- Email: [email protected]
Penicillin-sensitive Streptococcal Endocarditis
637
infective endocarditis.For purposes of treatment these, together with strains ofstrept. bovis,’8 have been arbitrarily divided into a penicillin-sensitive group (minimum inhibitory concentration [MIC] of benzylpenicillin <0 1 mg/1) and a less sensitive group (MIC >0 -1 1 mg/1). Unfortunately, the viridans streptococci are heterogeneous and vary in their cultural requirements. MICs and minimum bactericidal concentrations (MBCs) determined in vitro under one set of conditions may not accurately reflect the true sensitivity of the organism in the patient.9 In addition, the methods for MIC and MBC determination vary from laboratory to laboratory. Nevertheless, it is possible to draw some broad conclusions about treatment regimens.
High-dose penicillin (=10 megaunits [6 g] Penicillin-sensitive Streptococcal Endocarditis INFECTIVE endocarditis in the pre-antibiotic era was a relentless, fatal disease. When HORDER’ described the natural history of the untreated condition in 150 patients all but 1 (in whom the diagnosis was uncertain) had died within eighteen months of onset. The first glimmer of hope came when sulphonamides were used and an occasional patient was cured.2 The real breakthrough came with the introduction of penicillin: in 1944 LOEWE3 reported seven consecutive successfully treated patients. Trials by the U.K. Medical Research Council on the therapy of Streptococcus viridans endocarditis, summarised by CATES and CHRISTIE,4and similar work in the United States, provided the basis upon which many physicians have subsequently treated their patients. During these early studies the doses of penicillin were low-of the order of 500 000 units daily-and after four weeks’ treatment 10-15% of patients relapsed or died of uncontrolled infection. In almost all cases, however, relapse could be prevented by a further two to four weeks’ treatment, and deaths due to uncontrolled infections were also reduced. Since then our knowledge of the pathogenesis and treatment of the disease has
progressed. The vegetation
in bacterial endocarditis consists of small colonies of the causal organism enmeshed in a matrix of fibrin and platelets which prevents the penetration of phagocytes. During effective antibiotic treatment the vegetation is invaded by granulation tissue and fibroblasts, and healing occurs.5 Streptococci of the "viridans" group remain the commonest organisms isolated from patients with 1 Horder TJ. Infective endocarditis. Quart J Med 1909; 2: 289-324. 2 Lichtman SS Treatment of subacute bacterial endocarditis: current results. Ann Intern
Med 1943; 19: 787-94. L, Rosenblatt O, Green HJ, Russell M. Combined penicillin and heparin therapy of subacute bacterial endocarditis: report of seven consecutive successfully treated patients. JAMA 1944; 124: 144-49. 4. Cates JE, Christie RV. Subacute bacterial endocarditis. Quart J Med 1951; 20: 93-130. 5 Durack DT, Beeson PB. Experimental bacterial endocarditis. II. Survival of bacteria in endocardial vegetations. Br J Exp Pathol 1972; 53: 50-53. 3 Loewe
per
day)
for two weeks was associated with an unacceptably high relapse rate’° but recurrence after a four-week highdose course is unusual (about 1%)." Experience with a combination of penicillin and an aminoglycoside for Strept. viridans was reported by HUNTER in 1952.14 In vitro most strains of penicillin-sensitive viridans
streptococci are killed more quickly by the combination of penicillin and an aminoglycoside than by penicillin alone, 15 and in rabbits the combination sterilises experimentally induced vegetations in half the time taken by penicillin.’6," Workers at the Mayo Clinic have for many years been using combined therapy and their experience is reported in the proceedings of a symposium.18 In assessing the result, we must remember that they advise different treatment for patients who are shocked or suspected of having intracranial mycotic aneurysms, cerebritis, or thrombocytopenia (in whom the death rate is high), and for patients with eighth nerve or renal dysfunction. For the remaining patients they have used intramuscular procaine penicillin, 1’ 2 g 6-hourly, and streptomycin, 0’ 5 g 12-hourly, for two weeks; and in their hands the relapse rate is about 1%. HUNTER and 6. 7.
8.
9.
