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ETHYLENE OXIDE—A HUMAN CARCINOGEN?
201
infective endocarditis in which the participating laboratories used standardised techniques to measure serum bactericidal
titres,’ all patients with peak titres >32 and trough titres >16 were cured; however, many patients with lower titres were also cured, and the only indication of the value of the assay that the few bacteriological failures had low serum bactericidal titres. All of the failures were in patients with staphylococcal or pseudomonal endocarditis; in the were commoner streptococcal infection peak titres > 8 achieved in all cases and all the patients were cured. The value of the serum bactericidal test has also been investigated in osteomyelitis8 and in the treatment of gram-negative sepsis in cancer patients.9,10 In the latter group, Klastersky and his colleagues9 found the test was a valuable prognostic indicator (patients with a peak titre 8 fared better than those with lower titres) in bacteraemic but not in non-bacteraemic patients. Results of a later studylO indicated that higher peak titres ( 16) were needed if the patient was severely granulocytopenic. These studies require confirmation in other centres, with due regard to the need for standardised methods. What is the prescribing doctor to make of the value of the serum bactericidal test? It is not hard to believe that concentrations of antimicrobial agents in the bloodstream must exceed an inhibitory level for the offending microbe; nor is it difficult to understand that the level required for conditions in which therapeutic success depends heavily on the antimicrobial drug should be bactericidal. Moreover, it seems sensible to ensure that peak concentrations (which, by definition, are merely transient) should exceed the required level by a sizeable margin. Whether such concentrations need to be maintained so that trough levels will also exceed the required amount is hard to say; in any case, a reliably high trough level may be achievable only with difficulty with agents (like penicillins) that have short plasma half-lives, or with others (like aminoglycosides) for which there are constraints of potential toxicity. Measurement of serum antibiotic levels serves the important function of reassuring the physician that adequate drug concentrations are being achieved during the treatment of life-threatening infections; it is especially reassuring at the time of any switch from parenteral to oral therapy, as often occurs during the course of treatment of infective endocarditis. Whether the test has a broader value is harder to judge. Such evidence as exists suggests that the greatest value of the serum bactericidal test may lie in the treatment of infection in severely granulocytopenic patients and in those with endocarditis caused by problem organisms such as staphylococci or pseudomonas, since these are the conditions in which cure may crucially depend on high and prolonged bactericidal concentrations of antibiotics. Even in these cases it seems unreasonable to expect that any magic figure for peak and trough values will be conjured up to cover all eventualities. was
7.Weinstein
MP, Stratton CW, Ackley A, et al.Multicenter collaborative evaluation ofa standardized serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 1985; 78: 262-69. 8.Prober CG, Yeager AS. Use of the serum bactericidal titer to assess the adequacy of oral antibiotic therapy in the treatment of acute hematogenous osteomyelitis. J Pediat 1979; 95: 131-35. 9. Klastersky J, Meunier-Carpentier F, Prévost J-M. Significance of antimicrobial synergism for the outcome of gram negative sepsis. Am J Med Sci 1977; 273: 157-67. 10. Sculier JP, Klastersky J. Significance of serum bactericidal activity in gram-negative bacillary bacteremia in patients with and without granulocytopenia. Am J Med 1984; 76: 429-35.
