca, Enterobacter aerogenes, other
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Enterobacter spp., Citrobacter spp., and indole-positive Proteus; 99.9% of Proteus mirabilis; and 99.8% of

Enterobacter cloacae and Serratia marcescens.

3.2 Meropenem-vaborbactam tested against CRE

Among the 330 CRE isolates identified as part of the 2015 surveillance program for meropenem-

vaborbactam were 178 from Europe (3.4% of isolates of this region), 96 (1.9%) from North America, 47
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(8.4%) from Latin America, and 9 (1.3%) from Asia-Pacific countries (Table 2). These isolates were mostly

K. pneumoniae (266/330; 80.6%), but also Enterobacter cloacae (29), Serratia marcescens (12), E. coli

(11), Enterobacter aerogenes (4), K. oxytoca (3), Proteus mirabilis (2), and 1 each of Enterobacter

(Pluralibacter) gergoviae, Klebsiella variicola, and Raoultella spp. (Table 2).

The CRE isolates included 292 (88.5% of the CRE) that carried carbapenemase genes. A total of 209

(63.3% of the CRE; 1.8% of the overall Enterobacteriaceae population) isolates carried blaKPC, including

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genes encoding KPC-2 (90 isolates), KPC-3 (117), and KPC-17 (2) (Table 2). KPC-producing isolates

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were detected in North America (87 isolates; 1 also carrying blaNDM-1), Europe (89 isolates; 8 countries),

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Latin America (32 isolates; 1 also carrying blaNDM-1; 3 countries), and 1 isolate from the Asia-Pacific region

(Table 2). Two K. pneumoniae isolates carrying blaKPC also carried blaNDM-1: a KPC-17-producing isolate

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from Houston, Texas, and a KPC-2-producing isolate from Brazil. The latter 2 isolates were analysed with

the MBL-producing isolates.

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Genes encoding MBLs were detected among 52 CRE isolates, and the gene encoding NDM-1 was the

most common (48 isolates). One isolate carrying blaVIM-1 (Greece), 1 harbouring blaVIM-5 (Turkey), and 1

harbouring blaimp-64 (Colorado, USA) were also noted (Table 2). MBL-producing isolates belonged to the
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following bacterial species: K. pneumoniae (43), E. coli (6), E. cloacae (1), P. mirabilis (1), and S.

marcescens (1) and were collected in hospitals located in Europe (28 isolates), Latin America (15), Asia-
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Pacific (5), and North America (4).

OXA-48-like genes were detected among 47 isolates, including 7 isolates carrying blaOXA-232. OXA-48
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positive isolates were mainly detected in K. pneumoniae (44/47) and in 9 European countries (42/47;

Table 2), most commonly in Turkey (23 isolates). The remaining 5 were blaOXA-232-carrying K. pneumoniae
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isolates observed in Thailand. Ten isolates (6 carrying blaOXA-232 and 4 carrying blaOXA-48) also harboured

the gene encoding NDM-1, and these isolates were analysed with the remaining MBL-producing isolates.
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The 330 CRE isolates were from the following infection sources: BSI (104 isolates [31.5%]), IAI (26

[7.9%]), pneumonia in hospitalized patients (111 [33.6%]), SSSI (48 [14.5%]), UTI (39 [11.8%]), and

unknown other sites of infection (2 [0.6%]) (Table 2).

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The comparative activity of meropenem-vaborbactam and meropenem against CPE isolates is

summarized in Table 3. The activity of all comparator agents, meropenem alone, and meropenem-

vaborbactam against CRE is summarized in Table 4.

Meropenem-vaborbactam (MIC50/90, 0.25/1 mg/L [meropenem plus vaborbactam at a fixed 8 mg/L]; 99.5%

susceptible at the FDA breakpoint of ≤4/8 mg/L) was highly active against KPC-producing isolates that did

not carry MBLs, and only 1 isolate had an MIC value >4/8 mg/L. This isolate was a K. pneumoniae from

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Greece and displayed a meropenem-vaborbactam MIC value at 32/8 mg/L. This isolate was submitted to

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next generation sequencing and displayed no open reading frames displaying homology (>40%) to MBL

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genes. Sequencing analysis of the outer membrane proteins (OMP) identified a frame shift in OmpK35

that is likely to be incompatible with function, and the insertion of 134GD in the loop 3 of OmpK36.

