3
A n t i b i o t i c s in T r e a t m e n t of M a s t i t i s W. D. Schultze Milk Secretion and Mastitis Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705 Antibiotics have failed early expectations of chemo-sterilization of the mammary gland. Treatment before bacterial identification necessitates use of broad-spectrum drugs. Cure rates vary with the pathogen: low for Staphylococcus aureus, high for Streptococcus agalactiae. The most effective antibiotics against Gram-negative b a c i l l i are not approved for U.S. use. During lactation, therapy is usually limited to c l i n i cal cases, eliminating clinical signs in 90% of cases but achieving many fewer bacteriologic cures. Mass in-tramammary treatment at the end of lactation is common. Higher cure rates due to higher drug concentrations and long retention in the gland, plus avoidance of milk discard are advantages. Some degree of prophylaxis is afforded against the high new infection rate in the early nonlactating period. Evidence conflicts as to increased resistance to antibiotics as a result of mastitis treatment, but has been reported for populations of staphylococci, streptococci and coliform bacteria.
M a s t i t i s , which i s defined as inflammation of the mammary gland, i s the single most costly disease i n American agriculture Direct losses to the dairyman average $182 per cow, or i n excess of $2 b i l l i o n annually to the dairy industry, nearly 70% of these the r e s u l t of l o s t milk production. In addition to the d i r e c t losses, mastitis causes s i g n i f i c a n t reduction i n milk quality, for both f l u i d consumption and f o r processing, and i n n u t r i t i o n a l value. I t leads to a n t i b i o t i c resistance problems i n milk, meat and the environment, to premature c u l l i n g of c a t t l e , and to reduced sale value of young dairy stock. In mastitis problem herds, annual losses due to masti t i s may exceed $300 per cow. Mastitis i s nearly always caused by b a c t e r i a l infection. The introduction of benzyl p e n i c i l l i n for the treatment of intramammary infections (IMI) caused by Gram positive bacteria, followed by products containing other a n t i m i c r o b i a l agents, was a major advance i n T h i s chapter not subject to U . S . copyright. Published 1986, A m e r i c a n C h e m i c a l Society
24
A G R I C U L T U R A L USES O F ANTIBIOTICS
m a s t i t i s control. I t made possible f o r the f i r s t time a major reduc tion of the losses caused by c l i n i c a l m a s t i t i s (2). I t provided a p r a c t i c a l method of eliminating Streptococcus agalactiae, the predom inant pathogen a t that time. Hopes soared even to the extreme of forseeing that we might be able to accomplish chemosterilization of the mammary gland, and thus eradicate bovine mastitis. In a c t u a l i t y , t h i s has been f a r from the case. A n t i b i o t i c ther apy, although an important component of m a s t i t i s control strategy, i s much less e f f e c t i v e than could be desired. Farm advisors uniformly stress the p r i n c i p l e that treatment must not be r e l i e d upon to r e dress the disease promoting e f f e c t s of bad animal husbandry, unsani tary milking practices and defective milking machinery. M a s t i t i s i s a complex of infections, caused by a variety of microorganisms with inherent differences i n s e n s i t i v i t y to antimi c r o b i a l agents. Furthermore, s e n s i t i v i t y i n v i t r o does not assure e f f i c a c y i n