Research Article
19 February 2014

Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Organisms Collected from U.S. Medical Centers in 2012

ABSTRACT

The activities of the novel β-lactam–β-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli—8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates—were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Overall, 99.8% of Enterobacteriaceae strains were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Ceftazidime-avibactam was active against extended-spectrum β-lactamase (ESBL)-phenotype Escherichia coli and Klebsiella pneumoniae, meropenem-nonsusceptible (MIC ≥ 2 μg/ml) K. pneumoniae, and ceftazidime-nonsusceptible Enterobacter cloacae. Among ESBL-phenotype K. pneumoniae strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Among P. aeruginosa strains, 96.9% were inhibited at a ceftazidime-avibactam MIC of ≤8 μg/ml, and susceptibility rates for meropenem, ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible P. aeruginosa (MIC50/MIC90, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml). Acinetobacter spp. (ceftazidime-avibactam MIC50/MIC90, 16/>32 μg/ml) showed high rates of resistance to most tested agents. In summary, ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa.

INTRODUCTION

Bacterial isolates resistant to clinically available β-lactams represent an important challenge to successful treatment of serious infections (1). β-Lactamase-mediated resistance, in particular, represents a significant clinical threat because of the mobile nature of the genes encoding these enzymes. Two strategies have been used to restore the utility of β-lactam compounds: (i) the design/discovery of novel β-lactam molecules that are refractory to enzymatic inactivation and (ii) the inhibition of β-lactamases, thereby allowing the β-lactam to retain target concentrations at the sites of inhibition of penicillin-binding proteins (PBPs) (2).
The most recent β-lactamase inhibitor approved for clinical use in the United States was tazobactam in 1993 (3). Since then, the occurrence of Gram-negative bacteria expressing higher levels of β-lactamase production, multiple enzymes, inhibitor-resistant enzymes, and enzymes that are not inhibited by tazobactam and earlier inhibitors has increased substantially (4). Tazobactam, clavulanic acid, and sulbactam are essentially specific for certain class A β-lactamases; these inhibitors have negligible activity against class C enzymes and the class A carbapenemases, especially the Klebsiella pneumoniae carbapenemases (KPCs), which have become a major problem due to antimicrobial resistance in some geographic regions (57).
Avibactam (formerly NXL-104) is a member of a novel class of non-β-lactam β-lactamase inhibitors, the diazabicyclooctanes (DBOs) (8). Compared to current inhibitors available for clinical use, DBOs are more potent and have a broader spectrum and a different mechanism of action (2, 8). Avibactam effectively inactivates class A (including KPC), class C, and some class D β-lactamases, with low IC50 (the concentration resulting in 50% inhibition) values and low turnover numbers. Thus, avibactam protects β-lactams from hydrolysis by a variety of clinically relevant enzymes. Ceftazidime-avibactam is currently in phase 3 clinical trials for treatment of complicated intra-abdominal infections, urinary tract infections, and nosocomial pneumonia (identifiers NCT01499290, NCT01500239, NCT01599806, NCT01595438, and NCT01808092 [http://clinicaltrials.gov]). In this study, we evaluated the activity of ceftazidime combined with avibactam against a large collection of contemporary Gram-negative clinical isolates recovered in hospitals located in the United States during 2012.

MATERIALS AND METHODS

Bacterial isolates.

A total of 10,928 Gram-negative organisms, including 8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates, were consecutively collected from 73 U.S. hospitals from January to December 2012. These isolates were collected from bloodstream, respiratory tract, skin, and soft tissue infections according to defined protocols (9). Only clinically significant isolates were included in the study (1 per patient episode). Species identification was confirmed when necessary by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) using the Bruker Daltonics (Billerica, MA, USA) MALDI Biotyper following the manufacturer's instructions.

Antimicrobial susceptibility testing.

All isolates were susceptibility tested using the reference broth microdilution method as described by the CLSI (10). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Escherichia coli and Klebsiella sp. isolates were grouped as “extended-spectrum β-lactamase (ESBL) phenotype” and “non-ESBL phenotype” based on the CLSI screening criteria for ESBL production (11). Those isolates with positive ESBL screening tests, i.e., a MIC of >1 μg/ml for ceftazidime and/or ceftriaxone and/or aztreonam, were categorized as “ESBL phenotype” for the purpose of susceptibility-testing result analysis. Although other β-lactamases, such as AmpC and KPC, may also produce an ESBL phenotype, these strains were grouped together because they usually demonstrate resistance to various broad-spectrum β-lactam compounds. Categorical interpretations for all antimicrobials were those found in CLSI document M100-S23 (11) and EUCAST breakpoint tables (12). CLSI and EUCAST breakpoint criteria for ceftazidime alone were applied to ceftazidime-avibactam for comparison purposes only. Quality control (QC) was performed using E. coli ATCC 25922 and P. aeruginosa ATCC 27853. All QC results were within acceptable ranges as published in CLSI documents (11).

Screening for β-lactamases.

E. coli, Klebsiella spp., and Proteus mirabilis strains displaying the CLSI criteria for the ESBL phenotype (a MIC of >1 μg/ml for aztreonam and/or ceftazidime and/or ceftriaxone [11]), as well as all Enterobacteriaceae strains with ceftazidime-avibactam MICs of ≥16 μg/ml, 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 genes encoding CTX-M groups 1, 2, 8, 25, and 9; TEM wild-type (WT) and ESBL; SHV WT and ESBL; ACC; ACT/MIR; CMY-2-like variants (designated CMYII in the checkpoint kit); DHA; FOX; KPC; and NDM-1 (13). Reference PCR and/or sequencing were performed on strains with negative results with the Check-MDR CT101 kit (13).

