Synergism between 4-Hydroxyquinoline and Pyridone Coccidiostats

Abstract

Drug combinations containing a 4-hydroxyquinoline coccidiostat plus meticlorpindol exhibited anticoccidial activity against Eimeria acervulina and Eimeria tenella which was greater than equivalent levels of either coccidiostat alone. Combinations containing decoquinate, buquinolate, or amquinolate were shown to have nonadditive effects when combined with meticlorpindol. It was concluded that such drug combinations are synergistic in their action and that the two classes of anticoccidials probably act upon closely related, but nonidentical, metabolic pathways. During the study of a series of drug-tolerant strains of poultry coccidia we made the unexpected finding that a population of Eimeria acervulina which had developed resistance to meticlorpindol (3,5-dichloro-2,6-dimethyl-4pyridinol) showed a greater than expected sensitivity to decoquinate (ethyl-6-(decyloxy) 7-ethoxy-4-hydroxy-3-quinoline carboxylate). Further investigation revealed a situation of collateral sensitivity between decoquinate and meticlorpindol (Jeffers and Challey, 1973). The preexisting resistance of a strain of E. acervulina to decoquinate was reversed through the acquisition of resistance to meticlorpindol. Furthermore, it was shown that the induction of resistance to meticlorpindol served to enhance the sensitivity to decoquinate of an already sensitive strain of E. acervulina. It was hypothesized that populations resistant to meticlorpindol contain individuals capable of employing an alternative metabolic pathway not affected by meticlorpindol but which is readily blocked by decoquinate and related 4-hydroxyquinoline coccidiostats. Based on this hypothesis, it was thought that mixtures containing meticlorpindol and one of the 4-hydroxyquinoline coccidiostats might act synergistically. Experiments were designed to determine the anticoccidial activity of decoquinate and related 4-hydroxyquinoline coccidiostats in combination with meticlorpindol. We observed that all of the 4-hydroxyquinoline-meticlorpindol combinations which were examined showed anticoccidial activity which was markedly greater than equivalent levels of either compound administered alone. Because of the nonadditivity of this response, we conclude Received for publication 26 January 1973. that combinations of 4-hydroxyquinoline coccidiostats and meticlorpindol are synergistic in their effect upon coccidian endogenous development. MATERIALS AND METHODS A standard all-mash ration was used for all trials. The experimental drugs were thoroughly incorporated into the ration with the aid of a Hobart mixer. Trials were conducted with coccidiafree 16to 18-day-old Single Comb White Leghorn cockerels. The chicks were weighed and assigned in weight-balanced groups of 10 to clean finisher batteries. The chicks were given free access to the medicated rations at least 24 hr prior to oral inoculation with oocyst suspensions. Pure species cultures of coccidia which had never been exposed to anticoccidial drugs were employed. These cultures were all known to be fully sensitive to the anticoccidials used in this investigation. After preliminary studies, which showed oocyst output to be a highly sensitive indicator of drug action, we adopted this measurement as the major criterion of activity. The procedures employed for collection and enumeration of oocysts were as described by Jeffers and Challey (1973).