A landmark contribution to poultry science--prophylactic control of coccidiosis in poultry.

"Continuous feeding of low concentrations of sulfaquinoxaline for the control of coccidiosis in poultry" by L. C. Grumbles, J. P. Delaplane, and T. C. Higgins [Poult. Sci. (1948) 27:605-608] was the first paper to demonstrate that it was possible to control coccidiosis by the continuous inclusion of a low level of a drug in the feed of chickens. The principle involved (prevention or prophylaxis) has had a profound impact on our ability to grow chickens and turkeys under intensive conditions. Indeed, it is possible that the modern poultry industry could never have developed to its present extent without the advent of drugs used prophylactically to control coccidiosis. One particular insight was that use of a compound in this manner did not necessarily prevent the acquisition of immunity, an important principle that helps explain the continued efficacy of ionophorous antibiotics used today. The significance of this work to the poultry industry and individuals involved in research, whether employed by government, academia, or pharmaceutical companies, cannot be overstated. Economic benefits, in terms of improved productivity, have been demonstrated in numerous studies published in Poultry Science. In addition, the livelihoods of many poultry farmers have been helped by the control of a disease that in the past caused substantial morbidity and mortality in their flocks. The paper is brief and contains no critical science involving novel procedures but has had a profound influence on the health of poultry for the last 6 decades. For this reason, it is nominated as a landmark contribution from the first 100 yr of Poultry Science.

History of the discovery of sulfaquinoxaline as a coccidiostat.

Sulfaquinoxaline played an important part in the demotion of roast chicken from vaunted Sunday-dinner status to an unrespected position on the everyday menu of the Western world. It had its origins in the chemical synthetic program that sprang from the introduction of sulfonamide drugs into human medicine in the 1930s. The program was sustained through the years of World War II despite declining clinical use of that chemical class. Several sulfa drugs were known to be active against the sporozoan parasite (Plasmodium spp.) that causes malaria, but were not satisfactory in clinical practice. A sulfonamide that had a long plasma half-life would ipso facto be considered promising as an antimalarial drug. Sulfaquinoxaline, synthesized during the war, was such a compound. It proved too toxic to be used in human malaria, but was found to be a superior agent against another sporozoan parasite, Eimeria spp., the causative agent of coccidiosis in domestic chickens. In 1948 sulfaquinoxaline was introduced commercially as a poultry coccidiostat. It was not the first sulfonamide found active against Eimeria spp. in poultry, but its practical success in disease control firmly established the routine incorporation of anticoccidial drugs in poultry feed. In this way, the drug exerted a major impact on the worldwide production of poultry meat. Although it has long been eclipsed by other drugs in poultry management, it continues to be used in other host species. This article describes the discovery of sulfaquinoxaline as a practical therapeutic agent, and examines the way in which the discovery arose from a partnership between industry and academia.

Chemotherapy of caecal coccidiosis: efficacy of toltrazuril, sulphaquinoxaline/pyrimethamine and amprolium/ethopabate, given in drinking water, against field isolates of Eimeria tenella.

Treatment with toltrazuril, sulphaquinoxaline/pyrimethamine and amprolium/ethopabate prevented mortality in chickens infected with field isolates of Eimeria tenella. Amprolium/ethopabate was the most effective drug in reducing lesions caused by the parasites. Few oocysts of E tenella were produced in birds medicated with sulphaquinoxaline/pyrimethamine or amprolium/ethopabate and none in those medicated with toltrazuril.

Some pharmacokinetic aspects of four sulphonamides and trimethoprim, and their therapeutic efficacy in experimental Escherichia coli infection in poultry.