ETHYLENE OXIDE—A HUMAN CARCINOGEN? ETHYLENE oxide has been produced commercially since the 1914-18 War. Its main use is as a chemical intermediate in the manufacture of ethylene glycol (antifreeze) and nonionic detergents, but it also finds important application as a fumigant of foods such as cocoa beans and spices, and as a sterilant of cosmetics and of medical and surgical equipment. In Britain, at least 50 National Health Service hospitals have ethylene oxide sterilisers, and in the United States it has been estimated that as many as 75 000 health care workers may have been exposed to the chemica1.1 Concern about the chronic toxicity of ethylene oxide arises first from its mutagenicity. It is an alkylating agent with strong mutagenic potential as shown in bacteria, plants, fungi, insects, and cultured mammalian cells.2 When inhaled by mammals it induces chromosomal aberrations and sister chromatid exchanges.2 Animal studies also indicate a carcinogenic effect. In particular, rats chronically inhaling ethylene oxide at concentrations of 50 and 100 ppm have developed an excess of leukaemias, peritoneal mesotheliomas, and gliomas.3 Epidemiological data now suggest that the carcinogenicity of ethylene oxide may extend to man. In 1979, Hogstedt, Malmqvist, and Wadman reported 2 cases of myeloid leukaemia (1chronic and 1 acute) and 1 case of Waldenstrom’s macroglobulinaemia (subsequently reclassified as non-Hodgkin lymphoma) among the workforce of a small Swedish factory where ethylene oxide and methyl formate were used to sterilise hospital equipment.4 The patients had been exposed to time-weighted average ethylene oxide concentrations in the order of 20 ppm. This observation prompted a retrospective cohort study of workers at a second plant where ethylene oxide and other chemicals were manufactured.Among workers exposed to ethylene oxide, 2 deaths were attributed to chronic lymphocytic leukaemia and 1 to acute myeloid leukaemia by comparison with an expected 0-27 deaths from all types of leukaemia combined. A further five-year follow-up has now shown an additional death from acute blastic leukaemia at the first of these factories, and another patient (still alive) with chronic myeloid leukaemia at the second.6 Deaths from leukaemia have been reported in two other cohorts of ethylene oxide workers. Among 602 employees at nine West German plants making ethylene and propylene oxides and their derivatives there was 1 death from myeloid leukaemia with 0-25 deaths expectedand among another group of ethylene oxide manufacturers in Sweden 1 out of a
PJ, Memhardt TJ, Gordon J, et al. Ethylene oxide: An overview of toxicologic and epidemiologic research. Am J Ind Med 1984; 6: 103-15. 2. IARC monographs on the evaluation of the carcinogenic risk of chemicals to man. Vol 36. Allyl compounds, aldehydes, epoxides and peroxides. Lyon: International Agency for Research on Cancer, 1985. 3. Lynch DW, Lewis TR, Moorman WJ, et al. Carcinogenic and toxicologic effects of In: Prevention of occupational cancer-international symposium (Occupational safety and health series no 46). Geneva: International Labour Office, 1981: 249-59. 4. Hogstedt C, Malmqvist N, Wadman B. Leukaemia m workers exposed to ethylene oxide. JAMA 1979; 241: 1132-33 5. Hogstedt C, Rohlen O, Berndtsson BS, Axelson O, Ehrenberg L. A cohort study of mortality and cancer incidence in ethylene oxide production workers. Br J Ind Med 1. Landrigan
1979; 36: 276-80. 6.
Hogstedt C, Aringer L, Gustavsson A. Epidemiologic support for ethylene oxide as a cancer-causing agent. JAMA 1986, 255: 1575-78. 7. Thiess AM, Frentzel Beyme R, Link R, Stocker WG. Mortality study on employees exposed to alkylene oxides (ethylene oxide/propylene oxide) and their derivatives. In: Prevention of occupational cancer—international symposium (Occupational safety and health series no 46). Geneva: International Labour Office, 1981: 249-59.
202 total of 8 deaths was due to chronic myeloid leukaemia.6 In two of the four cohorts described have shown an excess of stomach cancer. In contrast, a study of 767 workers at an ethylene oxide manufacturing plant in the United States showed an overall deficit of cancer deaths (11 observed, 15-24 expected) and no cases of leukaemia.8 The recurrent finding of leukaemia in association with exposure to ethylene oxide is impressive, but the existence of a hazard cannot yet be regarded as established. The number of documented cases is small, particularly if one discounts the deaths in the initial Swedish case-report which gave rise to the hypothesis of leukaemogenesis. Moreover, the association has not been specific for any one type of leukaemia. Acute myeloid, chronic myeloid, and acute lymphoblastic leukaemias are all caused by ionising radiation, but there is no precedent for a hazard which predisposes also to chronic lymphocytic leukaemia. The association with gastric cancer has been found in only two investigations and may have occurred by chance or through the action of unknown confounding factors. All of the workforces studied have been exposed to other chemicals as well as ethylene oxide. Doubts about the safety of ethylene oxide are not confined to its carcinogenic potential: high rates of spontaneous abortion have been reported in Finnish hospital workers exposed to the compound.9 However, the abortion figures have yet to be corroborated elsewhere and the possible risk of cancer remains the main worry. Further information about the long-term toxicity of ethylene oxide is urgently required, and should emerge from epidemiological studies in progress in Britain and the United States. This will be important not only as a basis for the future regulation of exposure, but also as a contribution to our understanding of the relation between mutagenicity and human carcinogenicity. The demonstration of mutagenicity in short-term laboratory tests is often a criterion in deciding whether or not new chemicals should be produced commercially, but the extent to which mutagenicity predicts a capacity to cause cancer in man is still far from clear.
