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Antimicrob Agents Chemother. 2017 April; 61(4): e02083-16.
Published online 2017 March 24. Prepublished online 2017 January 9. doi:  10.1128/AAC.02083-16
PMCID: PMC5365649

Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Bacteria Isolated from Patients Hospitalized with Pneumonia in U.S. Medical Centers, 2011 to 2015

ABSTRACT

Bacterial isolates were collected from patients hospitalized with pneumonia (PHP), including ventilator-associated pneumonia (VAP), from 76 U.S. medical centers in 2011 to 2015. The Gram-negative organisms (n = 11,185, including 1,097 from VAP) were tested for susceptibility to ceftazidime-avibactam and comparators by the broth microdilution method. β-Lactamase-encoding genes were screened using a microarray-based assay on selected isolates. Pseudomonas aeruginosa and Klebsiella spp. were the most common Gram-negative bacteria isolated from PHP and VAP. Ceftazidime-avibactam was very active against P. aeruginosa (n = 3,402; MIC50/MIC90, 2 and 4 μg/ml; 96.6% susceptible), including isolates nonsusceptible to meropenem (86.3% susceptible to ceftazidime-avibactam), piperacillin-tazobactam (85.6% susceptible), or ceftazidime (80.6% susceptible). Ceftazidime-avibactam was also highly active against Enterobacteriaceae (MIC50/MIC90, 0.12 and 0.5 μg/ml; 99.9% susceptible), including carbapenem-resistant Enterobacteriaceae (CRE) (n = 189; MIC50/MIC90, 0.5 and 2 μg/ml; 98.0% susceptible) and multidrug-resistant (MDR) (n = 674; MIC50/MIC90, 0.25 and 1 μg/ml; 98.8% susceptible) and extensively drug-resistant (XDR) (n = 156; MIC50/MIC90, 0.5 and 2 μg/ml; 98.1% susceptible) Enterobacteriaceae isolates, as well as Klebsiella species isolates showing an extended-spectrum β-lactamase (ESBL) screening-positive phenotype (n = 433; MIC50/MIC90, 0.25 and 1 μg/ml; 99.5% susceptible). Among Enterobacter spp. (24.8% ceftazidime nonsusceptible), 99.8% of the isolates, including 99.4% of ceftazidime-nonsusceptible isolates, were susceptible to ceftazidime-avibactam. The most common β-lactamases detected among Klebsiella pneumoniae and E. coli isolates were K. pneumoniae carbapenemase (KPC)-like and CTX-M-15, respectively. Only 8 of 6,209 Enterobacteriaceae isolates (0.1%) were ceftazidime-avibactam nonsusceptible, three NDM-1-producing strains with ceftazidime-avibactam MIC values of >32 μg/ml and five isolates with ceftazidime-avibactam MIC values of 16 μg/ml and negative results for all β-lactamases tested. Susceptibility rates among isolates from VAP were generally similar or slightly higher than those from all PHP.

KEYWORDS: ceftazidime-avibactam, pneumonia, ventilator-associated pneumonia, Pseudomonas aeruginosa, NDM-1, Klebsiella pneumoniae carbapenemase

INTRODUCTION

Pneumonia is the second most common infection in hospitalized patients, and the initial antimicrobial management of patients with pneumonia is driven mainly by an understanding of the causative pathogens (1,3). Although Staphylococcus aureus is a significant cause of pneumonia in hospitalized patients, the importance of Gram-negative organisms, such as Pseudomonas aeruginosa and Enterobacteriaceae species, mainly Klebsiella pneumoniae, Enterobacter spp., and Escherichia coli, has increased substantially in recent years (4,6).