Pharmacokinetic studies in broilers and layers of different sulphonamides indicate a good absorption and a long elimination half-life (of sulphaquinoxaline, sulphadimidine and to a lesser degree sulphadiazine) resulting in high plasma concentrations during drinking water medication in the recommended therapeutic doses. In contrast drinking water medication with high concentrations of trimethoprim (up to 1,320 mg/liter) resulted in a maximal mean plasma concentration of 1.2 micrograms/ml. Very good therapeutic effects were demonstrated in broilers experimentally infected with a sulphonamide-susceptible E. coli strain when treated with sulphaquinoxaline (200 mg/liter), sulphadimidine sodium (2 gram/liter), sulphachloropyridazine 30 per cent (1 gram/liter) and to a lesser degree sulphadiazine sodium (250 mg/liter). Synergism was demonstrated between trimethoprim and sulphadiazine (1:5). The combination of trimethoprim with sulphaquinoxaline (1:3) did not induce better therapeutic effects than sulphaquinoxaline in proportional doses. However, significant synergism was demonstrated between trimethoprim and both sulphonamides in treatment of experimental infection with sulphonamide-resistant E. coli. No signs resembling sulphonamide intoxication were observed during these studies.

Evaluation of a mixture of trimethoprim and sulphaquinoxaline for the treatment of poultry: safety and palatability studies.

The safety of a 1:3 mixture of trimethoprim (TMP) and sulphaquinoxaline (SQX) for administration in food or water was assessed in broiler chickens, chicks of an egg laying strain and breeding fowl. The only effects recorded in six-week-old broilers medicated for seven days at levels ranging from 16 to 133 mg TMP plus SQX per kg bodyweight were decreases in water or food consumption, probably caused by unpalatability at overdosage levels, and associated decreases in weight gain and packed cell volume at an achieved overdose level of 4.4 times the recommended use concentration (RUC). Breeding fowl medicated at levels of 1 X or 3 X RUC for 14 days showed slightly reduced reproductive performance reflected by lowered egg production, egg weight and hatchability. These effects were temporary and performance equal to that of unmedicated birds was re-established by 14 days after medication ceased. Week-old chicks medicated for five days at levels from 0.7 to 4.7 X RUC showed normal growth rate over 12 days. Eleven-day-old chicks could not distinguish medicated from unmedicated water.

Evaluation of a mixture of trimethoprim and sulphaquinoxaline for the treatment of bacterial and coccidial diseases of poultry.

Representative experiments from work undertaken to develop a synergistic mixture of trimethoprim and sulphaquinoxaline for the preventive treatment of certain poultry diseases are described. Sulphaquinoxaline in the diet for four days was shown to achieve at least an 85 per cent higher blood level than nine other sulphonamides in chicks, and the efficacies of various trimethoprim/sulphaquinoxaline regimes in the diet or in the drinking water were demonstrated against pasteurellosis, colisepticaemia and five kinds of coccidiosis. Regimes for bacterial diseases were begun one day before infection but those for coccidial diseases were begun on the same day as infection or later. Overall, a total dose of 30 mg/kg bodyweight/day (trimethoprim/sulphaquinoxaline = 1:3) controlled these seven diseases. The same treatment was also shown to control sulphaquinoxaline-resistant strains of Escherichia coli and Eimeria acervulina. Although both drinking water and food were used for drug administration, twice the inclusion rate was required in food to that in water for equivalent efficacy. The significance of different modes of expression of dosages for bacterial and coccidial diseases is explained.

Eimeria stiedai in rabbits: the demonstration of responses to chemotherapy.

The activity of sulphaquinoxaline, robenidine, methyl benzoquate, clopidol and a mixture of methyl benzoquate and clopidol (Lerbek; Dow), was studied in rabbits infected with hepatic coccidiosis due to Eimeria stiedai. Growth inhibition, oocyst production and the activity in the serum of glutamate dehydrogenase and gamma glutamyltransferase were studied as indicators of parasite development. Only sulphaquinoxaline and Lerbek gave satisfactory control of this parasite. The latter formulation was more effective than either of its constituents used alone.

Control of fowl cholera in Hungary.

Experiences of the control of fowl cholera in large poultry farms in Hungary are reported. A vaccination method combined with sulfaquinoxaline treatment was developed against fowl cholera. Studies were carried out for the determination of the therapeutic and toxic doses of sulfaquinoxaline in fowls experimetnally infected with Pasteurella multocida. Field experiences with Sukvin, a sulfaquinoxaline containing vaccine, against this disease are reported. Sukvin was produced by Phylaxia Serum State Institute, Budapest, Hungary, and has been generally used in that country since 1967.

[Effectiveness of a number of anticoccidial agents. A brief survey taken in the field (author's transl)]. / De werkzaamheid van een aantal anticoccidiosismiddelen. Een momentopname in de praktijk.

