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Chloromycetin in Rickettsial Infections
953
Shigella.
Other
coliforms
and related organisms Bacterium, though groups within the genus are recognised without being accorded generic rank. Thus Escherichia, Aerobacter, Citrobacter, Eberthella, Erwinia, Alcaligenes, and Klebsiella, to mention some of the generic names found in American literature, are not used, and sound arguments against their adoption are given. The separation of some of these so-called genera-Klebsiella from Aerobacter, for example-is so ill defined that the site of origin, above or below the umbilicus, is often the deciding factor. British bacteriologists may think that some of these groups deserve generic rank but believe that recognition would be premature until we know better how to distinguish them. The sixth edition of Bergey’s Manual is not yet obtainable in this country, but earlier editions have each involved shifting many species from one genus to another, and we are told that the American Type Culture Collection, which adheres to Bergey’s nomenclature, has had to change the names of nearly all its cultures to conform with the 1948 edition of - the Manual. Unstable nomenclature of this kind does not appeal to bacteriologists here, and the only consistent users of Bergey names are biochemists, who must abide by the editorial policy of the Biochemical Journal. Names of species present a different problem ; confusion from synonyms (different names for the same organism) is greater than from homonyms (the same name given to different organisms). Some bacteria under the masquerade many names ; organisms themselves may be well known (Pseudomonas pyocyanea, Ps. aeruginosa) and the synonymy easily checked, or they may be less common (Bacillus polymyxa, B. aerosporus) when the multiple names will be more confusing. In many examples of synonymy the description appended to the first and legitimate specific name was vague or insufficient for a subsequent worker to identify the organism ; in others the second or subsequent name was bestowed because the author either did not know of the earlier name, or thought that the organisms were sufficiently different to justify distinct specific names. Homonymy is uncommon ; an example is Actinomyces bovis, which has been applied to both an aerobic and an anaerobic species, the former being regarded as a harmless saprophyte, the latter as the probable cause of actinomycosis. To avoid confusion the specific name israelii has been proposed for the anaerobe. What can be done to put matters straight ? Bacteriologists themselves, through the International Association of Microbiologists, have drawn up a code governing the acceptance of names already given and rules and recommendations for new names. This Bacteriological Code was approved by the fourth congress of the association at Copenhagen in 1947, and has recently been published.l The association also established a Nomenclature Committee which from its members elected a judicial commission to give " opinions " on the validity of proposed names of genera and species. The commission will draw up lists of proposed names so that homonyms may be avoided in choosing new names. Some names, invalid by strict application of the rules but sanctioned by common usage, may be allowed to stand and will be remain
as
1. J. Bact. 1948, 55, 287.
the commission as nomina conservanda;; others will appear on lists of nomina rejicienda. It is unlikely that these opinions and lists will be available before further confusion has arisen ; the Nomenclature Committee was first appointed in 1930 and so far only two generic names (Bacillus and Salmonella) have been approved. The committee has set up subcommittees to consider the family Enterobacteraceœ (Salmonella, Shigella, Bacterium) and the genus Streptococcus ; these subcommittees have to tackle thorny-problems and will do well if they can produce schemes acceptable to the differing viewpoints of bacteriologists. What, then, of the immediate future ? American workers, with a new edition of Bergey’s
published by
Manual as a stimulus, will presumably use new combinations and entirely new names, based on the recommendations of the Bacteriological Code. British bacteriologists are likely to remain faithful to the names they now use and to modify them when there is sufficient evidence that a change is needed. The list of species maintained- by the National Collection of Type Cultures, shortly appearing as a M.R.C. Memo, will be a valuable guide to current British practice.