Avibactam is a member of a novel class of non-β-lactam β-lactamase inhibitors, the diazabicyclooctanes (DBOs). Compared to currently available inhibitors for clinical use, DBOs are more potent and have a broader spectrum and a different mechanism of action. Avibactam effectively inactivates class A (including K. pneumoniae carbapenemase [KPC]), class C (AmpC), and some class D (OXA) β-lactamases with low 50% inhibitory concentration (IC50) (the concentration resulting in 50% inhibition) values and low turnover numbers (7). Avibactam does not inhibit metallo-β-lactamases (MBLs) (8, 9).

Ceftazidime-avibactam has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections, including pyelonephritis, in patients with limited or no alternative treatment options (10). In Europe, ceftazidime-avibactam is also approved for these indications and for the treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia (VAP) (11). In this study, we evaluated the activity of ceftazidime combined with avibactam when tested against a large collection of contemporary clinical isolates recovered from patients hospitalized with pneumonia (PHP) in U.S. medical centers in 2011 to 2015.

RESULTS

The frequencies of organisms isolated from PHP and VAP in 2015 are shown in Fig. 1. The five most common organisms in both groups (shown as percentages of the total for PHP and VAP) were as follows: S. aureus (29.8% and 27.1%), P. aeruginosa (20.9% and 22.7%), Klebsiella spp. (9.9% and 11.8%), E. coli (6.6% and 9.0%), and Enterobacter spp. (6.4% and 6.8%). Overall, Gram-negative organisms were isolated from 66.0% of patients, including 70.5% of those with VAP.

FIG 1
Frequency of occurrence of isolates from PHP in 2015.

Ceftazidime-avibactam was very active against P. aeruginosa (n = 3,402; MIC50/MIC90, 2 and 4 μg/ml; 96.6% susceptible), including isolates nonsusceptible to meropenem (MIC50/MIC90, 4 and 16 μg/ml; 86.3% susceptible to ceftazidime-avibactam), piperacillin-tazobactam (MIC50/MIC90, 4 and 16 μg/ml; 85.6% susceptible), or ceftazidime (MIC50/MIC90, 4 and 16 μg/ml; 80.6% susceptible) (Tables 1 and and2).2). Furthermore, ceftazidime-avibactam retained potent in vitro activity against P. aeruginosa isolates with multidrug-resistant (MDR) (MIC50/MIC90, 4 and 16 μg/ml; 82.7% susceptible) and extensively drug-resistant (XDR) (MIC50/MIC90, 8 and 32 μg/ml; 76.2% susceptible) phenotypes, as well as isolates nonsusceptible to meropenem, piperacillin-tazobactam, and ceftazidime (MIC50/MIC90, 8 and 32 μg/ml; 69.9% susceptible) (Table 1).

TABLE 1
Summary of ceftazidime-avibactam activities (MIC distributions) when tested against the main Gram-negative organisms isolated from patients hospitalized with pneumonia in U.S. medical centers (2011 to 2015)
TABLE 2
Susceptibility rates for ceftazidime-avibactam and comparator antimicrobial agents when tested against Gram-negative organisms isolated from patients hospitalized with pneumonia (all cases combined [PHP] and VAP; United States, 2011 to 2015)

The most active agent tested against P. aeruginosa was colistin (MIC50/MIC90, 1 and 2 μg/ml; 99.6% susceptible [Clinical and Laboratory Standards Institute {CLSI}]), followed by ceftazidime-avibactam (MIC50/MIC90, 2 and 4 μg/ml; 96.6% susceptible) and amikacin (MIC50/MIC90, 4 and 16 μg/ml; 95.3% susceptible), and no major differences were observed between the susceptibility rates of P. aeruginosa isolates from VAP compared to those from PHP (Tables 2 and and3).3). The addition of avibactam increased ceftazidime coverage (percentage inhibited at ≤8 μg/ml) from 82.4% to 96.6% (Tables 2 and and33).