A floor pen trial was carried out on broilers in 1975 to compare the anticoccidial efficacy of monensin1), 3,5 dinitro-o-toluamide2), clopidol3), amprolium + ethopabacte4), amprolium + ethopabate + sulfaquinoxaline + pyrimethamine5) and robenidine6) in the presence of untreated controls. 4,200 Hybro chicks were distributed over twenty-eight pens, each initially housing 150 birds. Four pen replicates were allocated to each of the seven treatments. With the exception of robenidine, all agents used resulted in a statistically significant (P less than or equal to 0,05) gain in final weight compared with the untreated controls. The feed conversion rate showed significant (P less than or equal to 0,05) improvement in the groups treated with monensin, robenidine, amprolium + ethopabate.

Effect of three coccidiostatics against toxoplasmosis in mice.

Duocoxin, nicrazine and amprol plus showed no therapeutic effect in 50 mice each of which was infected with 25,000 organisms of a virulent Toxoplasma strain.

Anticoccidial activity of eight compounds in domestic mink.

Eight compounds were tested for anticoccidial activity in 44 domestic mink (Mustela vision). A treatment group consisted of 4 mink exposed to 2 inoculumns of sporulated oocysts on day 0 and day 22 of the experiments. Each inoculum contained 2,000 Isospora laidlawi, 2,000 Eimeria vision, and 2,000 Eimeria sp. One compound was administered to each treatment group; a control of 4 juvenile mink and a control group of 4 adult mink were designated. All treatments were given each day for 30 days after the initial exposure, except lincomycin which was administered for 14 days. In juvenile mink (3 to 4 months old), amprolium at dose level of 0.012% and sulfaquinoxaline at dose level of 0.024% in the water inhibited almost all of the oocyst production when compared with that of the control group. Lincomycin injected at dose level of 5 mg/day/mink was ineffective in suppressing oocyst production. In adult mink (2 to 4 years) monensin sodium at dose level of 0.012% a commercial antiobiotic-sulfonamide mixture at dose level of 0.49%, and lasalocid solium at dose level of 0.01% in the feed inhibited almost 100% oocyst production. Lasalocid sodium at dose level of 0.10% in the feed was lethal to 3 to 4 mink. Sulfamethazine at dose level of 0.014% and sulfathiazole at 0.014% in the feed had limited anticoccidial activities.

Laboratory studies with some older anticoccidials.

Features of the anticoccidial activity of nicarbazin, amprolium, zoalene, sulphadimidine, diaveridine, Darvisul, spiramycin, chloramphenicol and oxytetracycline have been re-investigated both in vivo and in cell culture using Eimeria tenella. Of the drugs studied, only spiramycin was appreciably coccidiocidal, although nicarbazin and amprolium showed possibly slower coccidiocidal activity. In order to show activity against a particular stage in the life-cycle, higher concentrations of drug than those usually recommended for field usage had in most cases to be used. Under these conditions, parasites were usually inhibited as multinucleate 1st generation schizonts. With delayed medication, effects against 2nd generation parasites were in most cases found, and in many cases, although the parasites never matured to give viable merozoites, the large degenerating forms produced were able to cause extensive tissue destruction and haemorrhage. Methodology in this type of study is discussed in relation to more active and more recent anticoccidials, and some further experiments with robenidine reported.

In vitro and in vivo activity of 3-(1-methyl 1-5-nitro-2-imidazolylmethylideneamino)-2-oxazolidinone against Pasteurella.

Furazolidone was more active than 3-(1-methyl)-5-nitro-2-imidazolyl-methylideneamino)-2-oxazolidinone (MABN) against a series of 34 isolates of Pasteurella and 11 of Yersinia (formerly designated Pasteurella). However, the nitroimidazole was superior to furazolidone by both subcutaneous and oral routes against a series of mouse infections incited by strains of Pasteurella. It also was superior to furazolidone and sulfaquinoxaline when administered in the diet against two Pasteurella strains in a fowl cholera model infection in chickens. The good in vitro activity of MABN plus its low toxicity suggest its further study as an agent for fowl cholera and the shipping fever complex of cattle.