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The Potentiation of Erythromycin and Oxytetracycline Activity in Birds by Means of Terephthalic Acid
RESEARCH NOTES
comparable to or greater than those obtained at 200 gm. per ton of antibiotic in the absence of TA. On low calcium (0.18%) there were substantial serum concentrations when dietary antibiotics were 100 gm. per ton. TA added to this low-Ca diet raised serum concentrations at both the 100 gm. and 200 gm./ton level of antibiotic to an even greater extent, demonstrating additivity of these two potentiation methods. At these practical dietary antibiotic levels, OTC serum concentrations exceeded those of CTC, as had been found with an extremely high antibiotic level in the first experiment. When calcium in the ration was 2.25%, —within the normal range for layers— serum concentrations obtained with antibiotics at 500 gm. per ton were comparable to those brought about by 200 gm. per
235
ton on a diet containing 1.18% Ca. Terephthalic acid showed some ability to enhance antibiotic serum concentrations at both the 250 and 500 gm. per ton levels of antibiotic. REFERENCES Grove, D. C, and W. A. Randall, 1955. Assay Methods of Antibiotics, New York. Med. Encycl. Inc. Kent, R. E., and E. H. Peterson, 1958. Compositions containing a tetracycline-type antibiotic and terephthalic acid. U. S. Patent No. 2,855,340. Price, K. E., Z. Zolli, Jr., J. C. Atkinson and A. P. Collins, 1958a. Antibiotic inhibitors. III. Reversal of calcium inhibition of intestinal absorption of oxytetracycline in chickens by certain acids and acid salts. Antibiotics Annual, 195859, in press. Price, K. E., and Z. Zolli, Jr., 1958b. The influence of terephthalic acid on oxytetracycline serum levels in chickens. Studies on mode of action. I. To be published.
THE POTENTIATION OF ERYTHROMYCIN AND OXYTETRACYCLINE ACTIVITY IN BIRDS BY MEANS OF TEREPHTHALIC ACID E. H. PETERSON, W. L. HENDRIX AND L. D. BRADDY
Department of Animal Industry and Veterinary Science, University of Arkansas, FayetteviUe, Arkansas (Received for publication November 12, 1958)
In a previous report, Peterson (1958), the inclusion of terephthalic acid (TPA) in a poultry feed was shown to potentiate the blood sera concentration of chlortetracycline (aureomycin) in chickens slightly more than four times, and was associated also with a four fold increase in clinical activity as measured against experimental cecal coccidiosis. The optimum concentration of TPA was estimated to be approximately 0.5 percent addition to the feed. The studies have been extended to include observations on the potentiation of erythromycin and oxytetracycline (terramycin), and to determine with greater precision the optimum feed concentration
of TPA necessary for maximum potentiating effect. EXPERIMENTAL PROCEDURE AND RESULTS Chicks from two to three weeks of age were medicated with arbitrary concentrations of the test antibiotic in a standard starter mash with and without the addition of TPA, and infected 24 hours later with cecal coccidiosis (Eimeria tenella). The birds were weighed at the time of infection (0 day) and thereafter at the 3rd and 6th days. The weight differential occurring from 0 to the 3rd day may be regarded as a measure of drug tolerance
236
RESEARCH NOTES
TABLE 1.—Effect of combinations of terepkthalic acid in feeds with erythromycin and oxytetracycline on the clinical course of cecal coccidiosis in birds
Exp.