TABLE 3
Activities of ceftazidime-avibactam and comparator antimicrobial agents when tested against Gram-negative organisms isolated from patients hospitalized with pneumonia (United States, 2011 to 2015)

Ceftazidime-avibactam inhibited 99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 μg/ml (Tables 1 to to3)3) and was highly active against carbapenem-resistant Enterobacteriaceae (CRE) (n = 189; MIC50/MIC90, 0.5 and 2 μg/ml; 97.9% susceptible) and MDR (n = 674; MIC50/MIC90, 0.25 and 1 μg/ml; 98.8% susceptible) and XDR (n = 156; MIC50/MIC90, 0.5 and 2 μg/ml; 98.1% susceptible) isolates (Tables 1 and and2).2). Only 8 of 6,209 Enterobacteriaceae strains (0.1%) were ceftazidime-avibactam nonsusceptible: three NDM-1-producing strains (two K. pneumoniae and one E. coli) with ceftazidime-avibactam MIC values of >32 μg/ml (Table 4) and five isolates (two Serratia marcescens, one Enterobacter aerogenes, one Enterobacter cloacae, and one Providencia stuartii) with ceftazidime-avibactam MIC values of 16 μg/ml and negative results for all β-lactamases tested (data not shown).

TABLE 4
Ceftazidime-avibactam activity stratified by organism β-lactamase production

An extended-spectrum β-lactamase (ESBL) screening-positive phenotype (defined as a MIC of >1 μg/ml for ceftazidime, ceftriaxone, and/or aztreonam) was observed among 19.2, 20.8, 13.0, and 12.2% of E. coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis strains, respectively, and ceftazidime-avibactam retained potent in vitro activity against these organisms (Table 1). Ceftazidime-avibactam inhibited 99.5% of Klebsiella spp. isolates with an ESBL screening-positive phenotype (n = 433; MIC50/MIC90, 0.25 and 1 μg/ml), whereas only 64.7% of the organisms were susceptible to meropenem (Table 2). In addition, 98.7% of meropenem-nonsusceptible K. pneumoniae isolates (n = 150; MIC50/MIC90, 0.5 and 2 μg/ml) were susceptible to ceftazidime-avibactam (Table 1).

Among Enterobacter spp. (n = 1,304; 24.8% ceftazidime nonsusceptible), 99.8% of isolates (MIC50/MIC90, 0.12 and 0.5 μg/ml), including 99.4% of ceftazidime-nonsusceptible strains (MIC50/MIC90, 0.25 and 1 μg/ml), were ceftazidime-avibactam susceptible (Table 1). Meropenem and gentamicin were active against 92.9% and 88.6% of ceftazidime-nonsusceptible Enterobacter species isolates (Table 2). E. coli was the third most common Enterobacteriaceae species isolated from PHP and VAP (Fig. 1) and exhibited high rates of susceptibility to ceftazidime-avibactam (99.9%), meropenem (99.6%), and piperacillin-tazobactam (90.5%) (Table 2). In general, susceptibility rates among Enterobacteriaceae isolates from VAP were similar to or slightly higher than those from all PHP (Table 2), and no substantial yearly variation in susceptibility rates was noted (data not shown).

Ceftazidime-avibactam activity against K. pneumoniae (n = 371) and E. coli (n = 235) strains showing an ESBL screening-positive phenotype and stratified by β-lactamase production is presented in Table 4. The most common β-lactamases detected among K. pneumoniae isolates with an ESBL screening-positive phenotype (CLSI criteria) was KPC-like. A KPC-like-encoding gene was detected in 125 isolates (33.7%), and approximately half of the isolates (57/123; 46.3%) produced an ESBL and/or a plasmidic AmpC enzyme in addition to the KPC. The highest ceftazidime-avibactam MIC value among KPC-producing K. pneumoniae strains was only 2 μg/ml (MIC50/MIC90, 0.5 and 2 μg/ml) (Table 4). The second and third most common β-lactamases produced by K. pneumoniae were CTX-M-15 (n = 105 [28.3%]; ceftazidime-avibactam MIC50/MIC90, 0.25 and 1 μg/ml) and SHV-ESBL (n = 58 [15.6%]; MIC50/MIC90, 0.12 and 2 μg/ml), and only two isolates (0.5% of strains showing an ESBL screening-positive phenotype) produced an MBL, both NDM-1 (12) (Table 4). Among E. coli strains, CTX-M-15-like (113 strains [48.1%] and CTX-M-14 (46 strains [19.6%]) were the most common ESBLs detected. Furthermore, CMY-2-like was detected in 23 strains (9.8%), and only one strain (0.8%) produced an MBL (NDM-1). The highest ceftazidime-avibactam MIC value among E. coli isolates producing CTX-M-15, CTX-M-14, and/or CMY-2-like was only 1 μg/ml (Table 4).