addition,
with persistent fever included staphylococcal infection, extensive cardiac infection especially with abscess formation around the valve ring,3 and extracardiac infection often associated with emboli from the heart to other organs. In 8 (19%) patients the fever was related to extracardiac inflammation—eg, infected intravenous access sites and purulent arthritis. In 7 (17%) patients fever was attributed to the antimicrobial therapy; the drug being implicated either by the presence of a rash or by peripheral eosinophilia. Several antibiotics have been associated with fever, especially penicillin and its derivatives methicillin,4cloxacillin,sand piperacillin.6 Streptomycin and the other aminoglycosides have also been reported to cause fever,7,8 although the frequency of hypersensitivity with these drugs is very low. Most importantly, Douglas et al did not fmd that persistent fever was caused by antibiotic resistance. Thus, once a sound microbiological diagnosis has been made and a therapeutic regimen chosen, the antibiotics should not be changed unless drug-induced hypersensitivity is implicated. Persistent fever usually represents failure of medical therapy and early surgery should then be considered. Once the infection has responded to antibiotics, elective valve replacement for the haemodynamic consequences of infective endocarditis is as safe as for valves diseased by other mechanisms, with an operative mortality of about 5%.9,10 Early valve replacement before completion of antibiotic therapy, when indicated because of haemodynamic deterioration, embolism, extensive infection, and in cases where antimicrobial agents are ineffective (eg, fungal endocarditis), carries a higher mortality of up to 45%,10 although most centres report a mortality of less than 25 % .11-18 . However, medical management alone in such cases carries a substantially higher mortality, approaching 70%,10 especially with prosthetic endocarditis.10,19 Valve replacement should therefore be considered at any time during the course of infective endocarditis if medical’therapy appears to be failing.
3.
Zabalgoitia-Reyes M, Mehlman DI, Talano JV. Persistent fever with aortic valve endocarditis. Arch Intern Med 1985; 145: 327-28.
Assoc J 1975; 112: 1044. Portnoy J, Torshinsky A, Mendelson J, Kagan E. Febrile reactions after cloxacillin. Can Med Assoc J 1975, 112: 280. 6. Stead RJ, Kennedy HG, Hodson ME, Batten JC. Adverse reactions to piperacillin in cystic fibrosis. Lancet 1984; i: 857-58. 7. Feldbaum JS, Silverstein H. Streptomycin drug fever during treatment of bilateral Menières disease. Arch Otolaryngol 1984; 110: 538-39. 8. McEvoy GK, ed. Aminoglycosides—general statement. In: American Hospital Formulary Service—Drug Information. Bethesda: American Society of Hospital Pharmacists, 1986: 53. 9. Westaby S, Oakley CM, Sapsford RN, Bentall HH. Surgical treatment of infective endocarditis with special reference to prosthetic valve endocarditis. Br Med J 1983;
4. Smith JA. Febrile reactions after methicillin. Can Med
5.
FEVER IN INFECTIVE ENDOCARDITIS WHILST mortality from infective endocarditis has fallen since the introduction of effective antibiotics and valve replacement surgery, it still accounts for about 200 deaths a year in England and Wales.’ In the first report of its kind, Douglas and his colleagues2 recorded the changes in body temperature during treatment; they studied the records of 83 episodes of infectious endocarditis in 80 patients treated in the past decade. Half the patients responded within a week to appropriate antimicrobial agents by defervescence. Persistent fever occurred in 36% but eventually settled in 77% of these after an average of one month of therapy. In the remainder, pyrexia persisted until cardiac surgery or death. Recurrent fever occurred in 14%. Factors associated
8.
Morgan RW, Claxton KW, Divine BJ, Kaplan SD, Harris ethylene oxide workers J Occup Med 1981; 23: 767-70.
VB.
