J Antimicrob Chemother

doi:10.1093/jac/dky266

In vitro activity of ceftazidime/avibactam against isolates of

Enterobacteriaceae collected in European countries: INFORM global
surveillance 2012–15
Krystyna M. Kazmierczak1*, Boudewijn L. M. de Jonge2†, Gregory G. Stone2‡ and Daniel F. Sahm1

1
International Health Management Associates, Inc., Schaumburg, IL, USA; 2AstraZeneca Pharmaceuticals, Waltham, MA, USA

*Corresponding author. Tel: !1-847-303-5003; Fax: !1-847-303-5601; E-mail: kkazmierczak@ihmainc.com

†Present address: Pfizer, Cambridge, MA, USA.
‡Present address: Pfizer, Groton, CT, USA.

Received 5 November 2017; returned 2 March 2018; revised 1 June 2018; accepted 13 June 2018

Objectives: The activity of ceftazidime/avibactam was assessed against 24 750 isolates of Enterobacteriaceae
collected from 96 medical centres in 18 European countries as part of the International Network for Optimal
Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed
against subsets of isolates based on resistant phenotypes and b-lactamase content.
Methods: Antimicrobial susceptibility testing was performed using broth microdilution and the presence of
b-lactamase genes in isolates of interest was determined using PCR and sequencing.
Results: Ceftazidime/avibactam was the most active agent, compared with all other tested comparator agents,
against the overall collection of Enterobacteriaceae isolates (99.4% susceptible) and against subsets of
ceftazidime-non-susceptible (97.7% susceptible), colistin-resistant (98.2% susceptible), MDR (96.7% susceptible)
and meropenem-non-susceptible, MBL-negative (98.5% susceptible) isolates. At the country level, susceptibility
to ceftazidime/avibactam ranged from 96.3% to 100% among Enterobacteriaceae isolates, with decreased sus-
ceptibilities only observed in countries where MBLs were more frequently encountered (e.g. Greece and
Romania). Ceftazidime/avibactam was active against 99.7% of Enterobacteriaceae isolates that carried serine
b-lactamases, including ESBLs, AmpC cephalosporinases and carbapenemases (KPC, GES and OXA-48-like) in all
combinations. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs.
Conclusions: The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of
Enterobacteriaceae collected in European countries, including isolates that exhibit resistance to ceftazidime,
meropenem and colistin and combined resistance to agents from multiple drug classes.

Introduction K. pneumoniae.3 Future outbreaks of XDR and pandrug-resistant

Antimicrobial resistance is a growing problem in Europe and
around the globe. The European Antimicrobial Resistance
Surveillance Network (EARS-Net) reported that the percentages of
invasive Escherichia coli and Klebsiella pneumoniae isolates resist-
ant to third-generation cephalosporins, those additionally resist-
ant to fluoroquinolones and aminoglycosides, and K. pneumoniae
resistant to carbapenems increased significantly between 2012
and 2015.1 The European Survey of Carbapenemase-Producing
Enterobacteriaceae documented an increase in carbapenemase-
producing Enterobacteriaceae between 2013 and 2015 and a wor-
sening epidemiological situation in several countries.2 Use of the
last-line antimicrobials colistin and fosfomycin to treat infections
caused by carbapenemase-producing Enterobacteriaceae
has selected for resistance among carbapenemase-positive
Enterobacteriaceae in Europe are considered likely.2
Avibactam is a non-b-lactam b-lactamase inhibitor with in vitro
activity against Ambler class A, class C and some class D
b-lactamases.4,5 The combination of ceftazidime with avibactam
has demonstrated potent in vitro activity against serine
b-lactamase-producing Enterobacteriaceae that do not
harbour class B MBLs, including ESBL-positive, AmpC-positive,
carbapenemase-positive and carbapenemase-negative carbape-
nem-non-susceptible isolates with altered outer membrane per-
meability, as well as colistin-resistant carbapenemase-producing
Enterobacteriaceae.6–11 Reduced susceptibility to ceftazidime/avi-
bactam is predominantly conferred by MBL production4 or se-
quence alterations in target proteins.12–16 Additional resistance
mechanisms also play a role in some cases.17,18 Ceftazidime/avi-
bactam was recently approved in the EU for the treatment of adult

