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ANTISTREPTOLYSIN AND RHEUMATIC FEVER
479
tetracycline. These three tetracyclines have similar pharmacological and antibacterial properties, dosage, and complications. Indeed, their close chemical similarity robs them partly of therapeutic distinctiveness. A recent addition to the tetracycline family is demethylchlortetracycline, produced by a mutant strain of Streptomyces aureofaciens.6 Owing to its slower renal excretion7 it antibacterial activity provides higher and more sustained in the serum than its analogues.11Judged by in-vitro susceptibility of 861 strains of 15 different species of human pathogenic bacteria, demethylchlortetracycline was the most active tetracycline analogue, or as active as any other, against two-thirds of all strains; whereas chlortetracycline was more active against some grampositive organisms, and tetracycline was more active against some resistant strains of staphylococci.1o Chemical manipulations are also changing the face of erythromycin, first isolated in 1952 11 from Streptomyces erythreus and now a well-established alternative to penicillin, notably in the treatment of staphylococcal infections, and also indicated, in conjunction with antitoxin, in the management of diphtheria.. Higher blood levels, prolonged tissue concentrations, satisfactory clinical responses, and absence of toxicity are now claimed for propionyl erythromycin lauryl sulphate.12 13 The clinician endeavouring to keep abreast finds difficulty in deciphering new names, official and otherwise, which may relate to new antibiotics, to combinations of them, or to fresh analogues. Bewildered also by new dosage schedules, he is likely to retreat to the safety of his older, well-tried favourite. Commercial firms evidently recognise his dilemma; for, despite the advantages of the latest, they continue to produce its predecessors in deference to continuing demand. This is quite unlike consumer
demand in other industries. Few
men
would
prefer a 1950 to a 1960 motor-car, and fewer housewives would willingly choose a mark-1 washing-machine when its mark 4 is already on the market. If the increasing chaos is to be abated, the medical profession and the pharmaceutical industry will have to work still more closely together. Controlled clinical trials will define the relative merits of some agents. Last week, for instance, Dr. Fairbrother and Dr. Taylor 14 described a comparative trial of penicillins G and B. ANTISTREPTOLYSIN AND RHEUMATIC FEVER
ACCEPTANCE of the causal association between haemolytic streptococcal upper-respiratory infections and acute rheumatism rests largely on serological evidence; but Lawy 15 declares that this evidence is being differently interpreted by different workers. In the past thirty years reports from many parts of the world have shown with cumulative force that during an acute attack of rheumatic fever antibodies against one or more of the known antigens of group-A p-hasmolytic streptococci appear in the patient’s serum in high or 6. 7. 8. 9.
10. 11. 12. 13. 14. 15.
R. D., Sjolander, N. O., Hirsch, U., Jensen, E. R., Doerschuk, A. P. ibid. 1957, 79, 4561. Kunin, C. M., Dornbush, A. C., Finland, M. J. clin. Invest. 1959, 38, 1950. Kunin, C. M., Finland, M. New Engl. J. Med. 1958, 259, 999. Hirsch, H. A., Finland, M. ibid. 1959, 260, 1099. Hirsch, H. A., Finland, M. Amer. J. med. Sci. 1960, 239, 288. McGuire, J. M., Bunch, R. L., Anderson, R. C., Boaz, H. E., Flynn, E. H., Powell, H. M., Smith, J. W. Antibiot. Chemother. 1952, 2, 281. Reichelderfer, T. E., Baird, R. L., Ossofsky, H. J. Antibiotics Annual 1959-60; p. 899. Anderson, R. C., Lee, C. C., Worth, H. M., Harris, P. N. J. Amer. pharm. Ass. scientific edition, 1959, 48, 623. Fairbrother, R. W., Taylor, G. Lancet, Aug. 20, 1960, p. 400. Lawy, H. S. Ann. rheum. Dis. 1960, 19, 42.
McCormick, J.