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Notably, earlier studies of K. pneumoniae isolates from New York City found that decreased expression of

ompK36 reduced the effect of vaborbactam by 8- to 16-fold when compared to isolates with wild-type
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expression of ompK36 producing the same β-lactamases [17].

All β-lactam agents displayed limited activity against KPC-producing isolates and the most active agents

against these isolates were tigecycline (99.5% and 89.8% susceptible applying FDA and EUCAST
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breakpoints, respectively) and colistin (62.6% susceptible using EUCAST breakpoint; 4).

CRE isolates not carrying KPC-encoding genes displayed elevated MIC values for meropenem-
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vaborbactam (MIC50/90, 16/>32 mg/L [meropenem plus vaborbactam at a fixed 8 mg/L]; 31.4% susceptible

at <4/8 mg/L [FDA]), most β-lactams (susceptibility ranges were 0.8% to 9.9%), and other antimicrobial
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classes. The antimicrobial agents displaying greatest activity against these isolates were tigecycline

(98.3/87.6% susceptible [CLSI/EUCAST]), colistin (70.0% susceptible [EUCAST]), and amikacin

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(61.2/49.6% [CLSI/EUCAST]; Table 4).

The activity of meropenem-vaborbactam against isolates harbouring blaOXA-48-like without an MBL

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(MIC50/90, 16/32 mg/L [meropenem plus vaborbactam at a fixed 8 mg/L]; 24.3% susceptible [FDA]) or only

MBL-encoding genes (MIC50/90, 32/>32 mg/L [meropenem plus vaborbactam at a fixed 8 mg/L]; 3.8%

susceptible [FDA]) was similar to that of meropenem (MIC50/90, 16/32 mg/L; 2.7/5.4% susceptible

[CLSI/EUCAST] and MIC50/90, 32/>32 mg/L; 0.0/0.0% susceptible [CLSI/EUCAST], respectively).

Importantly, the percentage of susceptible isolates for the combination meropenem-vaborbactam was
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higher given the higher breakpoint recently approved (Table 4). These isolates displayed low

susceptibility rates against most comparator agents.

A total of 38 isolates yielded negative results for the carbapenemase-encoding genes tested, including

less frequent genes. These isolates were mainly K. pneumoniae from Europe (29/38; 76.3%; Table 2).

Meropenem-vaborbactam (81.6% susceptible [FDA]) was more active when compared to meropenem

alone (2.6/10.5% susceptible [CLSI/EUCAST]) against these isolates (Tables 4 and 5), which were also

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resistant to most comparator agents tested (Table 4).

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4 Conclusions

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The mainstays of CRE therapy have traditionally been agents from either the polymyxin (colistin or

polymyxin B) or aminoglycoside (amikacin, tobramycin, gentamicin) classes [5, 9]. Unfortunately, using

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these agents has been complicated by efficacy, pharmacokinetics, and toxicity issues [8]. Recently, the

combination of meropenem with a novel inhibitor of KPC serine carbapenemases, vaborbactam, was
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approved for treating cUTI, including pyelonephritis (The Medicines Company, 2017).

Our study results expand on results previously reported concerning the in vitro activity of meropenem-

vaborbactam against a global collection of CRE [18]. Meropenem-vaborbactam was the most active of
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the tested β-lactam agents against Enterobacteriaceae, with greatest activity against those strains

expressing KPC-like enzymes.

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Isolates producing KPC-like enzymes (1.8% of the overall Enterobacteriaceae population) continued to be

very prevalent among CRE isolates (63.3%), and genes encoding these enzymes represented the most
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common carbapenemases detected worldwide and in the various countries surveyed, including the

United States, Brazil, Italy, Poland, and Argentina (Table 2). Among the CRE isolates from the different
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infection sites, KPC-like enzymes were most prominent in isolates causing pneumonia in hospitalized

patients and in UTIs.

