Clinical Therapeutics/Volume ], Number ], 2015
Susceptibility Profile of Ceftolozane/Tazobactam and Other Parenteral Antimicrobials Against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa From US Hospitals Christina A. Sutherland, BS1; and David P. Nicolau, PharmD1,2 1
Center for Anti-Infective Research and Development, Hartford, Connecticut; and 2Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut
ABSTRACT Purpose: Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are frequently isolated pathogens in the hospital setting, and antimicrobial resistance among these organisms is on the rise. In an attempt to meet the challenge of gram-negative resistance, new therapies, including ceftolozane/tazobactam (C/T), were recently approved by the Food and Drug Administration, and others are in late-stage development. The purpose of this study is to describe the in vitro potency of C/T and other parenteral antimicrobials against a geographically diverse population of E coli, K pneumoniae, and P aeruginosa collected in US hospitals. Methods: In 2013 to 2014, 44 hospitals provided nonduplicate, nonurine isolates of E coli (n ¼ 1306), K pneumoniae (n ¼ 1205), and P aeruginosa (n ¼ 1257) from adult inpatients. MICs for C/T and 11 other antimicrobials were determined with broth microdilution methods. Findings: The carbapenems, C/T, and colistin displayed the highest percentage of susceptibility and lowest MIC90 against the Enterobacteriaceae, followed by piperacillin/tazobactam (TZP), cefepime, tobramycin, aztreonam, ceftriaxone, and ciprofloxacin. C/T displayed the greatest potency (MIC90 ¼ 2 mg/L) and 97% susceptibility of all compounds against P aeruginosa. In addition, C/T was highly active against P aeruginosa that were nonsusceptible to the carbapenems or TZP or were multidrug resistant and extended-spectrum β-lactamase–producing Enterobacteriaceae. Implications: This national survey reported high levels of nonsusceptibility to antimicrobials among both Enterobacteriaceae and P aeruginosa. In contrast, many of these resistant pathogens were
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susceptible to C/T. These data highlight the enhanced potency of C/T and its potential utility for commonly encountered gram-negative nosocomial pathogens. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: ceftolozane/tazobactam, Enterobacteriaceae, Pseudomonas aeruginosa, resistance.
INTRODUCTION Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are among the most frequently recovered gram-negative bacteria in the hospital setting.1 These pathogens are implicated as important causes of infection-related morbidity and mortality for a wide range of infections. Still more concerning is that these gram-negative pathogens are becoming increasingly resistant to many antimicrobials used in the care of hospitalized patients.2 In an attempt to address this unmet medical need in the management of gram-negative infections, a variety of new medicines are under development. Recently, several of these agents are under review by the US Food and Drug Administration (FDA). Ceftolozane/tazobactam (C/T) was recently approved by the FDA for the indications of complicated intra-abdominal infections in combination with metronidazole and complicated urinary tract infections, including pyelonephritis.3 This new cephalosporin/ β-lactamase inhibitor has activity against P aeruginosa, including drug-resistant strains, and other common Accepted for publication May 20, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.501 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics gram-negative pathogens, including the extendedspectrum β-lactamase (ESBL)-producing Enterobacteriaceae, particularly E coli.4,5 Like other β-lactams, ceftolozane exerts its bactericidal activity by inhibiting essential penicillin-binding proteins, resulting in inhibition of cell-wall synthesis and subsequent cell death. Tazobactam, which was widely used in combination with piperacillin, inhibits most class A β-lactamases and some AmpC cephalosporinases (plasmid-mediated) class C β-lactamases and thus protects ceftolozane from hydrolysis and broadens coverage to include some ESBL-producing Enterobacteriaceae. Although active against many gram-negative pathogens, C/T does not display clinically relevant potency against carbapenemresistant Acinetobacter or carbapenemase-producing Enterobacteriaceae. As a result of escalating resistance and its impact on viable treatment options, it is imperative that national surveillance programs be undertaken to provide clinicians with susceptibility data that will assist their efforts to make sound choices for both empiric and directed antimicrobial therapy. The purpose of this study was to evaluate the in vitro potency of parenteral antimicrobials and the newly approved agent, C/T, against a geographically diverse population of E coli, K pneumoniae, and P aeruginosa from US hospitals.
METHODS Consecutive nonduplicate, nonurine isolates of E coli, K pneumoniae, and P aeruginosa that were obtained from adult hospitalized patients as part of their routine medical management were requested. Collection occurred between June 2013 and September 2014. Organisms were identified at each participating site by using the methods normally used by their laboratories and were transferred to trypticase soy agar slants for shipping. Once received at the central processing laboratory (Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut) isolates were transferred onto trypticase soy agar plates that contained 5% blood for MIC determination. ChromID agar (Biomerieux, Paris, France) was used to identify mixed or irregular-looking cultures. The MIC determinations for C/T, cefepime (FEP), ceftriaxone (CRO), ceftazidime (CAZ), ciprofloxacin (CIP), colistin (CST), aztreonam (ATM), ertapenem (ETP), imipenem (IPM), piperacillin/tazobactam (TZP),
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meropenem (MEM), and tobramycin (TOB) were undertaken with Clinical Laboratory Standards Institute (CLSI) broth microdilution methods.6,7 Cubist Pharmaceuticals (Lexington, Massachusetts) provided C/T; all others antibiotics were purchased from Sigma (St. Louis, Missouri). MIC trays were prepared with the Biomek 3000 (Beckman Instruments, Inc, Fullerton, California). As recommended by CLSI, E coli 25922 and P aeruginosa 27853 were used as quality control strains, and colony counts were performed on each isolate to verify the correct inoculum. When available, the CLSI interpretative susceptibility criteria were used for each agent. Because no CST susceptibility breakpoints were established for E coli and K pneumoniae, the 2-mg/L cutoff value for P aeruginosa was applied to the Enterobacteriaceae. For C/T the FDA breakpoints of 2 mg/L for E coli and K pneumoniae and 4 mg/L for P aeruginosa were used.3,7 P aeruginosa were classified as multidrug resistant (MDR) if they displayed resistance to Z3 classes as represented by the following phenotypic resistance profiles: CIP, MIC Z 4 mg/L; IPM, MIC Z 8 mg/L; CAZ, MIC Z 32 mg/L; TZP, MIC Z 128 mg/L; and TOB, MIC Z 16 mg/L.8 A positive ESBL screen was defined as an organism with an MIC of Z1 mg/L to 2 of the following: ATM, CRO, or CAZ. Subsequent CLSI-defined ESBL confirmation studies were undertaken with CAZ and cefotaxime with and without clavulanate. CLSIdefined phenotypic confirmation studies that used clavulanic acid were undertaken for only the E coli and K pneumoniae that screened positive for ESBL production.9 In addition, isolates testing nonsusceptible (NS) to ETP, IPM, or MEM were evaluated for carbapenemase production by using the CarbaNP test.7 Carbapenemase production was not assessed in the P aeruginosa isolates.