RESULTS

Enterobacteriaceae.

Applying CLSI and EUCAST breakpoints for ceftazidime alone (≤4 and ≤1 μg/ml, respectively), ceftazidime-avibactam was the most active agent tested against Enterobacteriaceae (MIC50/MIC90, 0.12/0.25 μg/ml), with 99.8 and 99.3% inhibition at ≤4 and ≤1 μg/ml, respectively (Tables 1 and 2). The breakpoints for ceftazidime alone were applied to ceftazidime-avibactam for comparison purposes, since ceftazidime-avibactam breakpoints have not been established by the U.S. FDA, CLSI, or EUCAST. It is important to note, however, that ceftazidime-avibactam breakpoints could be higher than those established by ceftazidime, since ceftazidime breakpoints are based on the 1 g every 8 h (q8h), 30-min infusion dose (11) and ceftazidime-avibactam is dosed at 2 g q8h with 2 h infusion (identifiers NCT01499290, NCT01500239, NCT01599806, NCT01595438, and NCT01808092 [http://clinicaltrials.gov]).
TABLE 1
TABLE 1 Summary of ceftazidime-avibactam activities tested against the organisms and resistant subsets included in this report (United States, 2012)
Organism/resistant subsetNo. of isolatesNo. of isolates (cumulative %) inhibited at a MIC (μg/ml) ofa:
≤0.0150.030.060.120.250.5124816>16
Enterobacteriaceae8,640185 (2.1)1,043 (14.2)2,748 (46.0)3,052 (81.3)1,043 (93.4)373 (97.7)139 (99.3)30 (99.7)9 (99.8)12 (99.9)4 (>99.9)2 (100.0)
E. coli2,767131 (4.7)210 (12.3)1,171 (54.6)1,050 (92.6)167 (98.6)28 (99.6)9 (>99.9)1 (100.0)    
    ESBL phenotype3285 (1.5)6 (3.4)56 (20.4)168 (71.6)61 (90.2)22 (97.0)9 (99.7)1 (100.0)    
K. pneumoniae1,84722 (1.2)67 (4.8)625 (38.7)725 (77.9)217 (89.7)121 (96.2)49 (98.9)16 (99.7)3 (99.9)0 (99.9)0 (99.9)2 (100.0)
    ESBL phenotype2965 (1.7)0 (1.7)14 (6.4)58 (26.0)60 (46.3)89 (76.4)49 (92.9)16 (98.3)3 (99.3)0 (99.3)0 (99.3)2 (100.0)
    Meropenem nonsusceptibleb115  2 (1.7)10 (10.4)14 (22.6)43 (60.0)29 (85.2)12 (95.7)3 (98.3)0 (98.3)0 (98.3)2 (100.0)
K. oxytoca442 29 (6.6)205 (52.9)148 (86.4)41 (95.7)10 (98.0)9 (100.0)     
    ESBL phenotype44  2 (4.5)18 (45.5)10 (68.2)7 (84.1)7 (100.0)     
P. mirabilis68312 (1.8)437 (65.7)206 (95.9)23 (99.3)4 (99.9)1 (100.0)      
    ESBL phenotype33 11 (33.3)16 (81.8)5 (97.0)1 (100.0)       
E. cloacae9517 (0.7)11 (1.9)47 (6.8)453 (54.5)274 (83.3)109 (94.7)41 (99.1)6 (99.7)3 (100.0)   
    Ceftazidime nonsusceptiblec2003 (1.5)1 (2.0)3 (3.5)18 (12.5)49 (37.0)82 (78.0)35 (95.5)6 (98.5)3 (100.0)   
E. aerogenes3572 (0.6)11 (3.6)98 (31.1)155 (74.5)64 (92.4)24 (99.2)2 (99.7)0 (99.7)0 (99.7)0 (99.7)1 (100.0) 
    Ceftazidime nonsusceptiblec822 (2.4)1 (3.7)2 (6.1)23 (34.1)37 (79.3)14 (96.3)2 (98.8)0 (98.8)0 (98.8)0 (98.8)1 (100.0) 
M. morganii2953 (1.0)141 (48.8)94 (80.7)33 (91.9)16 (97.3)5 (99.0)2 (99.7)0 (99.7)0 (99.7)1 (100.0)  
C. koseri1862 (1.1)9 (5.9)101 (60.2)57 (90.9)12 (97.3)1 (97.8)4 (100.0)     
C. freundii185 2 (1.1)29 (16.8)84 (62.2)46 (87.0)13 (94.1)8 (98.4)2 (99.5)0 (99.5)0 (99.5)1 (100.0) 
S. marcescens506 2 (0.4)48 (9.9)250 (59.3)142 (87.4)49 (97.0)10 (99.0)2 (99.4)1 (99.6)1 (99.8)1 (100.0) 
P. vulgaris153 70 (45.8)74 (94.1)8 (99.3)0 (99.3)1 (100.0)      
Providencia spp.2686 (2.2)54 (22.4)50 (41.0)66 (65.7)60 (88.1)11 (92.2)5 (94.0)3 (95.1)2 (95.9)10 (99.6)1 (100.0) 
P. aeruginosa1,967  3 (0.2)2 (0.3)18 (1.2)105 (6.5)779 (46.1)608 (77.0)273 (90.9)119 (96.9)38 (98.9)22 (100.0)
    Meropenem nonsusceptibled354     4 (1.1)39 (12.1)84 (35.9)104 (65.3)78 (87.3)28 (95.2)17 (100.0)
    Ceftazidime nonsusceptiblee330     1 (0.3)26 (8.2)76 (31.2)86 (57.3)82 (82.1)37 (93.3)22 (100.0)
Acinetobacter spp.321    2 (0.6)0 (0.6)7 (2.8)8 (5.3)43 (18.7)40 (31.2)70 (53.0)151 (100.0)
a
Underlined values represent the percentages inhibited at the CLSI susceptible breakpoint for ceftazidime alone (11).
b
Defined according to the CLSI nonsusceptibility breakpoint of ≥2 μg/ml (11).
c
Defined according to the CLSI nonsusceptibility breakpoint of ≥8 μg/ml (11).
d
Defined according to the CLSI nonsusceptibility breakpoint of ≥4 μg/ml (11).
e
Defined according to the CLSI nonsusceptibility breakpoint of ≥16 μg/ml (11).