Only colistin (MIC50/MIC90, 1 and 2 μg/ml; 93.7% susceptible) exhibited good in vitro activity against Acinetobacter baumannii isolates (Table 3). Amikacin, the second most active compound, was active against only 63.4% of strains at the CLSI susceptible breakpoint, and all the other compounds had susceptibility rates of less than 50.0% (Table 3).

DISCUSSION

Prompt initiation of appropriate antimicrobial therapy is critical for the management of PHP, especially those with VAP, and empirical antimicrobial regimens should be guided primarily by an understanding of the causative pathogens and their antimicrobial resistance profiles (2). The frequency of occurrence of organisms observed in the present study for PHP is very similar to that reported for health care-associated pneumonia (HAP) and VAP by other investigators (2, 3, 6, 13). Although we were not able to separate community-acquired bacterial pneumonia (CABP) that required hospitalization from HAP, the fact that the main organisms responsible for CABP, such as Streptococcus pneumoniae and Haemophilus influenzae, represented a small percentage of isolates from PHP indicates that the vast majority of cases included in the study were HAP.

Interestingly, the frequency of occurrence of organisms isolated from VAP did not differ significantly from that observed with PHP. The top nine organisms were the same in both groups, with only small differences in the frequencies. It is important to note that the Gram-negative organisms were isolated from 66.0% of PHP and 70.5% of VAP cases in 2015, and P. aeruginosa and Enterobacteriaceae species comprised the vast majority of Gram-negative organisms.

In the present study, the antimicrobial susceptibilities of 11,185 Gram-negative isolates consecutively collected from hospitalized patients with pneumonia in U.S. medical centers were evaluated, and the results indicated that very few agents remain active against the most frequently isolated organisms. The carbapenems (meropenem and imipenem) and piperacillin-tazobactam showed only moderate coverage against P. aeruginosa and very limited activity against Klebsiella spp. with an ESBL screening-positive phenotype. Meropenem was active against only 79.1% of P. aeruginosa isolates and 64.7% of ESBL screening-positive phenotype Klebsiella spp.

Among other antimicrobial classes (non-β-lactams), the aminoglycosides were the most active compounds overall. Amikacin remained active against P. aeruginosa (95.3% and 89.9% susceptible by CLSI/EUCAST criteria) and Enterobacteriaceae (98.3% and 97.1% susceptible by CLSI/EUCAST criteria), whereas susceptibility rates for gentamicin were slightly lower (84.8% for P. aeruginosa and 91.1% for Enterobacteriaceae [CLSI]). Colistin exhibited good activity against P. aeruginosa and A. baumannii but was active against only 77.3% of Enterobacteriaceae isolates at the EUCAST susceptible breakpoint of ≤2 μg/ml (14). In contrast, tigecycline showed good in vitro activity against Enterobacteriaceae but very limited activity against P. aeruginosa (data not shown). Lastly, the fluoroquinolones levofloxacin and ciprofloxacin exhibited only moderate activity against P. aeruginosa and Enterobacteriaceae. Thus, no other agent tested provided better overall coverage than ceftazidime-avibactam.