RESULTS Forty-four hospitals, approximately equally divided across the East Coast, Central Region, and Western United States, provided 3759 nonduplicate, nonurine isolates as follows: E coli (n ¼ 1306), K pneumoniae (n ¼ 1205), and P aeruginosa (n ¼ 1257). Two thirds of the hospitals were classified as university teaching, and the remaining were community hospitals. The Enterobacteriaceae/P aeruginosa were obtained from the following sources (% of isolates): blood, 43%/14%;
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C.A. Sutherland and D.P. Nicolau respiratory tract, 18%/39%; wound, 18%/30%; body fluid, 11%/5%; and other, 10%/12%. Seventy-three percent of both the Enterobacteriaceae and P aeruginosa were collected from patients who resided outside the intensive care unit (ICU). The MIC90 and percentage of susceptibility for E coli and K pneumoniae are shown in Table I. For the Enterobacteriaceae, the highest susceptibility was displayed by CST (96%–98%), MEM (93%–99%), IPM (92%–98%), ETP (91%–98%), and C/T (89%– 98%) (Table I). The MIC distributions for E coli and K pneumoniae against the tested agents are shown in Tables II and III. Overall these data reveal that for the Enterobacteriaceae most MICs for the tested compounds fall a dilution or 2 below the susceptibility breakpoint, the exception to this is seen with ETP. In addition, we did not observe a difference in the susceptibility profile of the test agents for E coli or K pneumoniae that isolates within or outside the ICU. Of the 2511 Enterobacteriaceae collected, 442 (18%) of these isolates screened positive for ESBL production (E coli [n = 231] and K pneumoniae [n = 211]). Of these, 274 isolates or 11% of the total population, 146 for E coli and 128 for K pneumoniae, were confirmed positive for ESBL production. When considering only the Enterobacteriaceae-confirmed ESBL-positive isolates in the absence of detectable carbapenemases, the rank order susceptibility of the conventional non-carbapenem agents was as follows:
C/T, 82%; TZP, 67%; TOB, 42%; CIP, 13%; FEP, 9%; CAZ, 9%; ATM, 7%; and CRO, 2%. Although the C/T MIC90 was 16 mg/L for these ESBL-positive isolates, 71% of these organisms had MICs r 1 mg/L, 5% were 2 mg/L, 7% were 4 mg/L, and 6% were 8 mg/L. Of the total Enterobacteriaceae isolates collected, 127 (5%) were defined as NS to the carbapenems. Of these isolates, 4 E coli and 69 K pneumoniae were positive by using CarbaNP test. Because the β-lactams and C/T were not expected to have activity against these carbapenem-resistant Enterobacteriaceae, we evaluated the potency of non–β-lactam alternatives. The susceptibility of CST, CIP, and TOB for these isolates were 82%, 13%, and 0%, respectively. In addition, 194 Enterobacteriaceae (105 E coli and 89 K pneumoniae) were found to be NS to TZP. For this population of organisms E coli had 89% susceptibility to C/T and the K pneumoniae had 73% susceptibility. Among the P aeruginosa, C/T displayed (Table I) the greatest degree of susceptibility at 97% and potency (MIC90 ¼ 2 mg/L). The antipseudomonal potency of the test agents was further delineated in the MIC distributions as shown in Table IV. Ten percent (n ¼ 122) of the P aeruginosa population was defined as MDR. In this subset of MDR isolates, rank order of susceptibility was as follows: CST, 96% (MIC90 ¼ 2 mg/L); C/T, 77% (MIC90 ¼ 64 mg/L); TOB, 47% (MIC90 ¼ 128 mg/L); ATM,
Table I. MIC90 and percentage of susceptibility for Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
E coli (n ¼ 1306) MIC90, mg/L Susceptibility, % K pneumonia (n ¼ 1205) MIC90, mg/L Susceptibility, % P aeruginosa (n ¼ 1257) MIC90, mg/L Susceptibility, %
C/T
FEP
CRO
CAZ
CIP
CST
ATM
ETP
IPM
TZP
MEM
TOB
0.5 98
32 87
128 84
16 86
32 65
1 98
32 86
0.03 98
0.5 99
16 91
0.064 99
16 84
4 89
64 85
128 83
64 83
32 82
1 96
64 84
0.25 90
1 92
256 85
0.125 93
16 86
2 97
32 77
NT
64 77
16 72
2 96
32 70
NT
16 68
128 72
16 76
4 92
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CRO ¼ ceftriaxone; CST ¼ colistin; C/T ¼ ceftolozane/ tazobactam; ETP ¼ ertapenem; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; NT ¼ not tested; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam.
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Table II. Percentage of Escherichia coli inhibited at each MIC cutoff for the tested antimicrobials. MIC, mg/L
C/T
FEP
CRO
CAZ
CIP
CST
ATM
ETP
IMI
TZP
MEM
TOB
r0.5 1 2 4 8 16 Z32
93 4 1* 0 1 0 1
83 2 2* 0 1 1 11
83 1* 1 1 1 0 13
75 6 3 2* 2 2 10
64 1* 0 1 1 3 29
70 27 1* 1 0 0 1
82 1 2 1* 2 2 10
98* 0 1 0 0 0 1
96 3* 1 0 0 0 0
1 10 46 22 8 4* 9
99 0* 0 0 0 0 1
4 41 35 4* 3 5 8
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CRO ¼ ceftriaxone; CST ¼ colistin; C/T ¼ ceftolozane/ tazobactam; ETP ¼ ertapenem; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam. * Susceptibility cutoff MIC value for each compound.
