In-vitro activity of MK0787 (N-formimidoyl thienamycin) against Pseudomonas aeruginosa and other Gram-negative organisms and its stability to their β-lactamases

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Abstract
MICs of MK0787 for 95 clinical isolates of Pseudomonas aeruginosa (17 gentamicin-resistant and 45 carbenicillin resistant) and 107 other gentamicin-resistant Gram-negative organisms were determined. Against Ps. aeruginosa MICs ranged from 0·5–8 mg/l; mode: 2 mg/l. Resistance (MIC ≥ 32 mg/l) was observed in some isolates of Citrobacter freundii, Providencia spp., Proteus vulgaris, Enterobacter cloacae, Serratia spp. and Acinetobacter spp. Stability of MK0787 to characterized β-lactamases and also β-lactamase extracts from MK0787-resistant organisms was investigated. Only type IIIa (TEM) and IV (from Klebsiella aerogenes) enzymes hydrolysed MK0787 but the rate was slow and organisms that produced these enzymes remained sensitive to MK0787. Beta-lactamases from MK0787-resistant organisms had minimal or zero activity against MK0787 and could not account for the resistance of these organisms. Slight chemical instability of MK0787 was detected giving a 3–5%/h breakdown of a 0·1 mM solution in 10 mM phosphate buffer.

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