C The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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 Kazmierczak et al.
patients with complicated intra-abdominal or complicated urinary
tract infections, hospital-acquired pneumonia and infections
caused by aerobic Gram-negative bacteria in patients with limited
treatment options.19 This study reports the activity of ceftazidime/
avibactam and comparator agents against Enterobacteriaceae
collected in 18 European countries as part of the International
Network for Optimal Resistance Monitoring (INFORM) global sur-
veillance programme from 2012 to 2015.
Materials and methods
Isolate collection, antimicrobial susceptibility testing and screening for
b-lactamase genes are described in the Supplementary data (available as
Supplementary data at JAC Online).
Results
Of the 24 750 Enterobacteriaceae isolates collected, 99.4%
were susceptible to ceftazidime/avibactam (MICs 8 mg/L;
MIC90 " 0.5 mg/L), compared with susceptibility of 92.1%–97.2%
for carbapenems and amikacin and ,84% for other tested agents
including ceftazidime (Table 1). Ceftazidime/avibactam MIC90 val-
ues against individual species and species groups of
Enterobacteriaceae were 0.12–1 mg/L, with 98.6%–99.9% of the
isolates being susceptible (Table 1). The in vitro activity of ceftazi-
dime/avibactam was increased against isolates that did not carry
MBLs, with 99.9% testing as susceptible and the susceptibility of in-
dividual species increasing to 99.8%–100% (Table 1 and Table S1).
As expected, ceftazidime/avibactam was not active against MBL-
positive Enterobacteriaceae (MIC90 .128 mg/L; 9.2% susceptible),
with only colistin retaining good activity against these isolates
(MIC90 " 2 mg/L; 90.3% susceptible) (Table 1). Percentages of sus-
ceptibility to ceftazidime/avibactam ranged from 99.2% to 100%
(MIC90 " 0.25–0.5 mg/L) among all countries surveyed except
Romania (96.3% susceptible, MIC90 " 1 mg/L) and Greece (96.4%
susceptible, MIC90 " 1 mg/L) (Figure 1 and Tables S2 to S19). For
these two countries, susceptibility increased to 99.9% and 99.7%,
respectively, when MBL-positive isolates were excluded (Tables S8
and S14).
The distribution of b-lactamases among molecularly character-
ized isolates from each country is described in Tables S20 to S37.
CTX-M-type ESBLs predominated in all countries except Greece,
with CTX-M-15 composing 50% or greater of the detected ESBLs,
while SHV-type ESBLs predominated in Greece. TEM-, VEB-, PER-
and GES-type ESBLs were rare (Figure S1). The prevalence of AmpC
cephalosporinases varied by country, with CMY- and DHA-type
enzymes found most frequently (Figure S2). The prevalence of car-
bapenemases also varied, with OXA-48-like, KPC-type, VIM-type,
NDM-type and GES-type carbapenemases detected in 12, 10, 9, 7
and 2 countries, respectively (Figure S3). The highest percentages
of MBL-positive isolates were identified among Enterobacteriaceae
collected in Greece (3.5%) and Romania (3.6%), whereas MBL-
positive isolates represented ,1.0% of isolates collected in other
countries (Tables S2 to S19). No carbapenemases were detected in
isolates from Sweden or the Netherlands and no isolates carrying
IMP-type MBLs were detected in any country. Ceftazidime/avibac-
tam was very active against the majority of carbapenemase-
negative isolates, with 98.3%–100% of isolates carrying ESBLs,
AmpCs, broad-spectrum or inhibitor-resistant SHV- and TEM-type
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enzymes and combinations thereof testing as susceptible (MIC90
values ranging from 0.5 to 2 mg/L) (Table S38). Ceftazidime/avi-
bactam demonstrated good activity against isolates carrying KPC