Mortality among
9. Hemminki K, Mutanen P, Saloniemi I, Niemi M-L, Vainio H. Spontaneous abortions in hospital staff engaged in sterilising instruments with chemical agents. Br Med J 1982; 285: 1461-63. 1. Bayliss R, Clarke C, Oakley C, Somerville W, Whitfield AGW. The teeth and infective endocarditis. Br Heart J 1983; 50: 506-12. 2. Douglas A, Moore-Gillon J, Eykyn S. Fever during treatment of infective endocarditis. Lancet 1986; i: 1341-43.
287: 320-23. 10. Andersson P, Dubiel W, Eughoff E, Friman G, Hogg A, Nystrom S-O, Aberg T. Role of surgery in infective endocarditis. Acta Med Scand 1986; 219: 275-82. 11. Symbas PN, Vlasis SE, Zacharopoulos L, Hatcher CR, Arensberg D. Immediate and longterm outlook for valve replacement in acute bacterial endocarditis. Ann Surg 1982; 195: 721-25. 12. Nelson RJ, Harley DP, French WJ, Bayer AS. Favourable 10 year experience with valve procedures for active infective endocarditis. J Thorac Cardiovasc Surg 1984; 87: 493-502. 13. Lewis BS, Agathangelou NE, Colsen PR, Antunes M, Kinsley RH. Cardiac operation during active infective endocarditis. J Thorac Cardiovasc Surg 1982; 84: 579-84. 14. Cukingham RA, Carey JS, Wittig JH, Cimochowski GE. Early valve replacement in active infective endocarditis. J Thorac Cardiovasc Surg 1983; 85: 163-73. 15. Prager RL, Maples MD, Hammon JW, Friesinger GC, Bender HW. Early operative intervention in aortic bacterial endocarditis. Ann Thorac Surg 1981; 32: 347-50. 16. Perry LS, Tresch DD, Brooks HL, et al. Operanve approach to endocarditis. Am Heart J 1984; 108: 561-66. 17. Pelletier LC, Baillot R, Anger P, Dyrda I. Early valve replacement in active infective endocarditis. Can J Surg 1984; 27: 383-86. 18. Raychaudhury T, Cameron EWJ, Walbaum PR. Surgical management of prosthetic valve endocarditis. J Thorac Cardiovasc Surg 1983; 86: 112-14. 19. Moore-Gillon J, Eykyn SJ, Philips I. Prosthetic valve endocarditis. Br Med J 1983; 287: 739-41.
infective endocarditis in which the participating laboratories used standardised techniques to measure serum bactericidal
titres,’ all patients with peak titres >32 and trough titres >16 were cured; however, many patients with lower titres were also cured, and the only indication of the value of the assay that the few bacteriological failures had low serum bactericidal titres. All of the failures were in patients with staphylococcal or pseudomonal endocarditis; in the were commoner streptococcal infection peak titres > 8 achieved in all cases and all the patients were cured. The value of the serum bactericidal test has also been investigated in osteomyelitis8 and in the treatment of gram-negative sepsis in cancer patients.9,10 In the latter group, Klastersky and his colleagues9 found the test was a valuable prognostic indicator (patients with a peak titre 8 fared better than those with lower titres) in bacteraemic but not in non-bacteraemic patients. Results of a later studylO indicated that higher peak titres ( 16) were needed if the patient was severely granulocytopenic. These studies require confirmation in other centres, with due regard to the need for standardised methods. What is the prescribing doctor to make of the value of the serum bactericidal test? It is not hard to believe that concentrations of antimicrobial agents in the bloodstream must exceed an inhibitory level for the offending microbe; nor is it difficult to understand that the level required for conditions in which therapeutic success depends heavily on the antimicrobial drug should be bactericidal. Moreover, it seems sensible to ensure that peak concentrations (which, by definition, are merely transient) should exceed the required level by a sizeable margin. Whether such concentrations need to be maintained so that trough levels will also exceed the required amount is hard to say; in any case, a reliably high trough level may be achievable only with difficulty with agents (like penicillins) that have short plasma half-lives, or with others (like aminoglycosides) for which there are constraints of potential toxicity. Measurement of serum antibiotic levels serves the important function of reassuring the physician that adequate drug concentrations are being achieved during the treatment of life-threatening infections; it is especially reassuring at the time of any switch from parenteral to oral therapy, as often occurs during the course of treatment of infective endocarditis. Whether the test has a broader value is harder to judge. Such evidence as exists suggests that the greatest value of the serum bactericidal test may lie in the treatment of infection in severely granulocytopenic patients and in those with endocarditis caused by problem organisms such as staphylococci or pseudomonas, since these are the conditions in which cure may crucially depend on high and prolonged bactericidal concentrations of antibiotics. Even in these cases it seems unreasonable to expect that any magic figure for peak and trough values will be conjured up to cover all eventualities. was
7.Weinstein
MP, Stratton CW, Ackley A, et al.Multicenter collaborative evaluation ofa standardized serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 1985; 78: 262-69. 8.Prober CG, Yeager AS. Use of the serum bactericidal titer to assess the adequacy of oral antibiotic therapy in the treatment of acute hematogenous osteomyelitis. J Pediat 1979; 95: 131-35. 9. Klastersky J, Meunier-Carpentier F, Prévost J-M. Significance of antimicrobial synergism for the outcome of gram negative sepsis. Am J Med Sci 1977; 273: 157-67. 10. Sculier JP, Klastersky J. Significance of serum bactericidal activity in gram-negative bacillary bacteremia in patients with and without granulocytopenia. Am J Med 1984; 76: 429-35.
