Enterobacteriaceae
and
Pseudomonas aeruginosa
with Various
Resistance Patterns Isolated in U.S. Hospitals (2011-2012)
David J. Farrell,a,bRobert K. Flamm,aHelio S. Sader,a,cRonald N. Jonesa,d
JMI Laboratories, North Liberty, Iowa, USAa; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canadab; Division of Infectious
Diseases, Federal University of São Paulo, São Paulo, SP, Brazilc; Tufts University School of Medicine, Boston, Massachusetts, USAd
Ceftolozane/tazobactam, a novel antimicrobial agent with activity against
Pseudomonas aeruginosa
(including drug-resistant
strains) and other common Gram-negative pathogens (including most extended-spectrum-

-lactamase [ESBL]-producing
En-terobacteriaceae
strains), and comparator agents were susceptibility tested by a reference broth microdilution method against
7,071
Enterobacteriaceae
and 1,971
P. aeruginosa
isolates. Isolates were collected consecutively from patients in 32 medical
cen-ters across the United States during 2011 to 2012. Overall, 15.7% and 8.9% of
P. aeruginosa
isolates were classified as multidrug
resistant (MDR) and extensively drug resistant (XDR), and 8.4% and 1.2% of
Enterobacteriaceae
were classified as MDR and
XDR. No pandrug-resistant (PDR)
Enterobacteriaceae
isolates and only one PDR
P. aeruginosa
isolate were detected.
Ceftolo-zane/tazobactam was the most potent (MIC
50/90, 0.5/2
g/ml) agent tested against
P. aeruginosa
and demonstrated good activity
against 310 MDR strains (MIC
50/90, 2/8
g/ml) and 175 XDR strains (MIC
50/90, 4/16
g/ml). Ceftolozane/tazobactam exhibited
high overall activity (MIC
50/90, 0.25/1
g/ml) against
Enterobacteriaceae
and retained activity (MIC
50/90, 4/
>
32
g/ml) against
many 601 MDR strains but not against the 86 XDR strains (MIC
50,
>
32
g/ml). Ceftolozane/tazobactam was highly potent
(MIC
50/90, 0.25/0.5
g/ml) against 2,691
Escherichia coli
isolates and retained good activity against most ESBL-phenotype
E. coli
isolates (MIC
50/90, 0.5/4
g/ml), but activity was low against ESBL-phenotype
Klebsiella pneumoniae
isolates (MIC
50/90, 32/
>
32
g/ml), explained by the high rate (39.8%) of meropenem coresistance observed in this species phenotype. In summary,
ceftolo-zane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporary
Enterobacteriaceae
and
P. aeruginosa
isolates collected in U.S. medical centers. Importantly, ceftolozane/tazobactam retained potency against many
MDR and XDR strains.
C
eftolozane/tazobactam is a novel antibacterial agent with
ac-tivity against
Pseudomonas aeruginosa, including
drug-resis-tant strains, and other common Gram-negative pathogens,
in-cluding most extended-spectrum-

-lactamase (ESBL)-producing
Enterobacteriaceae
strains (
1
). Ceftolozane is a novel antibacterial
agent with potent activity (compared with ceftazidime) against
P.
aeruginosa, including drug-resistant strains, and
Enterobacteria-ceae
(with potency similar to that of other
oxyimino-aminothia-zolyl cephalosporins) (
1–6
). However, as with other
cephalospo-rins, ceftolozane’s activity is compromised in bacteria producing
ESBLs, stably derepressed AmpC

-lactamases, and
carbapen-emases (
1
,
7
). Tazobactam, a penicillanic acid-sulfone, is a
well-established

-lactamase inhibitor that broadens the coverage of

-lactam agents (
8
). Unlike clavulanate and sulbactam,
tazobac-tam is a moderate inhibitor of inducibly and constitutively
ex-pressed AmpC enzymes, although this activity is strain dependent
and is less potent against strains with totally derepressed AmpC

-lactamases (
9
).
During the past decade, nosocomial infections caused by
En-terobacteriaceae
and
P. aeruginosa
in intensive care units
world-wide have been increasing in prevalence along with increases in
antimicrobial resistance and associated increases in morbidity and
mortality (
10
,
11
). Empirical and targeted therapies to cover
in-fections with these organisms are increasingly limited.
Ceftolo-zane/tazobactam exploits ceftolozane’s potent activity against
P.
aeruginosa
and
Enterobacteriaceae
and broadens ceftolozane’s
spectrum of activity against
Enterobacteriaceae
(
1
), hence making
it an attractive option for clinical development for treatment of
some infections caused by multidrug-resistant (MDR)
Gram-neg-ative bacteria. Ceftolozane/tazobactam is currently in phase III
trials for the treatment of complicated urinary tract infections,
complicated intra-abdominal infections, and nosocomial
bacte-rial pneumonia. In the present study, we evaluated the potency of
ceftolozane/tazobactam and comparator drugs tested for the first
time against a large, contemporary (2011–2012) collection of
clin-ically collected
Enterobacteriaceae
and
P. aeruginosa
isolates
ob-tained from patients in U.S. hospitals.
MATERIALS AND METHODS
Sampling sites and organisms.A total of 7,071Enterobacteriaceaeand 1,971P. aeruginosaisolates were consecutively collected over 2 years (Jan-uary 2011 to December 2012) from 32 medical centers located across all nine U.S. census regions. All organisms were isolated from documented infections, and only one strain per patient infection episode was included in the surveillance collection. The isolates were derived primarily from bloodstream infections, skin and skin-structure infections (SSSI), and pneumonia in hospitalized patients, urinary tract infections in
hospital-Received20 August 2013 Returned for modification22 September 2013 Accepted1 October 2013
Published ahead of print7 October 2013
Address correspondence to David J. Farrell, david-farrell@jmilabs.com. Copyright © 2013, American Society for Microbiology. All Rights Reserved.
ized patients, and intra-abdominal infections according to a common surveillance design.