17% (MIC90 ¼ 128 mg/L); IPM, 14% (MIC90 ¼ 32 mg/L); MEM, 14% (MIC90 ¼ 64 mg/L); CIP, 12% (MIC90 ¼ 32 mg/L); FEP, 10% (MIC90 ¼ 128 mg/L); CAZ, 7% (MIC90 ¼ 128 mg/L); and TZP, 5% (MIC90 ¼ 512 mg/L). Although the MIC90 was 64 mg/L for C/T, 28% of these organisms had MICs r 1 mg/L, 25% were 2 mg/L, 24% were 4 mg/L, and 7% were 8 mg/L. When considering carbapenems, 31% (n ¼ 392) of the P aeruginosa were NS, defined as an MIC Z 4 mg/L to IPM. For this highly resistant population, CST and C/T displayed the highest potency with susceptibility of 96% and 93%, respectively, followed by TOB at
81%. All other agents, consisting of representative examples across classes, were found to have o60% susceptibility. In this subset of isolates, rank order susceptibility was as follows: CST, 96% (MIC90 ¼ 2 mg/L); C/T, 93% (MIC90 ¼ 4 mg/L); TOB, 81% (MIC90 ¼ 32 mg/L); FEP, 56% (MIC90 ¼ 32 mg/L); CAZ, 56% (MIC90 ¼ 128 mg/L); ATM, 54% (MIC90 ¼ 64 mg/L); TZP, 48% (MIC90 ¼ 256 mg/L); CIP, 46% (MIC90 ¼ 32 mg/L); and MEM, 34% (MIC90 ¼ 32 mg/L). Within the P aeruginosa population, 330 isolates (26%) displayed a phenotypic profile of nonsusceptibility
Table III. Percentage of K. pneumoniae inhibited at each MIC for the tested antimicrobials. MIC, mg/L
C/T
FEP
CRO
CAZ
CIP
CST
ATM
ETP
IMI
TZP
MEM
TOB
r0.5 1 2 4 8 16 Z32
80 8 1* 1 1 1 8
82 2 1* 1 1 1 12
82 1* 1 0 0 1 15
73 7 2 1* 1 1 15
80 2* 1 2 2 1 12
83 11 2* 1 1 1 1
82 1 1 0* 1 1 14
90* 2 0 1 0 1 6
78 14* 2 0 1 1 4
1 3 28 36 12 5* 15
92 1* 0 0 1 1 5
74 11 1 0* 2 5 7
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CRO ¼ ceftriaxone; CST ¼ colistin; C/T ¼ ceftolozane/ tazobactam; ETP ¼ ertapenem; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam. * Susceptibility cut-off MIC value for each compound.
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C.A. Sutherland and D.P. Nicolau
Table IV. Percentage of Pseudomonas aeruginosa inhibited at each MIC for the tested antimicrobials. MIC, mg/L
C/T
FEP
CAZ
CIP
CST
ATM
IMI
TZP
MEM
TOB
r1 2 4 8 16 Z32
83 9 5* 1 1 1
12 31 17 17* 12 11
6 34 26 11* 7 16
72* 5 6 4 5 8
86 10* 2 1 0 1
6 4 32 28* 13 17
47 21* 9 5 10 8
4 2 25 29 12* 28
66 10* 6 5 7 6
81 8 3* 1 1 6
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CST ¼ colistin; C/T ¼ ceftolozane/tazobactam; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam. * Susceptibility cut-off MIC value for each compound.
to TZP (MIC Z 32 mg/L). For these pseudomonal isolates, C/T was found to have 89% susceptibility with 75% of the isolates having an MIC r 2 mg/L (Table IV). Unlike the Enterobacteriaceae, we noted differing susceptibility profiles for Pseudomonas derived from the ICU and non-ICU setting. The susceptibility profile of FEP, CAZ, ATM, TZP, IMP, and MEM was 5% to 12% lower in Pseudomonas isolates from patients in the ICU. In contrast, little difference was observed between the potency of ICU and non-ICU P aeruginosa for C/T, CST, TOB, and CIP, although the overall susceptibility of CIP at 71% to 73% was much lower than the other 3 agents. In this subset of isolates, susceptibility (ICU vs non-ICU) was as follows: 95% versus 97% for CST, 95% versus 97% for C/T, 88% versus 93% for TOB, 72% versus 79% for FEP, 71% versus 73% for CIP, 70% versus 78% for MEM, 69% versus 80% for CAZ, 64% versus 72% for ATM, and 63% versus 75% for TZP.
DISCUSSION Over the past decade, the evolution of resistance in gramnegative pathogens has made the medical management of the infected patient increasingly challenging. It is for this reason that efforts to develop new antimicrobials were fostered by collaboration among government entities, the infectious diseases community, and the pharmaceutical industry.2 As a product of these collective efforts, C/T is the first agent to be approved by the FDA for clinical use. In addition to new therapies, it is also important to have contemporary surveillance data that reflect the current susceptibility of agents and new therapies.
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With the use of an isolate collection from 2011 to 2012, Farrell et al10 reported the antimicrobial activity of C/T against Enterobacteriaceae and P aeruginosa from US hospitals. When considering their E coli and K pneumoniae data with the use of the current FDA susceptibility breakpoint, C/T displayed 99% and 87% values, respectively, which are similar to those reported in our present study. Because of their escalating prevalence across the United States, ESBL-producing pathogens are an increasing clinical concern. In the earlier single center study by Titelman et al5 with ESBL-positive E coli (n ¼ 149) and K pneumoniae (n ¼ 20) predominantly due to CTX-M-14 or CTX-M-15, reported 93% C/T susceptibility with the use of the current FDA breakpoint. Although this value is similar to that reported for E coli (88%) in the previous 2011 to 2012 dataset, the 30% value for K pneumoniae in the 2011 to 2012 dataset is discordant with the earlier report.5,10 This inconsistency between the K pneumoniae in the 2 studies may be due to the differing ESBL enzyme composition among the K pneumoniae isolates. The 2011 to 2012 study did not use confirmation testing; as a result the K pneumoniae population in this study may have also included carbapenemases. Against the composite of phenotypically confirmed ESBL-positive Enterobacteriaceae derived from our more recent survey, the susceptibility of C/T was 82%. Although other agents are often considered active, only 67% of the ESBL-positive Enterobacteriaceae isolates in this study were susceptible to TZP, and the activity profiles of TOB, FEP, and CIP suggest a diminished role for empirical therapy with the use of conventional
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Clinical Therapeutics regimens. Although in vitro potency is only 1 variable in the clinical setting, recent data from Phase III trials have reported successful outcomes when C/T was used for ESBL infections.3 Previously, we have reported that ceftolozane alone or in combination with tazobactam displayed high in vitro potency against P aeruginosa with a variety of phenotypic resistance profiles, including isolates defined as MDR.8 In this study, C/T exhibited the highest percentage of susceptibility and the greatest potency among the 10 antimicrobials tested. Aside from C/T, all other β-lactams displayed relatively poor potency against this distribution of clinical P aeruginosa isolates with MIC90 values 3- to 4-fold greater than their respective breakpoints. CIP was among the least potent of the agents tested. MDR among pathogens, defined as resistance to Z3 antimicrobial classes, is an increasingly prevalent entity in hospitalized patients. Although Enterobacteriaceae with enzyme-mediated resistance and Acinetobacter spp may satisfy this criterion, P aeruginosa is a nosocomial pathogen that has a history of intrinsic or developed resistance to many commonly used agents. As such, this organism is frequently considered among the most difficult-totreat MDR pathogens.11 In our recent collection of P aeruginosa, 10% were MDR on the basis of therapeutic benchmarks. Although CST displayed the highest susceptibility (96%) and lowest MIC90 value (2 mg/L), concerns related to its pharmacodynamic optimization and toxicity make alternative therapies a necessity. C/T appears to retain in vitro activity against the majority (77%) of these MDR P aeruginosa, whereas other agents tested had susceptibility of 5% to 47%. Moreover, the activity of C/T against MDR P aeruginosa appears stable because our reported susceptibility is similar to the 79% reported in the 2011 to 2012 survey.10 Assessment of C/T potency against another distribution of P aeruginosa from a Canadian study found similar results to this present study.12 Susceptibility for C/T against all P aeruginosa isolates was 98% in the Canadian study and 97% in this present study. For P aeruginosa that were NS to the carbapenems the susceptibility for C/T in these isolates was 95% in the Canadian study and 93% in this present study. When considering TZP NS P aeruginosa, similar susceptibilities were observed in the Canadian study and this present survey (92% vs 89%).