(MIC90 " 4 mg/L; 98.9% susceptible; 1.5% of collected isolates),
GES (MICs 0.5–1 mg/L; 100% susceptible; 0.02% of collected iso-
lates) and OXA-48-like (MIC90 " 2 mg/L; 99.2% susceptible; 1.1%
of collected isolates) carbapenemases. Ceftazidime/avibactam
displayed no activity against MBL-positive Enterobacteriaceae
(0.5% of collected isolates), with only 12 isolates presumed to pro-
duce the carbapenemase in low quantity, testing with MICs
8 mg/L (Table S38).
The in vitro activity of ceftazidime/avibactam and comparators
was assessed against Enterobacteriaceae isolates that were non-
susceptible to currently used antimicrobials, including ceftazidime-
non-susceptible (25.2% of collected isolates), meropenem-non-
susceptible (2.8% of collected isolates), colistin-resistant (1.3% of
collected isolates, excluding isolates of Proteeae and Serratia spp.)
and MDR (16.1% of collected isolates) subsets (Tables S39 to S42).
Overall, 97.7% of ceftazidime-non-susceptible isolates were sus-
ceptible to ceftazidime/avibactam, compared with 81.4%–89.1%
susceptibility to carbapenems, colistin and tigecycline (Table S39).
Across the region, the percentage of ceftazidime-non-susceptible
isolates ranged from 7.9% to 50.2% (Figure S4). Greater than 97%
of ceftazidime-non-susceptible isolates remained susceptible to
ceftazidime/avibactam for all countries except Greece (86.0% sus-
ceptible) and Romania (89.3% susceptible), where the activity of
ceftazidime/avibactam was increased by 12.8% and 10.3%, re-
spectively, against ceftazidime-non-susceptible MBL-negative iso-
lates (Tables S8 and S14).
Ceftazidime/avibactam displayed reduced activity (83.3% sus-
ceptible) against meropenem-non-susceptible Enterobacteria-
ceae that nevertheless exceeded the activity of other tested
comparators, including tigecycline and colistin (0.4%–74.1% sus-
ceptible) (Table S40). The MIC90 values of ceftazidime/avibactam
against all meropenem-non-susceptible isolates and isolates of in-
dividual species were 128 to .128 mg/L; however, MIC90 values
were decreased 16- to .64-fold against the corresponding MBL-
negative, meropenem-non-susceptible subsets, yielding suscepti-
bilities of 85.7%–100% depending on the species. The percentages
of meropenem-non-susceptible isolates ranged from 0% to 14.2%
among countries (Figure S5). Ceftazidime/avibactam displayed
good activity in countries where meropenem non-susceptibility
was primarily conferred by production of serine b-lactamases (Bel-
gium, the Czech Republic, Italy, Portugal, Russia and Turkey), but
activity was reduced in countries with an elevated proportion of
MBLs amongst the carbapenemases (Hungary, the UK, Greece and
Romania) (Tables S3, S4, S8, S9, S10, S13, S14, S15, S18 and S19,
and Figure S3).
Ceftazidime/avibactam was active against 98.2% of colistin-
resistant isolates overall and was superior to tested comparators
(30.8%–81.0% susceptible). Although percentages of colistin re-
sistance ranged from 0.2% to 4.3% (Figure S6), susceptibility to
ceftazidime/avibactam was .96% for isolates from all countries
except Belgium (87.5% susceptible) and the UK (88.9% suscep-
tible) (Tables S3 and S19). Only three colistin-resistant, MBL-posi-
tive isolates were identified and these were K. pneumoniae
collected in Greece, Turkey and the UK that carried NDM-1.
Susceptibility of MDR Enterobacteriaceae to ceftazidime/avibac-
tam was 96.7% overall. The MIC90s of ceftazidime/avibactam
 Ceftazidime/avibactam against Enterobacteriaceae from Europe JAC
Table 1. In vitro activities of ceftazidime/avibactam and comparator antimicrobial agents tested against 24 750 isolates of Enterobacteriaceae col-
lected in Europe as part of the INFORM global surveillance programme from 2012 to 2015