rising titre. This response is specific, and denotes recent infection with these organisms. The antibody which has received most attention is that directed against streptolysin 0-a soluble haemolysin produced by streptococci of this group. Determination of antistreptolysin 0 (A.S.o.) has become a yardstick of streptococcal infection since Todd’s original work 16 with this antigen-antibody system. Finding streptolysin 0 antigenic, he devised a method for titrating A.s.o. which in convenience and reproducibility has not been superseded by methods introduced later for detecting antibodies to other streptococcal antigens. Todd, having shown that A.s.o. responses were
specifically related went on to
to
haemolytic streptococcal infections,
study A.s.o. in rheumatic fever, whose associa-
tion with
streptococcal infection had been stressed by Coburn. 17 He found that, whether or not a bacteriologically proved haemolytic streptococcal infection was observed before the onset, the sera from patients with rheumatic fever showed raised or rising A.S.O. titres as often as the sera of patients recovering from uncomplicated streptococcal infections. Lawy draws attention once again to the frequency of rise in A.s.o. titre after streptococcal infections-namely, about 80%. If antibodies to other
streptococcal antigens (streptokinase, hyaluronidase) are included, the figure for serological response approaches 100%. The pattern of the A.s.o. response in rheumatic fever has also been extensively studied. Some of the features believed by earlier workers to represent a response characteristic of rheumatic fever have not been substantiated. Magnitude of response, for example, is not related to severity of attack, nor persistence of titre to chronicity.18 It has been repeatedly confirmed, however, that the antibody response is usually somewhat higher in rheumatic fever than in non-rheumatic streptococcal infection.1o This corresponds to Stetson’s finding 20 that the attack-rate of rheumatic fever after streptococcal infection is higher in individuals showing a greater antibody response. This effect may be associated with repeated streptococcal infection, which, as Rantz 21 has shown, leads to the early development of an enhanced antistreptococcal response in childhood. But, although in rheumatic fever additional enhancement usually seems to occur, this is- not an invariable, or even a diagnostically useful, feature. For example, Holborow and Isdale 22 found that in very young children with acute rheumatism the A.s.o. titre may be significantly less raised, and less often raised, than in children 8-10 years old.22 In general, the test is clinically useful mainly in detecting the imprint of recent streptococcal infection, especially when bacteriological evidence is lacking. In initial attacks and recurrences of rheumatic fever positive serological findings are useful, and in the long-term management of cases negative tests at intervals provide a check on the efficacy of antibiotic prophylaxis against streptococcal infections. As Lawy has found, the A.s.o. test may also be useful in another non-suppurative complication of
streptococcal infection-acute nephritis. 16. Todd, E. W. Brit. J. exp. Path. 1932, 13, 248; J. Path. Bact. 1938, 47, 423. 17. Coburn, A. F. The Factor of Infection in the Rheumatic State. Baltimore, 1931. 18. Stollerman, G. H., Lewis, A. J., Schultz, I., Taranta, A. Amer. J. Med. 1956, 20, 163. 19. Anderson, H. C., Kunkel, H. G., McCarty, M. J. clin. Invest. 1948, 27, 425. 20. Stetson, C. A. Streptococcal Infections (edited by M. MeCarty); p. 208. New York, 1954. 21. Rantz, L. A., Maroney, M., di Caprio, J. M. Arch. intern. Med. 1951, 87, 360. 22. Holborow, E. J., Isdale, I. C. Lancet, 1956, i, 649.
tetracycline. These three tetracyclines have similar pharmacological and antibacterial properties, dosage, and complications. Indeed, their close chemical similarity robs them partly of therapeutic distinctiveness. A recent addition to the tetracycline family is demethylchlortetracycline, produced by a mutant strain of Streptomyces aureofaciens.6 Owing to its slower renal excretion7 it antibacterial activity provides higher and more sustained in the serum than its analogues.11Judged by in-vitro susceptibility of 861 strains of 15 different species of human pathogenic bacteria, demethylchlortetracycline was the most active tetracycline analogue, or as active as any other, against two-thirds of all strains; whereas chlortetracycline was more active against some grampositive organisms, and tetracycline was more active against some resistant strains of staphylococci.1o Chemical manipulations are also changing the face of erythromycin, first isolated in 1952 11 from Streptomyces erythreus and now a well-established alternative to penicillin, notably in the treatment of staphylococcal infections, and also indicated, in conjunction with antitoxin, in the management of diphtheria.. Higher blood levels, prolonged tissue concentrations, satisfactory clinical responses, and absence of toxicity are now claimed for propionyl erythromycin lauryl sulphate.12 13 The clinician endeavouring to keep abreast finds difficulty in deciphering new names, official and otherwise, which may relate to new antibiotics, to combinations of them, or to fresh analogues. Bewildered also by new dosage schedules, he is likely to retreat to the safety of his older, well-tried favourite. Commercial firms evidently recognise his dilemma; for, despite the advantages of the latest, they continue to produce its predecessors in deference to continuing demand. This is quite unlike consumer
demand in other industries. Few
men
would
prefer a 1950 to a 1960 motor-car, and fewer housewives would willingly choose a mark-1 washing-machine when its mark 4 is already on the market. If the increasing chaos is to be abated, the medical profession and the pharmaceutical industry will have to work still more closely together. Controlled clinical trials will define the relative merits of some agents. Last week, for instance, Dr. Fairbrother and Dr. Taylor 14 described a comparative trial of penicillins G and B. ANTISTREPTOLYSIN AND RHEUMATIC FEVER
ACCEPTANCE of the causal association between haemolytic streptococcal upper-respiratory infections and acute rheumatism rests largely on serological evidence; but Lawy 15 declares that this evidence is being differently interpreted by different workers. In the past thirty years reports from many parts of the world have shown with cumulative force that during an acute attack of rheumatic fever antibodies against one or more of the known antigens of group-A p-hasmolytic streptococci appear in the patient’s serum in high or 6. 7. 8. 9.