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Because of the increasing prevalence of enzymemediated mechanisms in Enterobacteriaceae and MDR P aeruginosa, the use of the group 2 carbapenems (ie, IPM, MEM, and doripenem) both as empiric and directed therapy has increased dramatically over the past decade. Because C/T may be considered as an option in patients previously exposed to carbapenems, we also evaluated the phenotypic profile of C/T and comparators against a collection of P aeruginosa defined as NS to the class representative, IPM. In our survey the prevalence of carbapenem-NS P aeruginosa was unexpectedly high because nearly one third of these recently collected nonurine isolates displayed nonsusceptibility to IPM. Against this collection of resistant P aeruginosa, only CST and C/T exhibited susceptibility rates of Z90%. Importantly, this value is similar to the 85% value reported in the 2011 to 2012 survey against MEM-NS P aeruginosa.10 As a result of wide-scale use of TZP in the hospital setting, the prevalence of NS gram-negative pathogens has risen sharply. Because C/T may be considered in patients previously exposed to TZP, we assessed the in vitro potency of C/T against this phenotypic profile. Against this collection of gram-negative isolates, C/T exhibited a susceptibility profile of 75% and 89% for the Enterobacteriaceae and P aeruginosa, respectively. Although not reported for Enterobacteriaceae, our finding of 89% susceptibility for TZP-NS P aeruginosa is similar to the 84% previously reported for C/T from 2011 to 2012.10 Moreover, the compound displayed considerable potency because most MICs were r2 mg/L. In areas of the world where high rates of nonsusceptibility to TZP were observed in the 3 gram-negative species studied, C/T may be considered a potent therapeutic alternative. Although C/T displayed enhanced potency for the organisms tested, note that the compound was not active against all ESBL-producing bacteria nor would it be expected to be active against carbapenemresistant Enterobacteriaceae or Acinetobacter species. As with any new antibiotic, susceptibility patterns could change with continued used, and as such continual monitoring of C/T activity is suggested. In addition, antimicrobial stewardship programs will be an important tool to ensure that C/T is used appropriately and thus will retain high potency for years to come. Although the study provides potency data for a variety of conventional antimicrobials used in
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C.A. Sutherland and D.P. Nicolau clinical practice, amikacin was not included in our testing protocol; thus, note that this agent may have retained activity against some of the MDR P aeruginosa. In addition, a limitation of the study was that we did not execute molecular testing on CarbaNP-positive isolates to confirm the genotypic profile of these organisms. Moreover, the CarbaNP test performed here may miss low-level carbapenemase activity mediated by metallo β-lactamases (IMP, VIM, NDM) and by the Ambler class D OXA β-lactamases. Although this study included a geographically diverse population of US hospitals, local susceptibility could differ markedly.
CONCLUSION Increasing resistance and its impact on the clinical utility of conventional antimicrobials is among the most concerning and challenging obstacles to the optimal care of the infected patient. Data derived from this contemporary surveillance program highlight the increasing resistance among the commonly used parenteral gram-negative therapies and the relative enhanced potency of C/T. Although this contemporary potency information supports the clinical usefulness of C/T, appropriate use of the compound in the patient care setting is required to maximize patient outcomes and to minimize the development of resistance.
ACKNOWLEDGMENTS We thank Mary Anne Banevicius, Henry Christensen, Jennifer Hull, Lucinda Lamb, Sara Robinson, Debra Santini, and Pamela Tessier for their collective efforts with MIC determination. This study was supported by a grant from Cubist Pharmaceuticals, Lexington, Massachusetts. Christina Sutherland and David Nicolau worked on the study design, data collection and interpretation, analysis, and writing of this project.
CONFLICTS OF INTEREST Cubist Pharmaceuticals was not involved in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. D.P. Nicolau has received research grants and is on the speakers’ bureau of Cubist Pharmaceuticals. The authors have indicated that they
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have no other conflicts of interest regarding the content of this article.
REFERENCES 1. Sievert DM, Ricks P, Edwards JR, et al. National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009– 2010. Infect Control Hosp Epidemiol. 2013;34:1–14. 2. Boucher HW, Talbot GH, Benjamin DK Jr, et al. Infectious Diseases Society of America. 10 x 20 Progress–development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56:1685–1694. 3. ZERBAXA (ceftolozane/tazobactam) for injection, for intravenous use. Initial U.S. approval 2014. Lexington, Mass: Cubist Pharmaceuticals; 2014. 4. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother. 2011;55:2390–2394. 5. Titelman E, Karlsson IM, Ge Y, Giske CG. In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Diagn Microbiol Infect Dis. 2011;70:137–141. 6. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. CLSI document M07-A9. Wayne, Pa: Clinical and Laboratory Standards Institute; 2012. 7. Clinical and Laboratory Standards Institute. 2014. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. CLSI document M100-S24 U. Wayne, Pa: Clinical and Laboratory Standards Institute; 2014. 8. Bulik CC, Christensen H, Nicolau DP. In vitro potency of CXA-101, a novel cephalosporin, against Pseudomonas aeruginosa displaying various resistance phenotypes, including multidrug resistance. Antimicrob Agents Chemother. 2010;54:557–559. 9. Dortet L, Poirel L, Nordmann P. Rapid identification of carbapenemase types in Enterobacteriaceae and Pseudomonas spp. by using a biochemical test. Antimicrob Agents Chemother. 2012;56:6437–6440. 10. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (2011– 2012). Antimicrob Agents Chemother. 2013;57:6305–6310.
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Clinical Therapeutics 11. Thabit AK, Crandon JL, Nicolau DP. Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. Expert Opin Pharmacother. 2015;16:159–177. 12. Walkty A, Karlowsky JA, Adam H, et al. In vitro activity of ceftolozanetazobactam against Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals in the CANWARD study, 2007 to 2012. Antimicrob Agents Chemother. 2013;57:5707–5709.