vivo. Additionally, pathogens have the capacity to gain resistance to a n t i b i o t i c s , p a r t i c u l a r l y under conditions of heavy and poorly controlled use. S e n s i t i v i t y of M a s t i t i s Pathogens to A n t i b i o t i c s A senior B r i t i s h government veterinarian stated i n 1962 (3), "When p e n i c i l l i n was f i r s t used i n treating mastitis only 2% of the strains of staphylococci recovered from cases of mastitis were re s i s t a n t to p e n i c i l l i n . Today the figure i s over 70%." Between 1958 and 1961, resistance to p e n i c i l l i n (PEN) increased from 62.0% to 70.6%. Resistance to streptomycin (STR), tetracycline and chloram phenicol also increased (4). A n t i b i o t i c resistance increased f o r i s o l a t e s of both mastitis staphylococci and streptococci i n Canada between 1960 and 1967 (5). In Belgium (6), Staphylococcus aureus strains i s o l a t e d from cases of bovine m a s t i t i s showed increase i n PEN resistance from 38% i n 1971 to 78% i n 1974, but then no further i n crease to 1980. The resistance s i t u a t i o n was reported to remain stable i n the Federal Republic of Germany between 1962 and 1975 (7), as also i n A u s t r a l i a between 1974 and 1979 (8) and Denmark, a t a very low l e v e l , for the period 1963 to 1978 (9). Inasmuch as s e l e c t i o n pressure i s considered responsible f o r de velopment of a n t i b i o t i c resistance, l o c a l differences i n drug usage may explain the widely varying resistance situations (10). Great d i s p a r i t i e s have been reported within nations as well as between them, f o r example, i n A u s t r a l i a (8) and Switzerland (11 ). In the United States, i t i s the common opinion (based on meagre and geographically r e s t r i c t e d data) that increasing a n t i b i o t i c re sistance among pathogens of bovine m a s t i t i s i s not a problem (12.13)» with the exception of resistance to PEN (14). A scan of reports ac cumulated over some 15 years (Table l ) supports the view, but also suggests a dramatic increase i n resistance to STR among staphylo cocci. I t i s noteworthy that none of the drugs to which Escherichia c o l i i s nearly always sensitive, namely gentamicin, polymyxin Β or chloramphenicol, are approved f o r use i n mastitis therapy i n the U.S. In the use of dry cow therapy (DCT) f o r m a s t i t i s control, we have a model s i t u a t i o n where a n t i b i o t i c s are introduced into the milk compartment a t high concentration and undergo slow d i s s i p a t i o n f o r up to 3 weeks (21,22,23) · In mass dry cow therapy (DCT), a l l cows i n a herd are infused i n a l l mammary quarters with an a n t i b i o t i c
b/
MD^
NY CA,IA,MD 92 95
—
23 37 40 11 23
100 100 53 31 30 58 55
42 90 92
^ One research herd of about 180 milking cows
Ρ0Β polymyxin Β
STR dihydrostreptomycin,
1973 1975 1977 1982 1983
15 8
48 24
—
1969 1973 1980
100 100 90
0 0 4
5 19
0
1976 1976 1983
9 30 39 31 61
2 3 46). Z i v (23) has summarized the desirable k i n e t i c and other properties of such a product. The f o l lowing a n t i b i o t i c formulations are presently approved by the U.S. Center for Veterinary Medicine, FDA f o r infusion into the dry mammary gland: erythromycin (300 mg), oxytetracycline-HCl (426 mg), benza thine c l o x a c i l l i n (500 mg), cephapirin benzathine (300 mg), novobio c i n (400 mg), p e n i c i l l i n (200,000 IU) & novobiocin (400 mg), p e n i c i l l i n (1 χ 10 IU) & dihydrostreptomycin (1 g), p e n i c i l l i n (200,000 