TABLE 2
TABLE 2 Activities of ceftazidime-avibactam and comparator antimicrobial agents
Organism (no. tested)/antimicrobial agentMIC (μg/ml)% S/% I/% Ra
5090CLSIEUCAST
Enterobacteriaceae (8,640)    
    Ceftazidime-avibactam0.120.25(99.8)b(99.3)c
    Ceftazidime0.12889.3/1.3/9.487.0/2.3/10.7
    Ceftriaxone≤0.06>886.2/1.0/12.886.2/1.0/12.8
    Ampicillin/sulbactam8>3254.5/16.8/28.754.5/0.0/45.5
    Piperacillin-tazobactam21691.8/3.2/5.188.4/3.3/8.2
    Meropenem≤0.06≤0.0698.4/0.1/1.598.5/0.4/1.1
    Levofloxacin≤0.12>481.6/2.3/16.180.0/1.6/18.4
    Gentamicin≤1490.5/1.6/7.988.4/2.1/9.5
    Tigecyclined0.25197.9/2.1/<0.191.7/6.2/2.1
E. coli (2,767)    
    Ceftazidime-avibactam0.060.12(100.0)b(>99.9)c
    Ceftazidime0.12291.8/1.5/6.789.2/2.6/8.2
    Ceftriaxone≤0.06>889.1/0.2/10.889.1/0.2/10.8
    Ampicillin/sulbactam8>3251.1/20.2/28.751.1/0.0/48.9
    Piperacillin-tazobactam2895.2/2.0/2.892.4/2.8/4.8
    Meropenem≤0.06≤0.0699.9/0.0/0.199.9/0.1/0.0
    Levofloxacin≤0.12>470.7/0.5/28.870.3/0.4/29.3
    Gentamicin≤1>887.3/0.5/12.286.3/1.0/12.7
    Tigecyclined0.120.12100.0/0.0/0.0100.0/0.0/0.0
ESBL phenotype (328)    
    Ceftazidime-avibactam0.120.25(100.0)b(99.7)c
    Ceftazidime16>3230.8/12.8/56.49.1/21.7/69.2
    Ceftriaxone>8>87.6/0.9/91.57.6/0.9/91.5
    Ampicillin/sulbactam32>3211.9/16.5/71.611.9/0.0/88.1
    Piperacillin-tazobactam8>6476.8/10.4/12.861.9/14.9/23.2
    Meropenem≤0.06≤0.0698.8/0.7/0.699.4/0.6/0.0
    Levofloxacin>4>423.8/1.5/74.722.6/1.2/76.2
    Gentamicin2>864.8/0.3/34.962.7/2.1/35.2
    Tigecyclined0.120.25100.0/0.0/0.0100.0/0.0/0.0
K. pneumoniae (1,847)    
    Ceftazidime-avibactam0.120.5(99.9)b(98.9)c
    Ceftazidime0.123285.4/1.3/13.384.1/1.4/14.6
    Ceftriaxone≤0.06>885.4/0.1/14.485.4/0.1/14.4
    Ampicillin/sulbactam8>3273.9/6.3/19.873.9/0.0/26.1
    Piperacillin-tazobactam4>6486.6/2.7/10.880.7/5.8/13.4
    Meropenem≤0.06≤0.0693.8/0.1/6.193.9/1.5/4.6
    Levofloxacin≤0.12>486.1/1.5/12.485.0/1.1/13.9
    Gentamicin≤1291.7/1.7/6.690.1/1.7/8.3
    Tigecyclined0.25199.2/0.7/0.195.3/3.9/0.8
ESBL phenotype (296)    
    Ceftazidime-avibactam0.51(99.3)b(92.9)c
    Ceftazidime>32>328.8/8.1/83.11.0/7.8/91.2
    Ceftriaxone>8>88.8/1.4/89.88.8/1.4/89.8
    Ampicillin/sulbactam>32>322.7/4.7/92.62.7/0.0/97.3
    Piperacillin-tazobactam>64>6424.4/11.9/63.717.3/7.1/75.6
    Meropenem≤0.06>861.1/1.1/37.862.2/9.1/28.7
    Levofloxacin>4>424.3/5.1/70.622.6/1.7/75.7
    Gentamicin4>851.4/10.8/37.842.6/8.8/48.6
    Tigecyclined0.5198.0/1.7/0.391.2/6.8/2.0
Meropenem nonsusceptible (MIC ≥ 2 μg/ml; 115)    
    Ceftazidime-avibactam0.52(98.3)b(85.2)c
    Ceftazidime>32>320.0/0.0/100.00.0/0.0/100.0
    Ceftriaxone>8>80.0/0.0/100.00.0/0.0/100.0
    Ampicillin/sulbactam>32>320.0/0.0/100.00.0/0.0/100.0
    Piperacillin-tazobactam>64>640.0/0.0/100.00.0/0.0/100.0
    Meropenem>8>80.0/2.6/97.42.6/23.5/73.9
    Levofloxacin>4>47.0/1.7/91.35.2/1.8/93.0
    Gentamicin8>848.7/17.4/33.933.0/15.7/51.3
    Tigecyclined0.5198.2/0.8/0.992.1/6.2/1.8
K. oxytoca (442)    
    Ceftazidime-avibactam0.060.25(100.0)b(100.0)c
    Ceftazidime0.120.596.8/0.5/2.795.2/1.6/3.2
    Ceftriaxone≤0.060.590.5/0.7/8.890.5/0.7/8.8
    Ampicillin/sulbactam83261.5/27.2/11.361.5/0.0/38.5
    Piperacillin-tazobactam2892.5/0.2/7.390.7/1.8/7.5
    Meropenem≤0.06≤0.0699.3/0.5/0.299.8/0.0/0.2
    Levofloxacin≤0.120.2597.7/0.3/2.096.4/1.3/2.3
    Gentamicin≤1≤196.6/1.7/1.896.4/0.1/3.4
    Tigecyclined0.120.2599.8/0.2/0.098.2/1.6/0.2
ESBL phenotype (44)    
    Ceftazidime-avibactam0.251(100.0)b(100.0)c
    Ceftazidime1>3268.2/4.5/27.352.3/15.9/31.8
    Ceftriaxone8>84.5/6.9/88.64.5/6.9/88.6
    Ampicillin/sulbactam>32>324.5/4.6/90.94.5/0.0/95.5
    Piperacillin-tazobactam>64>6425.0/2.3/72.720.5/4.5/75.0
    Meropenem≤0.06≤0.0693.2/4.5/2.397.7/0.0/2.3
    Levofloxacin≤0.12>477.3/2.2/20.568.2/9.1/22.7
    Gentamicin≤1>872.7/13.7/13.670.5/2.2/27.3
    Tigecyclined0.25197.7/2.3/0.095.5/2.2/2.3
P. mirabilis (683)    
    Ceftazidime-avibactam0.030.06(100.0)b(100.0)c
    Ceftazidime0.060.1299.1/0.9/0.097.4/1.6/0.9