Address correspondence to: David P. Nicolau, PharmD, FCCP, FIDSA, Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102. E-mail: david.nicolau@ hhchealth.org
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Susceptibility Profile of Ceftolozane/Tazobactam and Other Parenteral Antimicrobials Against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa From US Hospitals Christina A. Sutherland, BS1; and David P. Nicolau, PharmD1,2 1
Center for Anti-Infective Research and Development, Hartford, Connecticut; and 2Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut
ABSTRACT Purpose: Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are frequently isolated pathogens in the hospital setting, and antimicrobial resistance among these organisms is on the rise. In an attempt to meet the challenge of gram-negative resistance, new therapies, including ceftolozane/tazobactam (C/T), were recently approved by the Food and Drug Administration, and others are in late-stage development. The purpose of this study is to describe the in vitro potency of C/T and other parenteral antimicrobials against a geographically diverse population of E coli, K pneumoniae, and P aeruginosa collected in US hospitals. Methods: In 2013 to 2014, 44 hospitals provided nonduplicate, nonurine isolates of E coli (n ¼ 1306), K pneumoniae (n ¼ 1205), and P aeruginosa (n ¼ 1257) from adult inpatients. MICs for C/T and 11 other antimicrobials were determined with broth microdilution methods. Findings: The carbapenems, C/T, and colistin displayed the highest percentage of susceptibility and lowest MIC90 against the Enterobacteriaceae, followed by piperacillin/tazobactam (TZP), cefepime, tobramycin, aztreonam, ceftriaxone, and ciprofloxacin. C/T displayed the greatest potency (MIC90 ¼ 2 mg/L) and 97% susceptibility of all compounds against P aeruginosa. In addition, C/T was highly active against P aeruginosa that were nonsusceptible to the carbapenems or TZP or were multidrug resistant and extended-spectrum β-lactamase–producing Enterobacteriaceae. Implications: This national survey reported high levels of nonsusceptibility to antimicrobials among both Enterobacteriaceae and P aeruginosa. In contrast, many of these resistant pathogens were
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susceptible to C/T. These data highlight the enhanced potency of C/T and its potential utility for commonly encountered gram-negative nosocomial pathogens. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: ceftolozane/tazobactam, Enterobacteriaceae, Pseudomonas aeruginosa, resistance.
INTRODUCTION Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are among the most frequently recovered gram-negative bacteria in the hospital setting.1 These pathogens are implicated as important causes of infection-related morbidity and mortality for a wide range of infections. Still more concerning is that these gram-negative pathogens are becoming increasingly resistant to many antimicrobials used in the care of hospitalized patients.2 In an attempt to address this unmet medical need in the management of gram-negative infections, a variety of new medicines are under development. Recently, several of these agents are under review by the US Food and Drug Administration (FDA). Ceftolozane/tazobactam (C/T) was recently approved by the FDA for the indications of complicated intra-abdominal infections in combination with metronidazole and complicated urinary tract infections, including pyelonephritis.3 This new cephalosporin/ β-lactamase inhibitor has activity against P aeruginosa, including drug-resistant strains, and other common Accepted for publication May 20, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.501 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics gram-negative pathogens, including the extendedspectrum β-lactamase (ESBL)-producing Enterobacteriaceae, particularly E coli.4,5 Like other β-lactams, ceftolozane exerts its bactericidal activity by inhibiting essential penicillin-binding proteins, resulting in inhibition of cell-wall synthesis and subsequent cell death. Tazobactam, which was widely used in combination with piperacillin, inhibits most class A β-lactamases and some AmpC cephalosporinases (plasmid-mediated) class C β-lactamases and thus protects ceftolozane from hydrolysis and broadens coverage to include some ESBL-producing Enterobacteriaceae. Although active against many gram-negative pathogens, C/T does not display clinically relevant potency against carbapenemresistant Acinetobacter or carbapenemase-producing Enterobacteriaceae. As a result of escalating resistance and its impact on viable treatment options, it is imperative that national surveillance programs be undertaken to provide clinicians with susceptibility data that will assist their efforts to make sound choices for both empiric and directed antimicrobial therapy. The purpose of this study was to evaluate the in vitro potency of parenteral antimicrobials and the newly approved agent, C/T, against a geographically diverse population of E coli, K pneumoniae, and P aeruginosa from US hospitals.
METHODS Consecutive nonduplicate, nonurine isolates of E coli, K pneumoniae, and P aeruginosa that were obtained from adult hospitalized patients as part of their routine medical management were requested. Collection occurred between June 2013 and September 2014. Organisms were identified at each participating site by using the methods normally used by their laboratories and were transferred to trypticase soy agar slants for shipping. Once received at the central processing laboratory (Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut) isolates were transferred onto trypticase soy agar plates that contained 5% blood for MIC determination. ChromID agar (Biomerieux, Paris, France) was used to identify mixed or irregular-looking cultures. The MIC determinations for C/T, cefepime (FEP), ceftriaxone (CRO), ceftazidime (CAZ), ciprofloxacin (CIP), colistin (CST), aztreonam (ATM), ertapenem (ETP), imipenem (IPM), piperacillin/tazobactam (TZP),
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meropenem (MEM), and tobramycin (TOB) were undertaken with Clinical Laboratory Standards Institute (CLSI) broth microdilution methods.6,7 Cubist Pharmaceuticals (Lexington, Massachusetts) provided C/T; all others antibiotics were purchased from Sigma (St. Louis, Missouri). MIC trays were prepared with the Biomek 3000 (Beckman Instruments, Inc, Fullerton, California). As recommended by CLSI, E coli 25922 and P aeruginosa 27853 were used as quality control strains, and colony counts were performed on each isolate to verify the correct inoculum. When available, the CLSI interpretative susceptibility criteria were used for each agent. Because no CST susceptibility breakpoints were established for E coli and K pneumoniae, the 2-mg/L cutoff value for P aeruginosa was applied to the Enterobacteriaceae. For C/T the FDA breakpoints of 2 mg/L for E coli and K pneumoniae and 4 mg/L for P aeruginosa were used.3,7 P aeruginosa were classified as multidrug resistant (MDR) if they displayed resistance to Z3 classes as represented by the following phenotypic resistance profiles: CIP, MIC Z 4 mg/L; IPM, MIC Z 8 mg/L; CAZ, MIC Z 32 mg/L; TZP, MIC Z 128 mg/L; and TOB, MIC Z 16 mg/L.8 A positive ESBL screen was defined as an organism with an MIC of Z1 mg/L to 2 of the following: ATM, CRO, or CAZ. Subsequent CLSI-defined ESBL confirmation studies were undertaken with CAZ and cefotaxime with and without clavulanate. CLSIdefined phenotypic confirmation studies that used clavulanic acid were undertaken for only the E coli and K pneumoniae that screened positive for ESBL production.9 In addition, isolates testing nonsusceptible (NS) to ETP, IPM, or MEM were evaluated for carbapenemase production by using the CarbaNP test.7 Carbapenemase production was not assessed in the P aeruginosa isolates.