Lot
F e e d , cone, p.p .m. Ery
%
TPA
Death loss
OTC
Av.; gains (gm.) , days aftei c inf. 0-3
3-6
1 2
750 750
0.0 0.5
0/10 0/10
63.2 66.6
3.2 16.8
3 4
1,000 1,000
0.0 0.5
5/30 0/30
65.8 - 2 . 9 61.5 - 2 1 . 0
5 6
2,000 2,000
0.0 0.5
1/10 0/10
56.4 53.5
16.6 21.5
7 8
3,000 3,000
0.0 0.5
0/10 0/10
55.1 58.4
32.8 45.8
B
9 10 11 12 13*
1,500 750 500 375 0
0.0 0.5 0.5 0.5 0.5
0/40 0/40 3/30 1/41 0/10
59.2 60.8 57.2 58.7 62.2
14.3 17.7 6.5 6.4 -8.0
C
14 15
300 300
0.0 0.5
2/20 1/20
62.2 54.3
-3.0 8.0
16 17
400 400
0.0 0.5
0/20 0/20
60.3 64.0
1.8 15.3
18 19
500 500
0.0 0.5
0/10 0/10
51.8 62.8
12.0 21.6
20 21 22 23
780 390 260 195
0.0 0.5 0.5 0.5
1/30 0/30 2/30 3/30
61.3 56.3 63.3 63.5
57.0 43.9 4.6 7.0
A
D
* Infected controls for Exp's B and D.
and group uniformity, while that occurring from the 3rd to the 6th day is a measure of anti-coccidial effect. TABLE 2.—The titration of terephthalic acid activity in relationship with the potentiation of chlortetracycline Feed cone. Exp.
Lot
Av. gain:3 (gm.), days aflier inf.
%
ppm. CTC
TPA
0-3
3-6
E
24 25 26 27 28 29 30 31 32
175 175 175 175 175 175 175 175 175
0.0 0.1 0.2 0.3 0.4 0.5 0.6 1.0 2.0
58.3 62.2 60.2 62.4 50.7 46.7 61.1 54.7 56.5
17.5 38.4 38.0 45.8 42.7 63.5 51.4 64.6 59.2
F
33 34 35 36 37 38 39 40
175 175 175 175 175 175 175 175
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
63.1 67.6 59.6 53.3 61.5 60.5 59.2 59.3
18.2 18.9 22.8 39.7 39.1 41.3 38.1 34.0
The results are presented in Tables 1 and 2. In Table 1, Exp's A and C, the inclusion of TPA to poultry feeds containing either erythromycin or oxytetracycline is shown beyond any reasonable doubt to potentiate the activity of the antibiotic under the conditions of the test. In Exp's B and D, an endeavor was made to measure quantitatively the potentiating effect. An examination of lots 9-10, 20-21 indicates that an approximate double increase in activity occurred with both antibiotics in consequence of the addition of TPA. This potentiating effect, however, appeared definitely to be less than three times. The titration determinations with TPA are shown in Table 2, using in this case chlortetracycline as the test antibiotic. The results from two duplicate trials are shown, Exp's E and F. In Exp. E maximum potentiating effect was secured upon the addition of 0.5 percent of the acid to the ration. The growth rates in these lots, however, lacked uniformity. More uniform growth was secured in Exp. F, in which case maximum activity of the acid was attained at the 0.3 percent addition to the feed, with a plateau of activity apparently being reached at that concentration. SUMMARY
In the previous report mentioned, the inclusion of terephthalic acid in a poultry mash was shown to potentiate the blood sera concentration of chlortetracycline four times, and was associated also with a four fold increase in clinical activity as determined against experimental infection with cecal coccidiosis. The clinical procedure thus was indicated to be a valid criterion for measuring the potentiating effect. In the present trials, the potentiation of erythromycin and oxytetracycline with terephthalic acid was determined using the clinical method only. In the case of these antibiotics, the degree of potenti-
237
RESEARCH NOTES
ation as accurately as could be determined approximated a double increase in activity in both instances. The optimum concentration of terephthalic acid required for maximum potentiation effect appears in the case of chlortetracycline at least to be near 0.3 percent in the feed, with a plateau of activity ap-
parently being attained at that concentration. Concentrations less than 0.3 percent appear to be sub-optimum. REFERENCE Peterson, E. H., 1958. Potentiating effect of terephthalic acid upon absorption of chlortetracycline from the avian alimentary tract. Arkansas Agricultural Experiment Station Report Series 74.
