Abstract
This study evaluated the in vitro activity of ceftolozane-tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from hospitalized patients in the United States. Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 18,960 organisms (15,223 Enterobacteriaceae and 3,737 P. aeruginosa) were consecutively collected from 32 medical centers located in all nine U.S. census divisions from 2013 to 2016. Organisms were tested for susceptibility by broth microdilution. CLSI and EUCAST interpretive criteria were used. Ceftolozane-tazobactam (94.4% susceptible), amikacin (99.0% susceptible), and meropenem (98.0% susceptible) were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates tested, 1.9% (n = 286) were carbapenem-resistant Enterobacteriaceae (CRE) and 9.5% (n = 1,450) exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. Although ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (87.5% susceptible), it lacked useful activity against CRE. Ceftolozane-tazobactam was the most potent β-lactam agent tested against P. aeruginosa isolates, with 97.3% susceptible. Only colistin was more active, inhibiting 99.5% of isolates. Ceftolozane-tazobactam also maintained good activity against multidrug-resistant P. aeruginosa, with 88.6% susceptible. Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and was more active than available cephalosporins and piperacillin-tazobactam against Enterobacteriaceae.
Introduction
T
These findings underscore the continued importance of antibiotic resistance surveillance and the need to assess the potential impact of newly introduced and novel antibacterial agents targeting specific resistance phenotypes. Systematic and comprehensive antibiotic resistance surveillance is essential to document the extent of the resistance problem and to inform local, regional, national, and global efforts to combat the resistance challenge.
Ceftolozane-tazobactam is a novel antibacterial agent with activity against P. aeruginosa, including antibiotic-resistant strains, and other common GNB, including most ESBL-producing Enterobacteriaceae strains. 7 Ceftolozane-tazobactam has limited activity against Acinetobacter spp., Stenotrophomonas maltophilia, GPC, organisms producing carbapenemases or metallo-β-lactamases, or a minority of AmpC β-lactamases found in Enterobacteriaceae. Ceftolozane-tazobactam was recently approved to treat complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections. 8 A Phase 3 clinical trial of ceftolozane-tazobactam to treat nosocomial pneumonia is ongoing.
The Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) has monitored predominant pathogens and antimicrobial resistance patterns at U.S. hospitals as a part of the SENTRY Antimicrobial Surveillance Program since 2011. In 2012 North American antimicrobial resistance surveys, we described the in vitro activity of ceftolozane-tazobactam tested against Enterobacteriaceae and P. aeruginosa isolates from different infection sites.9,10 In this study, we update those observations and focus on the activity of ceftolozane-tazobactam and comparators against 18,960 isolates collected from 2013 through 2016 comprising Enterobacteriaceae (15,223 isolates) and P. aeruginosa (3,737 isolates) from patients hospitalized at 32 medical centers in the United States from all nine census divisions. The analysis includes the activity of ceftolozane-tazobactam against specific resistant phenotypes (e.g., ESBL non-CRE phenotype and MDR and extensively drug-resistant [XDR] strains of Enterobacteriaceae and P. aeruginosa) as well as the ceftolozane-tazobactam susceptibility among the nine U.S. census divisions.
Materials and Methods
A total of 18,960 non-duplicate gram-negative isolates (15,223 Enterobacteriaceae and 3,737 P. aeruginosa) were collected prospectively from 32 medical centers in the United States from 2013 to 2016. Participant centers submitted clinical bacterial isolates (one isolate per patient per infection episode) that were consecutively collected by infection type according to a common protocol. The common SENTRY protocol established the number of isolates for the target infection types and the period during which the isolates were collected. Each institution contributed either 250 or 500 isolates per year, with ∼50 isolates per target infection type. Isolates included in this study were from hospitalized patients with bloodstream infections (4,067 isolates, 21.5%), pneumonia (5,211 isolates, 27.5%), skin and skin structure infections (2,968 isolates, 15.7%), urinary tract infections (4,825 isolates, 25.4%), intra-abdominal infections (1,694 isolates, 8.9%), and other types of infections (195 isolates, 1.0%). Isolates were identified at each medical center and confirmed by the central laboratory (JMI Laboratories, North Liberty, Iowa) by using a matrix-assisted laser desorption ionization time-of-flight technology mass spectrometer (MALDI-TOF; Bruker, Billerica, MA) or other methods, as needed.
Minimal inhibitory concentrations (MICs) for all antibiotics were determined by using frozen broth microdilution panels according to Clinical and Laboratory Standards Institute (CLSI) standards. 11 All ceftolozane-tazobactam and piperacillin-tazobactam MIC tests used a fixed tazobactam concentration of 4 mg/L. Quality control and interpretation of results were performed according to CLSI M100–S27 and EUCAST v7.1.12,13 For colistin, only EUCAST interpretive criteria are available for Enterobacteriaceae. All MIC results for ATCC quality control strains were within published ranges.
Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis were grouped as “ESBL phenotype” based on the CLSI screening criteria for potential ESBL production, with MIC values of ≥2 mg/L for ceftazidime, ceftriaxone, or aztreonam. 12 CRE were defined as isolates displaying MIC values of ≥4 mg/L for imipenem (P. mirabilis and indole-positive Proteeae were not included due to the intrinsically elevated MIC values), meropenem, and/or doripenem. Since carbapenemase-producing isolates may also appear to have an ESBL phenotype, non-carbapenem-resistant ESBL-phenotype (ESBL non-CRE) isolates were analyzed.
P. aeruginosa isolates were considered meropenem-nonsusceptible if their MIC value was ≥4 mg/L, ceftazidime- or cefepime-nonsusceptible if their MIC was ≥16 mg/L, and piperacillin-tazobactam-nonsusceptible if their MIC was ≥32 mg/L.
Isolates were classified as MDR (resistant to at least 1 agent in ≥3 antimicrobial categories), XDR (resistant to at least 1 agent in all but 2 or fewer antimicrobial categories), or pan-drug resistant (resistant to all agents in all antimicrobial categories) based on CLSI criteria as described in Magiorakos et al. 14
Results
Ceftolozane-tazobactam activity against Enterobacteriaceae
Ceftolozane-tazobactam demonstrated high overall activity against 15,223 Enterobacteriaceae isolates, with 94.4% susceptible (MIC50/MIC90 0.25/1 mg/L, Tables 1 and 2) collected in the United States. Susceptibility to ceftolozane-tazobactam varied from 88.0% in the Mid-Atlantic division to 98.1% in the West North Central division (Table 2). Overall, ceftolozane-tazobactam was more active than cefepime (90.2% susceptible), ceftazidime (87.3% susceptible), and piperacillin-tazobactam (91.7% susceptible) but less active than meropenem (98.0% susceptible) and amikacin (99.0% susceptible; Table 3). In total, 1,450 isolates (9.5%) were screened positive for the ESBL, non-CRE phenotype (Table 1). Ceftolozane-tazobactam demonstrated good activity against these isolates, with 87.5% susceptible (MIC50/MIC90 0.5/4 mg/L) and was more active than piperacillin-tazobactam (75.7% susceptible; MIC50/MIC90 8/>64 mg/L) and the cephalosporins in this study (7.5–29.1% susceptible). Against this group of non-carbapenem-resistant strains, meropenem and amikacin were the most active. A total of 1,335 (8.8%) isolates were identified as MDR and 58.7% were susceptible to ceftolozane-tazobactam, which was more active than the other cephalosporins in this study (14.8–31.7% susceptible). Piperacillin-tazobactam had 46.6% susceptible whereas meropenem had 77.7% susceptible and amikacin had 88.9% susceptible. For 226 XDR isolates, all drugs except amikacin were less than 35% susceptible. As previously reported, ceftolozane-tazobactam lacked activity against CRE, with 4.5% susceptible [10].
CRE, carbapenem-resistant Enterobacteriaceae; EC, E. coli; ESBL, extended-spectrum β-lactamases; KOX, Klebsiella oxytoca; KPN, Klebsiella pneumoniae; MDR, multidrug-resistant; MICs, minimal inhibitory concentrations; PM, P. mirabilis; XDR, extensively drug-resistant.
States present in each U.S. census division are 1: New England: Massachusetts and Vermont, 2: Mid-Atlantic: New Jersey and New York, 3: East North Central: Indiana, Michigan, Ohio, and Wisconsin, 4: West North Central: Iowa, Missouri, and Nebraska, 5: South Atlantic: Florida, Georgia, and Virginia, 6: East South Central: Kentucky, 7: West South Central: Arkansas and Texas, 8: Mountain: Colorado and Utah, 9: Pacific: California, Hawaii, and Washington.
Interpretive criteria as published by CLSI. 12
Intermediate interpreted as susceptible-dose dependent.
CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum beta-lactamases; MDR, multidrug-resistant; XDR, extensively drug-resistant; EC, Escherichia coli; KPN, Klebsiella pneumoniae; KOX, Klebsiella oxytoca; PM, Proteus mirabilis.
For 6,281 E. coli isolates, 98.6% were susceptible to ceftolozane-tazobactam whereas 95.3% were susceptible to piperacillin-tazobactam and 87.9% were susceptible to cefepime (Table 3). Meropenem, colistin, and amikacin were the most active, all with 99.7% susceptible; 92.2% of 966 ESBL non-CRE E. coli were susceptible to ceftolozane-tazobactam. Only 16 E. coli were meropenem-nonsusceptible, which were also resistant to the other beta-lactams in this study. For 2,979 K. pneumoniae isolates, 90.6% were susceptible to ceftolozane-tazobactam (Table 1) whereas 87.5% were susceptible to piperacillin-tazobactam and 84.6% were susceptible to cefepime (Table 3). A total of 369 K. pneumoniae isolates were identified as ESBL non-CRE and 75.1% were susceptible to ceftolozane-tazobactam whereas only 60.4% were susceptible to piperacillin-tazobactam. Other enteric species tested against ceftolozane-tazobactam included 1,955 Enterobacter spp. (83.6% susceptible), 695 Citrobacter spp. (88.6% susceptible), 893 P. mirabilis (99.7% susceptible), and 894 Serratia spp. (96.9% susceptible; Table 1).
