The efficacy of ceftazidime combined with NXL104, a novel b-lactamase inhibitor, in a mouse model of kidney infections induced by b-lactamase producing Enterobacteriaceae
Abstract number: 1733_292
Borgonovi M., Miossec C., Lowther J.
Objectives: NXL104 is a novel b-lactamase inhibitor that has been shown in vitro and in vivo to inhibit both class A and class C b-lactamases. The occurrence of Enterobacteriaceae producing extended-spectrum b-lactamases and AmpC enzymes needs to be considered in the therapy of complicated urinary tract infections (UTI). The aim of the study was to demonstrate in a murine model that the combination of ceftazidime (CAZ) with NXL104 restored the bactericidal efficacy of CAZ against strains refractive to CAZ alone due to b-lactamases.
Methods: Kidney infections were induced in immunodepressed, anaesthetised male CD1 mice by direct injection of 104 cells in 0.02 ml of exponentially growing culture by 25 gauge needle. Typically the kidney bacterial burden increased by 1.5log10 within 48 hours. Therapy commenced subcutaneously 4 hours after infection bid for 2 days. Bacteria were enumerated in the kidneys of treated and control mice 48 hours post infection.
Results: CAZ alone was ineffective against all 6 strains tested compared to the non-treated control group. The combination CAZ/NXL104 (4:1) was effective in a dose range 1025 mg/kg in reducing the inoculum and preventing proliferation of Escherichia coli (one ClassA and one AmpC), Enterobacter cloacae (AmpC), Klebsiella pneumoniae (ClassA + AmpC), Morganella morganii (AmpC) and Citrobacter freundii (AmpC). In each case CAZ/NXL104 was significantly effective, reducing bacterial kidney burden by 2.6 to 4.5log10 compared to the CAZ treated group (p < 0.05, Bonferroni).
Conclusion: The combination CAZ/NXL104 (4:1) was effective against representative strains of CAZ-resistant Enterobacteriaceae species in a murine kidney infection model. This combination could represent a useful therapeutic option for the treatment of infections due to b-lactamase producing Enterobacteriaceae species, which are increasing in frequency in complicated UTI.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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