MIC (mg/L)
Percentage
Organism (no. of isolates)a Antimicrobial agent MIC50 MIC90 MIC range susceptibleb

Enterobacteriaceae, all (24 750) ceftazidime/avibactam 0.12 0.5 0.015 to .128 99.4
ceftazidime 0.25 64 0.015 to .128 74.8
cefepime 0.12 .16 0.12 to .16 78.7
aztreonam 0.12 64 0.015 to .128 75.0
piperacillin/tazobactam 2 128 0.25 to .128 77.3
doripenem 0.06 0.25 0.008 to .4 96.9
imipenem 0.25 2 0.03 to .8 92.1
meropenem 0.03 0.12 0.004 to .8 97.2
amikacin 2 8 0.25 to .32 93.6
colistin (n " 13 902)c 1 .4 0.12 to .4 82.8
tigecycline 0.5 2 0.015 to .8 83.3
levofloxacin 0.06 .4 0.03 to .4 76.1
Enterobacteriaceae, MBL-negative (24 619) ceftazidime/avibactam 0.12 0.5 0.015 to .128 99.9
ceftazidime 0.25 64 0.015 to .128 75.2
cefepime 0.12 .16 0.12 to .16 79.1
aztreonam 0.12 64 0.015 to .128 75.2
piperacillin/tazobactam 2 128 0.25 to .128 77.7
doripenem 0.06 0.25 0.008 to .4 97.4
imipenem 0.25 2 0.03 to .8 92.6
meropenem 0.03 0.12 0.004 to .8 97.6
amikacin 2 8 0.25 to .32 93.9
colistin (n " 13 809)c 1 .4 0.12 to .4 82.8
tigecycline 0.5 2 0.015 to .8 83.4
levofloxacin 0.06 .4 0.03 to .4 76.5
Enterobacteriaceae, MBL-positive (131) ceftazidime/avibactam .128 .128 1 to .128 9.2
ceftazidime .128 .128 16 to .128 0.0
cefepime .16 .16 0.12 to .16 3.1
aztreonam 64 .128 0.06 to .128 26.0
piperacillin/tazobactam .128 .128 16 to .128 0.0
doripenem .4 .4 0.12 to .4 6.9
imipenem .8 .8 0.5 to .8 3.8
meropenem .8 .8 0.25 to .8 14.5
amikacin 16 .32 1 to .32 35.1
colistin (n " 93)c 0.5 2 0.25 to .4 90.3
tigecycline 1 4 0.12 to .8 65.6
levofloxacin .4 .4 0.03 to .4 11.5
E. coli, all (8184) ceftazidime/avibactam 0.12 0.25 0.015 to .128 99.9
ceftazidime 0.25 16 0.015 to .128 80.2
cefepime 0.12 .16 0.12 to .16 80.5
aztreonam 0.12 32 0.015 to .128 79.0
piperacillin/tazobactam 2 32 0.25 to .128 84.0
doripenem 0.03 0.06 0.008 to .4 99.7
imipenem 0.25 0.25 0.03 to .8 99.6
meropenem 0.03 0.06 0.004 to .8 99.7
amikacin 4 8 0.25 to .32 94.0
colistin (n " 4369)c 0.5 1 0.12 to .4 99.6
tigecycline 0.25 0.5 0.015 to 8 98.9
levofloxacin 0.06 .4 0.03 to .4 69.9
K. pneumoniae, all (6719) ceftazidime/avibactam 0.12 1 0.015 to .128 98.9
ceftazidime 0.5 .128 0.015 to .128 59.7