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Meropenem-vaborbactam inhibited 99.5% of KPC-producing isolates that did not carry MBL-encoding

genes at ≤4/8 mg/L (FDA breakpoint for meropenem-vaborbactam). The single resistant strain was a K.

pneumoniae isolate harbouring an altered porin protein, providing support to the observations of Lapuebla

et al [17]. Increasingly, changes in the net penetration of carbapenems into the bacterial cell, mediated by
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alterations in the outer membrane porin proteins (eg, OmpK35, OmpK36), and in some instances coupled

with up-regulation of efflux pumps, have emerged as contributors to carbapenem resistance [8, 19].

As with other β-lactamase inhibitors clinically available or in late-development stages [8, 10],

vaborbactam does not inhibit MBL-producing isolates. Meropenem-vaborbactam displays limited activity

against isolates producing class D oxacillinases associated with resistance to carbapenems (Tables 3

and 4). KPC-producing strains were prominent among CRE isolates from UTI (69% of isolates) in the

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present study. Given the recent FDA approval for using meropenem-vaborbactam to treat cUTI, this

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combination might be an important addition to the armamentarium of against CRE caused infections.

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In summary, the meropenem-vaborbactam susceptibility testing data collected in 2015 from 86 medical

centers in 30 nations demonstrate sustained potency and spectrum against CRE isolates when compared

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to previous studies [17, 18, 20]. Specifically, these data suggest that meropenem-vaborbactam may be

an important treatment option for infections caused by wild-type, ESBL-, and KPC-producing strains of
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Enterobacteriaceae [7-10].
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Acknowledgements

We are grateful to L.M. Deshpande and A.P. Davis for performing the carbapenemase screening testing,

and to L.R. Duncan for his careful review of the manuscript.

Declarations

Funding: This study was performed by JMI Laboratories and supported by Rempex Pharmaceuticals

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Inc., a wholly owned subsidiary of The Medicines Company, which included funding for services related to

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preparing this manuscript.

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Competing Interests: JMI Laboratories contracted to perform services in 2017 for Achaogen, Allecra

Therapeutics, Allergan, Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas,

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Basilea Pharmaceutica, Bayer AG, BD, Becton, Dickinson and Co., Boston, CEM-102 Pharma, Cempra,

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

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

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

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

Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.
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Ethical Approval: Not required

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medicine" to antimicrobial chemotherapy? Expert Opin Pharmacother. 2016; 17: 761-781.

9. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of

infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017; 8: 403-416.

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10. Wong D, van Duin D. Novel beta-lactamase inhibitors: Unlocking their potential in therapy. Drugs.

2017; 77: 615-628.

11. Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, et al. Discovery of a cyclic

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12. Tarazi Z, Sabet M, Rubio-Aparicio D, Nolan T, Parkinson J, Lomovskaya O, et al. Efficacy of

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simulated human exposures of carbavance (Meropenem-RPX7009) against carbapenem-

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vaborbactam pharmacokinetic-pharmacodymanic analyses for efficacy based on data from

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tests for bacteria that grow aerobically; approved standard: ninth edition. Wayne, PA. CLSI, 2012

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resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae.

Antimicrob Agents Chemother. 2017; 61: e00567.