IU) & dihydrostreptomycin (300 mg), and procaine p e n i c i l l i n G (100,000 IU) (26). Varying estimates of therapeutic success from use of dry cow formulations have been reported (Table I I ) . Correction for spontane ous cure rate i n an appropriate control group i s necessary to pre clude serious overestimation of drug e f f i c a c y . Mass DCT i s a popular and commonly recommended strategy i n the U.S., the U.K., A u s t r a l i a , Ireland, the Federal Republic of Germany, France, the Netherlands, South A f r i c a and I s r a e l (54). Antimicrobial treatment at drying off i s r a r e l y practiced i n Austria, Czechoslovak i a , Hungary, Spain, Japan, Norway and Poland. New Zealand and most of the Scandinavian countries favor s e l e c t i v e DCT, i n which only those cows receive treatment who have either a history of c l i n i c a l mastitis during the preceding l a c t a t i o n or current signs of i n f e c t i o n (54). I t has been suggested that as m a s t i t i s control using the strategies common among the English-speaking countries reduces d i s ease prevalence we must rethink the question of mass versus s e l e c t i v e therapy (55). b
Selective Dry Cow Therapy. Two c r i t e r i a are c r i t i c a l to the success of a regimen for s e l e c t i v e DCT: the a b i l i t y to detect and thus
8&
67^
7
Streptococcus uberis only
Percentage computed by correcting f o r author's reported spontaneous cure rate
Percent of infected quarters rendered noninfected
34
b/
61
Procaine p e n i c i l l i n G (200,000 IU); novobiocin (0.4 g)
(0.4 g)
35*/
Procaine p e n i c i l l i n G (500,000 IU); novobiocin (0.6 g)
Novobiocin
lOO^
90^
77-
Neomycin-SO, (0.5 g); benzathine p e n i c i l l i n V (325,000 IU)
45^
75
65
62
Neomycin-SO^ (0.5 g)
59^
90
5 6 ^ '
b/
combined 97
τ τ
Streptococcus : other
7&
9 1
97
Streptococcus agalactiae
Benzathine c l o x a c i l l i n (0.5 g)
Benzathine c l o x a c i l l i n (0.5 g)
84
76
Benzathine p e n i c i l l i n G (200,000 IU); dihydrostreptomycin-SO^ (0.4 g)
Benzathine c l o x a c i l l i n (1 g)
87
Procaine p e n i c i l l i n G (1 χ 10°IU); dihydrostreptoraycin-SO^ (1 g)
Staphylococcus aureus
E f f i c a c y of Dry Cow Therapy Against Intramammary Infections
A n t i b i o t i c s i n formulation
Table I I .
b/
31-b/
89
n
Coliform bacteria
52
51
50
49
48
49
48
47
46
41
References
30
A G R I C U L T U R A L USES O F ANTIBIOTICS
select for treatment a high proportion of cows with IMI present at drying o f f , and achievement of a degree of prophylaxis not greatly i n f e r i o r to that afforded by mass DCT. Studies of e f f i c i e n c y of detection have not been encouraging. Selection for treatment of i n d i v i d u a l quarters according to t h e i r strong reaction i n the Whiteside test (a rough measure of inflammation of the gland) (56) detected only 39% of infected quarters and predictably would have permitted 80% of a l l staphylococcal infections to persist into the next l a c t a t i o n . Treating a l l quarters of cows which had had c l i n i c a l mastitis during the previous l a c t a t i o n (57) would have missed 34% of quarters infected at drying off and 39% of those which subsequently became i n fected during the dry period. A comparison of s e l e c t i o n c r i t e r i a i n cluding mastitis history, somatic c e l l count history and current C a l i f o r n i a mastitis test score, alone and i n combination (58), showed predictions ranging from 50% to 92% of infected cows, but included from 49% to 80% of the noninfected