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In vivo effectiveness and dose response of BAL30376 in murine peritonitis sepsis model caused by Pseudomonas aeruginosa or by extended-spectrum b-lactamase producing Escherichia coli

Abstract number: P572

Navon-Venezia S., Page M., Schmitt-Hoffmann A., Carmeli Y.

Pseudomonas aeruginosa (PA) and extended spectrum beta lactamase (ESBL) E. coli are common nosocomial pathogens often affecting immunocompromised patients that are difficult to treat. Against these pathogens we aimed to study in a lethal mice peritonitis sepsis model of infection the in vivo efficacy of a new monobactam beta lactamase inhibitor combination, BAL30376 specifically designed to overcome most resistance mechanisms in non-fermenters and Enterobacteriaceae, including metallo betalactamases and ESBLs.

Methods: PA and ESBL E. coli with MIC < 0.0625 mg/L for BAL30376 were used as infecting bacteria in the in vivo model. Neutropenia was induced in ICR mice (23–25 g) and peritonitis was induced by intraperitoneal inoculation of either PA or ESBL E. coli. Efficacy was studied at various bacterial inocula: 5×102–1×104 cfu /mouse (1–50 LD50) for PA, and 4–8×106 cfu /mouse (4–8 LD50) for ESBL E. coli. Mice (n = 12) were treated with BAL30376 three times a day given ip for three days. Dose effect was studied at a range of doses between 6.25 to 100 mg/Kg. Survival was monitored for seven days post infection and compared with control groups (A saline placebo group and a meropenem treated group) using log rank test.

Results: In two sets of experiments PA peritonitis (at 6x LD50) resulted in 70–100% mortality in placebo group. BAL30376 had 100% protection at doses geqslant R: gt-or-equal, slanted 25 mg/Kg (p < 0.01) similarly to the meropenem treated group. Lower doses of BAL30376 were moderately protective. ESBL E. coli peritonitis was studied in two experiments (4–8x LD50) and resulted in 100% mortality in placebo group. BAL30376 had 100% protection at doses geqslant R: gt-or-equal, slanted 12.5 mg/Kg (p < 0.01). With both pathogen studied at various inocula and dosages of BAL30376 dose effect were confirmed.

Conclusions: BAL30376 was highly effective in treating lethal peritonitis and sepsis caused by PA or ESBL E. coli in murine model.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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