Antimicrobial susceptibility testing.MIC values were determined using the reference Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (M07-A9) (12). Quality control (QC) ranges and interpretive criteria for comparator compounds used the CLSI M100-S23 guidelines (13). The ESBL phenotype was defined as a MIC ofⱖ2
g/ml for ceftazidime or ceftriaxone or aztreonam (13). To better evalu-ate the activities of ceftolozane/tazobactam against-lactam-resistant En-terobacteriaceaeandP. aeruginosa, strains were stratified by patterns of susceptibility to ceftazidime and meropenem. MDR, extensively drug-resistant (XDR), and pandrug-drug-resistant (PDR) bacteria were classified as such per recently recommended guidelines (14) using the following anti-microbial class representative agents and CLSI interpretive criteria (13): forP. aeruginosa, ceftazidime (MIC ofⱖ16g/ml), meropenem (ⱖ4
g/ml), piperacillin-tazobactam (ⱖ32/4g/ml), levofloxacin (ⱖ4g/ ml), gentamicin (ⱖ8g/ml), and colistin (ⱖ4g/ml); and for Enterobac-teriaceae, ceftriaxone (ⱖ2g/ml), meropenem (ⱖ2g/ml), piperacillin-tazobactam (ⱖ32/4g/ml), levofloxacin (ⱖ4g/ml), gentamicin (ⱖ8
g/ml), tigecycline (ⱖ4g/ml), and colistin (ⱖ4g/ml). Classifications were based on the following recommended parameters: MDR⫽ nonsus-ceptible toⱖ1 agent inⱖ3 antimicrobial classes; XDR⫽nonsusceptible toⱖ1 agent in all butⱕ2 antimicrobial classes; PDR⫽nonsusceptible to all antimicrobial classes (14).
RESULTS
Ceftolozane/tazobactam activity against
Enterobacteriaceae
.
Cef-tolozane/tazobactam demonstrated high overall activity (MIC
50,
0.25
g/ml; MIC
90, 1
g/ml) against 7,071
Enterobacteriaceae
iso-lates collected in the United States during 2011 to 2012 (
Table 1
and
Table 2
). Using MIC
90values, ceftolozane/tazobactam
showed potency identical to that of cefepime, was 16-fold more
active than ceftazidime and piperacillin-tazobactam (MIC
90for
both, 16
g/ml), was at least 16-fold more potent than ceftriaxone
(MIC
90,
⬎
8
g/ml), and was second in potency against all tested
compounds only to meropenem (MIC
90,
ⱕ
0.06
g/ml;
Table 2
).
Against 601 (8.5%) MDR isolates, meropenem (MIC
50/90,
ⱕ
0.06/
⬎
8
g/ml; 77.0% susceptible), ceftolozane/tazobactam
(MIC
50/90, 4/
⬎
32
g/ml), tigecycline (MIC
50/90, 0.5/2
g/ml;
92.3% susceptible), and colistin (MIC
50/90, 0.5/
⬎
4
g/ml) were
the only agents tested to retain activity at the MIC
50level (
Table 2
).
Ceftolozane/tazobactam was not active against most XDR strains
(n
⫽
86; 1.2%) (MIC
50/90,
⬎
32/
⬎
32
g/ml), with tigecycline
be-ing the most active agent (87.1% susceptible), followed by
mero-penem and gentamicin, with low susceptibility rates of only 22.1%
and 20.9%, respectively (
Table 2
). No PDR
Enterobacteriaceae
iso-lates were collected in this study.
Ceftolozane/tazobactam was highly potent (MIC
50/90, 0.25/0.5
g/ml), inhibiting 99.0% of 2,691
Escherichia coli
isolates at a MIC
of
ⱕ
4
g/ml and 100.0% of 2,364 non-ESBL-phenotype isolates at
a MIC of
ⱕ
2
g/ml (
Table 1
). Similarly, ceftolozane/tazobactam
activity was high against non-ESBL-phenotype
Klebsiella
pneu-moniae,
Klebsiella oxytoca, and
Proteus mirabilis
(MIC
90for all
three, 0.5
g/ml;
Table 1
). Although ceftolozane/tazobactam was
active against most ESBL-phenotype
E. coli
isolates (MIC
50/90,
0.5/4
g/ml), its potency was much lower against
ESBL-pheno-type
K. pneumoniae
(MIC
50/90, 32/
⬎
32
g/ml;
Table 1
). This
ob-served lower activity for ceftolozane/tazobactam in
ESBL-pheno-type
K. pneumoniae
can be explained by the higher rate of
meropenem resistance (i.e., carbapenemases) observed in this
phe-notype (39.8%) compared with ESBL-phephe-notype
E. coli
(1.5%;
Table 2
), supported by the higher activity (MIC
90, 1
g/ml) observed
against meropenem-susceptible
K. pneumoniae
(
Table 1
).
Tested against
Enterobacter
spp.,
Citrobacter
spp., and
Serratia
spp., ceftolozane/tazobactam exhibited 8-fold-greater activity
(MIC
50, 0.25 to 0.5
g/ml) than piperacillin-tazobactam (MIC
50,
2 to 4
g/ml), activity similar to that of ceftriaxone (MIC
50, 0.12 to
0.25
g/ml) and ceftazidime (MIC
50, 0.25
g/ml for all three
gen-era), and activity similar to or lower than that of cefepime (MIC
50,
ⱕ
0.5
g/ml;
Table 2
). Ceftolozane/tazobactam was also very
ac-tive (MIC
50/90, 0.25/1
g/ml) against 368 indole-positive
Proteus
spp. (
Table 1
).