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Table 1. Continued

MIC (mg/L)
Percentage
a
Organism (no. of isolates) Antimicrobial agent MIC50 MIC90 MIC range susceptibleb

cefepime 0.12 .16 0.12 to .16 61.6

aztreonam 0.12 .128 0.015 to .128 61.0
piperacillin/tazobactam 4 .128 0.25 to .128 60.1
doripenem 0.06 1 0.008 to .4 90.8
imipenem 0.25 2 0.03 to .8 91.2
meropenem 0.06 1 0.004 to .8 91.3
amikacin 2 16 0.25 to .32 89.2
colistin (n " 4201)c 1 1 0.12 to .4 95.6
tigecycline 0.5 2 0.03 to .8 86.3
levofloxacin 0.12 .4 0.03 to .4 67.8
K. oxytoca, all (1539) ceftazidime/avibactam 0.12 0.25 0.015 to .128 99.7
ceftazidime 0.12 1 0.015 to .128 92.3
cefepime 0.12 1 0.12 to .16 90.6
aztreonam 0.12 32 0.015 to .128 83.6
piperacillin/tazobactam 2 .128 0.25 to .128 85.1
doripenem 0.06 0.12 0.015 to .4 99.1
imipenem 0.25 0.5 0.03 to .8 98.9
meropenem 0.03 0.06 0.004 to .8 99.2
amikacin 2 4 0.25 to .32 98.2
colistin (n " 848)c 0.5 1 0.12 to .4 99.5
tigecycline 0.25 1 0.015–4 96.6
levofloxacin 0.06 0.25 0.03 to .4 94.4
Enterobacter spp., all (2878)d ceftazidime/avibactam 0.25 1 0.015 to .128 98.6
ceftazidime 0.5 128 0.015 to .128 63.9
cefepime 0.12 4 0.12 to .16 82.6
aztreonam 0.12 64 0.015 to .128 65.8
piperacillin/tazobactam 4 128 0.25 to .128 67.0
doripenem 0.06 0.25 0.008 to .4 97.9
imipenem 0.5 2 0.03 to .8 97.1
meropenem 0.06 0.12 0.004 to .8 98.3
amikacin 2 4 0.25 to .32 96.5
colistin (n " 1559)c 1 1 0.12 to .4 95.7
tigecycline 0.5 1 0.015 to .8 90.5
levofloxacin 0.06 2 0.03 to .4 89.7
Citrobacter spp., all (1359)e ceftazidime/avibactam 0.12 0.5 0.015 to .128 99.7
ceftazidime 0.25 128 0.015 to .128 77.5
cefepime 0.12 1 0.12 to .16 90.7
aztreonam 0.12 32 0.015 to .128 77.8
piperacillin/tazobactam 4 64 0.25 to .128 78.7
doripenem 0.06 0.12 0.008 to 4 99.2
imipenem 0.5 1 0.03 to .8 98.9
meropenem 0.03 0.06 0.004 to .8 99.2
amikacin 2 4 0.25 to .32 98.6
colistin (n " 737)c 0.5 1 0.12 to .4 99.7
tigecycline 0.25 1 0.015–4 96.1
levofloxacin 0.06 1 0.03 to .4 91.1
Proteeae, all (3390)f ceftazidime/avibactam 0.06 0.12 0.015 to .128 99.7
ceftazidime 0.06 2 0.015 to .128 89.1
cefepime 0.12 0.5 0.12 to .16 92.1
aztreonam 0.015 0.5 0.015 to .128 93.3
piperacillin/tazobactam 0.5 2 0.25 to .128 97.3

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 Ceftazidime/avibactam against Enterobacteriaceae from Europe JAC
Table 1. Continued

MIC (mg/L)
Percentage
a
Organism (no. of isolates) Antimicrobial agent MIC50 MIC90 MIC range susceptibleb

doripenem 0.25 0.5 0.008 to .4 99.0

imipenem 2 4 0.03 to .8 65.0
meropenem 0.06 0.25 0.004 to 8 99.9
amikacin 4 8 0.5 to .32 94.4
colistin (n " 1810)c .4 .4 0.5 to .4 0.4
tigecycline 2 8 0.03 to .8 25.0
levofloxacin 0.06 .4 0.03 to .4 78.6
Other Enterobacteriaceae, all (681)g ceftazidime/avibactam 0.25 0.5 0.015 to .128 99.3
ceftazidime 0.25 2 0.03 to .128 88.4
cefepime 0.12 1 0.12 to .16 90.0
aztreonam 0.12 8 0.015 to .128 87.1
piperacillin/tazobactam 2 16 0.25 to .128 89.3
doripenem 0.12 0.25 0.015 to .4 98.2
imipenem 0.5 2 0.12 to .8 96.9
meropenem 0.06 0.12 0.008 to .8 98.4
amikacin 2 4 0.5 to .32 93.5
colistin (n " 378)c .4 .4 0.25 to .4 18.0
tigecycline 1 2 0.06 to .8 71.5
levofloxacin 0.12 1 0.03 to .4 90.7

