TOXICITY OF ANTIBIOTICS AND ANTIFUNGALS ON CULTURED HUMAN CORNEAL CELLS - EFFECT OF MIXING, EXPOSURE AND CONCENTRATION

Toxic effects of topical drugs may be masked by manifestations of the disease they cure, The toxicity of drug mixtures has not been thorough ly studied, We therefore investigated cytopathic effects on primary cu ltures of human corneal cells of six topical antimicrobials singly and in combinations of any two, to determine the combined toxicity rankin g and the interaction between duration of exposure and concentration, Preconfluent cultures were exposed to fixed dilutions of single drugs, or to equal-dilution mixtures of two drugs, for 7 and 14 days, Dimini shing concentrations of single drugs were applied sequentially to cult ures for 14 days. The number of metabolically competent cells was asse ssed by measuring hexosaminidase and total protein, Toxic effects depe nded on substance, concentration and exposure, The scale of toxicity d etermined for single drugs after 7 days of exposure was: gentamicin > econazole greater than or equal to methicillin greater than or equal t o clotrimazole greater than or equal to miconazole greater than or equ al to chloramphenicol, After 14 days this order changed: in particular chloramphenicol showed a highly increased toxicity, The order of dimi nishing effects was: gentamicin > chloramphenicol greater than or equa l to methicillin > miconazole > econazole > clotrimazole. A clear redu ction in cytopathic effects was observed when drug concentration was d ecreased progressively only in cultures treated,vith gentamicin or met hicillin, All drug combinations were more toxic than their components at equal dilution, Combinations containing chloramphenicol ranked most toxic overall, those containing econazole least, A tapering off combi nation regime did not improve cell survival. These in vitro toxicity d ata complement clinical studies and suggest ways in which topical drug s can be chosen to minimise toxic effects to corneal surface.