In-vitro and in-vivo synergic activity and fractional inhibitory concentration (FIC of the components of a semisynthetic streptogramin, RP 59500

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Abstract
RP 59500 is a new semisynthetic injectable streptogramin antibiotic composed of two compounds which interact synergically, RP 57669 and RP 54476, derived from pristinamycin IA and pristinamycin IIB, respectively. The bacteristatic and bactericidal activities of RP 57669 and RP 54476 alone or combined in various proportions were tested by the chequerboard dilution technique. The fractional inhibitory concentration (FIC index was determined for 14 Staphylococcus aureus isolates (including methicillin- and macrolide-resistant strains) and one culture collection strain. The FIC index was found to be much lower than 0·5, indicating the presence of synergy for all strains tested, whatever their resistance pattern. The ED 50 of RP 57669 and RP 54476 in various combinations were also determined in three experimental murine models of septicaemia, caused by either S. aureus or Streptococcus pneumoniae , and a thigh abscess model caused by S. aureus . The combinations which performed best in the model of septicaemia were those in which the RP 57669: RP 54476 ratio ranged from 16:84 to 92:8, while those active against the thigh abscess model had ratios ranging from 8:92 to 84:16. That the drugs were active over a wide range of ratios suggests that synergy will be maintained even if one drug is cleared more rapidly than the other. The combination of 30:70, referred to as RP 59500, was selected for further studies, both in vitro and in various experimental models of infections.

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