RESULTS Forty-four hospitals, approximately equally divided across the East Coast, Central Region, and Western United States, provided 3759 nonduplicate, nonurine isolates as follows: E coli (n ¼ 1306), K pneumoniae (n ¼ 1205), and P aeruginosa (n ¼ 1257). Two thirds of the hospitals were classified as university teaching, and the remaining were community hospitals. The Enterobacteriaceae/P aeruginosa were obtained from the following sources (% of isolates): blood, 43%/14%;
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C.A. Sutherland and D.P. Nicolau respiratory tract, 18%/39%; wound, 18%/30%; body fluid, 11%/5%; and other, 10%/12%. Seventy-three percent of both the Enterobacteriaceae and P aeruginosa were collected from patients who resided outside the intensive care unit (ICU). The MIC90 and percentage of susceptibility for E coli and K pneumoniae are shown in Table I. For the Enterobacteriaceae, the highest susceptibility was displayed by CST (96%–98%), MEM (93%–99%), IPM (92%–98%), ETP (91%–98%), and C/T (89%– 98%) (Table I). The MIC distributions for E coli and K pneumoniae against the tested agents are shown in Tables II and III. Overall these data reveal that for the Enterobacteriaceae most MICs for the tested compounds fall a dilution or 2 below the susceptibility breakpoint, the exception to this is seen with ETP. In addition, we did not observe a difference in the susceptibility profile of the test agents for E coli or K pneumoniae that isolates within or outside the ICU. Of the 2511 Enterobacteriaceae collected, 442 (18%) of these isolates screened positive for ESBL production (E coli [n = 231] and K pneumoniae [n = 211]). Of these, 274 isolates or 11% of the total population, 146 for E coli and 128 for K pneumoniae, were confirmed positive for ESBL production. When considering only the Enterobacteriaceae-confirmed ESBL-positive isolates in the absence of detectable carbapenemases, the rank order susceptibility of the conventional non-carbapenem agents was as follows:
C/T, 82%; TZP, 67%; TOB, 42%; CIP, 13%; FEP, 9%; CAZ, 9%; ATM, 7%; and CRO, 2%. Although the C/T MIC90 was 16 mg/L for these ESBL-positive isolates, 71% of these organisms had MICs r 1 mg/L, 5% were 2 mg/L, 7% were 4 mg/L, and 6% were 8 mg/L. Of the total Enterobacteriaceae isolates collected, 127 (5%) were defined as NS to the carbapenems. Of these isolates, 4 E coli and 69 K pneumoniae were positive by using CarbaNP test. Because the β-lactams and C/T were not expected to have activity against these carbapenem-resistant Enterobacteriaceae, we evaluated the potency of non–β-lactam alternatives. The susceptibility of CST, CIP, and TOB for these isolates were 82%, 13%, and 0%, respectively. In addition, 194 Enterobacteriaceae (105 E coli and 89 K pneumoniae) were found to be NS to TZP. For this population of organisms E coli had 89% susceptibility to C/T and the K pneumoniae had 73% susceptibility. Among the P aeruginosa, C/T displayed (Table I) the greatest degree of susceptibility at 97% and potency (MIC90 ¼ 2 mg/L). The antipseudomonal potency of the test agents was further delineated in the MIC distributions as shown in Table IV. Ten percent (n ¼ 122) of the P aeruginosa population was defined as MDR. In this subset of MDR isolates, rank order of susceptibility was as follows: CST, 96% (MIC90 ¼ 2 mg/L); C/T, 77% (MIC90 ¼ 64 mg/L); TOB, 47% (MIC90 ¼ 128 mg/L); ATM,
Table I. MIC90 and percentage of susceptibility for Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
E coli (n ¼ 1306) MIC90, mg/L Susceptibility, % K pneumonia (n ¼ 1205) MIC90, mg/L Susceptibility, % P aeruginosa (n ¼ 1257) MIC90, mg/L Susceptibility, %
C/T
FEP
CRO
CAZ
CIP
CST
ATM
ETP
IPM
TZP
MEM
TOB
0.5 98
32 87
128 84
16 86
32 65
1 98
32 86
0.03 98
0.5 99
16 91
0.064 99
16 84
4 89
64 85
128 83
64 83
32 82
1 96
64 84
0.25 90
1 92
256 85
0.125 93
16 86
2 97
32 77
NT
64 77
16 72
2 96
32 70
NT
16 68
128 72
16 76
4 92
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CRO ¼ ceftriaxone; CST ¼ colistin; C/T ¼ ceftolozane/ tazobactam; ETP ¼ ertapenem; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; NT ¼ not tested; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam.
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Table II. Percentage of Escherichia coli inhibited at each MIC cutoff for the tested antimicrobials. MIC, mg/L
C/T
FEP
CRO
CAZ
CIP
CST
ATM
ETP
IMI
TZP
MEM
TOB
r0.5 1 2 4 8 16 Z32
93 4 1* 0 1 0 1
83 2 2* 0 1 1 11
83 1* 1 1 1 0 13
75 6 3 2* 2 2 10
64 1* 0 1 1 3 29
70 27 1* 1 0 0 1
82 1 2 1* 2 2 10
98* 0 1 0 0 0 1
96 3* 1 0 0 0 0
1 10 46 22 8 4* 9
99 0* 0 0 0 0 1
4 41 35 4* 3 5 8
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CRO ¼ ceftriaxone; CST ¼ colistin; C/T ¼ ceftolozane/ tazobactam; ETP ¼ ertapenem; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam. * Susceptibility cutoff MIC value for each compound.