Kaye D Infecting micro-organisms. In: Kaye D, ed. Infective endocarditis. University Park Press, 1977: 43-54. Hoppes WL, Lerner PI. Non-enterococcal group D streptococcal endocarditis caused by Streptococcus bovis. Ann Intern Med 1974; 81: 588-93. Moellering RC, Watson BK, Kunz LJ Endocarditis due to group D streptococci: comparison of disease caused by Streptococcus bovis with that produced by enterococci. Am J Med 1974; 57: 239-50 Wilson WR, Thompson RL, Wilkowske CJ, Washington JA, Giuliani ER, Geraci JE. Short term therapy for streptococcal infective endocarditis, combined intramuscular administration of penicillin and streptomycin. JAMA 1981; 245: 360-63.
Stein L Streptococcus viridans subacute bacterial endocarditis. Two schedule with penicillin. JAMA 1952; 149: 542-45. 11. Hoppes WL. Treatment of bacterial endocarditis caused by penicillin sensitive streptococci. Arch Intern Med 1977; 137: 1122-23. 12. Karchmer AW, Moellering RC, Maki DG, Swartz MN Single antibiotic therapy for streptococcal endocarditis. JAMA 1979; 241: 1801-06. 13 Malacoff RF, Frank E, Andriole VT. Streptococcal endocarditis (non-enterococcal, non-group A ): single vs combination therapy. JAMA 1979; 241: 1807-10. 14. Hunter TH. The treatment of some bacterial infections of the heart and pericardium. Bull NY Acad Med 1952; 28: 213-28. 15. Wolfe JC, Johnson WD. Penicillin sensitive streptococcal endocarditis in vitro and clinical observations on penicillin streptomycin therapy Ann Intern Med 1974; 81: 178-81. 16. Durack DT, Pelletier LL, Petersdorf RG. Chemotherapy of experimental streptococcal endocarditis. II. Synergism between penicillin and streptomycin against penicillin sensitive streptococci J Clin Invest 1974; 53: 829-33. 17. Sande MA, Irvin RG Penicillin aminoglycoside synergy in experimental Streptococcus viridans endocarditis J Infect Dis 1974; 129: 572-76 18. Wilson WR, Giuliani ER, Geraci JE Treatment of penicillin sensitive streptococcal endocarditis. Mayo Clin Proc 1982; 57: 95-100. 10.
Hamburger M, weeks
treatment
638
PATERSON, 18 summarising experience with this type of course up to 1956, found an overall relapse rate about 6% and TOMPSETT et al.,i9 in 1958, reported recurrence in four of thirty-five courses of treatment (11 TOMPSETT used patient relapsed twice). but earlier both these dihydrostreptomycin reports seem at variance with the Mayo experience. Because of the unacceptably high relapse rates during these earlier studies, other groups have used penicillin for four weeks combined with streptomycin for the first two weeks. 15,20 Despite the success of this regimen, endocarditis will quickly recur in some patients. 21 In the experience of GRAy/2 four weeks of oral amoxycillin and probenecid has been effective for penicillin-sensitive Strept. viridans endocarditis, but the number of patients reported upon is smaller than the aggregate experience for other regimens. Close supervision and monitoring of such therapy would be essential. How should the antibiotic treatment be monitored? The serum bactericidal titre (back titration, minimum bactericidal dilution) has been widely used. In animals the rate of killing of streptococci in vegetations is related to the penicillin dose, the interval between doses,23 and the addition or not of an aminoglycoside. 11,17 In the rabbit, 1-hour post-dose serum bactericidal titres less than 1 in 8 are of very uncertain effect in reducing the numbers of bacteria per gram of vegetation, while above this titre the effect is much more predictable. This test may therefore be useful in showing that a threshold value has been reached; above it, higher doses and shorter intervals between doses may shorten the period of treatment needed. Variations in this level for different antibiotics and combinations of antibiotics may perhaps explain the wide variation of both peak and trough serum bactericidal titres chosen by different workers to indicate adequate treatment-a difficulty compounded by differences in methodology.z4 Despite the obvious advantages of short regimens, the occasional patient will relapse after "appropriate" treatment. Such patients tend to have had symptoms for a long time before diagnosis" and this fits in with experimental evidence that the metabolic activity of some organisms in established vegetations is very low. In this state organisms are much more resistant to antibiotic action.Most of the relapses described by CATES and CHRISTIE4occurred within one month of the end of treatment, and more recent experience accords with this.13,2l Careful follow-up including blood culture, as 19.