ETHYLENE OXIDE—A HUMAN CARCINOGEN? ETHYLENE oxide has been produced commercially since the 1914-18 War. Its main use is as a chemical intermediate in the manufacture of ethylene glycol (antifreeze) and nonionic detergents, but it also finds important application as a fumigant of foods such as cocoa beans and spices, and as a sterilant of cosmetics and of medical and surgical equipment. In Britain, at least 50 National Health Service hospitals have ethylene oxide sterilisers, and in the United States it has been estimated that as many as 75 000 health care workers may have been exposed to the chemica1.1 Concern about the chronic toxicity of ethylene oxide arises first from its mutagenicity. It is an alkylating agent with strong mutagenic potential as shown in bacteria, plants, fungi, insects, and cultured mammalian cells.2 When inhaled by mammals it induces chromosomal aberrations and sister chromatid exchanges.2 Animal studies also indicate a carcinogenic effect. In particular, rats chronically inhaling ethylene oxide at concentrations of 50 and 100 ppm have developed an excess of leukaemias, peritoneal mesotheliomas, and gliomas.3 Epidemiological data now suggest that the carcinogenicity of ethylene oxide may extend to man. In 1979, Hogstedt, Malmqvist, and Wadman reported 2 cases of myeloid leukaemia (1chronic and 1 acute) and 1 case of Waldenstrom’s macroglobulinaemia (subsequently reclassified as non-Hodgkin lymphoma) among the workforce of a small Swedish factory where ethylene oxide and methyl formate were used to sterilise hospital equipment.4 The patients had been exposed to time-weighted average ethylene oxide concentrations in the order of 20 ppm. This observation prompted a retrospective cohort study of workers at a second plant where ethylene oxide and other chemicals were manufactured.Among workers exposed to ethylene oxide, 2 deaths were attributed to chronic lymphocytic leukaemia and 1 to acute myeloid leukaemia by comparison with an expected 0-27 deaths from all types of leukaemia combined. A further five-year follow-up has now shown an additional death from acute blastic leukaemia at the first of these factories, and another patient (still alive) with chronic myeloid leukaemia at the second.6 Deaths from leukaemia have been reported in two other cohorts of ethylene oxide workers. Among 602 employees at nine West German plants making ethylene and propylene oxides and their derivatives there was 1 death from myeloid leukaemia with 0-25 deaths expectedand among another group of ethylene oxide manufacturers in Sweden 1 out of a
PJ, Memhardt TJ, Gordon J, et al. Ethylene oxide: An overview of toxicologic and epidemiologic research. Am J Ind Med 1984; 6: 103-15. 2. IARC monographs on the evaluation of the carcinogenic risk of chemicals to man. Vol 36. Allyl compounds, aldehydes, epoxides and peroxides. Lyon: International Agency for Research on Cancer, 1985. 3. Lynch DW, Lewis TR, Moorman WJ, et al. Carcinogenic and toxicologic effects of In: Prevention of occupational cancer-international symposium (Occupational safety and health series no 46). Geneva: International Labour Office, 1981: 249-59. 4. Hogstedt C, Malmqvist N, Wadman B. Leukaemia m workers exposed to ethylene oxide. JAMA 1979; 241: 1132-33 5. Hogstedt C, Rohlen O, Berndtsson BS, Axelson O, Ehrenberg L. A cohort study of mortality and cancer incidence in ethylene oxide production workers. Br J Ind Med 1. Landrigan
1979; 36: 276-80. 6.