Ceftolozane-tazobactam activity against P. aeruginosa
As mentioned, ceftolozane has enhanced activity against P. aeruginosa. In this study ceftolozane-tazobactam was tested against 3,737 contemporary isolates of P. aeruginosa. The MIC distribution of ceftolozane-tazobactam against P. aeruginosa with various resistance phenotypes is shown in Table 4. Ceftolozane-tazobactam overall susceptibility was 97.3% (MIC50/MIC90 0.5/2 mg/L). For the nine U.S. census divisions, the susceptibility of P. aeruginosa varied from 94.2% in the Pacific division to 99.5% in the West North Central division (Table 5). Susceptibilities of ceftolozane-tazobactam and comparators against various resistant phenotypes are shown in Table 6. Overall susceptibility to cefepime was 86.3%, 85.2% were susceptible to ceftazidime, and 80.9% were susceptible to meropenem and piperacillin-tazobactam. The only drug more active against P. aeruginosa isolates than ceftolozane-tazobactam was colistin (99.5% susceptible). A total of 783 MDR P. aeruginosa isolates were identified and 88.6% were susceptible to ceftolozane-tazobactam whereas 77.6% of 348 XDR isolates were susceptible to ceftolozane-tazobactam (Table 6). For both groups, colistin had the highest susceptibility at 99.2% and 98.6%, respectively. Ceftolozane-tazobactam maintained susceptibility to ceftazidime-nonsusceptible isolates, with 82.1% susceptible. Isolates that were meropenem-nonsusceptible were 88.6% susceptible to ceftolozane-tazobactam, piperacillin-tazobactam-nonsusceptible isolates were 87.4% susceptible, and isolates nonsusceptible to the four β-lactams in this study (meropenem, piperacillin-tazobactam, ceftazidime, and cefepime) ceftolozane-tazobactam susceptibility were 70.5%.
PSA, P. aeruginosa; NS, nonsusceptible.
States present in each U.S. Census Division are 1: New England: Massachusetts and Vermont, 2: Mid-Atlantic: New Jersey and New York, 3: East North Central: Indiana, Michigan, Ohio, and Wisconsin, 4: West North Central: Iowa, Missouri, and Nebraska, 5: South Atlantic: Florida, Georgia, and Virginia, 6: East South Central: Kentucky, 7: West South Central: Arkansas and Texas, 8: Mountain: Colorado and Utah, 9: Pacific: California, Hawaii, and Washington.
Interpretive criteria as published by CLSI. 12
Discussion
Results of this study extend those reported regarding the in vitro activity of ceftolozane-tazobactam against U.S. strains of Enterobacteriaceae and P. aeruginosa.9,15,16 Ceftolozane-tazobactam was the most active of the tested β-lactam agents against P. aeruginosa and was second to meropenem against Enterobacteriaceae. Although ceftolozane-tazobactam had little activity against CRE strains of Enterobacteriaceae, it retained activity against most ESBL non-CRE phenotype strains, second only to meropenem. Likewise, ceftolozane-tazobactam was more active than the other anti-pseudomonal β-lactam agents tested against strains of P. aeruginosa that were nonsusceptible to ceftazidime and meropenem. Among the non-β-lactam comparator agents, colistin and amikacin were the most active against Enterobacteriaceae and P. aeruginosa, including against various resistant phenotypes.
Ceftolozane-tazobactam maintained excellent activity when comparing this study with the previous U.S. surveillance results. 9 The 2011–2012 surveillance study had ceftolozane-tazobactam susceptibility of 93.3% for Enterobacteriaceae and 96.1% susceptibility for P. aeruginosa, whereas the current study with 2013–2016 data shows 94.4% susceptibility for Enterobacteriaceae and 97.3% susceptibility for P. aeruginosa. Susceptibilities to the other agents tested were also similar. It should be noted that the first study had 9,042 isolates collected over 2 years, whereas this study has 18,960 isolates collected over 4 years. A majority of the same medical centers participated in both studies.
Interestingly, between the U.S. census divisions, ceftolozane-tazobactam susceptibility varied by as much as 10% for Enterobacteriaceae and 5% for P. aeruginosa, suggesting differences in the prevalence of local resistance mechanisms.
In summary, ceftolozane-tazobactam has maintained very good activity against Enterobacteriaceae, including those with ESBL non-CRE phenotype, and remains the most active β-lactam against P. aeruginosa. Ceftolozane-tazobactam is an important therapy to be considered for early treatment of hospitalized patients with serious infections. 17
Footnotes
Acknowledgment
The authors would like to thank the U.S. hospitals participating in the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS).
Disclosure Statement
This study was performed by JMI Laboratories and supported by Merck & Co., Inc., Kenilworth, NJ USA, which included funding for services related to preparing this article. JMI Laboratories contracted to perform services in 2016 for Achaogen, Actelion, Allecra Therapeutics, Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc., Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc., Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics, The Medicines Company, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals, Inc., Wockhardt, Zavante Therapeutics, Inc. There are no speakers' bureaus or stock options to declare.