20. 21. 22.
Tompsett R, Robbins C, Bernstein C Short term penicillin and dihydrostreptomycin therapy of streptococcal endocarditis. Am J Med 1958; 24: 57-67. Tompsett R, Hurst ML. Bacterial endocarditis: selected aspects of treatment. Trans Am Clin Climatol Assoc 1971; 83: 95-101. Phair JP, Tan JS. Infective endocarditis: an American Heart Association symposium, Dallas: American Heart Association, 1977. Gray IR Management of infective endocarditis J Roy Coll Phys, Lond 1981; 15: 173-78.
J, Kaye D. Antibiotic concentrations in serum, serum bactericidal activity therapy of streptococcal endocarditis in rabbits. Antimicrob Ag Chemother 1977, 12: 479-83. Washington JA. The role of the microbiology laboratory in the diagnosis and
23 Carrizosa
and results of
24.
antimicrobial treatment of infective endocarditis. Mayo Clin Proc 1982; 57: 22-32.
advocated by the Mayo group,25 is important to detect relapse and assess the need for valve replacement. Most patients who relapse will respond to a further course of the same treatment. When treatments are compared in terms of recurrence rates, relapse with organisms not eradicated can be hard to distinguish from reinfection with a different strain. With the new methods of identification,26 the distinction should be easier than it was-provided that the original infecting organism has been kept. Strains occurring on prosthetic valves, the less sensitive and increasingly recognised strains of pyridoxal-dependent streptococci, together with those patients who experience penicillin side-effects: all
require special consideration. 18I Which regimen is best? As EDELMAN 27 has pointed out, we will probably never know which gives the lowest relapse rate, because of the daunting time-scale and cost of a trial. We do, however, have a basis for of new treatments, in terms of both efficacy toxicity-for instance, GRAY’s oral amoxycillin probenecid therapy, or the substitution of gentamicin for streptomycin in combination regimens. This could be done in multicentre collaborative trials if one laboratory acted as a reference centre for identification and MIC determinations. assessment
and and
Running, Jumping, and... Amenorrhoea OF women athletes at the Tokyo Olympics (1964), 90% reported normal menstrual function,’ whereas at Montreal (1976) 59% had some irregularity.2 Whether or not this was a real increase, there has certainly been an upsurge in the reporting of menstrual abnormalities associated with physical exercise. Most of the new work comes from the United States where, the jogging epidemic apart (18 million in the United States3), an increase in female athleticism has been fostered by "Title IX", which requires equal sports opportunities for the sexes in schools.3 In the data on menstrual abnormalities it is important to distinguish between the different physical activities and the age at which they started. Where training starts before the menarche, as in gymnastics and ballet dancing, then the menarche is delayed by about 3 years 1-6 and the incidence of secondary WR, Giuliani ER, Danielson GK, Geraci JE. General considerations in the diagnosis and treatment of infective endocarditis. Mayo Clin Proc 1982; 57: 81-85. 26. Waitkins SA, Anderson DR, Todd FK. An evaluation of the API Strep. identification system. Med Lab Sci 1981, 38: 35-39. 27. Edelman R. Controlled study of streptococcal endocarditis—a problem of feasibility JAMA 1979; 242: 1612-13. 1. Zaharieva E. Survey of sportswomen at the Tokyo Olympics. J Sports Med 1965, 5: 25. Wilson
215-19. 2. Webb WL, Millan
DL, Stolz CJ. Gynecological Survey of American female athletes competing at the Montreal Olympic Games. J Sports Med 1979; 19: 405-12. 3. McArthur JW. Influence of body mass, body composition and exercise. In: Flamingi C, Givens JR, ed. The gonadotrophins: basic science and clinical aspects in females (Serono Symp no. 42). London and New York: Academic Press, 1982. 4. Frisch RE, Wystrak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 1980; 303: 17-19. 5. Warren MP. The effects of exercise on pubertal progression and reproductive function in girls. J Clin Endocrinol Metab 1980; 51: 1150-57. 6. Abraham SF, Beumont PJV, Fraser IS, Llewellyn-Jones D. Body weight, exercise and menstrual status among ballet dancers in training. Br J Obstet Gynaecol 1982; 89: 507-10.