THE EFFECT ON FERTILITY OF APPLYING AN ANTI-PICKING SOLUTION (THRAM) TO BREEDING STOCK G. C. HODGSON AND J. F. RICHARDS Poultry Department, University of Manitoba, Winnipeg, Canada (Received for publication November 19,1958)
Thram is an anti-picking solution which may be sprayed or brushed on birds to aid in the control of cannibalism and feather picking, an action which the manufacturer claims is due to the offensive taste of the product. (S. B. Penick and Co., 1957). No reports of the effect of Thram on fertility could be found in the literature. The following experiment was conducted to determine if the use of Thram on breeding birds might lessen the frequency of mating and hence reduce fertility. Thirty-two adult females and four males were randomly selected and distributed into four identical floor pens with one male and eight females in each. They were fed breeding mash and water ad libitum. Table 1 shows the design of the treatments. To overcome the effect of selective mating on fertility the males were interchanged three times weekly between pens 1 and 3, and 2 and 4, respectively. The birds were confined to their pens for two weeks before Thram was applied. During the two days prior to commencing treatment, the eggs from all pens were saved, incubated for four days and then
broken out to ascertain fertility. The same technique for determining fertility was followed throughout the entire experimental period. Having ascertained that fertility was at a high level in all pens prior to the application of Thram, the females in pens 3 and 4, and the males in pens 2 and 4 were sprayed with undiluted Thram. The females in pen 3 and all birds in pen 4 were crowded into a corner and each group was treated with about 0.5 lbs. of the undiluted solution applied with a hand sprayer. The male from pen 2 was sprayed individually (Table 1). TABLE 1.—Plan of the experiment Pens
1
Sex Male Female
2
3
4
Untreated Treated
Treated Treated
Treatments Untreated Untreated
Treated Untreated
The same treatment was repeated thereafter at weekly intervals. The eggs from all pens were saved and settings made twice weekly. Table 2 shows the percent fertility determined for each pen during the test. It will be noted that there was as much week
comparable to or greater than those obtained at 200 gm. per ton of antibiotic in the absence of TA. On low calcium (0.18%) there were substantial serum concentrations when dietary antibiotics were 100 gm. per ton. TA added to this low-Ca diet raised serum concentrations at both the 100 gm. and 200 gm./ton level of antibiotic to an even greater extent, demonstrating additivity of these two potentiation methods. At these practical dietary antibiotic levels, OTC serum concentrations exceeded those of CTC, as had been found with an extremely high antibiotic level in the first experiment. When calcium in the ration was 2.25%, —within the normal range for layers— serum concentrations obtained with antibiotics at 500 gm. per ton were comparable to those brought about by 200 gm. per
235
ton on a diet containing 1.18% Ca. Terephthalic acid showed some ability to enhance antibiotic serum concentrations at both the 250 and 500 gm. per ton levels of antibiotic. REFERENCES Grove, D. C, and W. A. Randall, 1955. Assay Methods of Antibiotics, New York. Med. Encycl. Inc. Kent, R. E., and E. H. Peterson, 1958. Compositions containing a tetracycline-type antibiotic and terephthalic acid. U. S. Patent No. 2,855,340. Price, K. E., Z. Zolli, Jr., J. C. Atkinson and A. P. Collins, 1958a. Antibiotic inhibitors. III. Reversal of calcium inhibition of intestinal absorption of oxytetracycline in chickens by certain acids and acid salts. Antibiotics Annual, 195859, in press. Price, K. E., and Z. Zolli, Jr., 1958b. The influence of terephthalic acid on oxytetracycline serum levels in chickens. Studies on mode of action. I. To be published.
