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A total of 521 unique clinical isolates from cancer patients with primarily (>90%) bloodstream infections were tested for susceptibility to ceftazidime-avibactam and comparators using broth microdilution methods. Ceftazidime-avibactam inhibited 97.8% of all Enterobacteriaceae (n = 321) at the susceptibility breakpoint of ≤8/4 μg/ml (there were 7 nonsusceptible strains). It was also active against Pseudomonas aeruginosa (91.7% isolates susceptible, n = 121), including many isolates not susceptible to meropenem, cefepime, ceftazidime, piperacillin-tazobactam, or other comparators.
Gram-negative bacteria (GNB) cause ~25% to 30% of bacterial infections in neutropenic cancer patients and are associated with greater morbidity and mortality than Gram-positive organisms (1). The provision of potent, empirical Gram-negative coverage when a neutropenic patient develops fever has become an established standard of care (2). Several recent reports have documented the increasing frequency of multidrug-resistant GNB in cancer patients (3,–7). The susceptibility of the causative pathogen to the initial regimen is an important determinant of clinical outcome. Thus, empirical therapy of febrile neutropenic patients with currently recommended agents (ceftazidime, cefepime, piperacillin-tazobactam, and carbapenems) may no longer be appropriate against many GNB in this setting (4, 8, 9).
Ceftazidime-avibactam is a novel combination of the non-β-lactam β-lactamase inhibitor avibactam and the extended-spectrum ceftazidime (10). Avibactam protects ceftazidime from being hydrolyzed by many enzymes, including Amber class A (extended-spectrum β-lactamase [ESBL] and Klebsiella pneumoniae carbapenemase [KPC]), class C (AmpC), and several class D β-lactamases, but not against metallo-β-lactamases, such as New Delhi metallo-β-lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM), and imipenemase (IMP) (11). Its combination with ceftazidime restores the activity of avibactam against organisms producing these enzymes. Ceftazidime-avibactam has been approved by the U.S. FDA for treating complicated urinary tract infections and, in combination with metronidazole, for treating complicated intra-abdominal infections (12). It is also being evaluated for the treatment of hospital-acquired pneumonia. It has not been evaluated for the empirical treatment of cancer patients with fever and neutropenia or for any other indications in this setting. With the increasing frequency of resistant GNB in this patient population, we feel that it may have a potentially important therapeutic role. Consequently, we compared the in vitro activity of ceftazidime-avibactam with those of several currently used agents against recent clinical isolates recovered from patients treated at our institution, a National Cancer Institute (NC)-designated comprehensive cancer center.
A total of 521 unique patient isolates (497 GNB and 24 methicillin-susceptible Staphylococcus aureus) recovered between 2010 and 2014 were tested. The majority of isolates (>90%) were from blood cultures, and the remaining isolates (10%) were recovered from respiratory tract infections. Only the first isolate per unique patient was collected to avoid duplication. We performed CLSI-recommended broth microdilution tests (13) using validated MIC panels from Thermo Fisher Scientific, Inc. (Oakwood, OH, USA). Ceftazidime-avibactam breakpoints approved by the U.S. FDA and CLSI (≤8/4 μg/ml for susceptibility and ≥16 μg/ml for resistance) were used for all Enterobacteriaceae and for Pseudomonas aeruginosa (14). The susceptibility interpretations for comparator agents were those found in the CLSI document M100-S26 (15) or in the manufacturer's package insert. Escherichia coli ATCC 25922, P. aeruginosa ATCC 27853, and Klebsiella pneumoniae ATCC 700603 were used as quality control strains to ensure the validity of our results.
