A mouse model of staphylococcal
sepsis was used to evaluate the efficacy of
RNAIII-inhibiting peptide (RIP) combined with the
cathelicidin BMAP-28. Preliminary in vitro studies showed that both
peptides, alone or combined, were able to inhibit the
lipoteichoic acid-induced production of
tumor necrosis factor alpha and
nitric oxide by RAW 264.7 cells. For in vivo experiments, the main outcome measures were lethality, quantitative blood cultures, and detection of
tumor necrosis factor alpha and
interleukin 6 plasma levels. BALB/c mice were injected i.v. with 2.0 x 10(6) colony-forming units of live Staphylococcus aureus ATCC 25923 or with 5.0 x 10(8) heat-killed cells of the same strain. All animals were randomized to receive i.v. isotonic
sodium chloride solution, 10-mg/kg RIP, alone or in combination with 2-mg/kg
BMAP-28, 7-mg/kg
imipenem, or 7-mg/kg
vancomycin, immediately and at 6 hours after bacterial challenge. In in vivo experiments performed with live bacteria, all compounds reduced lethality rates and
bacteremia when compared with controls. In general, combined-treated groups had significantly lower
bacteremia when compared with single-treated groups. Lowest lethality rates and
bacteremia were obtained when RIP was administered in combination with
BMAP-28 or
vancomycin. In the experiments performed using heat-killed organisms, only
BMAP-28 demonstrated significant efficacy on lethality rates and
cytokines plasma levels when compared with controls. RIP combined with
BMAP-28 exhibited the highest efficacy on all main outcome measurements. These data were observed on both immediate and
delayed treatments. These results highlight the capacity of RIP and
BMAP-28 to reduce the septic effects of bacterial cell components and
exotoxins, and suggest their potential use in the treatment of severe staphylococcus-associated
sepsis.