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. 2009 Aug;64(2):326-9.
doi: 10.1093/jac/dkp197. Epub 2009 Jun 2.

In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases

Thérèse Stachyra  1 , Premavathy Levasseur, Marie-Claude Péchereau, Anne-Marie Girard, Monique Claudon, Christine Miossec, Michael T Black
Affiliations

In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases

Thérèse Stachyra et al. J Antimicrob Chemother. 2009 Aug.

Abstract

Background: NXL104 is a novel-structure beta-lactamase inhibitor with potent activity against both class A and class C enzymes. Among the class A carbapenemases, KPC-type enzymes are now spreading rapidly and KPC-related carbapenemase resistance is an emerging phenomenon of great clinical importance. The activity of NXL104 against KPC beta-lactamases was examined.

Methods: Enzymatic activity of purified recombinant KPC-2 was measured with nitrocefin as reporter substrate and inhibition by NXL104 was measured by determination of IC(50) values. Antimicrobial susceptibility testing of various beta-lactams combined with a fixed concentration of NXL104 at 4 mg/L against strains producing KPC enzymes was performed by the broth microdilution method.

Results: NXL104 was a potent inhibitor of KPC-2 with an IC(50) of 38 nM. NXL104 restored the antimicrobial activity of ceftazidime, ceftriaxone, imipenem and piperacillin against Enterobacteriaceae strains producing KPC-2 or KPC-3. MIC values of ceftazidime against KPC producers were reduced by up to 1000-fold by combination with NXL104.

Conclusions: NXL104 inhibitory activity is unique in terms of spectrum, encompassing class A extended-spectrum beta-lactamases, class C enzymes and class A carbapenemases. Given the limited therapeutic options available for infections caused by multiresistant Enterobacteriaceae isolates, NXL104 beta-lactamase inhibitor is a promising agent to be used in combination with a beta-lactam to protect its antibacterial activity.

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Figures

Figure 1
Figure 1
Chemical structure of NXL104.
See this image and copyright information in PMC

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