a
MBL-negative and MBL-positive subsets were composed of isolates in which no gene or one gene encoding an MBL, respectively, was detected by
PCR assay.
b
Percentage of susceptibility was determined according to EUCAST 2016 breakpoints.
c
Values are for colistin tested without 0.002% polysorbate-80; isolates collected in 2014–15 only.
d
Enterobacter spp. included E. aerogenes (n " 971), E. asburiae (n " 141), E. cancerogenus (n " 1), E. cloacae (n " 1692), E. hormaechei (n " 1), E. kobei
(n " 54) and E. ludwigii (n " 18).
e
Citrobacter spp. included C. amalonaticus (n " 16), C. braakii (n " 92), C. diversus (n " 1), C. farmeri (n " 5), C. freundii (n " 744), C. koseri (n " 486),
C. murliniae (n " 4), C. sedlakii (n " 7), C. youngae (n " 1) and Citrobacter, species unknown (n " 3).
f
Proteeae included Morganella morganii (n " 701), Proteus hauseri (n " 3), Proteus mirabilis (n " 1592), Proteus penneri (n " 28), Proteus vulgaris
(n " 829), Providencia alcalifaciens (n " 12), Providencia rettgeri (n " 101) and Providencia stuartii (n " 124).
g
Other Enterobacteriaceae included Escherichia fergusonii (n " 1), Escherichia hermannii (n " 1), Hafnia alvei (n " 4), Klebsiella variicola (n " 4),
Pantoea agglomerans (n " 1), Pluralibacter gergoviae (n " 1), Raoultella ornithinolytica (n " 49), Raoultella planticola (n " 18), Raoultella terrigena
(n " 2), Serratia liquefaciens (n " 11), Serratia marcescens (n " 584), Serratia odorifera (n " 1) and Serratia ureilytica (n " 4).

against MDR isolates ranged from 0.5 to 4 mg/L for all species except
the subset of MDR Enterobacter spp. isolates, 10% of which carried
MBLs. MDR rates ranged from 2.3% to 39.8%, with .93% of isolates
remaining susceptible to ceftazidime/avibactam in 16 countries
(Figure S7). Activity was reduced against MDR isolates collected in
Greece (83.8% susceptible) and Romania (84.9% susceptible) and
was increased by 14.8% and 14.6%, respectively, against the corre-
sponding subsets of MBL-negative MDR isolates (Tables S8 and S14).
Ceftazidime/avibactam displayed comparable or superior activity to
other agents tested, including carbapenems, colistin and tigecycline,
against MDR isolates collected from individual countries and from
the region as a whole (Tables S2 to S19 and S42).
Discussion
Ceftazidime/avibactam demonstrated potent in vitro activity
against Enterobacteriaceae isolates collected in Europe, including
subsets of isolates that are non-susceptible to ceftazidime or
meropenem, resistant to colistin or have an MDR phenotype.
Ceftazidime/avibactam was active in vitro against 99.7% of
molecularly characterized MBL-negative isolates carrying all
combinations of class A, C and D b-lactamases, including
carbapenemase-producing Enterobacteriaceae carrying KPC,
GES or OXA-48-like enzymes, regardless of species or country of
origin. The activity of ceftazidime/avibactam was adversely
affected by the presence of class B MBLs. In addition, 14 isolates
of Enterobacteriaceae (8 K. pneumoniae, 2 E. coli, 1 Enterobacter
aerogenes, 1 Klebsiella oxytoca, 1 Providencia stuartii and 1 Ser-
ratia marcescens) that lacked the MBLs screened as part of this
study tested as non-susceptible to ceftazidime/avibactam.
These isolates were found in Italy, Russia, Belgium, Greece and
Hungary, and may harbour known or as-yet-undefined resist-
ance mechanisms.12–14,17
The observed distribution of ESBL and carbapenemase types
was in general agreement with published reports.2,3,20 The overall
resistance patterns were similar to those reported by EARS-Net,
with higher percentages of resistance primarily found in southern
and eastern Europe.1 Among countries included in both studies,
the highest percentages of carbapenem-non-susceptible
Enterobacteriaceae were observed in Italy, Greece and Romania.