cows. Selection for DCT of cows drying o f f with a history of mastitis treatment during l a c t a t i o n or with one or more quarters p o s i t i v e to bactériologie culturing at drying o f f (17) was successful, of course, i n clearing most previously infected glands. The o v e r a l l r e s u l t , however, was a net gain of 1.4% i n infected quarters at the next calving, occasioned by the f a i l u r e to control new dry period IMI among untreated cows and peripartum IMI among both groups. Prophylactic E f f i c a c y of Dry Cow Therapy. Prophylactic efficacy might be expected to go hand i n hand with e f f i c i e n c y of selecting i n fected animals, f o r the new i n f e c t i o n r a t e i n the dry period tends to be higher among cows entering the period with at least one quarter infected (17,59). Some a u t h o r i t i e s , however, question the very existence of prophylaxis as an aspect of DCT (60). Nonetheless, one of the e a r l i e s t uses of a n t i b i o t i c s against bovine mastitis was the prevention of "summer m a s t i t i s " (a special form of the disease not seen i n the U.S.) by treating every cow at drying o f f (61). F i e l d t r i a l s have demonstrated better than 90% control of t h i s disease entity through DCT (62,63,64). Experimental design of most studies has been inadequate to provide convincing evidence of prophylactic e f f i c a c y . Contributing to the problem, designs i n which new IMI at the beginning of the dry period are lumped with new IMI at calving obscure the effects of prophylaxis. They imply an u n r e a l i s t i c expectation of DCT, for peripartum i n f e c t i o n must be treated as a separate problem. I t cannot be attacked merely by stretching the persistence i n the gland of longacting products for DCT. After attempting to correct for biases i n selection of animals for treatment (51), prophylactic efficacy of a p e n i c i l l i n - n o v o b i o c i n formulation was estimated at nearly 50%. Some studies i n which evidence of prophylaxis against new IMI i n the early dry period has been adduced have noted great differences i n t h i s r e gard among a n t i b i o t i c formulations (65) or among species of pathogen (53). I t seems reasonable to expect prophylaxis as a benefit of dry cow therapy but currently there i s i n s u f f i c i e n t documentation to permit a good estimate of i t s magnitude. In addition to DCT, recommended mastitis control i n the U.S. i n cludes the dipping of the cow's teats i n a germicide immediately after each milking. This strategy commonly results i n a lowered prevalence of IMI i n a dairy herd, but also a s h i f t i n pathogen
3.
SCHULTZE
Antibiotics
in Treatment of
Mastitis
31
d i s t r i b u t i o n . E f f i c a c y of current mastitis control i s greatest against S^. aureus and Str. agalactiae, for which species cow-to-cow transmission seems of primary importance. We see an increasing number of dairy herds i n which the mastitis problem stems c h i e f l y from exposure of teat ends between milkings, to pathogens o r i g i n a t i n g i n the cow's environment: streptococci other than Str. agalactiae and Gram-negative b a c i l l i members of the coliform group (66). For such herds, r e s t r i c t e d application of DCT would seem reasonable i f the s a c r i f i c e of p o t e n t i a l prophylaxis i n the early dry period were not too great. A n t i b i o t i c A c t i v i t y and Phagocytosis S e n s i t i v i t y of m a s t i t i s pathogens to an a n t i b i o t i c i n v i t r o merely