Short communicationIn vitro activity of avibactam (NXL104) in combination with β-lactams against Gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniae☆
Introduction
Extended-spectrum β-lactamase (ESBL)-, AmpC-, KPC-, NDM- and OXA-48-producing Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa are amongst the most important and frequently isolated nosocomial pathogens and are often resistant to many classes of antibiotics [1], [2], [3], [4]. PER-1 in P. aeruginosa and A. baumannii and CTX-M in Enterobacteriaceae are the most prevalent ESBLs in Turkey [5], [6], [7]. In addition, increasing numbers of Enterobacteriaceae strains (mainly Klebsiella pneumoniae) with OXA-48 carbapenemase have been encountered [8].
Combinations of β-lactams and β-lactamase inhibitors have been widely used in the treatment of human infections. Although there are some very successful combinations, most inhibitors act only against class A β-lactamases, remaining ineffective against class B, C and D β-lactamases. Avibactam (formerly NXL104) (in development by AstraZeneca/Novexel, Romainville, France) is a novel non-β-lactam β-lactamase inhibitor with potent activity against class A TEM-, SHV-, KPC- and CTX-M-types and class C β-lactamases as well as a variable level of activity against class D enzymes. The combination of ceftazidime with avibactam is being developed to treat infections caused by Gram-negative bacteria, including those resistant to many currently used antibiotics [1], [2], [3].
The objective of this study was to investigate the in vitro antibacterial activity of combinations of imipenem, cefepime and ceftazidime with avibactam in Gram-negative bacteria including Enterobacteriaceae, P. aeruginosa and A. baumannii.
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Materials and methods
Ninety-four unique clinical isolates of Gram-negative bacteria were obtained from a wide range of inpatient and outpatient infections. Identification of the isolates was performed by conventional methods including sugar fermentation, motility, and catalase, oxidase, citrate, urease, indole and H2S production as well as using the API GN system (bioMérieux, Paris, France).
Minimum inhibitory concentrations (MICs) were determined using the Clinical and Laboratory Standards Institute (CLSI) agar
Results
Table 1 shows the MIC distributions of imipenem, cefepime and ceftazidime, alone and in combination with avibactam. Fourteen P. aeruginosa isolates harbouring PER-1 β-lactamase (two of which also produced OXA-10 β-lactamase) were tested. Susceptibility breakpoints are not available for β-lactams/avibactam, therefore the breakpoints for imipenem, cefepime and ceftazidime alone were used (Table 1). Using CLSI breakpoints, the susceptibility rates of P. aeruginosa isolates were as follows:
Discussion
The rising prevalence of antibiotic-resistant P. aeruginosa, A. baumannii and Enterobacteriaceae producing carbapenemases and ESBLs is one of the largest resistance problems of recent years. PER-1 and OXA enzymes in P. aeruginosa and A. baumannii and OXA-48 enzyme in Enterobacteriaceae are the most prevalent ESBLs and carbapenemases in Istanbul Medical Faculty and in Turkey [5], [8].
Class D carbapenemases consist of OXA-type β-lactamases frequently detected in A. baumannii. There are four
Conclusions
Combinations of avibactam with imipenem, cefepime and ceftazidime could represent a promising therapeutic strategy to treat infections due to OXA-48 carbapenemase- and CTX-M-15-type ESBL-producing K. pneumoniae and E. coli isolates.
Acknowledgement
The authors thank Dr Christine Miossec for providing avibactam (Novexel, Romainville, France).
Funding: No funding sources.
Competing interests: None declared.
Ethical approval: Not required.
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This study was presented as a poster at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 12–15 September 2010, Boston, MA.