Ceftolozane/tazobactam activity against
P. aeruginosa
.
Cef-tolozane/tazobactam was the most potent (MIC
50/90, 0.5/2
g/ml)
agent tested against 1,971
P. aeruginosa
isolates, inhibiting 96.1%
at a MIC of
ⱕ
4
g/ml (
Tables 3
and
4
). Ceftolozane/tazobactam
was at least 4-fold more active than ceftazidime (MIC
50/90, 2/32
g/ml), at least 8-fold more active than cefepime (MIC
50/90, 4/16
g/ml), at least 16-fold more active than piperacillin-tazobactam
(MIC
50/90, 8/
⬎
64
g/ml), and slightly more potent than
mero-penem (MIC
50/90, 0.5/8
g/ml) when tested against the entire
col-lection of
P. aeruginosa
isolates (
Table 4
). After colistin (MIC
50/90,
1/2
g/ml; 98.4% susceptible), ceftolozane/tazobactam was the
most active (MIC
50/90, 2/8
g/ml) agent tested against 310 MDR
P. aeruginosa
isolates, with resistance for all other agents ranging
from 36.5% for gentamicin to 70.6% for levofloxacin (
Table 4
).
Similarly, against 175 XDR strains, ceftolozane/tazobactam
re-tained activity (MIC
50/90, 4/16
g/ml), whereas resistance to other
agents was high—ranging from 49.7% for gentamicin to 88.0%
for levofloxacin (
Table 4
). Most XDR strains remained susceptible
to colistin (97.7% susceptible), while in contrast, high levels of
resistance to ceftazidime (73.7% resistant) and meropenem
(76.0% resistant) were observed (
Table 4
). Only one PDR
P.
aeruginosa
strain was detected, and ceftolozane/tazobactam
dem-onstrated no observable activity (MIC,
⬎
32
g/ml;
Table 3
)
against this strain. Ceftolozane/tazobactam also had good activity
against many ceftazidime-nonsusceptible (MIC
50/90, 4/8
g/ml),
meropenem-nonsusceptible (MIC
50/90, 1/8
g/ml),
piperacillin-tazobactam-nonsusceptible (MIC
50/90, 2/8
g/ml),
cefepime-nonsusceptible (MIC
50/90, 4/8
g/ml),
levofloxacin-nonsuscep-tible (MIC
50/90, 1/8
g/ml), and gentamicin-nonsusceptible
(MIC
50/90, 1/8
g/ml) isolates (
Table 3
). Ceftolozane/tazobactam
also had moderate activity against many isolates with combined
ceftazidime and meropenem nonsusceptibility (MIC
50/90, 4/32
g/ml) and combined ceftazidime and meropenem and
pipera-cillin-tazobactam nonsusceptibility (MIC
50/90, 4/32
g/ml;
Ta-ble 3
).
DISCUSSION
Resistance mechanisms in
Enterobacteriaceae
and
P. aeruginosa
are extremely diverse, and there is currently no antimicrobial
agent or combination that allows complete coverage of these
im-portant pathogens in the hospital setting. In
in vitro
studies to
date, ceftolozane/tazobactam has demonstrated the greatest
over-all
in vitro
activity, compared with other agents tested, against this
combined group of Gram-negative pathogens (
1
,
7
,
15
). The data
from this large multicenter U.S. surveillance study confirm the
data presented in earlier studies and demonstrate that
ceftolo-zane/tazobactam had high
in vitro
potency and a broad spectrum
of activity against many nosocomial isolates of
Enterobacteriaceae
and
P. aeruginosa
circulating in the United States during 2011 and
Farrell et al.TABLE 1Cumulative MIC distributions of ceftolozane/tazobactam againstEnterobacteriaceaeby resistance phenotype
Organisma(n)
No. of isolates (cumulative %) inhibited at ceftolozane/tazobactam MIC (g/ml) of:
MIC50 MIC90
0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 ⬎32
Enterobacteriaceaeb(7,071) 3 (0.0) 15 (0.3) 1,536 (22.0) 2,977 (64.1) 1,495 (85.2) 432 (91.3) 139 (93.3) 100 (94.7) 97 (96.1) 66 (97.0) 82 (98.2) 129 (100.0) 0.25 1
MDR (601) 0 (0.0) 0 (0.0) 2 (0.3) 41 (7.2) 117 (26.6) 60 (36.6) 47 (44.4) 58 (54.1) 52 (62.7) 34 (68.4) 68 (79.7) 122 (100.0) 4 ⬎32 XDR (86) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (2.3) 2 (4.7) 3 (8.1) 4 (12.8) 6 (19.8) 15 (37.2) 54 (100.0) ⬎32 ⬎32
Escherichia coli(2,691) 1 (0.0) 6 (0.3) 999 (37.4) 1,301 (85.7) 256 (95.2) 61 (97.5) 29 (98.6) 11 (99.0) 9 (99.3) 6 (99.6) 7 (99.8) 5 (100.0) 0.25 0.5