indicates p o t e n t i a l therapeutic e f f i c a c y . The data from c l i n i c a l t r i a l s r e f l e c t a l e s s encouraging r e a l i t y , i n which both pathogen and host c h a r a c t e r i s t i c s influence the outcome (67). Some pathogens are highly tissue-invasive. Once sequestered and metabolically i n a c t i v e within i n f e c t i o n f o c i they are unaffected by a n t i b i o t i c s that act by disruption of c e l l wall synthesis, such as p e n i c i l l i n s and cephalosporins . The aim of antimicrobial therapy i s to k i l l or temporarily i n activate a s u f f i c i e n t proportion of the population of invading bact e r i a to permit host defense mechanisms to accomplish s t e r i l i z a t i o n of the affected t i s s u e (67). Phagocytosis of c e l l s of the pathogen by several classes of blood-derived leukocytes i s a c r i t i c a l element i n the process. However, i n t r a c e l l u l a r s u r v i v a l within phagocytic c e l l s can be a s i g n i f i c a n t contributor to f a i l u r e of a n t i b i o t i c therapy (68). At least i n the case of Staphylococcus aureus, phagocytos i s i s not always followed by k i l l i n g , and can indeed protect the engulfed bacteria from exposure to c l o x a c i l l i n for up to 4 days. Furthermore, a n t i b i o t i c s and formulation vehicles used i n i n t r a mammary infusion therapy against mastitis can have a deleterious effect on the v i a b i l i t y and phagocytic a c t i v i t y of neutrophilic leukocytes i s o l a t e d from bovine milk. In an i n v i t r o assay for phagocytos i s of 32p_i b ;L d is, aureus, the percentage of phagocytosis was s i g n i f i c a n t l y reduced by addition to the incubation mixture of tiamulin, nitrofurantoin, rifampin, chloramphenicol or amikacin i n quantities r e f l e c t i v e of t h e i r concentration i n milk 6 h after i n j e c t i o n into a mammary gland (69). Also, gentamicin, t e t r a c y c l i n e , and novobiocinp e n i c i l l i n were i n h i b i t o r y at a concentration similar to that i n milk immediately a f t e r i n j e c t i o n . Incubation with chloramphenicol, novob i o c i n - p e n i c i l l i n or tiamulin also a f f e c t s o v e r a l l neutrophil v i a b i l i t y , as measured by exclusion of trypan blue dye from the c e l l (7Q). Disruption of the morphology and function of bovine milk neutrophils was produced i n vivo by intramammary infusion of t e t r a c y c l i n e , gentamicin or chloramphenicol (71). a
e
e
Coda Nowadays, one stated objective of much of the more imaginative masti t i s research i s the reduction i n our dependence on a n t i b i o t i c s and other exogenous chemicals to control bovine m a s t i t i s . Achievement of t h i s goal i s nowhere i n sight. And so, we are l e f t dependent upon antimicrobial therapy, despite i t s many l i m i t a t i o n s , as a major element i n control strategy for bovine m a s t i t i s .
32
AGRICULTURAL USES OF ANTIBIOTICS
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3. SCHULTZE 31.
Antibiotics in Treatment of Mastitis
33
