Noncytotoxic combinations of topical antimicrobial agents for use with cultured skin substitutes

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Abstract
Cultured skin grafts are destroyed more easily than split-thickness skin grafts by common burn wound organisms, including gram-negative and gram-positive bacteria and fungi. To increase the survival and engraftment of cultured skin grafts, formulations of antimicrobial agents were tested for cytotoxicity to cultured human keratinocytes and fibroblasts and for activity against common organisms from burn wounds. On the basis of previous studies, a base formulation containing neomycin (40 micrograms/ml), polymyxin B (700 U/ml), and mupirocin (40 micrograms/ml) was prepared, to which ciprofloxacin (20 micrograms/ml) or norfloxacin (20 micrograms/ml) and amphotericin B (0.25 microgram/ml) or nystatin (100 U/ml) were added. Toxicity to cultured human cells was determined by the growth response of cell cultures (n = 6) to each drug combination over 4 days. Activity against clinical isolates (n = 40) of Staphylococcus aureus, Pseudomonas aeruginosa, other gram-negative bacteria, and Candida spp. was determined by the wet disc assay. Analysis of variance testing showed no significant differences in the growth of keratinocytes or fibroblasts under control or experimental conditions. Medium without antimicrobial agents was not effective against any of the 40 microbial strains tested. The base formulation was effective against all bacterial strains tested but against none of the fungi, while all experimental formulations were effective against all microbial strains tested. These findings suggest that neomycin, mupirocin, and polymyxin B may be combined with a quinolone and an antimycotic agent to provide broad antimicrobial activity for a formulation for topical use with cultured skin on burns. However, the formulations described here are strictly experimental and are not recommended for clinical use without further evaluation.