Non-ESBL phenotype (2,364) 1 (0.0) 6 (0.3) 990 (42.2) 1,208 (93.3) 150 (99.6) 8 (100.0) 1 (100.0) 0.25 0.25 ESBL phenotype (327) 0 (0.0) 0 (0.0) 9 (2.8) 93 (31.2) 106 (63.6) 53 (79.8) 28 (88.4) 11 (91.7) 9 (94.5) 6 (96.3) 7 (98.5) 5 (100.0) 0.5 4 MEM-S (2,683) 1 (0.0) 6 (0.3) 999 (37.5) 1,301 (86.0) 256 (95.5) 61 (97.8) 29 (98.9) 10 (99.3) 8 (99.6) 2 (99.6) 6 (99.9) 4 (100.0) 0.25 0.5 MEM-NS (8) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (12.5) 1 (25.0) 4 (75.0) 1 (87.5) 1 (100.0) 16
Klebsiellaspp. (1,589) 1 (0.1) 5 (0.4) 342 (21.9) 682 (64.8) 243 (80.1) 104 (86.7) 30 (88.5) 23 (90.0) 13 (90.8) 12 (91.6) 42 (94.2) 92 (100.0) 0.25 8
K. pneumoniae(1,298) 0 (0.0) 5 (0.4) 231 (18.2) 566 (61.8) 205 (77.6) 96 (85.0) 25 (86.9) 15 (88.1) 13 (89.1) 12 (90.0) 41 (93.1) 89 (100.0) 0.25 32
Non-ESBL phenotype (1,054) 0 (0.0) 5 (0.5) 229 (22.2) 557 (75.0) 186 (92.7) 72 (99.5) 5 (100.0) 0.25 0.5 ESBL phenotype (244) 0 (0.0) 0 (0.0) 2 (0.8) 9 (4.5) 19 (12.3) 24 (22.1) 20 (30.3) 15 (36.5) 13 (41.8) 12 (46.7) 41 (63.5) 89 (100.0) 32 ⬎32 MEM-S (1,198) 0 (0.0) 5 (0.4) 231 (19.7) 566 (66.9) 205 (84.1) 96 (92.1) 25 (94.2) 15 (95.4) 9 (96.2) 5 (96.6) 10 (97.4) 31 (100.0) 0.25 1 MEM-NS (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (4.0) 7 (11.0) 31 (42.0) 58 (100.0) ⬎32 ⬎32
K. oxytoca(283) 1 (0.4) 0 (0.4) 110 (39.2) 112 (78.8) 36 (91.5) 7 (94.0) 5 (95.8) 8 (98.6) 0 (98.6) 0 (98.6) 1 (98.9) 3 (100.0) 0.25 0.5
Non-ESBL phenotype (244) 1 (0.4) 0 (0.4) 109 (45.1) 109 (89.8) 22 (98.8) 3 (100.0) 0.25 0.5
ESBL phenotype (39) 0 (0.0) 0 (0.0) 1 (2.6) 3 (10.3) 14 (46.2) 4 (56.4) 5 (69.2) 8 (89.7) 0 (89.7) 0 (89.7) 1 (92.3) 3 (100.0) 1 32
Enterobacterspp. (1,029) 1 (0.1) 2 (0.3) 93 (9.3) 457 (53.7) 205 (73.7) 57 (79.2) 46 (83.7) 45 (88.0) 56 (93.5) 32 (96.6) 17 (98.3) 18 (100.0) 0.25 8
CAZ-S (766) 1 (0.1) 2 (0.4) 91 (12.3) 443 (70.1) 188 (94.6) 35 (99.2) 6 (100.0) 0.25 0.5
CAZ-NS (249) 0 (0.0) 0 (0.0) 0 (0.0) 5 (2.0) 16 (8.4) 22 (17.3) 40 (33.3) 45 (51.4) 55 (73.5) 31 (85.9) 17 (92.8) 18 (100.0) 4 32
Citrobacterspp. (381) 0 (0.0) 1 (0.3) 59 (15.7) 207 (70.1) 52 (83.7) 7 (85.6) 5 (86.9) 9 (89.2) 9 (91.6) 13 (95.0) 11 (97.9) 8 (100.0) 0.25 8
Proteus mirabilis(414) 0 (0.0) 0 (0.0) 3 (0.7) 126 (31.2) 260 (94.0) 24 (99.8) 1 (100.0) 0.5 0.5
Non-ESBL phenotype (398) 0 (0.0) 0 (0.0) 3 (0.8) 125 (32.2) 250 (95.0) 20 (100.0) 0.5 0.5
ESBL phenotype (16) 0 (0.0) 0 (0.0) 0 (0.0) 1 (6.3) 10 (68.8) 4 (93.8) 1 (100.0) 0.5 1
Indole-positiveProteusspp. (368) 0 (0.0) 1 (0.3) 33 (9.2) 169 (55.2) 103 (83.2) 27 (90.5) 12 (93.8) 6 (95.4) 6 (97.0) 3 (97.8) 4 (98.9) 4 (100.0) 0.25 1
Serratiaspp. (573) 0 (0.0) 0 (0.0) 2 (0.3) 24 (4.5) 366 (68.4) 152 (94.9) 16 (97.7) 6 (98.8) 4 (99.5) 0 (99.5) 1 (99.7) 2 (100.0) 0.5 1
aAbbreviations: MDR, multidrug-resistant; XDR, extensively drug resistant; PDR, pan-drug resistant; NS, nonsusceptible; R, resistant; S, susceptible; CAZ, ceftazidime; CAZ, ceftazidime; CAZ, ceftazidime; MEM, meropenem; MEM, meropenem; ESBL, extended-spectrum-lactamase.
bIncludes (number of isolates)Citrobacter amalonaticus(9),Citrobacter braakii(12),Citrobacter farmeri(1),Citrobacter freundii(174),Citrobacter koseri(138),Citrobacter sedlakii(2),Citrobacter youngae(3),Enterobacter aerogenes (265),Enterobacter amnigenus(1),Enterobacter asburiae(15),Enterobacter cloacae(730),Enterobacter cloacaecomplex (1),Enterobacter intermedius(1),Enterobacter sakazakii(4),Escherichia coli(2691),Klebsiella oxytoca(283),
Klebsiella ozaenae(3),Klebsiella planticola(1),Klebsiella pneumoniae(1298),Morganella morganii(256),Pantoea agglomerans(14),Proteus mirabilis(414),Proteus vulgaris(38),Providencia rettgeri(34),Providencia stuartii(37),
Salmonella enteritidis(1),Salmonella typhi(2),Serratia liquefaciens(14),Serratia marcescens(552),Serratia odorifera(1),Serratia rubidaea(3), group BSalmonella(1), group DSalmonella(1), non-species-identifiedCitrobacter(42),
non-species-identifiedEnterobacter(12), non-species-identifiedKlebsiella(4), non-species-identifiedProteus(3), non-species-identifiedSalmonella(7), and non-species-identifiedSerratia(3).
