0329. Beneficial effects of azithromycin combined with ceftazidime without activity against P. aeruginosa in a murine sepsis model of peritonitis by Pseudomonas aeruginosa
© Pachón-Ibañez et al; licensee Springer. 2014
Published: 26 September 2014
Despite a proper management, the mortality of patients with severe sepsis and septic shock is very high. During sepsis, an uncontrolled cascade of inflammatory mediators is triggered, leading to tissue damage that can cause death. Macrolides, apart from their antibiotic properties, are capable of modulating inflammatory response. Macrolides inhibit the production and secretion of pro-inflammatory cytokines (IL-1, IL-6, IL-8 and TNF-α) levels and increase anti-inflammatory cytokines such as IL-10.
To demonstrate whether the use of azithromycin (AZM) in a murine sepsis model of P. aeruginosa increases ceftazidime (CFZ) efficacy.
MIC/MBC and bactericidal activity (time-killed curves using 1MIC) were performed using four clinical isolates of P. aeruginosa. The bactericidal activity on Pa4, chosen for the in vivo study, was carried out too at the maximum plasma concentration (Cmax) in mice. Pharmacokinetic/pharmacodynamic (PK/PD) parameters of CFZ and AZM were calculated (HPLC-MS/MS). The activity of each antimicrobial agent and its combination was assessed in a murine peritonitis model (n=15), using the minimum lethal dose (MLD) of Pa4 as inoculum. Treatment were: 100 mg/kg/ip/12h for CFZ and 30 mg/kg/ip/24h for AZM, during 72 hours; a group of 15 untreated mice were used as control (CON). CFU/g spleen, mortality and blood cultures were compared.
In vivo studies
Log UFC/g Spleen (Mean ± SD)
8.40 ± 0.32
6.57 ± 0.61
7.58 ± 0.31
4.63 ± 0.77
Positive blood culture (%)
The combination of AZM with CFZ increases bacterial clearance from spleen and blood and delays the time to mortality in a murine sepsis model by P. aeruginosa.
This project (PI10/01563) was funded by the "Fondo de Investigación Sanitaria", Instituto de Salud Carlos III.
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