The sigB gene of Staphylococcus aureus, coding for the alternate sigma factor B, has been deleted by allelic replacement mutagenesis. The mutant grew as well as the parent in vitro, although it was deficient in clumping factor, coagulase, and pigment. In two murine and one rat infection model the mutant showed no reduction in virulence.

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Efficacy of candidate antibacterial treatments must be demonstrated in animal models of infection as part of the discovery and development process, preferably in models which mimic the intended clinical indication. A method for inducing robust lung infections in immunocompetent rats and mice is described which allows for the assessment of treatments in a model of serious pneumonia caused by S. pneumoniae, H. influenzae, P. aeruginosa, K. pneumoniae or A. baumannii. Animals are anesthetized, and an agar-based inoculum is deposited deep into the lung via nonsurgical intratracheal intubation. The resulting infection is consistent, reproducible, and stable for at least 48 h and up to 96 h for most isolates. Studies with marketed antibacterials have demonstrated good correlation between in vivo efficacy and in vitro susceptibility, and concordance between pharmacokinetic/pharmacodynamic targets determined in this model and clinically accepted targets has been observed. Although there is an initial time investment when learning the technique, it can be performed quickly and efficiently once proficiency is achieved. Benefits of the model include elimination of the neutropenic requirement, increased robustness and reproducibility, ability to study more pathogens and isolates, improved flexibility in study design and establishment of a challenging infection in an immunocompetent host.

SK&F 107647, a novel synthetic low molecular weight peptide, has been shown to be a potent hematoregulatory agent. We have previously demonstrated that SK&F 107647 administration can prolong survival in both immunosuppressed and normal mice challenged with the opportunistic fungal pathogen Candida albicans. Additionally, we have determined the effect of prophylactic SK&F 107647 treatment combined with conventional antifungal therapy on the survival of mice challenged with a lethal dose of C. albicans. Prophylactic treatment with SK&F 107647 or therapeutic treatment with the antifungals fluconazole or amphotericin B significantly increased the survival rates of immunosuppressed mice challenged with a lethal dose of C. albicans. However, the combination of SK&F 107647 treatment followed by antifungal therapy resulted in statistically significant increases in survival over that observed with either therapy alone. These results indicated that the hematoregulatory factor(s) elicited by SK&F 107647 enhance the survival of mice treated with conventional therapies in a model of experimental systemic candidiasis. Key words: SK&F 107647, Candida albicans, hematoregulatory, fluconazole, amphotericin B.

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