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19. Shin SY, Bae IK, Kim J, Jeong SH, Yong D, Kim JM, et al. Resistance to carbapenems in sequence

type 11 Klebsiella pneumoniae is related to DHA-1 and loss of OmpK35 and/or OmpK36. J Med

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Table 1 In vitro activity of meropenem-vaborbactam and comparators against Enterobacteriaceae clinical isolates from a 2015 global surveillance

program

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% susceptible a

Organism group (no. tested) Meropenem-vaborbactam Meropenem Cefepime Amikacin Gentamicin Tigecycline Colistin

Enterobacteriaceae (11,559)

CRE Enterobacteriaceae (330)

99.3%

73.9%
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96.9%

1.8%
83.9%

3.6%
98.1%

61.2%
87.1%

45.2%
98.2%

99.1%
82.1%

65.6%
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Escherichia coli (4,921) 99.8% 99.8% 83.9% 99.6% 86.1% >99.9% 99.7%

ESBL SP phenotype E. coli (976) 99.2% 98.8% 20.5% 98.2% 62.4% 99.9% 99.4%

Klebsiella pneumoniae (2,458) 97.0% 88.3% 68.7% 93.4% 80.0% 99.1% 94.1%
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ESBL SP phenotype K. pneumoniae (843) 91.2% 65.8% 8.7% 80.9% 45.1% 98.6% 85.2%

Klebsiella oxytoca (507) 100.0% 99.4% 94.9% 100.0% 97.4% 100.0% 99.4%
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ESBL SP phenotype K. oxytoca (62) 100.0% 95.2% 58.1% 100.0% 82.3% 100.0% 98.4%

Enterobacter cloacae species complex (1,050) 99.8% 97.2% 83.7% 98.3% 88.5% 99.2% 78.9%

Enterobacter aerogenes (313) 100.0% 98.4% 96.5% 99.7% 98.1% 99.7% 97.4%
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Other Enterobacter spp. (7) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 71.4%

Citrobacter koseri (219) 100.0% 100.0% 100.0% 100.0% 99.1% 100.0% 99.5%
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Citrobacter freundii species complex (280) 100.0% 100.0% 95.7% 99.6% 94.3% 100.0% 99.6%
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% susceptible a

Organism group (no. tested) Meropenem-vaborbactam Meropenem Cefepime Amikacin Gentamicin Tigecycline Colistin

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Other Citrobacter spp. (13) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Proteus mirabilis (701) 99.9% 99.7% 94.4% 98.9% 86.0% 78.5% 0.1%

ESBL SP phenotype P. mirabilis (74) 98.6% 98.6% 47.3% 90.5% 43.2% 55.4% 0.0%

Indole-positive Proteeae (420)

Morganella morganii (244)

100.0%

100.0%
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100.0%
97.6%

99.2%
99.5%

100.0%
89.8%

88.5%
96.0%

97.5%
1.2%

0.0%
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Proteus vulgaris group (80) 100.0% 100.0% 100.0% 100.0% 97.5% 98.8% 6.2%

Providencia rettgeri (47) 100.0% 100.0% 100.0% 100.0% 97.9% 95.7% 0.0%

Providencia stuartii (49) 100.0% 100.0% 83.7% 95.9% 75.5% 83.7% 0.0%
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Serratia marcescens (504) 99.8% 97.8% 96.0% 99.0% 98.2% 99.2% 4.6%

a % susceptible using CLSI M100-S26 criteria (FDA breakpoints used for M-V and tigecycline; EUCAST breakpoints used for colistin).
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Table 2 Carbapenemase enzyme screening results for 330 Enterobacteriaceae (CRE) isolates by species and region

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Grouping No. No. of positive carbapenemase results No. tested

tested negative

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IMP-64 NDM-1 NDM-9 VIM-1 VIM-5 OXA-232 OXA-48 KPC-17 KPC-2 KPC-3

Overall 330 1 48 1 1 1 7 40 2 90 117 38

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By organism

Enterobacter aerogenes 4 1 3

Enterobacter cloacae species 29 1 1 9 11 7

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complex

Escherichia coli 11 5 1 1 1 1 1 1
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Klebsiella oxytoca 3 1 2

Klebsiella pneumoniae 266 43 6 38 2 73 95 25

Klebsiella variicola 1 1
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Pluralibacter gergoviae 1 1

Proteus mirabilis 2 1 1
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Unspeciated Raoultella 1 1
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Serratia marcescens 12 1 5 5 1