THE POTENTIATION OF ERYTHROMYCIN AND OXYTETRACYCLINE ACTIVITY IN BIRDS BY MEANS OF TEREPHTHALIC ACID E. H. PETERSON, W. L. HENDRIX AND L. D. BRADDY
Department of Animal Industry and Veterinary Science, University of Arkansas, FayetteviUe, Arkansas (Received for publication November 12, 1958)
In a previous report, Peterson (1958), the inclusion of terephthalic acid (TPA) in a poultry feed was shown to potentiate the blood sera concentration of chlortetracycline (aureomycin) in chickens slightly more than four times, and was associated also with a four fold increase in clinical activity as measured against experimental cecal coccidiosis. The optimum concentration of TPA was estimated to be approximately 0.5 percent addition to the feed. The studies have been extended to include observations on the potentiation of erythromycin and oxytetracycline (terramycin), and to determine with greater precision the optimum feed concentration
of TPA necessary for maximum potentiating effect. EXPERIMENTAL PROCEDURE AND RESULTS Chicks from two to three weeks of age were medicated with arbitrary concentrations of the test antibiotic in a standard starter mash with and without the addition of TPA, and infected 24 hours later with cecal coccidiosis (Eimeria tenella). The birds were weighed at the time of infection (0 day) and thereafter at the 3rd and 6th days. The weight differential occurring from 0 to the 3rd day may be regarded as a measure of drug tolerance
236
RESEARCH NOTES
TABLE 1.—Effect of combinations of terepkthalic acid in feeds with erythromycin and oxytetracycline on the clinical course of cecal coccidiosis in birds
Exp.
Lot
F e e d , cone, p.p .m. Ery
%
TPA
Death loss
OTC
Av.; gains (gm.) , days aftei c inf. 0-3
3-6
1 2
750 750
0.0 0.5
0/10 0/10
63.2 66.6
3.2 16.8
3 4
1,000 1,000
0.0 0.5
5/30 0/30
65.8 - 2 . 9 61.5 - 2 1 . 0
5 6
2,000 2,000
0.0 0.5
1/10 0/10
56.4 53.5
16.6 21.5
7 8
3,000 3,000
0.0 0.5
0/10 0/10
55.1 58.4
32.8 45.8
B
9 10 11 12 13*
1,500 750 500 375 0
0.0 0.5 0.5 0.5 0.5
0/40 0/40 3/30 1/41 0/10
59.2 60.8 57.2 58.7 62.2
14.3 17.7 6.5 6.4 -8.0
C
14 15
300 300
0.0 0.5
2/20 1/20
62.2 54.3
-3.0 8.0
16 17
400 400
0.0 0.5
0/20 0/20
60.3 64.0
1.8 15.3
18 19
500 500
0.0 0.5
0/10 0/10
51.8 62.8
12.0 21.6
20 21 22 23
780 390 260 195
0.0 0.5 0.5 0.5
1/30 0/30 2/30 3/30
61.3 56.3 63.3 63.5
57.0 43.9 4.6 7.0
A
D
* Infected controls for Exp's B and D.
and group uniformity, while that occurring from the 3rd to the 6th day is a measure of anti-coccidial effect. TABLE 2.—The titration of terephthalic acid activity in relationship with the potentiation of chlortetracycline Feed cone. Exp.
Lot
Av. gain:3 (gm.), days aflier inf.