Ceftazidime-avibactam inhibited 97.8% of all Enterobacteriaceae (n = 321), including all ESBL− E. coli isolates (MIC90, 0.25/4 μg ml), all Citrobacter spp. (n = 4), all ESBL− Klebsiella spp. (n = 33; MIC90, 0.12/4 μg/ml), all ESBL+ Klebsiella spp. (n = 34; MIC90, 1.0/4 μg/ml), and all Serratia marcescens isolates (n = 30; MIC90, 1.0/4 μg/ml) (Table 1). Ceftazidime-avibactam also inhibited 98% of ESBL+ E. coli isolates (one of 50 isolates was nonsusceptible) with an MIC90 of 1.0/4 μg/ml. Additionally, 82.1% of carbapenem-resistant Klebsiella species (CRE; n = 28) were susceptible to ceftazidime-avibactam. The 6 nonsusceptible CRE isolates were not tested for the production of metallo-β-lactamases. Ceftazidime-avibactam and meropenem inhibited 97.6% of the Enterobacter spp. tested at their respective susceptibility breakpoints. Regarding other agents, 95.2% were susceptible to cefepime, 88.1% to trimethoprim-sulfamethoxazole, 85.7% to tigecycline, and 71.4% each to ceftazidime and piperacillin-tazobactam. Overall, ceftazidime-avibactam had the most potent activity against Enterobacteriaceae. Ceftazidime-avibactam also had potent in vitro activity against P. aeruginosa. It inhibited 98.6% of P. aeruginosa isolates that were not considered multidrug resistant (MDR; n = 70) at or below the susceptibility breakpoint, with only one of 70 such isolates being nonsusceptible. Regarding comparator agents, 91.4% of P. aeruginosa isolates were susceptible to meropenem, 87.1% to ceftazidime alone, 88.6% to cefepime, and 85.7% to piperacillin-tazobactam. Additionally, 42 of 51 (82.4%) MDR P. aeruginosa isolates were susceptible to ceftazidime-avibactam. In comparison, only 21.6% of these isolates were susceptible to meropenem, 35.3% were susceptible to piperacillin-tazobactam, and 37.3% were susceptible to cefepime. Most of the agents tested, including ceftazidime-avibactam, had moderate to poor activity against Stenotrophomonas maltophilia and Acinetobacter species. All 24 methicillin-susceptible Staphylococcus aureus (MSSA) isolates were susceptible to each of the agents tested.
The proportion of Enterobacteriaceae and P. aeruginosa isolates resistant to ceftazidime-avibactam and comparator agents is depicted in Table 2. Overall, ceftazidime-avibactam was associated with the lowest level of resistance. Among non-CRE Enterobacteriaceae, only 1 isolate (0.3%) was resistant to ceftazidime-avibactam, and 10 (3.5%) were resistant to tigecycline, 44 (15.3%) to piperacillin-tazobactam, 67 (23.3%) to cefepime, 88 (30.6%) to ceftazidime, and 131 (45.5%) to trimethoprim-sulfamethoxazole. By definition, each of these isolates was susceptible to meropenem. Six CRE isolates (18.2%) were resistant to ceftazidime-avibactam. Among the comparators, resistance rates ranged from 30.3% for tigecycline and trimethoprim-sulfamethoxazole to 100% for meropenem, piperacillin-tazobactam, cefepime, and ceftazidime. Lower levels of resistance were seen among non-MDR P. aeruginosa isolates (ranging from 1.4% for ceftazidime-avibactam to 11.4% for ceftazidime) than among MDR− P. aeruginosa isolates (17.6% for ceftazidime-avibactam, and ranging from 29.4% to 62.7% for comparators). The MIC distributions for individual organisms and antimicrobial agents are presented in Table 3. Distributions for ceftazidime-avibactam trended toward lower MICs for resistant organisms than with standard of care antimicrobial agents.
To our knowledge, ours is the only study evaluating the in vitro activity of ceftazidime-avibactam against common Gram-negative pathogens isolated from cancer patients. We have also shown that ceftazidime-avibactam is active against MSSA, a very common pathogen isolated in our cancer patient population. Our data demonstrate that ceftazidime-avibactam has the most potent in vitro activity among all the agents tested, including activity against many isolates that are resistant to comparator agents commonly used in cancer patients. Although our data are from a single institution and may not represent national or global trends, they are similar to data from other large studies that have tested isolates from multiple centers, different patient populations, and various sites of infection, including the bloodstream, the urinary tract, the respiratory tract, and skin/skin structure sites (16, 17). Another potential limitation of our study is that the CRE isolates were not tested for metallo-β-lactamase production. Since the completion of this in vitro study, a diverse group of metallo-β-lactamase-producing Enterobacteriaceae have been isolated from bloodstream infections in patients treated at our institution (18). These do not appear to be related to an ongoing outbreak and are of great concern. The higher rate of resistance to ceftazidime-avibactam reported in the Aitken study might be related to the emergence of resistance to ceftazidime-avibactam in the tested isolates that were obtained from a later period (2015) than the isolates tested in this current study (2010 to 2014). Nevertheless, based on our data, we conclude that the in vitro activity of ceftazidime-avibactam is potent and sufficiently broad to warrant its evaluation for treating various infections in cancer patients, including empirical therapy of febrile episodes in patients with neutropenia.
This study was supported by a research grant from Allergan. Allergan was involved in the design of the study but had no involvement in the collection, analysis, or interpretation of the data or the publication process. MD Anderson Cancer Center received no compensation for preparing the manuscript.