17% (MIC90 ¼ 128 mg/L); IPM, 14% (MIC90 ¼ 32 mg/L); MEM, 14% (MIC90 ¼ 64 mg/L); CIP, 12% (MIC90 ¼ 32 mg/L); FEP, 10% (MIC90 ¼ 128 mg/L); CAZ, 7% (MIC90 ¼ 128 mg/L); and TZP, 5% (MIC90 ¼ 512 mg/L). Although the MIC90 was 64 mg/L for C/T, 28% of these organisms had MICs r 1 mg/L, 25% were 2 mg/L, 24% were 4 mg/L, and 7% were 8 mg/L. When considering carbapenems, 31% (n ¼ 392) of the P aeruginosa were NS, defined as an MIC Z 4 mg/L to IPM. For this highly resistant population, CST and C/T displayed the highest potency with susceptibility of 96% and 93%, respectively, followed by TOB at
81%. All other agents, consisting of representative examples across classes, were found to have o60% susceptibility. In this subset of isolates, rank order susceptibility was as follows: CST, 96% (MIC90 ¼ 2 mg/L); C/T, 93% (MIC90 ¼ 4 mg/L); TOB, 81% (MIC90 ¼ 32 mg/L); FEP, 56% (MIC90 ¼ 32 mg/L); CAZ, 56% (MIC90 ¼ 128 mg/L); ATM, 54% (MIC90 ¼ 64 mg/L); TZP, 48% (MIC90 ¼ 256 mg/L); CIP, 46% (MIC90 ¼ 32 mg/L); and MEM, 34% (MIC90 ¼ 32 mg/L). Within the P aeruginosa population, 330 isolates (26%) displayed a phenotypic profile of nonsusceptibility
Table III. Percentage of K. pneumoniae inhibited at each MIC for the tested antimicrobials. MIC, mg/L
C/T
FEP
CRO
CAZ
CIP
CST
ATM
ETP
IMI
TZP
MEM
TOB
r0.5 1 2 4 8 16 Z32
80 8 1* 1 1 1 8
82 2 1* 1 1 1 12
82 1* 1 0 0 1 15
73 7 2 1* 1 1 15
80 2* 1 2 2 1 12
83 11 2* 1 1 1 1
82 1 1 0* 1 1 14
90* 2 0 1 0 1 6
78 14* 2 0 1 1 4
1 3 28 36 12 5* 15
92 1* 0 0 1 1 5
74 11 1 0* 2 5 7
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CRO ¼ ceftriaxone; CST ¼ colistin; C/T ¼ ceftolozane/ tazobactam; ETP ¼ ertapenem; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam. * Susceptibility cut-off MIC value for each compound.
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Table IV. Percentage of Pseudomonas aeruginosa inhibited at each MIC for the tested antimicrobials. MIC, mg/L
C/T
FEP
CAZ
CIP
CST
ATM
IMI
TZP
MEM
TOB
r1 2 4 8 16 Z32
83 9 5* 1 1 1
12 31 17 17* 12 11
6 34 26 11* 7 16
72* 5 6 4 5 8
86 10* 2 1 0 1
6 4 32 28* 13 17
47 21* 9 5 10 8
4 2 25 29 12* 28
66 10* 6 5 7 6
81 8 3* 1 1 6
ATM ¼ aztreonam; CAZ ¼ ceftazidime; CIP ¼ ciprofloxacin; CST ¼ colistin; C/T ¼ ceftolozane/tazobactam; FEP ¼ cefepime; IPM ¼ imipenem; MEM ¼ meropenem; TOB ¼ tobramycin; TZP ¼ piperacillin/tazobactam. * Susceptibility cut-off MIC value for each compound.
to TZP (MIC Z 32 mg/L). For these pseudomonal isolates, C/T was found to have 89% susceptibility with 75% of the isolates having an MIC r 2 mg/L (Table IV). Unlike the Enterobacteriaceae, we noted differing susceptibility profiles for Pseudomonas derived from the ICU and non-ICU setting. The susceptibility profile of FEP, CAZ, ATM, TZP, IMP, and MEM was 5% to 12% lower in Pseudomonas isolates from patients in the ICU. In contrast, little difference was observed between the potency of ICU and non-ICU P aeruginosa for C/T, CST, TOB, and CIP, although the overall susceptibility of CIP at 71% to 73% was much lower than the other 3 agents. In this subset of isolates, susceptibility (ICU vs non-ICU) was as follows: 95% versus 97% for CST, 95% versus 97% for C/T, 88% versus 93% for TOB, 72% versus 79% for FEP, 71% versus 73% for CIP, 70% versus 78% for MEM, 69% versus 80% for CAZ, 64% versus 72% for ATM, and 63% versus 75% for TZP.
DISCUSSION Over the past decade, the evolution of resistance in gramnegative pathogens has made the medical management of the infected patient increasingly challenging. It is for this reason that efforts to develop new antimicrobials were fostered by collaboration among government entities, the infectious diseases community, and the pharmaceutical industry.2 As a product of these collective efforts, C/T is the first agent to be approved by the FDA for clinical use. In addition to new therapies, it is also important to have contemporary surveillance data that reflect the current susceptibility of agents and new therapies.
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With the use of an isolate collection from 2011 to 2012, Farrell et al10 reported the antimicrobial activity of C/T against Enterobacteriaceae and P aeruginosa from US hospitals. When considering their E coli and K pneumoniae data with the use of the current FDA susceptibility breakpoint, C/T displayed 99% and 87% values, respectively, which are similar to those reported in our present study. Because of their escalating prevalence across the United States, ESBL-producing pathogens are an increasing clinical concern. In the earlier single center study by Titelman et al5 with ESBL-positive E coli (n ¼ 149) and K pneumoniae (n ¼ 20) predominantly due to CTX-M-14 or CTX-M-15, reported 93% C/T susceptibility with the use of the current FDA breakpoint. Although this value is similar to that reported for E coli (88%) in the previous 2011 to 2012 dataset, the 30% value for K pneumoniae in the 2011 to 2012 dataset is discordant with the earlier report.5,10 This inconsistency between the K pneumoniae in the 2 studies may be due to the differing ESBL enzyme composition among the K pneumoniae isolates. The 2011 to 2012 study did not use confirmation testing; as a result the K pneumoniae population in this study may have also included carbapenemases. Against the composite of phenotypically confirmed ESBL-positive Enterobacteriaceae derived from our more recent survey, the susceptibility of C/T was 82%. Although other agents are often considered active, only 67% of the ESBL-positive Enterobacteriaceae isolates in this study were susceptible to TZP, and the activity profiles of TOB, FEP, and CIP suggest a diminished role for empirical therapy with the use of conventional
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Clinical Therapeutics regimens. Although in vitro potency is only 1 variable in the clinical setting, recent data from Phase III trials have reported successful outcomes when C/T was used for ESBL infections.3 Previously, we have reported that ceftolozane alone or in combination with tazobactam displayed high in vitro potency against P aeruginosa with a variety of phenotypic resistance profiles, including isolates defined as MDR.8 In this study, C/T exhibited the highest percentage of susceptibility and the greatest potency among the 10 antimicrobials tested. Aside from C/T, all other β-lactams displayed relatively poor potency against this distribution of clinical P aeruginosa isolates with MIC90 values 3- to 4-fold greater than their respective breakpoints. CIP was among the least potent of the agents tested. MDR among pathogens, defined as resistance to Z3 antimicrobial classes, is an increasingly prevalent entity in hospitalized patients. Although Enterobacteriaceae with enzyme-mediated resistance and Acinetobacter spp may satisfy this criterion, P aeruginosa is a nosocomial pathogen that has a history of intrinsic or developed resistance to many commonly used agents. As such, this organism is frequently considered among the most difficult-totreat MDR pathogens.11 In our recent collection of P aeruginosa, 10% were MDR on the basis of therapeutic benchmarks. Although CST displayed the highest susceptibility (96%) and lowest MIC90 value (2 mg/L), concerns related to its pharmacodynamic optimization and toxicity make alternative therapies a necessity. C/T appears to retain in vitro activity against the majority (77%) of these MDR P aeruginosa, whereas other agents tested had susceptibility of 5% to 47%. Moreover, the activity of C/T against MDR P aeruginosa appears stable because our reported susceptibility is similar to the 79% reported in the 2011 to 2012 survey.10 Assessment of C/T potency against another distribution of P aeruginosa from a Canadian study found similar results to this present study.12 Susceptibility for C/T against all P aeruginosa isolates was 98% in the Canadian study and 97% in this present study. For P aeruginosa that were NS to the carbapenems the susceptibility for C/T in these isolates was 95% in the Canadian study and 93% in this present study. When considering TZP NS P aeruginosa, similar susceptibilities were observed in the Canadian study and this present survey (92% vs 89%).