infective endocarditis.For purposes of treatment these, together with strains ofstrept. bovis,’8 have been arbitrarily divided into a penicillin-sensitive group (minimum inhibitory concentration [MIC] of benzylpenicillin <0 1 mg/1) and a less sensitive group (MIC >0 -1 1 mg/1). Unfortunately, the viridans streptococci are heterogeneous and vary in their cultural requirements. MICs and minimum bactericidal concentrations (MBCs) determined in vitro under one set of conditions may not accurately reflect the true sensitivity of the organism in the patient.9 In addition, the methods for MIC and MBC determination vary from laboratory to laboratory. Nevertheless, it is possible to draw some broad conclusions about treatment regimens.
High-dose penicillin (=10 megaunits [6 g] Penicillin-sensitive Streptococcal Endocarditis INFECTIVE endocarditis in the pre-antibiotic era was a relentless, fatal disease. When HORDER’ described the natural history of the untreated condition in 150 patients all but 1 (in whom the diagnosis was uncertain) had died within eighteen months of onset. The first glimmer of hope came when sulphonamides were used and an occasional patient was cured.2 The real breakthrough came with the introduction of penicillin: in 1944 LOEWE3 reported seven consecutive successfully treated patients. Trials by the U.K. Medical Research Council on the therapy of Streptococcus viridans endocarditis, summarised by CATES and CHRISTIE,4and similar work in the United States, provided the basis upon which many physicians have subsequently treated their patients. During these early studies the doses of penicillin were low-of the order of 500 000 units daily-and after four weeks’ treatment 10-15% of patients relapsed or died of uncontrolled infection. In almost all cases, however, relapse could be prevented by a further two to four weeks’ treatment, and deaths due to uncontrolled infections were also reduced. Since then our knowledge of the pathogenesis and treatment of the disease has
progressed. The vegetation
in bacterial endocarditis consists of small colonies of the causal organism enmeshed in a matrix of fibrin and platelets which prevents the penetration of phagocytes. During effective antibiotic treatment the vegetation is invaded by granulation tissue and fibroblasts, and healing occurs.5 Streptococci of the "viridans" group remain the commonest organisms isolated from patients with 1 Horder TJ. Infective endocarditis. Quart J Med 1909; 2: 289-324. 2 Lichtman SS Treatment of subacute bacterial endocarditis: current results. Ann Intern
Med 1943; 19: 787-94. L, Rosenblatt O, Green HJ, Russell M. Combined penicillin and heparin therapy of subacute bacterial endocarditis: report of seven consecutive successfully treated patients. JAMA 1944; 124: 144-49. 4. Cates JE, Christie RV. Subacute bacterial endocarditis. Quart J Med 1951; 20: 93-130. 5 Durack DT, Beeson PB. Experimental bacterial endocarditis. II. Survival of bacteria in endocardial vegetations. Br J Exp Pathol 1972; 53: 50-53. 3 Loewe
per
day)
for two weeks was associated with an unacceptably high relapse rate’° but recurrence after a four-week highdose course is unusual (about 1%)." Experience with a combination of penicillin and an aminoglycoside for Strept. viridans was reported by HUNTER in 1952.14 In vitro most strains of penicillin-sensitive viridans
streptococci are killed more quickly by the combination of penicillin and an aminoglycoside than by penicillin alone, 15 and in rabbits the combination sterilises experimentally induced vegetations in half the time taken by penicillin.’6," Workers at the Mayo Clinic have for many years been using combined therapy and their experience is reported in the proceedings of a symposium.18 In assessing the result, we must remember that they advise different treatment for patients who are shocked or suspected of having intracranial mycotic aneurysms, cerebritis, or thrombocytopenia (in whom the death rate is high), and for patients with eighth nerve or renal dysfunction. For the remaining patients they have used intramuscular procaine penicillin, 1’ 2 g 6-hourly, and streptomycin, 0’ 5 g 12-hourly, for two weeks; and in their hands the relapse rate is about 1%. HUNTER and 6. 7.
8.
9.