%
ppm. CTC
TPA
0-3
3-6
E
24 25 26 27 28 29 30 31 32
175 175 175 175 175 175 175 175 175
0.0 0.1 0.2 0.3 0.4 0.5 0.6 1.0 2.0
58.3 62.2 60.2 62.4 50.7 46.7 61.1 54.7 56.5
17.5 38.4 38.0 45.8 42.7 63.5 51.4 64.6 59.2
F
33 34 35 36 37 38 39 40
175 175 175 175 175 175 175 175
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
63.1 67.6 59.6 53.3 61.5 60.5 59.2 59.3
18.2 18.9 22.8 39.7 39.1 41.3 38.1 34.0
The results are presented in Tables 1 and 2. In Table 1, Exp's A and C, the inclusion of TPA to poultry feeds containing either erythromycin or oxytetracycline is shown beyond any reasonable doubt to potentiate the activity of the antibiotic under the conditions of the test. In Exp's B and D, an endeavor was made to measure quantitatively the potentiating effect. An examination of lots 9-10, 20-21 indicates that an approximate double increase in activity occurred with both antibiotics in consequence of the addition of TPA. This potentiating effect, however, appeared definitely to be less than three times. The titration determinations with TPA are shown in Table 2, using in this case chlortetracycline as the test antibiotic. The results from two duplicate trials are shown, Exp's E and F. In Exp. E maximum potentiating effect was secured upon the addition of 0.5 percent of the acid to the ration. The growth rates in these lots, however, lacked uniformity. More uniform growth was secured in Exp. F, in which case maximum activity of the acid was attained at the 0.3 percent addition to the feed, with a plateau of activity apparently being reached at that concentration. SUMMARY
In the previous report mentioned, the inclusion of terephthalic acid in a poultry mash was shown to potentiate the blood sera concentration of chlortetracycline four times, and was associated also with a four fold increase in clinical activity as determined against experimental infection with cecal coccidiosis. The clinical procedure thus was indicated to be a valid criterion for measuring the potentiating effect. In the present trials, the potentiation of erythromycin and oxytetracycline with terephthalic acid was determined using the clinical method only. In the case of these antibiotics, the degree of potenti-
237
RESEARCH NOTES
ation as accurately as could be determined approximated a double increase in activity in both instances. The optimum concentration of terephthalic acid required for maximum potentiation effect appears in the case of chlortetracycline at least to be near 0.3 percent in the feed, with a plateau of activity ap-
parently being attained at that concentration. Concentrations less than 0.3 percent appear to be sub-optimum. REFERENCE Peterson, E. H., 1958. Potentiating effect of terephthalic acid upon absorption of chlortetracycline from the avian alimentary tract. Arkansas Agricultural Experiment Station Report Series 74.
THE EFFECT ON FERTILITY OF APPLYING AN ANTI-PICKING SOLUTION (THRAM) TO BREEDING STOCK G. C. HODGSON AND J. F. RICHARDS Poultry Department, University of Manitoba, Winnipeg, Canada (Received for publication November 19,1958)
Thram is an anti-picking solution which may be sprayed or brushed on birds to aid in the control of cannibalism and feather picking, an action which the manufacturer claims is due to the offensive taste of the product. (S. B. Penick and Co., 1957). No reports of the effect of Thram on fertility could be found in the literature. The following experiment was conducted to determine if the use of Thram on breeding birds might lessen the frequency of mating and hence reduce fertility. Thirty-two adult females and four males were randomly selected and distributed into four identical floor pens with one male and eight females in each. They were fed breeding mash and water ad libitum. Table 1 shows the design of the treatments. To overcome the effect of selective mating on fertility the males were interchanged three times weekly between pens 1 and 3, and 2 and 4, respectively. The birds were confined to their pens for two weeks before Thram was applied. During the two days prior to commencing treatment, the eggs from all pens were saved, incubated for four days and then
broken out to ascertain fertility. The same technique for determining fertility was followed throughout the entire experimental period. Having ascertained that fertility was at a high level in all pens prior to the application of Thram, the females in pens 3 and 4, and the males in pens 2 and 4 were sprayed with undiluted Thram. The females in pen 3 and all birds in pen 4 were crowded into a corner and each group was treated with about 0.5 lbs. of the undiluted solution applied with a hand sprayer. The male from pen 2 was sprayed individually (Table 1). TABLE 1.—Plan of the experiment Pens
1
Sex Male Female
2
3
4
Untreated Treated
Treated Treated
Treatments Untreated Untreated
Treated Untreated
The same treatment was repeated thereafter at weekly intervals. The eggs from all pens were saved and settings made twice weekly. Table 2 shows the percent fertility determined for each pen during the test. It will be noted that there was as much week