    Ceftriaxone≤0.06≤0.0695.3/1.2/3.595.3/1.2/3.5
    Ampicillin/sulbactam11688.4/6.8/4.788.4/0.0/11.6
    Piperacillin-tazobactam≤0.5199.7/0.2/0.199.6/0.2/0.3
    Meropenem≤0.060.12100.0/0.0/0.0100.0/0.0/0.0
    Levofloxacin≤0.12>475.5/5.4/19.171.4/4.1/24.5
    Gentamicin≤1888.7/2.6/8.784.6/4.2/11.3
    Tigecyclined2482.9/16.8/0.342.3/40.6/17.1
ESBL phenotype (33)    
    Ceftazidime-avibactam0.060.12(100.0)b(100.0)c
    Ceftazidime2881.8/18.2/0.045.5/36.3/18.2
    Ceftriaxone>8>83.0/24.3/72.73.0/24.3/72.7
    Ampicillin/sulbactam163230.3/24.2/45.530.3/0.0/69.7
    Piperacillin-tazobactam14100.0/0.0/0.097.0/3.0/0.0
    Meropenem≤0.060.12100.0/0.0/0.0100.0/0.0/0.0
    Levofloxacin>4>433.3/15.2/51.521.2/12.1/66.7
    Gentamicin2>860.6/6.1/33.360.6/0.0/39.4
    Tigecyclined2481.8/18.2/0.048.5/33.3/18.2
E. cloacae (951)    
    Ceftazidime-avibactam0.120.5(100.0)b(99.1)c
    Ceftazidime0.25>3279.0/1.0/20.076.9/2.1/21.0
    Ceftriaxone0.25>874.4/1.8/23.874.4/1.8/23.8
    Ampicillin/sulbactam16>3232.5/20.9/46.632.5/0.0/67.5
    Piperacillin-tazobactam26485.0/7.1/7.980.9/4.1/15.0
    Meropenem≤0.06≤0.0699.5/0.0/0.599.5/0.2/0.3
    Ciprofloxacin≤0.030.592.5/2.1/5.491.5/1.0/7.5
    Levofloxacin≤0.120.594.1/2.0/3.992.5/1.6/5.9
    Gentamicin≤1≤194.5/0.9/4.694.2/0.3/5.5
    Tigecyclined0.25198.5/1.5/0.094.4/4.1/1.5
Ceftazidime nonsusceptible (MIC ≥ 8 μg/ml; 200)    
    Ceftazidime-avibactam0.51(100.0)b(95.5)c
    Ceftazidime>32>320.0/5.0/95.00.0/0.0/100.0
    Ceftriaxone>8>80.0/0.0/100.00.0/0.0/100.0
    Ampicillin/sulbactam>32>321.0/2.5/96.51.0/0.0/99.0
    Piperacillin-tazobactam64>6429.1/33.2/37.717.1/12.0/70.9
    Meropenem≤0.060.2597.5/0.0/2.597.5/1.0/1.5
    Levofloxacin≤0.12>476.9/8.0/15.173.4/3.5/23.1
    Gentamicin≤1>877.4/3.5/19.176.4/1.0/22.6
    Tigecyclined0.25294.5/5.5/0.085.0/9.5/5.5
E. aerogenes (357)    
    Ceftazidime-avibactam0.120.25(99.7)b(99.7)c
    Ceftazidime0.253277.0/1.7/21.374.2/2.8/23.0
    Ceftriaxone0.12>873.6/2.3/24.173.6/2.3/24.1
    Ampicillin/sulbactam16>3240.3/22.2/37.540.3/0.0/59.7
    Piperacillin-tazobactam46480.6/14.7/4.873.8/6.8/19.4
    Meropenem≤0.06≤0.0699.4/0.3/0.399.7/0.3/0.0
    Levofloxacin≤0.120.2596.9/1.1/2.095.5/1.4/3.1
    Gentamicin≤1≤197.2/0.6/2.296.4/0.8/2.8
    Tigecyclineb0.250.599.2/0.8/0.095.8/3.4/0.8
Ceftazidime nonsusceptible (MIC, ≥ 8 μg/ml; 82)    
    Ceftazidime-avibactam0.250.5(98.8)b(98.8)c
    Ceftazidime32>320.0/7.3/92.70.0/0.0/100.0
    Ceftriaxone>8>80.0/1.2/98.80.0/1.2/98.8
    Ampicillin/sulbactam>32>320.0/1.2/98.80.0/0.0/100.0
    Piperacillin-tazobactam64>6422.0/57.3/20.711.0/11.0/78.0
    Meropenem≤0.060.1297.6/1.2/1.298.8/1.2/0.0
    Levofloxacin≤0.12290.2/3.7/6.185.4/4.8/9.8
    Gentamicin≤1491.5/2.4/6.187.8/3.7/8.5
    Tigecyclined0.25197.6/2.4/0.096.3/1.3/2.4
M. morganii (295)    
    Ceftazidime-avibactam0.060.12(99.7)b(99.7)c
    Ceftazidime0.121685.8/4.0/10.277.3/8.5/14.2
    Ceftriaxone≤0.06486.7/2.7/10.686.7/2.7/10.6
    Ampicillin/sulbactam163223.5/36.7/39.823.5/0.0/76.5
    Piperacillin-tazobactam≤0.5296.6/1.4/2.095.9/0.6/3.4
    Meropenem≤0.060.12100.0/0.0/0.0100.0/0.0/0.0
    Levofloxacin≤0.12>470.4/8.5/21.166.0/4.4/29.6
    Gentamicin≤1>883.3/2.2/14.679.6/3.7/16.7
    Tigecyclined0.5295.9/4.1/0.086.1/9.9/4.1
C. koseri (186)    
    Ceftazidime-avibactam0.060.12(100.0)b(100.0)c
    Ceftazidime0.120.598.4/0.5/1.196.2/2.2/1.6
    Ceftriaxone≤0.060.2598.4/0.0/1.698.4/0.0/1.6
    Ampicillin/sulbactam2895.7/1.6/2.795.7/0.0/4.3
    Piperacillin-tazobactam2898.4/1.1/0.594.6/3.9/1.6
    Meropenem≤0.06≤0.06100.0/0.0/0.0100.0/0.0/0.0
    Levofloxacin≤0.12≤0.1299.5/0.0/0.598.4/1.1/0.5
    Gentamicin≤1≤199.5/0.0/0.599.5/0.0/0.5
    Tigecyclineb0.120.25100.0/0.0/0.099.5/0.5/0.0
C. freundii (185)    
    Ceftazidime-avibactam0.120.5(99.5)b(98.4)c
    Ceftazidime0.5>3276.8/1.0/22.273.5/3.3/23.2
    Ceftriaxone0.25>875.0/1.1/23.975.0/1.1/23.9
    Ampicillin/sulbactam8>3260.3/9.3/30.460.3/0.0/39.7
    Piperacillin-tazobactam46482.1/9.2/8.774.5/7.6/17.9
    Meropenem≤0.06≤0.0697.8/0.7/1.698.4/1.1/0.5