Hogstedt C, Aringer L, Gustavsson A. Epidemiologic support for ethylene oxide as a cancer-causing agent. JAMA 1986, 255: 1575-78. 7. Thiess AM, Frentzel Beyme R, Link R, Stocker WG. Mortality study on employees exposed to alkylene oxides (ethylene oxide/propylene oxide) and their derivatives. In: Prevention of occupational cancer—international symposium (Occupational safety and health series no 46). Geneva: International Labour Office, 1981: 249-59.
202 total of 8 deaths was due to chronic myeloid leukaemia.6 In two of the four cohorts described have shown an excess of stomach cancer. In contrast, a study of 767 workers at an ethylene oxide manufacturing plant in the United States showed an overall deficit of cancer deaths (11 observed, 15-24 expected) and no cases of leukaemia.8 The recurrent finding of leukaemia in association with exposure to ethylene oxide is impressive, but the existence of a hazard cannot yet be regarded as established. The number of documented cases is small, particularly if one discounts the deaths in the initial Swedish case-report which gave rise to the hypothesis of leukaemogenesis. Moreover, the association has not been specific for any one type of leukaemia. Acute myeloid, chronic myeloid, and acute lymphoblastic leukaemias are all caused by ionising radiation, but there is no precedent for a hazard which predisposes also to chronic lymphocytic leukaemia. The association with gastric cancer has been found in only two investigations and may have occurred by chance or through the action of unknown confounding factors. All of the workforces studied have been exposed to other chemicals as well as ethylene oxide. Doubts about the safety of ethylene oxide are not confined to its carcinogenic potential: high rates of spontaneous abortion have been reported in Finnish hospital workers exposed to the compound.9 However, the abortion figures have yet to be corroborated elsewhere and the possible risk of cancer remains the main worry. Further information about the long-term toxicity of ethylene oxide is urgently required, and should emerge from epidemiological studies in progress in Britain and the United States. This will be important not only as a basis for the future regulation of exposure, but also as a contribution to our understanding of the relation between mutagenicity and human carcinogenicity. The demonstration of mutagenicity in short-term laboratory tests is often a criterion in deciding whether or not new chemicals should be produced commercially, but the extent to which mutagenicity predicts a capacity to cause cancer in man is still far from clear.
addition,
with persistent fever included staphylococcal infection, extensive cardiac infection especially with abscess formation around the valve ring,3 and extracardiac infection often associated with emboli from the heart to other organs. In 8 (19%) patients the fever was related to extracardiac inflammation—eg, infected intravenous access sites and purulent arthritis. In 7 (17%) patients fever was attributed to the antimicrobial therapy; the drug being implicated either by the presence of a rash or by peripheral eosinophilia. Several antibiotics have been associated with fever, especially penicillin and its derivatives methicillin,4cloxacillin,sand piperacillin.6 Streptomycin and the other aminoglycosides have also been reported to cause fever,7,8 although the frequency of hypersensitivity with these drugs is very low. Most importantly, Douglas et al did not fmd that persistent fever was caused by antibiotic resistance. Thus, once a sound microbiological diagnosis has been made and a therapeutic regimen chosen, the antibiotics should not be changed unless drug-induced hypersensitivity is implicated. Persistent fever usually represents failure of medical therapy and early surgery should then be considered. Once the infection has responded to antibiotics, elective valve replacement for the haemodynamic consequences of infective endocarditis is as safe as for valves diseased by other mechanisms, with an operative mortality of about 5%.9,10 Early valve replacement before completion of antibiotic therapy, when indicated because of haemodynamic deterioration, embolism, extensive infection, and in cases where antimicrobial agents are ineffective (eg, fungal endocarditis), carries a higher mortality of up to 45%,10 although most centres report a mortality of less than 25 % .11-18 . However, medical management alone in such cases carries a substantially higher mortality, approaching 70%,10 especially with prosthetic endocarditis.10,19 Valve replacement should therefore be considered at any time during the course of infective endocarditis if medical’therapy appears to be failing.
3.
Zabalgoitia-Reyes M, Mehlman DI, Talano JV. Persistent fever with aortic valve endocarditis. Arch Intern Med 1985; 145: 327-28.