Ceftolozane/Tazobactam
U.S.
Surveillance
(2011-2012)
2013
Volume
57
Number
12
2012. In addition, this larger set of contemporary data supports
the previously reported activity against a collection of
ceftazi-dime- and/or carbapenem-resistant
Enterobacteriaceae
and
P.
aeruginosa
isolates (
1
).
TABLE 2Antimicrobial activity of ceftolozane/tazobactam and various
comparator agents againstEnterobacteriaceaecollected in the U.S. during 2011 to 2012
Organism(s) and antimicrobial agenta(no.
tested) MIC50 MIC90
% susceptibleb
% resistantb
Enterobacteriaceae—all isolates (7,071)
Ceftolozane/tazobactam 0.25 1 —c —
Ceftazidime 0.12 16 88.1 10.5 Ceftriaxone ⱕ0.06 ⬎8 85.2 13.8
Cefepime ⱕ0.5 1 94.0 5.0
Meropenem ⱕ0.06 ⱕ0.06 98.0 1.8 Piperacillin-tazobactam 2 16 90.9 5.8 Aztreonam ⱕ0.12 16 88.0 10.5 Levofloxacin ⱕ0.12 ⬎4 81.9 16.1
Gentamicin ⱕ1 4 90.7 8.2
Tigecyclined 0.25 1 98.2 0.1
Colistin 0.5 ⬎4 — —
Enterobacteriaceae—MDR (601)
Ceftolozane/tazobactam 4 ⬎32 — — Ceftazidime 32 ⬎32 22.0 71.7 Ceftriaxone ⬎8 ⬎8 11.0 87.7
Cefepime 16 ⬎16 46.9 44.1
Meropenem ⱕ0.06 ⬎8 77.0 20.5 Piperacillin-tazobactam 64 ⬎64 34.6 46.3 Aztreonam ⬎16 ⬎16 22.0 74.2 Levofloxacin ⬎4 ⬎4 17.8 72.9 Gentamicin ⬎8 ⬎8 40.8 50.1 Tigecyclined 0.5 2 92.3 0.2
Colistin 0.5 ⬎4 — —
Enterobacteriaceae—XDR (86)
Ceftolozane/tazobactam ⬎32 ⬎32 — — Ceftazidime ⬎32 ⬎32 2.3 96.5 Ceftriaxone ⬎8 ⬎8 0.0 100.0 Cefepime ⬎16 ⬎16 15.1 73.3
Meropenem ⬎8 ⬎8 22.1 70.9
Piperacillin-tazobactam ⬎64 ⬎64 2.3 81.4 Aztreonam ⬎16 ⬎16 3.5 93.0 Levofloxacin ⬎4 ⬎4 0.0 93.0 Gentamicin ⬎8 ⬎8 20.9 61.6 Tigecyclined 0.5 4 87.1 0.0
Colistin ⬎4 ⬎4 — —
E. coli, ESBL phenotype (327)
Ceftolozane/tazobactam 0.5 4 — — Ceftazidime 16 ⬎32 31.8 55.7 Ceftriaxone ⬎8 ⬎8 8.3 90.2
Cefepime 16 ⬎16 44.5 48.8
Meropenem ⱕ0.06 ⬎8 97.6 1.5 Piperacillin-tazobactam 8 ⬎64 77.4 13.5 Aztreonam ⬎16 ⬎16 23.2 63.9 Levofloxacin ⬎4 ⬎4 22.6 75.5
Gentamicin 2 ⬎8 63.0 36.7
Tigecyclined 0.12 0.25 100.0 0.0
Colistin ⱕ0.25 0.5 — —
K. pneumoniae, ESBL phenotype (244)
Ceftolozane/tazobactam 32 ⬎32 — —
TABLE 2(Continued)
Organism(s) and antimicrobial agenta(no.