Kaye D Infecting micro-organisms. In: Kaye D, ed. Infective endocarditis. University Park Press, 1977: 43-54. Hoppes WL, Lerner PI. Non-enterococcal group D streptococcal endocarditis caused by Streptococcus bovis. Ann Intern Med 1974; 81: 588-93. Moellering RC, Watson BK, Kunz LJ Endocarditis due to group D streptococci: comparison of disease caused by Streptococcus bovis with that produced by enterococci. Am J Med 1974; 57: 239-50 Wilson WR, Thompson RL, Wilkowske CJ, Washington JA, Giuliani ER, Geraci JE. Short term therapy for streptococcal infective endocarditis, combined intramuscular administration of penicillin and streptomycin. JAMA 1981; 245: 360-63.
Stein L Streptococcus viridans subacute bacterial endocarditis. Two schedule with penicillin. JAMA 1952; 149: 542-45. 11. Hoppes WL. Treatment of bacterial endocarditis caused by penicillin sensitive streptococci. Arch Intern Med 1977; 137: 1122-23. 12. Karchmer AW, Moellering RC, Maki DG, Swartz MN Single antibiotic therapy for streptococcal endocarditis. JAMA 1979; 241: 1801-06. 13 Malacoff RF, Frank E, Andriole VT. Streptococcal endocarditis (non-enterococcal, non-group A ): single vs combination therapy. JAMA 1979; 241: 1807-10. 14. Hunter TH. The treatment of some bacterial infections of the heart and pericardium. Bull NY Acad Med 1952; 28: 213-28. 15. Wolfe JC, Johnson WD. Penicillin sensitive streptococcal endocarditis in vitro and clinical observations on penicillin streptomycin therapy Ann Intern Med 1974; 81: 178-81. 16. Durack DT, Pelletier LL, Petersdorf RG. Chemotherapy of experimental streptococcal endocarditis. II. Synergism between penicillin and streptomycin against penicillin sensitive streptococci J Clin Invest 1974; 53: 829-33. 17. Sande MA, Irvin RG Penicillin aminoglycoside synergy in experimental Streptococcus viridans endocarditis J Infect Dis 1974; 129: 572-76 18. Wilson WR, Giuliani ER, Geraci JE Treatment of penicillin sensitive streptococcal endocarditis. Mayo Clin Proc 1982; 57: 95-100. 10.
Hamburger M, weeks
treatment
638
PATERSON, 18 summarising experience with this type of course up to 1956, found an overall relapse rate about 6% and TOMPSETT et al.,i9 in 1958, reported recurrence in four of thirty-five courses of treatment (11 TOMPSETT used patient relapsed twice). but earlier both these dihydrostreptomycin reports seem at variance with the Mayo experience. Because of the unacceptably high relapse rates during these earlier studies, other groups have used penicillin for four weeks combined with streptomycin for the first two weeks. 15,20 Despite the success of this regimen, endocarditis will quickly recur in some patients. 21 In the experience of GRAy/2 four weeks of oral amoxycillin and probenecid has been effective for penicillin-sensitive Strept. viridans endocarditis, but the number of patients reported upon is smaller than the aggregate experience for other regimens. Close supervision and monitoring of such therapy would be essential. How should the antibiotic treatment be monitored? The serum bactericidal titre (back titration, minimum bactericidal dilution) has been widely used. In animals the rate of killing of streptococci in vegetations is related to the penicillin dose, the interval between doses,23 and the addition or not of an aminoglycoside. 11,17 In the rabbit, 1-hour post-dose serum bactericidal titres less than 1 in 8 are of very uncertain effect in reducing the numbers of bacteria per gram of vegetation, while above this titre the effect is much more predictable. This test may therefore be useful in showing that a threshold value has been reached; above it, higher doses and shorter intervals between doses may shorten the period of treatment needed. Variations in this level for different antibiotics and combinations of antibiotics may perhaps explain the wide variation of both peak and trough serum bactericidal titres chosen by different workers to indicate adequate treatment-a difficulty compounded by differences in methodology.z4 Despite the obvious advantages of short regimens, the occasional patient will relapse after "appropriate" treatment. Such patients tend to have had symptoms for a long time before diagnosis" and this fits in with experimental evidence that the metabolic activity of some organisms in established vegetations is very low. In this state organisms are much more resistant to antibiotic action.Most of the relapses described by CATES and CHRISTIE4occurred within one month of the end of treatment, and more recent experience accords with this.13,2l Careful follow-up including blood culture, as 19.
