Ceftazidime/avibactam tested against Gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia

https://doi.org/10.1016/j.ijantimicag.2015.02.022Get rights and content

Highlights

  • Susceptibility rates were generally lower among isolates from intensive care unit (ICU) compared with non-ICU patients.

  • The occurrence of extended-spectrum β-lactamase (ESBL), multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes were clearly higher among Enterobacteriaceae from ICU compared with non-ICU patients.

  • Ceftazidime/avibactam exhibited potent activity against a large collection (n = 13,820) of Enterobacteriaceae isolates from ICU and non-ICU patients, including ESBL- and KPC-producing as well as MDR and XDR strains.

  • Overall, 99.9% of Enterobacteriaceae were inhibited at a ceftazidime/avibactam MIC of ≤8 mg/L.

  • Ceftazidime/avibactam inhibited 97.0% of Pseudomonas aeruginosa at an MIC of ≤8 mg/L, including 80.7% of ceftazidime-non-susceptible and 87.0% of meropenem-non-susceptible isolates.

Abstract

Ceftazidime/avibactam consists of ceftazidime combined with the novel non-β-lactam β-lactamase inhibitor avibactam, which inhibits Ambler classes A, C and some D enzymes. Clinical isolates were collected from 71 US medical centres in 2012–2013 and were tested for susceptibility at a central laboratory by reference broth microdilution methods. Results for 4381 bacterial isolates from intensive care unit (ICU) patients as well as those from ventilator-associated pneumonia (VAP) (n = 435) were analysed and compared with those of 14 483 organisms from non-ICU patients. β-Lactamase-encoding genes were evaluated for 966 Enterobacteriaceae by a microarray-based assay. Ceftazidime/avibactam was active against 99.8/100.0% of Enterobacteriaceae (MIC90, 0.25/0.25 mg/L) from ICU/non-ICU patients (2948/10,872 strains), including isolates from VAP (99.1%), multidrug-resistant (MDR) strains (99.3%), extensively drug-resistant (XDR) strains (96.5%) and meropenem-non-susceptible strains (98.0%), at MICs of ≤8 mg/L. Against Enterobacteriaceae, susceptibility rates for ceftazidime, piperacillin/tazobactam and meropenem (ICU/non-ICU) were 86.1/91.8%, 88.0/94.3% and 97.8/99.2%, respectively. Meropenem was active against 75.1/85.4% of MDR Enterobacteriaceae and 8.1/27.1% of XDR Enterobacteriaceae from ICU/non-ICU patients. When tested against Pseudomonas aeruginosa, ceftazidime/avibactam inhibited 95.6/97.5% of isolates from ICU/non-ICU (842/2240 isolates), 97.3% of isolates from VAP, 80.7% of ceftazidime-non-susceptible and 80.7% of MDR isolates at ≤8 mg/L. Susceptibility rates for P. aeruginosa from ICU/non-ICU were 77.7/86.9% for ceftazidime, 71.2/82.2% for piperacillin/tazobactam and 76.6/84.7% for meropenem. In summary, lower susceptibility rates were observed among ICU compared with non-ICU isolates. Ceftazidime/avibactam exhibited potent activity against a large collection of Gram-negative organisms from ICU and non-ICU patients and provided greater coverage than currently available β-lactams.

Introduction

Antimicrobial resistance has become an important determinant of clinical outcome, and higher rates of antimicrobial resistance are expected in the intensive care unit (ICU) owing to multiple factors, including increased use of broad-spectrum antimicrobials, high occurrence of invasive procedures and increased chance of transmission of resistant bacteria among patients [1]. Furthermore, infections caused by Gram-negative bacteria have characteristics that are of particular concern. These organisms are highly efficient at upregulating or acquiring genes that confer antimicrobial resistance, especially in the presence of antimicrobial selective pressure [2]. Although several drugs have been approved for the treatment of Gram-positive infections in recent years, the number of novel agents in development for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative organisms remains limited [3].

Ceftazidime/avibactam consists of ceftazidime combined with the novel non-β-lactam β-lactamase inhibitor avibactam. Ceftazidime/avibactam combination has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, in patients with limited or no alternative treatment options [4]. Ceftazidime/avibactam is also under clinical development for the treatment of nosocomial pneumonia (http://clinicaltrials.gov; NCT01808092). Avibactam (formerly NXL-104) is a member of a novel class of non-β-lactam β-lactamase inhibitors, the diazabicyclooctanes. Compared with current inhibitors available for clinical use, diazabicyclooctanes are more potent, have a broader spectrum and a different mechanism of action [5]. Avibactam protects β-lactams from hydrolysis by a variety of clinically relevant enzymes.

In this study, the activity of ceftazidime combined with avibactam was evaluated against a large collection of contemporary aerobic Gram-negative clinical isolates recovered from patients in hospitals located in the USA during 2012–2013. In addition, the antimicrobial susceptibility patterns of organisms isolated from hospitalised patients in ICUs, as well as those from ventilator-associated pneumonia (VAP), were assessed and compared with those from non-ICU patients of the same hospitals during the same time period.

Section snippets

Organism collection

Isolates were collected from 71 US medical centres in 2012–2013 as part of the International Network for Optimal Resistance Monitoring (INFORM) programme [6]. Only one isolate per patient was included in the surveillance study. During the study period, a total of 18,864 Gram-negative organisms were collected, including 4381 isolates from ICU patients and 14,483 isolates from non-ICU patients. Among these, 435 isolates were from VAP. All ICU and non-ICU isolates were deemed clinically

Results

The most common Gram-negative organisms isolated from ICU and non-ICU patients were P. aeruginosa (n = 842; 19.2%) and E. coli (n = 3817; 26.4%), respectively (Table 1). P. aeruginosa was also the most common Gram-negative organism isolated from VAP (n = 185) and accounted for 42.5% of cases. P. aeruginosa, Enterobacter spp. (13.8%), Klebsiella pneumoniae (10.8%), E. coli (9.4%) and Serratia marcescens (9.4%) combined were isolated from 85.9% of VAP cases (Table 1).

Ceftazidime/avibactam exhibited

Discussion

Serious infections due to Gram-negative pathogens are associated with significant morbidity, and multidrug resistance further increases mortality [14], [15], [16]. Studies evaluating the influence of ESBL, KPC and metallo-β-lactamase (MBL) production on mortality have revealed higher mortality rates for infections caused by organisms producing these enzymes, most likely related to the severity of these infections and to delays in appropriate antimicrobial therapy [17], [18], [19], [20]. In one

Funding

Sponsored in part by Actavis.

Competing interests

JMI Laboratories, Inc. has received research and educational grants in 2012–2014 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Exela, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, MethylGene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex,

Ethical approval

Not required.

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