tested) MIC50 MIC90
% susceptibleb
% resistantb
Ceftazidime ⬎32 ⬎32 5.3 88.5 Ceftriaxone ⬎8 ⬎8 5.3 93.4 Cefepime ⬎16 ⬎16 27.9 60.7 Meropenem ⱕ0.06 ⬎8 59.0 39.8 Piperacillin-tazobactam ⬎64 ⬎64 25.4 65.2 Aztreonam ⬎16 ⬎16 7.8 91.0 Levofloxacin ⬎4 ⬎4 20.1 76.6
Gentamicin 4 ⬎8 50.8 39.8
Tigecyclined 0.5 2 97.1 0.0
Colistin 0.5 ⬎4 — —
Enterobacterspp. (1,029)
Ceftolozane/tazobactam 0.25 8 — — Ceftazidime 0.25 ⬎32 75.6 22.1 Ceftriaxone 0.25 ⬎8 71.6 25.9
Cefepime ⱕ0.5 2 96.3 2.6
Meropenem ⱕ0.06 ⱕ0.06 98.6 1.1 Piperacillin-tazobactam 4 64 81.5 8.1 Aztreonam ⱕ0.12 ⬎16 76.9 19.2 Levofloxacin ⱕ0.12 0.5 94.7 3.9 Gentamicin ⱕ1 ⱕ1 94.8 4.3 Tigecyclined 0.25 0.5 98.5 0.0
Colistin 0.5 ⬎4 — —
Citrobacterspp. (381)
Ceftolozane/tazobactam 0.25 8 — — Ceftazidime 0.25 ⬎32 84.8 15.2 Ceftriaxone 0.12 ⬎8 84.3 15.2
Cefepime ⱕ0.5 1 97.4 1.1
Meropenem ⱕ0.06 ⱕ0.06 97.9 1.8 Piperacillin-tazobactam 2 64 87.1 7.9 Aztreonam ⱕ0.12 ⬎16 84.8 13.4 Levofloxacin ⱕ0.12 2 91.9 5.0 Gentamicin ⱕ1 ⱕ1 95.5 4.2 Tigecyclined 0.12 0.5 100.0 0.0
Colistin 0.5 1 — —
Serratiaspp. (573)
Ceftolozane/tazobactam 0.5 1 — — Ceftazidime 0.25 0.5 97.7 1.7 Ceftriaxone 0.25 1 91.4 6.8 Cefepime ⱕ0.5 ⱕ0.5 99.1 0.3 Meropenem ⱕ0.06 ⱕ0.06 99.1 0.5 Piperacillin-tazobactam 2 4 96.9 0.9 Aztreonam ⱕ0.12 0.5 97.5 2.3 Levofloxacin ⱕ0.12 0.5 96.5 1.0
Gentamicin ⱕ1 2 97.7 2.3
Tigecyclined 0.5 1 99.0 0.3
Colistin ⬎4 ⬎4 — —
a
Abbreviations: MDR, multidrug resistant; XDR, extensively drug resistant; PDR, pan-drug resistant; ESBL, extended-spectrum-lactamase.
b
According to CLSI interpretive criteria (13).
c—, no published interpretive criteria.
d
In the absence of CLSI interpretive criteria, U.S. FDA interpretive criteria were applied (Tygacil Product Insert, 2012).
Farrell et al.
For
this
investigation,
as
described
in
Materials
and
Methods,
we
classified
MDR,
XDR,
and
PDR
for
both
Enterobacteriaceae
and
P.
aeruginosa
according
to
guidelines
recently
published
by
international
expert
panel
(
14
).
To
achieve
this,
we
tested
repre-sentative
antimicrobials
from
different
classes
in
our
laboratory
determine
nonsusceptibility
within
each
class.
In
addition,
used
current
(2013)
CLSI
MIC
interpretive
criteria
to
determine
nonsusceptibility
(
13
).
It
should
be
noted
that
current
(2013)
European
Committee
on
Antimicrobial
Susceptibility
Testing
(EUCAST)
interpretive
criteria
(
16
)
differ
from
the
CLSI
interpre-tive
criteria
for
many
of
the
organism/antimicrobial
combinations
(for
example,
for
Enterobacteriaceae
,
nonsusceptibility
to
mero-penem
is
ⱖ
2
g/ml
by
CLSI
and
ⱖ
4
g/ml
by
EUCAST).
With
these
caveats,
these
data
show
that,
although
the
level
was
reduced,
ceftolozane/tazobactam
retained
good
activity
against
MDR
XDR
strains
of
P.
aeruginosa
and
MDR
strains
of
Enterobacteriace-ae
—
but
low
activity
against
most
strains
of
XDR
Enterobacteria-ceae
due
to
the
high
prevalence
of
carbapenemase-producing
pneumoniae
in
the
XDR
population
(
Table
2
).
This
is
in
contrast
TABLE 3Cumulative MIC distributions of ceftolozane/tazobactam againstP. aeruginosaby resistance phenotype
P. aeruginosaresistance status (no. of isolates tested)a
No. of isolates (cumulative %) inhibited at ceftolozane/tazobactam MIC (g/ml) of:
MIC50 MIC90
0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 ⬎32
All isolates (1,971) 0 (0.0) 2 (0.1) 3 (0.3) 72 (3.9) 958 (52.5) 594 (82.6) 152 (90.4) 113 (96.1) 47 (98.5) 10 (99.0) 4 (99.2) 16 (100.0) 0.5 2 MDR (310) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.6) 9 (3.5) 79 (29.0) 81 (55.2) 74 (79.0) 35 (90.3) 10 (93.5) 4 (94.8) 16 (100.0) 2 8 XDR (175) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.1) 28 (17.1) 50 (45.7) 44 (70.9) 26 (85.7) 8 (90.3) 2 (91.4) 15 (100.0) 4 16 PDR (1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100.0) ⬎32 ⬎32 CAZ-S (1,633) 0 (0.0) 2 (0.1) 3 (0.3) 72 (4.7) 957 (63.3) 542 (96.5) 53 (99.8) 4 (100.0) 0.5 1 CAZ-NS (338) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.3) 52 (15.7) 99 (45.0) 109 (77.2) 47 (91.1) 10 (94.1) 4 (95.3) 16 (100.0) 4 8 MEM-S (1,583) 0 (0.0) 2 (0.1) 3 (0.3) 69 (4.7) 899 (61.5) 450 (89.9) 80 (94.9) 60 (98.7) 18 (99.9) 1 (99.9) 0 (99.9) 1 (100.0) 0.5 2 MEM-NS (388) 0 (0.0) 0 (0.0) 0 (0.0) 3 (0.8) 59 (16.0) 144 (53.1) 72 (71.6) 53 (85.3) 29 (92.8) 9 (95.1) 4 (96.1) 15 (100.0) 1 8 CAZ-NS, MEM-NS (183) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 24 (13.1) 50 (40.4) 52 (68.9) 29 (84.7) 9 (89.6) 