    Levofloxacin≤0.12485.4/5.3/9.280.5/4.9/14.6
    Gentamicin≤1>887.6/0.5/11.987.0/0.6/12.4
    Tigecyclined0.25198.9/1.1/0.092.9/6.0/1.1
S. marcescens (506)    
    Ceftazidime-avibactam0.120.5(99.6)b(99.0)c
    Ceftazidime0.250.597.4/0.1/2.496.6/0.9/2.6
    Ceftriaxone0.25289.8/2.4/7.889.8/2.4/7.8
    Ampicillin/sulbactam32>329.1/15.0/75.99.1/0.0/90.9
    Piperacillin-tazobactam2496.6/2.4/1.094.4/2.1/3.4
    Meropenem≤0.06≤0.0699.2/0.3/0.499.6/0.2/0.2
    Levofloxacin≤0.12194.7/2.8/2.491.3/3.4/5.3
    Gentamicin≤1297.0/0.8/2.295.1/1.9/3.0
    Tigecyclined0.5199.0/1.0/0.094.3/4.7/1.0
P. vulgaris (153)    
    Ceftazidime-avibactam0.060.06(100.0)b(100.0)c
    Ceftazidime0.060.12100.0/0.0/0.0100.0/0.0/0.0
    Ceftriaxone0.12472.8/9.3/17.972.8/9.3/17.9
    Ampicillin/sulbactam81665.4/32.0/2.665.4/0.0/34.6
    Piperacillin-tazobactam≤0.5199.3/0.0/0.799.3/0.0/0.7
    Meropenem≤0.060.12100.0/0.0/0.0100.0/0.0/0.0
    Levofloxacin≤0.12≤0.1298.7/0.6/0.798.7/0.0/1.3
    Gentamicin≤1298.7/1.3/0.094.7/4.0/1.3
    Tigecyclined0.5198.7/1.3/0.090.9/7.8/1.3
Providencia spp.e (268)    
    Ceftazidime-avibactam0.120.5(95.90)b(94.0)c
    Ceftazidime0.12490.7/1.8/7.585.1/5.7/9.3
    Ceftriaxone≤0.06190.3/2.2/7.590.3/2.2/7.5
    Ampicillin/sulbactam163236.0/29.9/34.136.0/0.0/64.0
    Piperacillin-tazobactam1894.4/1.5/4.192.2/2.2/5.6
    Meropenem≤0.060.1299.2/0.3/0.499.6/0.0/0.4
    Levofloxacin2>451.5/13.8/34.745.9/5.6/48.5
    Gentamicin4>872.1/16.2/11.749.8/22.3/27.9
    Tigecyclined1295.1/4.9/0.076.0/19.1/4.9
P. aeruginosa (1,967)    
    Ceftazidime-avibactam24(96.9)b(96.9)c
    Ceftazidime23283.2/3.8/13.083.2/0.0/16.8
    Cefepime21683.8/8.2/8.083.8/0.0/16.2
    Piperacillin-tazobactam8>6478.3/8.9/12.878.3/0.0/21.7
    Meropenem0.5882.0/5.6/12.482.0/11.4/6.6
    Ciprofloxacin0.12>477.5/5.0/17.572.1/5.4/22.5
    Levofloxacin0.5>475.3/6.5/18.266.7/8.6/24.7
    Gentamicin≤1888.8/3.4/7.888.8/0.0/11.2
    Amikacin2897.5/1.3/1.294.0/3.5/2.5
    Colistin1298.6/1.4/0.198.6/0.0/1.4
Meropenem nonsusceptible (MIC ≥ 4 μg/ml; 354)    
    Ceftazidime-avibactam416(87.3)b(87.3)c
    Ceftazidime16>3249.2/10.7/40.149.2/0.0/50.8
    Cefepime16>1646.6/24.0/29.446.6/0.0/53.4
    Piperacillin-tazobactam64>6436.4/23.2/40.436.4/0.0/63.6
    Meropenem8>80.0/31.4/68.60.0/63.3/36.7
    Ciprofloxacin4>437.6/6.7/55.730.5/7.1/62.4
    Levofloxacin>4>433.6/8.2/58.221.8/11.8/66.4
    Gentamicin4>864.7/7.6/27.764.7/0.0/35.3
    Amikacin41692.7/4.2/3.184.2/8.5/7.3
    Colistin1297.7/1.7/0.697.7/0.0/2.3
Ceftazidime nonsusceptible (MIC ≥ 16 μg/ml; 330)    
    Ceftazidime-avibactam416(82.1)b(82.1)c
    Ceftazidime32>320.0/22.7/77.30.0/0.0/100.0
    Cefepime16>1620.0/36.1/43.920.0/0.0/80.0
    Piperacillin-tazobactam>64>644.5/22.8/72.74.5/0.0/95.5
    Meropenem4>845.3/9.4/45.345.3/28.6/26.1
    Ciprofloxacin2>442.4/8.2/49.436.7/5.7/57.6
    Levofloxacin>4>439.4/9.7/50.930.3/9.1/60.6
    Gentamicin2>867.3/6.3/26.467.3/0.0/32.7
    Amikacin41693.0/3.4/3.685.8/7.2/7.0
    Colistin1299.1/0.7/0.399.1/0.0/0.9
Acinetobacter spp. (321)    
    Ceftazidime-avibactam16>32(31.2)b-/-/-
    Ceftazidime32>3241.7/5.3/53.0-/-/-
    Cefepime>16>1640.5/6.5/53.0-/-/-
    Piperacillin-tazobactam>64>6441.3/0.1/58.8-/-/-
    Ampicillin/sulbactam16>3248.9/15.0/36.1-/-/-
    Meropenem8>847.0/5.0/48.045.5/6.5/48.0
    Ciprofloxacin>4>441.7/0.0/58.341.7/0.0/58.3
    Levofloxacin>4>442.1/2.4/55.541.7/0.4/57.9
    Gentamicin4>850.2/4.0/45.850.2/0.0/49.8
    Amikacin8>3267.9/4.7/27.462.3/5.6/32.1
    Colistin1296.6/0.0/3.496.6/0.0/3.4
a
Criteria as published by the CLSI (11) and EUCAST (12). S, susceptible; I, intermediate; R, resistant.
b
Percentage inhibited at the CLSI susceptible breakpoint for ceftazidime alone; for comparison only (11).
c
Percentage inhibited at the EUCAST susceptible breakpoint for ceftazidime alone; for comparison only (12).
d
Due to the lack of CLSI breakpoints, U.S. FDA breakpoints were applied instead (31).
e
Includes Providencia alcalifaciens (3 strains), Providencia rettgeri (111 strains), and Providencia stuartii (154 strains).