20. 21. 22.
Tompsett R, Robbins C, Bernstein C Short term penicillin and dihydrostreptomycin therapy of streptococcal endocarditis. Am J Med 1958; 24: 57-67. Tompsett R, Hurst ML. Bacterial endocarditis: selected aspects of treatment. Trans Am Clin Climatol Assoc 1971; 83: 95-101. Phair JP, Tan JS. Infective endocarditis: an American Heart Association symposium, Dallas: American Heart Association, 1977. Gray IR Management of infective endocarditis J Roy Coll Phys, Lond 1981; 15: 173-78.
J, Kaye D. Antibiotic concentrations in serum, serum bactericidal activity therapy of streptococcal endocarditis in rabbits. Antimicrob Ag Chemother 1977, 12: 479-83. Washington JA. The role of the microbiology laboratory in the diagnosis and
23 Carrizosa
and results of
24.
antimicrobial treatment of infective endocarditis. Mayo Clin Proc 1982; 57: 22-32.
advocated by the Mayo group,25 is important to detect relapse and assess the need for valve replacement. Most patients who relapse will respond to a further course of the same treatment. When treatments are compared in terms of recurrence rates, relapse with organisms not eradicated can be hard to distinguish from reinfection with a different strain. With the new methods of identification,26 the distinction should be easier than it was-provided that the original infecting organism has been kept. Strains occurring on prosthetic valves, the less sensitive and increasingly recognised strains of pyridoxal-dependent streptococci, together with those patients who experience penicillin side-effects: all
require special consideration. 18I Which regimen is best? As EDELMAN 27 has pointed out, we will probably never know which gives the lowest relapse rate, because of the daunting time-scale and cost of a trial. We do, however, have a basis for of new treatments, in terms of both efficacy toxicity-for instance, GRAY’s oral amoxycillin probenecid therapy, or the substitution of gentamicin for streptomycin in combination regimens. This could be done in multicentre collaborative trials if one laboratory acted as a reference centre for identification and MIC determinations. assessment
and and
Running, Jumping, and... Amenorrhoea OF women athletes at the Tokyo Olympics (1964), 90% reported normal menstrual function,’ whereas at Montreal (1976) 59% had some irregularity.2 Whether or not this was a real increase, there has certainly been an upsurge in the reporting of menstrual abnormalities associated with physical exercise. Most of the new work comes from the United States where, the jogging epidemic apart (18 million in the United States3), an increase in female athleticism has been fostered by "Title IX", which requires equal sports opportunities for the sexes in schools.3 In the data on menstrual abnormalities it is important to distinguish between the different physical activities and the age at which they started. Where training starts before the menarche, as in gymnastics and ballet dancing, then the menarche is delayed by about 3 years 1-6 and the incidence of secondary WR, Giuliani ER, Danielson GK, Geraci JE. General considerations in the diagnosis and treatment of infective endocarditis. Mayo Clin Proc 1982; 57: 81-85. 26. Waitkins SA, Anderson DR, Todd FK. An evaluation of the API Strep. identification system. Med Lab Sci 1981, 38: 35-39. 27. Edelman R. Controlled study of streptococcal endocarditis—a problem of feasibility JAMA 1979; 242: 1612-13. 1. Zaharieva E. Survey of sportswomen at the Tokyo Olympics. J Sports Med 1965, 5: 25. Wilson
215-19. 2. Webb WL, Millan
DL, Stolz CJ. Gynecological Survey of American female athletes competing at the Montreal Olympic Games. J Sports Med 1979; 19: 405-12. 3. McArthur JW. Influence of body mass, body composition and exercise. In: Flamingi C, Givens JR, ed. The gonadotrophins: basic science and clinical aspects in females (Serono Symp no. 42). London and New York: Academic Press, 1982. 4. Frisch RE, Wystrak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 1980; 303: 17-19. 5. Warren MP. The effects of exercise on pubertal progression and reproductive function in girls. J Clin Endocrinol Metab 1980; 51: 1150-57. 6. Abraham SF, Beumont PJV, Fraser IS, Llewellyn-Jones D. Body weight, exercise and menstrual status among ballet dancers in training. Br J Obstet Gynaecol 1982; 89: 507-10.