The molecular characterization of Enterobacteriaceae isolates showing an ESBL screening-positive phenotype (i.e., MIC, >1 μg/ml for ceftriaxone, ceftazidime, or aztreonam) revealed interesting results. Among K. pneumoniae, one-third of the isolates (125/371) produced a KPC-like β-lactamase, which confers resistance to all β-lactams and β-lactamase inhibitor combinations currently available for clinical use in the United States, except ceftazidime-avibactam. Furthermore, an MBL-encoding gene was detected in only two K. pneumoniae isolates (0.5%) (12). Among E. coli isolates, two-thirds of the isolates produced CTX-M-15-like or CTX-M-14-like (159/235), and only one MBL-producing strain was detected. In summary, ceftazidime-avibactam was highly active against all β-lactamase-producing Enterobacteriaceae except three MBL-producing strains (all NDM-1 producers), which still remain very uncommon in U.S. medical centers.

The selection of appropriate antimicrobials should consider local microbial epidemiology, patient risk factors for MDR organisms, and patient-specific characteristics that may influence treatment options. Although resistance rates and microbial epidemiology may vary substantially from hospital to hospital, results from a large, well-monitored surveillance network, such as those presented here, can provide useful information by detecting signs of emerging pathogen populations/resistance patterns, as well as trends of antimicrobial resistance mechanisms. Limitations of the study include the lack of differentiation between CABP that needs hospitalization and HAP; thus, it is possible that some of the comparators may have shown better activity against the subset of isolates from patients hospitalized with CABP than against the organism collection evaluated in this investigation. Another limitation of the study is the fact that the criteria used to categorize a bacterial isolate as “clinically significant” were not defined in the study protocol and were based on local algorithms, which may vary among participating medical centers. However, it is very unlikely that these limitations introduced significant bias into the study. It is also important to note that avibactam does not inhibit metallo-β-lactamases, and ceftazidime-avibactam may be less active against MDR and XDR Enterobacteriaceae in geographic regions where these β-lactamases are more prevalent. Despite the limitations of the study, the results presented here indicate that ceftazidime-avibactam is very active against the vast majority of P. aeruginosa and Enterobacteriaceae isolates from patients with pneumonia hospitalized in U.S. medical centers, including isolates showing MDR and XDR phenotypes. These in vitro results support further development of ceftazidime-avibactam for treatment of HAP and VAP in the United States.

MATERIALS AND METHODS

Bacterial isolates.

Isolates were collected from 76 medical centers distributed among 37 states from all nine U.S. census regions in 2011 to 2015 as part of the International Network for Optimal Resistance Monitoring (INFORM) program (15). Each participating center was requested to collect consecutive bacterial isolates from lower respiratory tract sites determined to be significant by local criteria as the reported probable cause of pneumonia. Only isolates from invasive sampling (transtracheal aspiration, bronchoalveolar lavage, protected brush samples, qualified sputum samples, etc.) were accepted. Although all bacterial species were collected, the INFORM program evaluates the antimicrobial susceptibility of only Enterobacteriaceae, P. aeruginosa, and A. baumannii. Therefore, the frequency of occurrence of organisms described in Results above was based on all the organisms collected from PHP in the same participating medical centers in 2015 (n = 5,417, including 543 from VAP). Species identification was confirmed by standard biochemical tests and using the MALDI Biotyper (Bruker Daltonics, Billerica, MA, USA) according to the manufacturer's instructions where necessary.

Susceptibility testing.

Broth microdilution test methods were conducted according to the CLSI guidelines to determine the antimicrobial susceptibility of ceftazidime-avibactam (inhibitor at a fixed concentration of 4 μg/ml) and comparator agents (16). Concurrent quality control (QC) testing was performed to ensure proper test conditions and procedures. The QC strains included E. coli ATCC 25922 and 35218, K. pneumoniae ATCC 700603, and P. aeruginosa ATCC 27853. All QC results were within published ranges. CLSI and EUCAST susceptibility interpretive criteria (M100-S26) (14, 17) were used to determine susceptibility and resistance rates for comparator agents. Furthermore, U.S. FDA and EUCAST breakpoint criteria were applied for ceftazidime-avibactam when testing Enterobacteriaceae and P. aeruginosa, i.e., susceptible at ≤8 μg/ml and resistant at ≥16 μg/ml (10, 14).