Only 6 of 8,640 strains (0.07%) had a ceftazidime-avibactam MIC at ≥16 μg/ml (Table 1) (11). The highest ceftazidime-avibactam MIC among E. coli strains (2,767 strains) was only 2 μg/ml (one isolate). The ESBL screen-positive phenotype strains were very susceptible to ceftazidime-avibactam (MIC50/MIC90, 0.12/0.25 μg/ml), and all non-ESBL-phenotype strains were inhibited at a ceftazidime-avibactam MIC of ≤0.5 μg/ml (Tables 1 and 2). Ceftazidime-avibactam was also active against K. pneumoniae (1,847 strains; MIC50/MIC90, 0.12/0.5 μg/ml) and Klebsiella oxytoca (442 strains; MIC50/MIC90, 0.06/0.25 μg/ml), including ESBL-phenotype strains (MIC90, 1 μg/ml for both species) (Table 2). Among meropenem-nonsusceptible (MIC, ≥2 μg/ml) K. pneumoniae strains (115 strains; MIC50/MIC90, 0.5/2 μg/ml), ceftazidime-avibactam inhibited 98.3% of the isolates at ≤4 μg/ml (Table 1). Only two K. pneumoniae strains had ceftazidime-avibactam MICs of >4 μg/ml, both at >32 μg/ml. These strains were isolated in a single medical center in Denver, CO, and further evaluation showed that they produced NDM-1 and were clonally related (14). Furthermore, ceftazidime-avibactam exhibited potent activity against P. mirabilis, with a MIC90 of 0.06 μg/ml and the highest MIC at 0.5 μg/ml (Tables 1 and 2).
An ESBL phenotype was noted among 701 (12.2%) Enterobacteriaceae isolates and included 328 E. coli (11.9% of the overall samples for this species), 296 K. pneumoniae (16.0%), 44 K. oxytoca (10.0%), and 33 P. mirabilis (4.8%) isolates; a complete analysis of the molecular characterization of these strains has been previously reported by Castanheira et al. (15). In summary, CTX-M group 1 (CTX-M-15-like) was the most common β-lactamase detected among ESBL-phenotype strains (303/701; 43.2%), followed by SHV ESBL (176/701; 25.1%), KPC (118/701; 16.8%), CTX-M-14-like (72/701; 10.3%), and CMY-2-like (64/701). Among E. coli strains, CTX-M type was the most common β-lactamase identified (75.9% of strains), followed by non-ESBL TEM type (41.2%) and CMY type (15.2%), whereas among K. pneumoniae strains, SHV type (53.4%) and CTX-M type (33.8%) were the most common ESBLs and KPC was identified among 37.8% of the strains. Other enzymes were also detected in a small number of strains (15).
When tested against Enterobacter cloacae, ceftazidime-avibactam (MIC50/MIC90, 0.12/0.5 μg/ml) inhibited 100.0% of the strains at MICs of 4 μg/ml or less, including ceftazidime-nonsusceptible strains (200 strains tested; ceftazidime-avibactam MIC50/MIC90, 0.5/1 μg/ml) (Tables 1 and 2). Ceftazidime-avibactam inhibited 99.7% (356 of 357) of Enterobacter aerogenes strains (MIC50/MIC90, 0.12/0.25 μg/ml) at ≤1 μg/ml; one strain had a ceftazidime-avibactam MIC of 16 μg/ml (Table 1).
Ceftazidime-avibactam exhibited potent activity against Morganella morganii (MIC50/MIC90, 0.06/0.12 μg/ml; 99.7% inhibited at ≤1 μg/ml), Citrobacter koseri (MIC50/MIC90, 0.06/0.12 μg/ml; 100.0% inhibited at ≤1 μg/ml), Citrobacter freundii (MIC50/MIC90, 0.12/0.5 μg/ml; 98.4 and 99.5% inhibited at ≤1 and ≤4 μg/ml, respectively), Serratia marcescens (MIC50/MIC90, 0.12/0.5 μg/ml; 99.0 and 99.6% inhibited at ≤1 and ≤4 μg/ml, respectively), Proteus vulgaris (MIC50/MIC90, 0.06/0.06 μg/ml; 100.0% inhibited at ≤0.5 μg/ml), and Providencia spp. (MIC50/MIC90, 0.12/0.5 μg/ml; 94.0 and 95.9% inhibited at ≤1 and ≤4 μg/ml, respectively) (Tables 1 and 2).
Six Enterobacteriaceae strains (0.07%) exhibited ceftazidime-avibactam MICs of ≥16 μg/ml, including two NDM-1-producing K. pneumoniae strains with ceftazidime-avibactam MICs of >16 μg/ml and four organisms (C. freundii, E. aerogenes, Providencia stuartii, and S. marcescens) with ceftazidime-avibactam MICs of 16 μg/ml that were susceptible to meropenem and had negative results for all ESBL- and carbapenemase-encoding genes tested. Twelve additional Enterobacteriaceae strains exhibited a ceftazidime-avibactam MICs of 8 μg/ml: 10 Providencia spp., 1 S. marcescens strain, and one M. morganii strain.

