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