Resistant subsets.

E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis isolates were grouped as “ESBL screening-positive phenotype” based on the CLSI screening criteria for ESBL production, i.e., a MIC of >1 μg/ml for ceftazidime, ceftriaxone, and/or aztreonam (17), for the purpose of analysis of susceptibility testing results. Although other β-lactamases, such as AmpC and KPC, may also produce an ESBL screening-positive phenotype, these strains were grouped together because they usually demonstrate resistance to various broad-spectrum β-lactam compounds. CRE was defined as resistant (MIC, ≥4 μg/ml [CLSI]) to imipenem (imipenem was not applied to P. mirabilis and indole-positive Proteeae), meropenem, or doripenem. Further, isolates were categorized as MDR, XDR, or pan-drug-resistant (PDR) according to criteria published by Magiorakos et al. (18), i.e., MDR is defined as nonsusceptible to ≥1 agent in ≥3 antimicrobial classes, XDR as nonsusceptible to ≥1 agent in all but ≤2 antimicrobial classes, and PDR as nonsusceptible (CLSI criteria) to all antimicrobial classes tested. The antimicrobial classes and representative drugs used in the analysis were broad-spectrum cephalosporins (ceftriaxone, ceftazidime, and cefepime), carbapenems (imipenem, meropenem, and doripenem), broad-spectrum penicillin combined with a β-lactamase inhibitor (piperacillin-tazobactam), fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (gentamicin, tobramycin, and amikacin), glycylcyclines (tigecycline), and the polymyxins (colistin) (EUCAST criteria) for Enterobacteriaceae, and antipseudomonal cephalosporins (ceftazidime and cefepime), carbapenems (imipenem, meropenem, and doripenem), broad-spectrum penicillins combined with a β-lactamase inhibitor (piperacillin-tazobactam), fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (gentamicin, tobramycin, and amikacin), and the polymyxins (colistin) for P. aeruginosa.

Screening for β-lactamases.

E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis isolates displaying the CLSI ESBL phenotypic criteria described above were tested for β-lactamase-encoding genes using the microarray-based assay Check-MDR CT101 kit (Check-Points, Wageningen, Netherlands). The assay was performed according to the manufacturer's instructions. The kit has the capability to detect CTX-M groups 1, 2, 8 plus 25, and 9; TEM wild type (WT) and ESBL; SHV WT and ESBL; ACC; ACT/MIR; CMYII; DHA; FOX; KPC; and NDM-1 (19).

ACKNOWLEDGMENTS

We thank all participants of the INFORM program for providing bacterial isolates.

This study was supported by Allergan.

Allergan was involved in the study design and the decision to present the results, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript. Allergan had no involvement in the collection, analysis, and interpretation of data. JMI Laboratories, Inc., contracted to perform services in 2016 for Achaogen, Actelion, Allecra, Allergan, Ampliphi, API, Astellas, AstraZeneca, Basilea, Bayer, BD, Biomodels, Cardeas, CEM-102 Pharma, Cempra, Cidara, Cormedix, CSA Biotech, Cubist, Debiopharm, Dipexium, Duke, Durata, Entasis, Fortress, Fox Chase Chemical, GSK, Medpace, Melinta, Merck, Micurx, Motif, N8 Medical, Nabriva, Nexcida, Novartis, Paratek, Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synolgoic, TGV Therapeutics, the Medicines Company, Theravance, ThermoFisher, Venatorx, Wockhardt, and Zavante. Some JMI employees are advisors/consultants for Allergan, Astellas, Cubist, Pfizer, Cempra and Theravance. There are no speakers' bureaus or stock options to declare.

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