P. aeruginosa and Acinetobacter spp.

Ceftazidime-avibactam (MIC50/MIC90, 2/4 μg/ml; 96.9% inhibited at ≤8 μg/ml) exhibited greater in vitro activity than ceftazidime alone (MIC50/MIC90, 2/32 μg/ml; 83.2% susceptible at ≤8 μg/ml) when tested against P. aeruginosa (Tables 1 and 2). Moreover, ceftazidime-avibactam inhibited 82.1% of ceftazidime-nonsusceptible P. aeruginosa isolates (ceftazidime MIC, ≥16 μg/ml; 330 isolates tested) at ≤8 μg/ml (Table 1). Ceftazidime-avibactam also showed potent activity against meropenem-nonsusceptible P. aeruginosa (meropenem MIC, ≥4 μg/ml; 354 isolates tested), inhibiting 87.3% of strains at ≤8 μg/ml (Table 1). The most active antimicrobials tested against meropenem-nonsusceptible P. aeruginosa were ceftazidime-avibactam (MIC50/MIC90, 4/16 μg/ml), amikacin (MIC50/MIC90, 4/16 μg/ml; 92.7% susceptible [CLSI criteria]), and colistin (MIC50/MIC90, 1/2 μg/ml, 97.7% susceptible) (Table 2).
Ceftazidime-avibactam exhibited limited activity against Acinetobacter spp. (MIC50/MIC90, 16/>32 μg/ml; 31.2% inhibited at ≤8 μg/ml). Colistin (MIC50/MIC90, 1/2 μg/ml; 96.6% susceptible) and amikacin (MIC50/MIC90, 8/>32 μg/ml; 67.9% susceptible) were the most active compounds tested against this organism; all other compounds tested exhibited ≤50% susceptibility (Table 2).