4 (91.8) 15 (100.0) 4 32 P/T-S (1,513) 0 (0.0) 2 (0.1) 3 (0.3) 71 (5.0) 931 (66.6) 459 (96.9) 39 (99.5) 4 (99.7) 2 (99.9) 1 (99.9) 0 (99.9) 1 (100.0) 0.5 1 P/T-NS (458) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.2) 27 (6.1) 135 (35.6) 113 (60.3) 109 (84.1) 45 (93.9) 9 (95.9) 4 (96.7) 15 (100.0) 2 8 CAZ-NS, MEM-NS, P/T-NS (175) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 22 (12.6) 47 (39.4) 51 (68.6) 29 (85.1) 8 (89.7) 4 (92.0) 14 (100.0) 4 32 Cefepime-S (1,624) 0 (0.0) 2 (0.1) 3 (0.3) 71 (4.7) 955 (63.5) 534 (96.4) 49 (99.4) 9 (99.9) 0 (99.9) 0 (99.9) 0 (99.9) 1 (100.0) 0.5 1 Cefepime-NS (347) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.3) 3 (1.2) 60 (18.4) 103 (48.1) 104 (78.1) 47 (91.6) 10 (94.5) 4 (95.7) 15 (100.0) 4 8 Levofloxacin-S (1,477) 0 (0.0) 2 (0.1) 3 (0.3) 62 (4.5) 866 (63.2) 403 (90.5) 69 (95.1) 51 (98.6) 17 (99.7) 0 (99.7) 2 (99.9) 2 (100.0) 0.5 1 Levofloxacin-NS (494) 0 (0.0) 0 (0.0) 0 (0.0) 10 (2.0) 92 (20.7) 191 (59.3) 83 (76.1) 62 (88.7) 30 (94.7) 10 (96.8) 2 (97.2) 14 (100.0) 1 8 Gentamicin-S (1,758) 0 (0.0) 2 (0.1) 3 (0.3) 69 (4.2) 934 (57.3) 513 (86.5) 103 (92.4) 87 (97.3) 34 (99.3) 3 (99.4) 4 (99.7) 6 (100.0) 0.5 2 Gentamicin-NS (213) 0 (0.0) 0 (0.0) 0 (0.0) 3 (1.4) 24 (12.7) 81 (50.7) 49 (73.7) 26 (85.9) 13 (92.0) 7 (95.3) 0 (95.3) 10 (100.0) 1 8
to other agents (except colistin) that demonstrated reduced
sus-ceptibility (MDR/XDR)—22.6/9.1% ceftazidime-susceptible and
19.4/7.4% meropenem-susceptible
P. aeruginosa
(
Table 3
) isolates
and 22.0/2.3% ceftazidime-susceptible and 77.0/22.1%
mero-penem-susceptible
Enterobacteriaceae
isolates (
Table 1
). Overall,
in this U.S. surveillance study performed from 2011 through 2012,
15.7% of
P. aeruginosa
isolates were classified as MDR and 8.9%
were classified as XDR (
Table 3
), and 8.4% of
Enterobacteriaceae
isolates were classified as MDR and only 1.2% as XDR (
Table 1
).
Only one strain was classified as PDR. In this study, ceftolozane/
tazobactam activity was most compromised against the XDR
En-terobacteriaceae
(only 1.2% of
Enterobacteriaceae
isolates).
In summary, these data for ceftolozane/tazobactam that have
been collected over 2 years from 32 medical centers located across
all nine U.S. census regions demonstrate high potency and
broad-spectrum activity of this antibacterial agent tested against
contem-porary
Enterobacteriaceae
and
P. aeruginosa
strains. Importantly,
ceftolozane/tazobactam retained clear activity against many MDR
and XDR strains. The
in vitro
surveillance data presented here,
coupled with favorable results published from pharmacokinetic,
safety, animal infection, and
in vitro
studies (
15
,
17–20
), suggest
the potential usefulness of ceftolozane/tazobactam for the
treat-ment of some infections caused by MDR Gram-negative
organ-isms and warrant further clinical development.
ACKNOWLEDGMENTS
We express our appreciation to S. Benning, M. Stilwell, and M. Janecheck in the preparation of the manuscript and to the JMI staff members for scientific assistance in performing this study.
This study was funded by research grants from Cubist Pharmaceuti-cals (Lexington, MA). Cubist PharmaceutiPharmaceuti-cals was involved in the study design and decision to present these results. Cubist Pharmaceuticals had no involvement in the collection, analysis, or interpretation of data. JMI Laboratories, Inc., has received research and educational grants in 2009 to 2011 from Achaogen, Aires, American Proficiency Institute (API), Ana-cor, Astellas, AstraZeneca, Bayer, bioMérieux, Cempra, Cerexa, Contra-fect, Cubist Pharmaceuticals, Daiichi, Dipexium, Enanta, Furiex, Glaxo-SmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Paratek, Pfizer, PPD Therapeutics, Pre-mier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, ThermoFisher, TREK Diag-nostics, and some other corporations. Some JMI employees are advisors/ consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, J&J, and Theravance. In regard to speaker bureaus and stock options, we declare that we have no conflicts of interest.
REFERENCES
1.Sader HS, Rhomberg PR, Farrell DJ, Jones RN.2011. Antimicrobial
activity of CXA-101, a novel cephalosporin tested in combination with tazobactam againstEnterobacteriaceae,Pseudomonas aeruginosa, and Bac-teroides fragilisstrains having various resistance phenotypes. Antimicrob. Agents Chemother.55:2390 –2394.