Klastrup, O. In "Proc. Symposium on Mastitis Therapy, Copenhag en"; Novo Industri A/S: Bagsvaerd, Copenhagen, 1982; pp. 1-7. 32. Senze, Α.; Jakubowski, S. Zeszyt. nauk. wyzsz. Szkol. roln., Wroclaw 1957, No. 10 (Weterynaria III), 135-49 (summary in Ger.) 33. Morris, R. S. Aust. vet. J . 1973, 49, 153-6. 34. Plommet, M.; Le Loudec, C. In "Proc. IDF Seminar on Mastitis Control 1975"; International Dairy Federation Doc. 85: Brussels, 1975; pp. 265-81. 35. McDermott, M. P.; Erb, H. N . ; Natzke, R. P.; Barnes, F. D.; Bray, D. J . Dairy Sci. 1983, 66, 1198-1203. 36. Bakken, G. Acta Agric. Scand. 1981, 31, 273-86. 37. Bakken, G.; Gudding, R. Acta Agric. Scand. 1982, 32, 17-22. 38. Woolford, M.W.;Williamson, J . H . ; Copeman, P. J. Α.; Napper, A. R.; Phillips, D. S. M.; Uljee, E. Proc. 35th Ruakura Farm ers' Conf., Hamilton, N.Z., 1983, pp. 115-9. 39. Smith, K. L.; Todhunter, D. A. Proc. 21st Annu. Mtg. Nat. Mast i t i s Coun., 1982, pp. 87-100. 40. Eberhart, R. J. Proc. 21st Annu. Mtg. Nat. Mastitis Coun., 1982, pp. 101-11. 41. Dodd, F. H . ; Westgarth, D. R.; Neave, F. K . ; Kingwill, R. G. J . Dairy Sci. 1969, 52, 689-95. 42. Dodd, F. H . ; Griffin, T. K. In "Proc. IDF Seminar on Mastitis Control 1975"; International Dairy Federation Doc. 85: Brussels, 1975; pp. 282-302. 43. Roberts, S. J.; Meek, Α. M.; Natzke, R. P.; Guthrie, R. Proc. 19th World Vet. Cong., Mexico City, 1971, 3, 935-9. 44. Funke, H. Acta Vet. Scand. 1961, 2 (Suppl. 1), 1-88. 45. Smith, Α.; Neave, F. K . ; Dodd, F. H . ; Jones, Α.; Gore, D. N. J . Dairy Res. 1967, 34, 47-57. 46. Ziv, G . ; Saran-Rosenzuaig, Α.; Gluckmann, E. Zbl. Vet. Med. Β 1973, 20, 425-34. 47. Bäckström, G.; Johansson, Α.; Petersson, O.; Winsö, S. Svensk Veterinärtid. 1980, 32, 83-5. 48. Smith, Α.; Westgarth, D. R.; Jones, M. R.; Neave, F. K . ; Dodd, F. H . ; Brander, G. C. Vet. Rec. 1967, 81, 504-10. 49. Postle, D. S.; Natzke, R. P. Vet.Med./S.A.C. 1974, 69, 1535-9. 50. Pankey, J . W.; Barker, R. M.; Twomey, Α.; Duirs, G. N.Z. Vet. J. 1982, 30, 50-2. 51. Schultze, W. D.; Mercer, H. D. Am. J. Vet. Res. 1976, 37, 12759. 52. Pankey, J . W.; Barker, R. M.; Twomey, Α.; Duirs, G. N.Z. Vet. J. 1982, 30, 13-5. 53. Swenson, G. H. Can. J. comp. Med. 1979, 43, 440-7. 54. IDF Group A.2 (Bovine Mastitis) "International Progress in Mastitis Control 1983"; International Dairy Federation Bull. 187: Brussels, 1985; 20 pp. 55. Schultze, W. D. Proc. 14th Annu. Mtg. Nat. Mastitis Coun., 1975, pp. 41-53. 56. Natzke, R. P. J . Dairy Sci. 1971, 54, 1895-1901. 57. Schultze, W. D.; Casman, Ε. Α.; Lillie, J . H. J . Dairy Sci. 1974, 57, 643 (Abstr.). 58. Rindsig, R. B.; Rodewald, R. G . ; Smith, A. R.; Thomsen, Ν. K . ; Spahr, S. L. J . Dairy Sci. 1979, 62, 1335-9. 59. Neave, F. K . ; Dodd, F. H . ; Henriques, E. J . Dairy Res. 1950, 17, 37-49.
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Ziv, G. In "Progress in Control of Bovine Mastitis: IDF Semin ar, Kiel"; Kieler Milchwirtschaftl. Forschungsber. 1986 (In Press). Wilson, C. D. In "Mastitis Control and Herd Management"; Bramley, A. J.; Dodd, F. H . ; Griffin, T. Κ., eds.; N.I.R.D.: Reading, 1981; pp. 113-27. Pearson, J . K. L. Vet. Rec. 1950, 62, 166-8. Pearson, J . K. L . Vet. Rec. 1951, 63, 215-20. Franke, V . ; Tolle, Α.; Reichmuth, J.; Beimgraben, J . In "Heifer Mastitis Seminar, Stockholm-Helsinki"; Svensk Husdjursskötsel: Eskilstuna, 1983; Chap. 2. Natzke, R. P.; Everett, R. W.; Bray, D. R. J . Dairy Sci. 1975, 58, 1828-35. Smith, K. L.; Todhunter, D. Α.; Schoenberger, P. S. J . Dairy Sci. 1985, 68, 1531-53. Craven, N . ; Williams, M. R.; Anderson, J . C. Proc. 4th Int. Sympos. Antibiotics in Agric., 1984, pp. 175-92. Craven, N . ; Anderson, J. C. J . Dairy Res. 1984, 51, 513-23. Ziv, G.; Paape, M. J.; Dulin, A. M. Am. J. Vet. Res. 1983, 44, 385-8. Nickerson, S. C.; Paape, M. J.; Dulin, A. M. Am. J. Vet. Res. (In Press). Nickerson, S. C.; Paape, M. J.; Dulin, A. M. J . Dairy Sci. 1984, 67 (Suppl. 1), 85 (Abstr.).
RECEIVED February 18, 1986