Assoc J 1975; 112: 1044. Portnoy J, Torshinsky A, Mendelson J, Kagan E. Febrile reactions after cloxacillin. Can Med Assoc J 1975, 112: 280. 6. Stead RJ, Kennedy HG, Hodson ME, Batten JC. Adverse reactions to piperacillin in cystic fibrosis. Lancet 1984; i: 857-58. 7. Feldbaum JS, Silverstein H. Streptomycin drug fever during treatment of bilateral Menières disease. Arch Otolaryngol 1984; 110: 538-39. 8. McEvoy GK, ed. Aminoglycosides—general statement. In: American Hospital Formulary Service—Drug Information. Bethesda: American Society of Hospital Pharmacists, 1986: 53. 9. Westaby S, Oakley CM, Sapsford RN, Bentall HH. Surgical treatment of infective endocarditis with special reference to prosthetic valve endocarditis. Br Med J 1983;
4. Smith JA. Febrile reactions after methicillin. Can Med
5.
FEVER IN INFECTIVE ENDOCARDITIS WHILST mortality from infective endocarditis has fallen since the introduction of effective antibiotics and valve replacement surgery, it still accounts for about 200 deaths a year in England and Wales.’ In the first report of its kind, Douglas and his colleagues2 recorded the changes in body temperature during treatment; they studied the records of 83 episodes of infectious endocarditis in 80 patients treated in the past decade. Half the patients responded within a week to appropriate antimicrobial agents by defervescence. Persistent fever occurred in 36% but eventually settled in 77% of these after an average of one month of therapy. In the remainder, pyrexia persisted until cardiac surgery or death. Recurrent fever occurred in 14%. Factors associated
8.
Morgan RW, Claxton KW, Divine BJ, Kaplan SD, Harris ethylene oxide workers J Occup Med 1981; 23: 767-70.
VB.
Mortality among
9. Hemminki K, Mutanen P, Saloniemi I, Niemi M-L, Vainio H. Spontaneous abortions in hospital staff engaged in sterilising instruments with chemical agents. Br Med J 1982; 285: 1461-63. 1. Bayliss R, Clarke C, Oakley C, Somerville W, Whitfield AGW. The teeth and infective endocarditis. Br Heart J 1983; 50: 506-12. 2. Douglas A, Moore-Gillon J, Eykyn S. Fever during treatment of infective endocarditis. Lancet 1986; i: 1341-43.
287: 320-23. 10. Andersson P, Dubiel W, Eughoff E, Friman G, Hogg A, Nystrom S-O, Aberg T. Role of surgery in infective endocarditis. Acta Med Scand 1986; 219: 275-82. 11. Symbas PN, Vlasis SE, Zacharopoulos L, Hatcher CR, Arensberg D. Immediate and longterm outlook for valve replacement in acute bacterial endocarditis. Ann Surg 1982; 195: 721-25. 12. Nelson RJ, Harley DP, French WJ, Bayer AS. Favourable 10 year experience with valve procedures for active infective endocarditis. J Thorac Cardiovasc Surg 1984; 87: 493-502. 13. Lewis BS, Agathangelou NE, Colsen PR, Antunes M, Kinsley RH. Cardiac operation during active infective endocarditis. J Thorac Cardiovasc Surg 1982; 84: 579-84. 14. Cukingham RA, Carey JS, Wittig JH, Cimochowski GE. Early valve replacement in active infective endocarditis. J Thorac Cardiovasc Surg 1983; 85: 163-73. 15. Prager RL, Maples MD, Hammon JW, Friesinger GC, Bender HW. Early operative intervention in aortic bacterial endocarditis. Ann Thorac Surg 1981; 32: 347-50. 16. Perry LS, Tresch DD, Brooks HL, et al. Operanve approach to endocarditis. Am Heart J 1984; 108: 561-66. 17. Pelletier LC, Baillot R, Anger P, Dyrda I. Early valve replacement in active infective endocarditis. Can J Surg 1984; 27: 383-86. 18. Raychaudhury T, Cameron EWJ, Walbaum PR. Surgical management of prosthetic valve endocarditis. J Thorac Cardiovasc Surg 1983; 86: 112-14. 19. Moore-Gillon J, Eykyn SJ, Philips I. Prosthetic valve endocarditis. Br Med J 1983; 287: 739-41.