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By continent/country

Asia-Pacific 9 5 5 1 2

Singapore 1 1

Thailand 8 5
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Europe 178 26 1 1 2 40 28 61 29

Belarus 9 7 1 3

Belgium 1 1
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France 1 1

Germany 2 2
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Greece 11 2 1 8

Israel 1 1

Italy 56 2 7 48 1
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Poland 34 11 7 16

Portugal 3 2 1
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Romania 3 3
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Russia 12 6 2 2 1 1

Slovenia 1 1 1

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Spain 6 4 1 2

Sweden 2 2

Turkey 36 10 1 1 22 1 5

Latin America 47 15
US 32 1
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Argentina 7 7

Brazil 24 1 24

Chile 1 1
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Mexico 15 14 1
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United States 96 1 2 1 2 29 56 6

By infection type
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Bloodstream infection 104 21 1 1 3 14 2 24 33 11

Intra-abdominal infection 26 1 7 9 9
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Other sites 2 1 1
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Pneumonia in hospitalized 111 1 13 3 12 29 50 9

patients

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Skin and skin structure 48 9 1 1 10 17 9 5

infection

Urinary tract infection 39 5 3 12 15 4

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Table 3 Antimicrobial activity of meropenem-vaborbactam and meropenem tested against the CRE isolates

No. of isolates at MIC (mg/L; cumulative %)

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Organism / organism group (no. of isolates) MIC50 MIC90
≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >

CRE

Meropenem-vaborbactam (330) a

Meropenem (330)
21

6.4
51

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21.8
16

26.7
12

30.3
37

41.5
36

52.4

0
34

62.7

6
23

69.7

15
14

73.9

48
9

76.7

44
22

83.3

62
32

93.0

48
23

100.0

107
0.5

16
32

>32
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0.0 1.8 6.4 20.9 34.2 53.0 67.6 100.0

Carbapenemase-producing Enterobacteriaceae (CPE)

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21 51 16 12 36 28 25 14 10 6 19 31 23
Meropenem-vaborbactam (292)a 0.5 32
7.2 24.7 30.1 34.2 46.6 56.2 64.7 69.5 72.9 75.0 81.5 92.1 100.0
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0 5 12 32 33 55 48 107
Meropenem (292) 32 >32
0.0 1.7 5.8 16.8 28.1 46.9 63.4 100.0
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KPC producers

21 51 16 12 36 28 23 12 6 0 0 1
Meropenem-vaborbactam (206) a 0.25 1
10.2 35.0 42.7 48.5 66.0 79.6 90.8 96.6 99.5 99.5 99.5 100.0
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Meropenem (206) 0 4 11 28 25 32 23 83 32 >32

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No. of isolates at MIC (mg/L; cumulative %)
Organism / organism group (no. of isolates) MIC50 MIC90
≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >

CR
0.0 1.9 7.3 20.9 33.0 48.5 59.7 100.0

Non-KPC producers

Meropenem-vaborbactam (121) a
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0.0
1

0.8
8

7.4

0
11

16.5

2
10

24.8

4
8

31.4

20
9

38.8

19
22

57.0

30
31

82.6

25
21

100.0

21
16 >32
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Meropenem (121) 16 >32
0.0 1.7 5.0 21.5 37.2 62.0 82.6 100.0

OXA-48-like producers
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0 1 1 1 2 1 3 4 11 12 1
Meropenem-vaborbactam (37) a 16 32
0.0 2.7 5.4 8.1 13.5 16.2 24.3 35.1 64.9 97.3 100.0
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0 1 1 3 5 16 9 2
Meropenem (37) 16 32
0.0 2.7 5.4 13.5 27.0 70.3 94.6 100.0
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MBL producers

0 1 1 2 8 18 22
Meropenem-vaborbactam (52) a 32 >32
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0.0 1.9 3.8 7.7 23.1 57.7 100.0

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No. of isolates at MIC (mg/L; cumulative %)
Organism / organism group (no. of isolates) MIC50 MIC90
≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >

CR
0 1 3 8 16 24
Meropenem (52) 32 >32
0.0 1.9 7.7 23.1 53.8 100.0

Carbapenemase negative

Meropenem-vaborbactam (38)a
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2 16
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0.0 2.6 23.7 47.4 71.1 81.6 89.5 97.4 100.0

0 1 3 16 11 7
Meropenem (38) 4 16
0.0 2.6 10.5 52.6 81.6 100.0

a All results reflect the MIC value for meropenem with vaborbactam at a fixed 8 mg/L.
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Table 4 Activity of meropenem-vaborbactam and comparator agents when tested against CRE isolates

Organism (no. tested) MIC (mg/L) %S / %I / %R

Range
antimicrobial agent 50% 90% CLSIa EUCASTa

CRE (330)

Meropenem-vaborbactamb 0.5 32 ≤0.015 – >32 73.9 / 2.7 / 23.3c

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Meropenem 16 >32 1 – >32 1.8 / 4.5 / 93.6 6.4 / 27.9 / 65.8

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Minocycline 4 >8 0.25 – >8 64.5 / 17.0 / 18.5

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Tigecycline 0.5 2 0.12 – 4 99.1 / 0.9 / 0.0d 88.8 / 10.3 / 0.9

Amikacin 16 >32 0.5 – >32 61.2 / 17.3 / 21.5 47.9 / 13.3 / 38.8

Colistin

Gentamicin
0.25

8
>8

>8
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≤0.06 – >8

0.12 – >8 45.2 / 7.6 / 47.3

65.6 / / 34.4

42.1 / 3.0 / 54.8

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Levofloxacin >4 >4 ≤0.03 – >4 14.8 / 3.6 / 81.5 8.5 / 2.7 / 88.8

Carbapenemase-producing Enterobacteriaceae (CPE) (292)

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Meropenem-vaborbactamb 0.5 32 ≤0.015 – >32 72.9 / 2.1 / 25.0c

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Meropenem 32 >32 1 – >32 1.7 / 4.1 / 94.2 5.8 / 22.3 / 71.9

Minocycline 4 >8 0.25 – >8 64.0 / 18.2 / 17.8

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Tigecycline 0.5 2 0.12 – 4 99.3 / 0.7 / 0.0d 89.4 / 9.9 / 0.7

Amikacin 16 >32 0.5 – >32 57.5 / 19.2 / 23.3 44.2 / 13.4 / 42.5
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Colistin 0.25 >8 ≤0.06 – >8 64.2 / / 35.8

Gentamicin 8 >8 0.12 – >8 44.9 / 8.6 / 46.6 41.4 / 3.4 / 55.1
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Levofloxacin >4 >4 ≤0.03 – >4 12.7 / 3.4 / 83.9 6.2 / 2.4 / 91.4

KPC producers (206)

Meropenem-vaborbactamb 0.25 1 ≤0.015 – 32 99.5 / 0.0 / 0.5c

Meropenem 32 >32 1 – >32 1.9/5.3/92.7 7.3/25.7/67.0

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Organism (no. tested) MIC (mg/L) %S / %I / %R

Range
antimicrobial agent 50% 90% CLSIa EUCASTa

Minocycline 4 8 0.5 – >8 76.7 / 14.1 / 9.2

Tigecycline 0.5 2 0.12 – 4 99.5 / 0.5 / 0.0d 89.8/9.7/0.5

Amikacin 16 >32 0.5 – >32 61.7/26.2/11.7 47.1/14.6/38.3

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Gentamicin 2 >8 0.12 – >8 56.8/11.7/31.6 52.4/4.4/43.2

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Levofloxacin >4 >4 ≤0.03 – >4 12.6/1.9/85.4 4.9/2.9/92.2

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Non-KPC producers (121)

Meropenem-vaborbactamb 16 >32 0.25 – >32 31.4 / 7.4 / 61.2c

Meropenem

Minocycline
16

8
>32

>8
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1 – >32

0.25 – >8
1.7 / 3.3 / 95.0

43.8 / 22.3 / 33.9

5.0 / 32.2 / 62.8
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Tigecycline 0.5 2 0.12 – 4 98.3 / 1.7 / 0.0d 87.6 / 10.7 / 1.7