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SWE
99.9

DNK 100

RUS
99.5
NLD
GBR
POL
99.8 100 DEU 99.9
BEL
99.8 99.9

CZE 100

AUT
FRA 99.7 HUN 99.8
100 ROU
96.3
ITA
99.2

PRT ESP
TUR
99.8
96.4 99.5
99.9
GRC

Figure 1. Percentages of Enterobacteriaceae isolates susceptible to ceftazidime/avibactam, by country. Susceptible, MIC 8 mg/L; resistant, MIC
16 mg/L. AUT, Austria; BEL, Belgium; CZE, the Czech Republic; DNK, Denmark; FRA, France; DEU, Germany; GRC, Greece; HUN, Hungary; ITA, Italy;
NLD, the Netherlands; POL, Poland; PRT, Portugal; ROU, Romania; RUS, Russia; ESP, Spain; SWE, Sweden; TUR, Turkey; GBR, the UK.

Good agreement was also observed for countries with the highest
percentages of polymyxin-resistant (Greece and Italy) and MDR
(Italy, Romania, Greece, Poland, Hungary and the Czech Republic)
isolates.1 High percentages of colistin-resistant (Turkey) and MDR
(Russia and Turkey) Enterobacteriaceae were also found in coun-
tries not surveyed by EARS-Net. Differences in the activity of cef-
tazidime/avibactam were not observed across the different
countries surveyed, with the exception of those countries that
showed an elevated incidence of MBL-producing isolates.
Ceftazidime/avibactam provides a valuable alternative for
treatment of infections caused by Enterobacteriaceae isolates re-
sistant to many commonly used and last-line agents. However,
country- and site-specific differences in the incidence of MBL-
mediated resistance must be taken into account when assessing
the value of ceftazidime/avibactam for a particular setting.
Acknowledgements
Some of the data were presented previously at the European Congress
of Clinical Microbiology and Infectious Diseases (2016, Abstract A0332;
2016, Abstract A0334; 2017, Abstract A1295).
We thank all INFORM participants, International Health Management
Associates, Inc. (IHMA) laboratory personnel and all members of the
AstraZeneca global surveillance programme for their contributions to
the programme. We acknowledge Henry Li and Mark Estabrook of IHMA
for assistance with compiling the Supplementary Tables.
Funding
This work was sponsored by AstraZeneca Pharmaceuticals as part of
the International Network for Optimal Resistance Monitoring (INFORM)
global surveillance programme, which also included compensation fees
for manuscript preparation.
Transparency declarations
AstraZeneca’s rights to ceftazidime/avibactam were acquired by Pfizer in
December 2016. The sponsor approved the overall study design. All in-
vestigative sites were recruited and study supplies were provided by
IHMA. Analysis of the final MIC and molecular data was performed by
IHMA. Medical writing and editorial support were provided by K. M. K., an
employee of IHMA, and B. L. M. de J. and G. G. S., employees of and
shareholders in AstraZeneca at the time of the study. All authors pro-
vided analysis input, and read and approved the final manuscript. K. M.
K. and D. F. S. are employees of IHMA and do not have a personal finan-
cial interest in the sponsor of this paper (AstraZeneca Pharmaceuticals).
B. L. M. de J. and G. G. S. are currently employees of Pfizer.

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 Ceftazidime/avibactam against Enterobacteriaceae from Europe
Supplementary data
Materials and methods, Figures S1 to S7 and Tables S1 to S42 are avail-
able as Supplementary data at JAC Online.
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