2.Livermore DM, Mushtaq S, Ge Y, Warner M.2009. Activity of
cepha-losporin CXA-101 (FR264205) againstPseudomonas aeruginosaand Burk-holderia cepaciagroup strains and isolates. Int. J. Antimicrob. Agents34: 402– 406.
3.Moya B, Zamorano L, Juan C, Perez JL, Ge Y, Oliver A.2010. Activity
of a new cephalosporin, CXA-101 (FR264205), against beta-lactam-resistantPseudomonas aeruginosamutants selected in vitro and after an-tipseudomonal treatment of intensive care unit patients. Antimicrob. Agents Chemother.54:1213–1217.
4.Takeda S, Ishii Y, Hatano K, Tateda K, Yamaguchi K.2007. Stability of
FR264205 against AmpC beta-lactamase ofPseudomonas aeruginosa. Int. J. Antimicrob. Agents30:443– 445.
5.Bulik CC, Christensen H, Nicolau DP.2010. In vitro potency of
CXA-101, a novel cephalosporin, againstPseudomonas aeruginosadisplaying various resistance phenotypes, including multidrug resistance. Antimi-crob. Agents Chemother.54:557–559.
6.Giske CG, Ge J, Nordmann P.2009. Activity of cephalosporin CXA-101
(FR264205) and comparators against extended-spectrum-{beta}-lactamase-producing Pseudomonas aeruginosa. J. Antimicrob. Che-mother.64:430 – 431.
7.Titelman E, Karlsson IM, Ge Y, Giske CG.2011. In vitro activity of
CXA-101 plus tazobactam (CXA-201) against 14- and CTX-M-15-producingEscherichia coliandKlebsiella pneumoniae. Diagn. Micro-biol. Infect. Dis.70:137–141.
8.English AR, Retsema JA, Girard AE, Lynch JE, Barth WE.1978.
CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother.14:414 – 419.
9.Akova M, Yang Y, Livermore DM.1990. Interactions of tazobactam and
clavulanate with inducibly- and constitutively-expressed class I beta-lactamases. J. Antimicrob. Chemother.25:199 –208.
10. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno
R, Lipman J, Gomersall C, Sakr Y, Reinhart K, EPIC II Group of
Investigators.2009. International study of the prevalence and outcomes
of infection in intensive care units. JAMA302:2323–2329.
11. Rosenthal VD, Bijie H, Maki DG, Mehta Y, Apisarnthanarak A,
Me-deiros EA, Leblebicioglu H, Fisher D, Alvarez-Moreno C, Khader IA, Del Rocio Gonzalez Martinez M, Cuellar LE, Navoa-Ng JA, Abouqal R, Guanche Garcell H, Mitrev Z, Pirez Garcia MC, Hamdi A, Duenas L, Cancel E, Gurskis V, Rasslan O, Ahmed A, Kanj SS, Ugalde OC, Mapp T, Raka L, Yuet Meng C, Thu le TA, Ghazal S, Gikas A, Narvaez LP, Mejia N, Hadjieva N, Gamar Elanbya MO, Guzman Siritt ME,
Jayat-illeke K; INICC members. 2012. International Nosocomial Infection
Control Consortium (INICC) report, data summary of 36 countries, for 2004 –2009. Am. J. Infect. Control40:396 – 407.
12. Clinical and Laboratory Standards Institute.2012. M07-A9. Methods
for dilution antimicrobial susceptibility tests for bacteria that grow aero-bically; approved standard: ninth edition. Clinical and Laboratory Stan-dards Institute, Wayne, PA.
13. Clinical and Laboratory Standards Institute.2013. M100-S23.
Per-formance standards for antimicrobial susceptibility testing: 23rd infor-mational supplement. Clinical and Laboratory Standards Institute, Wayne, PA.
14. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske
CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Pater-son DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT,
Monnet DL.2012. Multidrug-resistant, extensively drug-resistant and
pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect.18: 268 –281.
15. Craig WA, Andes DR.28 December 2012. In vivo activities of
ceftolo-zane, a new cephalosporin, with and without tazobactam against Pseu-domonas aeruginosaand enterobacteriaceae, including strains with ex-tended-spectrum beta-lactamases, in the thighs of neutropenic mice. Antimicrob. Agents Chemother. doi:10.1128/AAC.01590-12.
16. EUCAST,January 2013. Breakpoint tables for interpretation of MICs and
zone diameters. Version 3.0.http://www.eucast.org/clinical_breakpoints/. Accessed 2 January 2013.
17. Ge Y, Whitehouse MJ, Friedland I, Talbot GH.2010. Pharmacokinetics
and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single- and multiple-dose intra-venous infusions. Antimicrob. Agents Chemother.54:3427–3431.
18. Chandorkar G, Huntington JA, Gotfried MH, Rodvold KA, Umeh O.
2012. Intrapulmonary penetration of ceftolozane/tazobactam and pipera-cillin/tazobactam in healthy adult subjects. J. Antimicrob. Chemother. 67:2463–2469.
19. Vanscoy B, Mendes RE, Castanheira M, McCauley J, Bhavnani SM,
Forrest A, Jones RN, Okusanya OO, Friedrich L, Steenbergen J,
Am-brose PG.2013. Relationship between ceftolozane/tazobactam exposure
and drug-resistance amplification in a hollow-fiber infection model. An-timicrob. Agents Chemother.57:4134 – 4138.
20. VanScoy B, Mendes RE, Nicasio AM, Castanheira M, Bulik CC,
Oku-sanya OO, Bhavnani SM, Forrest A, Jones RN, Friedrich LV,
Steenber-gen JN, Ambrose PG. 2013. Pharmacokinetics-pharmacodynamics of
tazobactam in combination with ceftolozane in an in vitro infection model. Antimicrob. Agents Chemother.57:2809 –2814.
Farrell et al.