Amikacin 16 >32 1 – >32 61.2 / 0.8 / 38.0 49.6 / 11.6 / 38.8

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Colistin 0.12 >8 ≤0.06 – >8 70.0 / / 30.0

Gentamicin >8 >8 0.12 – >8 26.4 / 0.8 / 72.7 25.6 / 0.8 / 73.6
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Levofloxacin >4 >4 ≤0.03 – >4 18.2 / 6.6 / 75.2 14.0 / 2.5 / 83.5

OXA-48-like producers (37)

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Meropenem-vaborbactamb 16 32 0.12 – >32 24.3/10.8 / 64.9c

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Meropenem 16 32 1 – >32 2.7 / 2.7 / 94.6 5.4 / 21.6 / 73.0

Minocycline >8 >8 0.25 – >8 29.7/16.2/54.1

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Tetracycline >16 >16 1 – >16 24.3/5.4/70.3

Tigecycline 0.5 1 0.12 – 1 100.0 / 0.0 / 0.0d 100.0 / 0.0 / 0.0

Amikacin 4 >32 1 – >32 86.5 / 0.0 / 13.5 78.4 / 8.1 / 13.5

Colistin 8 >8 0.12 – >8 45.9 / / 54.1

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Organism (no. tested) MIC (mg/L) %S / %I / %R

Range
antimicrobial agent 50% 90% CLSIa EUCASTa

Gentamicin >8 >8 0.25 – >8 16.2/2.7 / 81.1 10.8/5.4/83.8

Levofloxacin >4 >4 0.06 – >4 10.8/8.1/81.1 5.4/2.7/91.9

MBL producers (52)

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Meropenem-vaborbactamb 32 >32 2 – >32 3.8/3.8 / 92.3c

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Meropenem 32 >32 4 – >32 0.0 / 0.0 / 100.0 0.0 / 7.7 / 92.3

CR
Minocycline 8 >8 1 – >8 40.4/34.6/25.0

Tetracycline >16 >16 1 – >16 23.1/3.8/73.1

Tigecycline

Amikacin
0.5

>32
2

>32
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0.12 – 4

1 – >32
98.1/1.9 / 0.0d

21.2/1.9/76.9
80.8/17.3/1.9

9.6/11.5/78.8
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Colistin 0.12 >8 0.12 – >8 82.4 / / 17.6

Gentamicin >8 >8 0.12 – >8 19.2/0.0/80.8 19.2/0.0/80.8

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Levofloxacin >4 >4 0.06 – >4 13.5/5.8/80.8 11.5/0.0/88.5

Carbapenemase negative (38)

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Meropenem-vaborbactamb 2 16 0.25 – 32 81.6 / 7.9 / 10.5c

Meropenem 4 16 1 – 16 2.6 / 7.9 / 89.5 10.5 / 71.1 / 18.4

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Minocycline 4 >8 0.5 – >8 68.4 / 7.9 / 23.7

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Tigecycline 0.5 2 0.12 – 4 97.4 / 2.6 / 0.0d 84.2 / 13.2 / 2.6

Amikacin 4 32 1 – >32 89.5 / 2.6 / 7.9 76.3 / 13.2 / 10.5

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Colistin 0.12 >8 ≤0.06 – >8 76.3 / / 23.7

Gentamicin >8 >8 0.25 – >8 47.4 / 0.0 / 52.6 47.4 / 0.0 / 52.6

Levofloxacin >4 >4 ≤0.03 – >4 31.6 / 5.3 / 63.2 26.3 / 5.3 / 68.4

a Criteria as published by CLSI (2017) and EUCAST (2017).

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b All results reflect the MIC value for meropenem with vaborbactam at a fixed 8 mg/L.

c Breakpoints from FDA Package Insert.

d Breakpoints from FDA Package Insert revised 12/2014.

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