DISCUSSION

The increasing trend of antimicrobial resistance is most troublesome for Gram-negative bacteria, because there has been little successful development of new antimicrobial agents targeting this group of organisms (16, 17). We are now facing infections caused by pandrug-resistant (PDR) or extremely drug-resistant (XDR) organisms, which are resistant to all (PDR) or almost all (XDR) antimicrobial agents currently available for clinical use (18). Thus, the use of second-line and more toxic compounds, such as the polymyxins, is rapidly increasing in some geographic regions, and new antimicrobial agents for treatment of infections caused by resistant Gram-negative organisms are desperately needed (16).
The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) remained extremely low for approximately 20 years after the approval of the first carbapenem for clinical use in 1985 (19, 20). However, in the last few years, the occurrence of carbapenemase-producing Enterobacteriaceae has increased rapidly in some geographic regions (6). In particular, clonal K. pneumoniae strains with KPCs (class A carbapenemases) have disseminated widely in the United States, Israel, and some European countries (5, 7, 13, 20, 21).
P. aeruginosa and Acinetobacter spp. represent major causes of hospital-acquired infections, particularly pneumonia, and are often resistant to multiple antimicrobial agents (17). These organisms demonstrate intrinsic decreased susceptibility to a wide variety of antimicrobials because of low outer membrane permeability; this allows secondary adaptive resistance mechanisms to work more efficiently, including β-lactamases and efflux pumps (22).
Ceftazidime is a well-established cephalosporin with an excellent safety profile and broad-spectrum activity against Gram-negative organisms, including P. aeruginosa (23). However, similar to other cephalosporins, ceftazidime can be hydrolyzed by some class A enzymes, including ESBLs and KPCs, and class C enzymes. Avibactam is a novel non-β-lactam β-lactamase inhibitor that protects β-lactams from hydrolysis by Ambler class A and C β-lactamases and some class D (OXA) enzymes (8, 24, 25). The results of the present study clearly demonstrate that avibactam restores ceftazidime activity against Enterobacteriaceae producing the β-lactamases most commonly found in U.S. hospitals, including ESBLs and KPCs (13). Ceftazidime-avibactam inhibited all ESBL- and KPC-producing Enterobacteriaceae strains at MICs of ≤4 μg/ml. Furthermore, ceftazidime-avibactam inhibited all E. cloacae and 98.8% (81/82) of E. aerogenes strains showing an AmpC-derepressed phenotype (i.e., ceftazidime-nonsusceptible strains). Eleven of 18 (66.7%) Enterobacteriaceae isolates with an elevated ceftazidime-avibactam MIC value (>4 μg/ml) were represented by Providencia spp. (10 P. stuartii and one P. rettgeri strains) (Table 1).
Ceftazidime-avibactam was also active against P. aeruginosa and inhibited 96.9% of strains at ≤8 μg/ml. Ceftazidime-avibactam (MIC50/MIC90, 2/4 μg/ml) exhibited greater anti-P. aeruginosa activity than ceftazidime (MIC50/MIC90, 2/32 μg/ml; 83.2% susceptible) and inhibited 82.1% of ceftazidime-nonsusceptible strains at ≤8 μg/ml. Moreover, ceftazidime-avibactam was highly active against meropenem-nonsusceptible strains (MIC50/MIC90, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml). Similar to other β-lactams and to most antimicrobial agents tested, ceftazidime-avibactam showed limited activity against Acinetobacter spp. and metallo-β-lactamase-producing strains of Enterobacteriaceae; the latter are extremely rare in U.S. hospitals (13, 14).
In summary, ceftazidime-avibactam was active against a large collection of contemporary (2012) Gram-negative organisms isolated from patients in U.S. hospitals, including organisms resistant to most currently available agents, such as KPC-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa. The results of this study corroborate other investigations demonstrating potent in vitro activity against multidrug-resistant strains of Enterobacteriaceae (2628) and P. aeruginosa (29, 30) and indicate that the use of avibactam, a broad-spectrum β-lactamase inhibitor, in combination with a well-known β-lactam, such as ceftazidime, could become a valuable addition to the limited armamentarium currently available to treat serious Gram-negative infections.

ACKNOWLEDGMENTS

This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design of the study but had no involvement in the collection, analysis, and interpretation of data. Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc.
JMI Laboratories, Inc. received research and educational grants from 2011 to 2013 from Achaogen, Actelion, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Basilea, bioMérieux, Cardeas, Cempra, Cerexa, Cubist, Dipexium, Durata, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Methylgene, Nabriva, Novartis, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Roche, Seachaid, Shionogi, The Medicines Co., Theravance, ThermoFisher, and Vertex. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. We have no speaker bureaus or stock options to declare.

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Published In

cover image Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Volume 58Number 3March 2014
Pages: 1684 - 1692
PubMed: 24379201

History

Received: 6 November 2013
Returned for modification: 7 December 2013
Accepted: 21 December 2013
Published online: 19 February 2014

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Contributors

Authors

Helio S. Sader
JMI Laboratories, North Liberty, Iowa, USA
Mariana Castanheira
JMI Laboratories, North Liberty, Iowa, USA
Robert K. Flamm
JMI Laboratories, North Liberty, Iowa, USA
David J. Farrell
JMI Laboratories, North Liberty, Iowa, USA
Ronald N. Jones
JMI Laboratories, North Liberty, Iowa, USA

Notes

Address correspondence to Helio S. Sader, [email protected].

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