Comparison of the investigational drug, LY146032, with vancomycin in experimental pneumonia due to methicillin-resistant Staphylococcus aureus.

The efficacy of LY146032 was compared with that of vancomycin in experimental pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). Emphysematous hamsters were challenged intratracheally with MRSA and given LY146032 (20 mg/kg 24h), vancomycin (40 mg/kg/24h) or normal saline by subcutaneous injection. Following infection with 2 X 10(9) cfu, survival among antibiotic-treated animals was significantly greater than that of the control group (P less than 0.01 at 96 h); however, no significant difference in survival between the hamsters given LY146032 and vancomycin was seen. To evaluate the influence of the antibiotics on the rate of bacterial killing within the lungs (pulmonary clearance), animals were challenged with a high inoculum (1 X 10(9) cfu) or low inoculum (1 X 10(6) cfu). Animals treated with LY146032 demonstrated a significant advantage in pulmonary clearance versus controls at both inocula; however, animals treated with vancomycin showed a statistically significant increase in pulmonary clearance versus controls only at the lower inoculum. We conclude that in this experimental model, LY146032 was as effective as vancomycin in treating infection with MRSA.

Protease inhibitor eglin-c affects superoxide anion release but not bacterial killing by human polymorphonuclear leukocytes.

In order to assess the influence of the protease inhibitor eglin-c on superoxide anion (O-2) release by human polymorphonuclear leukocytes (PMN), cells were secured from normal donors and stimulated with phorbol myristate acetate (PMA), opsonized zymosan, or n-formyl-methionyl-leucyl-phenylalanine (FMLP). In the presence of 100 micrograms/ml eglin-c, the activation time was prolonged and the maximum linear rate of O-2 formation was depressed following stimulation with PMA; a concentration of 1000 micrograms/ml eglin-c was required to produce a similar effect with opsonized zymosan. Eglin-c did not influence the activation time following stimulation with FMLP, but at 2000 micrograms/ml, the protease inhibitor attenuated the rate of O-2 production in response to the chemotactic peptide. In the presence of cytochalasin B, the inhibitory effect of eglin-c on O-2 release following stimulation with FMLP became more pronounced. In spite of these alterations in O-2 formation, the protease inhibitor did not impair the bactericidal activity of PMN against Staphylococcus aureus. Therefore, we conclude that although eglin-c can disrupt the activation and the activity of the superoxide-generating system of human PMN, the effect is stimulus dependent and is not associated with an alteration in the microbicidal capacity of neutrophils against S. aureus.