10. 11. 12. 13. 14. 15.
R. D., Sjolander, N. O., Hirsch, U., Jensen, E. R., Doerschuk, A. P. ibid. 1957, 79, 4561. Kunin, C. M., Dornbush, A. C., Finland, M. J. clin. Invest. 1959, 38, 1950. Kunin, C. M., Finland, M. New Engl. J. Med. 1958, 259, 999. Hirsch, H. A., Finland, M. ibid. 1959, 260, 1099. Hirsch, H. A., Finland, M. Amer. J. med. Sci. 1960, 239, 288. McGuire, J. M., Bunch, R. L., Anderson, R. C., Boaz, H. E., Flynn, E. H., Powell, H. M., Smith, J. W. Antibiot. Chemother. 1952, 2, 281. Reichelderfer, T. E., Baird, R. L., Ossofsky, H. J. Antibiotics Annual 1959-60; p. 899. Anderson, R. C., Lee, C. C., Worth, H. M., Harris, P. N. J. Amer. pharm. Ass. scientific edition, 1959, 48, 623. Fairbrother, R. W., Taylor, G. Lancet, Aug. 20, 1960, p. 400. Lawy, H. S. Ann. rheum. Dis. 1960, 19, 42.
McCormick, J.
rising titre. This response is specific, and denotes recent infection with these organisms. The antibody which has received most attention is that directed against streptolysin 0-a soluble haemolysin produced by streptococci of this group. Determination of antistreptolysin 0 (A.S.o.) has become a yardstick of streptococcal infection since Todd’s original work 16 with this antigen-antibody system. Finding streptolysin 0 antigenic, he devised a method for titrating A.s.o. which in convenience and reproducibility has not been superseded by methods introduced later for detecting antibodies to other streptococcal antigens. Todd, having shown that A.s.o. responses were
specifically related went on to
to
haemolytic streptococcal infections,
study A.s.o. in rheumatic fever, whose associa-
tion with
streptococcal infection had been stressed by Coburn. 17 He found that, whether or not a bacteriologically proved haemolytic streptococcal infection was observed before the onset, the sera from patients with rheumatic fever showed raised or rising A.S.O. titres as often as the sera of patients recovering from uncomplicated streptococcal infections. Lawy draws attention once again to the frequency of rise in A.s.o. titre after streptococcal infections-namely, about 80%. If antibodies to other
streptococcal antigens (streptokinase, hyaluronidase) are included, the figure for serological response approaches 100%. The pattern of the A.s.o. response in rheumatic fever has also been extensively studied. Some of the features believed by earlier workers to represent a response characteristic of rheumatic fever have not been substantiated. Magnitude of response, for example, is not related to severity of attack, nor persistence of titre to chronicity.18 It has been repeatedly confirmed, however, that the antibody response is usually somewhat higher in rheumatic fever than in non-rheumatic streptococcal infection.1o This corresponds to Stetson’s finding 20 that the attack-rate of rheumatic fever after streptococcal infection is higher in individuals showing a greater antibody response. This effect may be associated with repeated streptococcal infection, which, as Rantz 21 has shown, leads to the early development of an enhanced antistreptococcal response in childhood. But, although in rheumatic fever additional enhancement usually seems to occur, this is- not an invariable, or even a diagnostically useful, feature. For example, Holborow and Isdale 22 found that in very young children with acute rheumatism the A.s.o. titre may be significantly less raised, and less often raised, than in children 8-10 years old.22 In general, the test is clinically useful mainly in detecting the imprint of recent streptococcal infection, especially when bacteriological evidence is lacking. In initial attacks and recurrences of rheumatic fever positive serological findings are useful, and in the long-term management of cases negative tests at intervals provide a check on the efficacy of antibiotic prophylaxis against streptococcal infections. As Lawy has found, the A.s.o. test may also be useful in another non-suppurative complication of
streptococcal infection-acute nephritis. 16. Todd, E. W. Brit. J. exp. Path. 1932, 13, 248; J. Path. Bact. 1938, 47, 423. 17. Coburn, A. F. The Factor of Infection in the Rheumatic State. Baltimore, 1931. 18. Stollerman, G. H., Lewis, A. J., Schultz, I., Taranta, A. Amer. J. Med. 1956, 20, 163. 19. Anderson, H. C., Kunkel, H. G., McCarty, M. J. clin. Invest. 1948, 27, 425. 20. Stetson, C. A. Streptococcal Infections (edited by M. MeCarty); p. 208. New York, 1954. 21. Rantz, L. A., Maroney, M., di Caprio, J. M. Arch. intern. Med. 1951, 87, 360. 22. Holborow, E. J., Isdale, I. C. Lancet, 1956, i, 649.