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Because of the increasing prevalence of enzymemediated mechanisms in Enterobacteriaceae and MDR P aeruginosa, the use of the group 2 carbapenems (ie, IPM, MEM, and doripenem) both as empiric and directed therapy has increased dramatically over the past decade. Because C/T may be considered as an option in patients previously exposed to carbapenems, we also evaluated the phenotypic profile of C/T and comparators against a collection of P aeruginosa defined as NS to the class representative, IPM. In our survey the prevalence of carbapenem-NS P aeruginosa was unexpectedly high because nearly one third of these recently collected nonurine isolates displayed nonsusceptibility to IPM. Against this collection of resistant P aeruginosa, only CST and C/T exhibited susceptibility rates of Z90%. Importantly, this value is similar to the 85% value reported in the 2011 to 2012 survey against MEM-NS P aeruginosa.10 As a result of wide-scale use of TZP in the hospital setting, the prevalence of NS gram-negative pathogens has risen sharply. Because C/T may be considered in patients previously exposed to TZP, we assessed the in vitro potency of C/T against this phenotypic profile. Against this collection of gram-negative isolates, C/T exhibited a susceptibility profile of 75% and 89% for the Enterobacteriaceae and P aeruginosa, respectively. Although not reported for Enterobacteriaceae, our finding of 89% susceptibility for TZP-NS P aeruginosa is similar to the 84% previously reported for C/T from 2011 to 2012.10 Moreover, the compound displayed considerable potency because most MICs were r2 mg/L. In areas of the world where high rates of nonsusceptibility to TZP were observed in the 3 gram-negative species studied, C/T may be considered a potent therapeutic alternative. Although C/T displayed enhanced potency for the organisms tested, note that the compound was not active against all ESBL-producing bacteria nor would it be expected to be active against carbapenemresistant Enterobacteriaceae or Acinetobacter species. As with any new antibiotic, susceptibility patterns could change with continued used, and as such continual monitoring of C/T activity is suggested. In addition, antimicrobial stewardship programs will be an important tool to ensure that C/T is used appropriately and thus will retain high potency for years to come. Although the study provides potency data for a variety of conventional antimicrobials used in
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C.A. Sutherland and D.P. Nicolau clinical practice, amikacin was not included in our testing protocol; thus, note that this agent may have retained activity against some of the MDR P aeruginosa. In addition, a limitation of the study was that we did not execute molecular testing on CarbaNP-positive isolates to confirm the genotypic profile of these organisms. Moreover, the CarbaNP test performed here may miss low-level carbapenemase activity mediated by metallo β-lactamases (IMP, VIM, NDM) and by the Ambler class D OXA β-lactamases. Although this study included a geographically diverse population of US hospitals, local susceptibility could differ markedly.
CONCLUSION Increasing resistance and its impact on the clinical utility of conventional antimicrobials is among the most concerning and challenging obstacles to the optimal care of the infected patient. Data derived from this contemporary surveillance program highlight the increasing resistance among the commonly used parenteral gram-negative therapies and the relative enhanced potency of C/T. Although this contemporary potency information supports the clinical usefulness of C/T, appropriate use of the compound in the patient care setting is required to maximize patient outcomes and to minimize the development of resistance.
ACKNOWLEDGMENTS We thank Mary Anne Banevicius, Henry Christensen, Jennifer Hull, Lucinda Lamb, Sara Robinson, Debra Santini, and Pamela Tessier for their collective efforts with MIC determination. This study was supported by a grant from Cubist Pharmaceuticals, Lexington, Massachusetts. Christina Sutherland and David Nicolau worked on the study design, data collection and interpretation, analysis, and writing of this project.
CONFLICTS OF INTEREST Cubist Pharmaceuticals was not involved in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. D.P. Nicolau has received research grants and is on the speakers’ bureau of Cubist Pharmaceuticals. The authors have indicated that they
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have no other conflicts of interest regarding the content of this article.
REFERENCES 1. Sievert DM, Ricks P, Edwards JR, et al. National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009– 2010. Infect Control Hosp Epidemiol. 2013;34:1–14. 2. Boucher HW, Talbot GH, Benjamin DK Jr, et al. Infectious Diseases Society of America. 10 x 20 Progress–development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56:1685–1694. 3. ZERBAXA (ceftolozane/tazobactam) for injection, for intravenous use. Initial U.S. approval 2014. Lexington, Mass: Cubist Pharmaceuticals; 2014. 4. Sader HS, Rhomberg PR, Farrell DJ, Jones RN. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother. 2011;55:2390–2394. 5. Titelman E, Karlsson IM, Ge Y, Giske CG. In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Diagn Microbiol Infect Dis. 2011;70:137–141. 6. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. CLSI document M07-A9. Wayne, Pa: Clinical and Laboratory Standards Institute; 2012. 7. Clinical and Laboratory Standards Institute. 2014. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. CLSI document M100-S24 U. Wayne, Pa: Clinical and Laboratory Standards Institute; 2014. 8. Bulik CC, Christensen H, Nicolau DP. In vitro potency of CXA-101, a novel cephalosporin, against Pseudomonas aeruginosa displaying various resistance phenotypes, including multidrug resistance. Antimicrob Agents Chemother. 2010;54:557–559. 9. Dortet L, Poirel L, Nordmann P. Rapid identification of carbapenemase types in Enterobacteriaceae and Pseudomonas spp. by using a biochemical test. Antimicrob Agents Chemother. 2012;56:6437–6440. 10. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (2011– 2012). Antimicrob Agents Chemother. 2013;57:6305–6310.
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Clinical Therapeutics 11. Thabit AK, Crandon JL, Nicolau DP. Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. Expert Opin Pharmacother. 2015;16:159–177. 12. Walkty A, Karlowsky JA, Adam H, et al. In vitro activity of ceftolozanetazobactam against Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals in the CANWARD study, 2007 to 2012. Antimicrob Agents Chemother. 2013;57:5707–5709.
Address correspondence to: David P. Nicolau, PharmD, FCCP, FIDSA, Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102. E-mail: david.nicolau@ hhchealth.org
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