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In vitro activity of avibactam (NXL104) in combination with β-lactams against Gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniae

https://doi.org/10.1016/j.ijantimicag.2011.09.012Get rights and content

Abstract

The objective of this study was to investigate the in vitro antibacterial activity of avibactam (formerly NXL104) in combination with imipenem, cefepime or ceftazidime against Gram-negative bacteria. Bacterial isolates included: Pseudomonas aeruginosa harbouring PER-1 β-lactamase (n = 14); Acinetobacter baumannii harbouring PER-1, OXA-51 and OXA-58 (n = 20); carbapenem-non-susceptible Klebsiella pneumoniae (n = 25) and Escherichia coli (n = 1) harbouring OXA-48; carbapenem-non-susceptible E. coli (n = 1) harbouring both IMP-1 metallo-β-lactamase and extended-spectrum β-lactamase (ESBL); carbapenem-non-susceptible Serratia marcescens (n = 1); and carbapenem-susceptible E. coli (n = 20) and K. pneumoniae isolates (n = 12) with CTX-M-15 ESBL. Minimum inhibitory concentrations (MICs) of imipenem, cefepime and ceftazidime were determined in combination with 4 mg/L avibactam by the Clinical and Laboratory Standards Institute (CLSI) method on Mueller–Hinton agar. Imipenem/avibactam and ceftazidime/avibactam displayed limited potency against A. baumannii isolates, whereas cefepime/avibactam and ceftazidime/avibactam were active against P. aeruginosa. Klebsiella pneumoniae isolates with OXA-48 β-lactamase were resistant to imipenem [MIC for 90% of the organisms (MIC90) ≥4 mg/L]. MIC90 values for the combination of avibactam 4 mg/L with imipenem, cefepime and ceftazidime were in the susceptible range for all strains (MIC90  0.5 mg/L). All E. coli and K. pneumoniae isolates with CTX-M-15 β-lactamase were inhibited at ≤1 mg/L for combinations with avibactam and 100% were susceptible by CLSI breakpoint criteria to imipenem, cefepime and ceftazidime. In conclusion, combinations of imipenem, cefepime and ceftazidime with avibactam may present a promising therapeutic strategy to treat infections due to K. pneumoniae with OXA-48 enzyme as well as K. pneumoniae and E. coli with CTX-M-15 enzyme.

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.

Section snippets

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.

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