Chloromycetin
in Rickettsial Infections
THE efficacy of the antibiotic, chloromycetin, in scrub typhus is likely to prove a discovery of capital importance. The first results of the Anglo-American clinical trial proceeding in Malaya suggest that we at last have a potent remedy for the rickettsial diseases. The antibiotic was isolated in 1947 by EHRLICH and colleaguesin Detroit from a soil actinomycete, and its active principle, obtained in crystalline form, was found to differ from any antibiotic so far described in containing both nitrogen and non-ionic chlorine. In laboratory infections chloromycetin, weight for weight, appeared more effective against R. prowazeki in chick embryos than any other agent tested under these experimental conditions, and large doses produced no symptoms in animals. These encouraging laboratory results demanded clinical trial in human typhus infection, and satisfactory results were claimed in a few cases of epidemic typhus in Mexico early this year. Since March, SMADEL and other researchworkers from the U.S. Army and the University of Maryland have been collaborating with LEWTHWAITE and SAvooR of Kuala Lumpur in a clinical trial in scrub typhus, and preliminary results were reported2 at the International Congress on Tropical Medicine 3 at Washington, D.C., in May. Scrub typhus, or tsutsugamushi fever, was one of the major medical problems of the Burma campaign. The disease is indigenous to a large part of tropical and. subtropical Asia, but its extent was not realised until large numbers of troops were put into jungle previously unvisited by white men. It has long been recognised in Malaya, and much work has been done on it there by LEWTHWAITE and his colleagues at the Institute for Medical Research, Kuala Lumpur; so it is fitting that this institute was chosen as the headquarters of the trial. The vector of the disease is a 1. Ehrlich, J., Bartz, Q. R., Smith, R. M., Joslyn, D. A., Burkholder, P. R. Science, 1947, 106, 417. See annotation, Lancet, 1947, ii, 952. 2. Smadel, J. E., Woodward, T. E., Ley, H. L. jun., Philip, C. B., Traub, R., Lewthwaite, R., Savoor, S. R. Released by the Department of the Army, Technical Information Office, Washington, D.C. 3. See Lancet, May 29, p. 842.
954 not unlike our own " harvester " that picnic parties encounter in the September corn stubble, but
mite,
picked up in the tropics by walking through the lalang grass. The overgrown rubber plantations are now being cleared after the Japanese occupation, and the disease, always endemic, is being encountered again among the native workers. So far 25 patients have been treated with the drug, while a control
group of 12 untreated cases have been observed during the same period. The treated and untreated come from the same areas and in some cases from the same plantations, so the strains of R. tsutsugamushi are likely to be of similar virulence. The mean ages of the two groups-an important factor in any typhus infection-were the same. The diagnosis was proved in each instance, either by recovering the rickettsia from the blood or by demonstrating satisfactory titres for agglutination against an OXK strain of In the treated group nobody developed Proteus. complications or died ; the average duration of fever after the first dose was 31 hours, and the average total
Annotations TREATMENT OF ARTERIAL EMBOLISM
ARTERIAL embolism is a complication of cardiac or vascular disease, and its effects depend on the site and size of the embolus as well as on the severity of the primary disease. The variation of these three factors offers such a formidable range of combinations that any statistical analysis of the results of treatment is almost foredoomed to failure. A surgeon who is called in during the course of a disabling disease to treat a complication may be forgiven some preoccupation with that complication, but his claims for the value of treatment must be based on their effect on the patient as a whole. In the case of embolism affecting a limb artery the surgeon’s aim is usually to save the limb, and there is a tendency to assess results purely on the rate of limb survival without reference to its usefulness to the patient. Warren and Linton,l analysing experience of arterial embolism at the Massachusetts General Hospital, conclude that arterial embolectomy is the treatment of choice in embolism of a peripheral artery, mainly on the grounds that the cases operated on show a higher proportion of limb survival than those treated by conservative methods. It is difficult to judge the validity of their claim because it is not clear what determined the choice between operation and other methods, but since all surgeons insist on the importance of the time interval it is reasonable to suppose that this plays some part in selection. Apart from one case operated on at 60 hours, their longest interval between onset and operation was 11 hours. It must also be supposed that the patient’s general condition was also a criterion in selection, though it is recorded that two patients selected for surgery died on their way to the operating-theatre. If any useful comparison is to be made between surgery and conservative treatment, both should be tried in the most favourable cases-i.e., those with a brief interval since the embolism and a reasonable prognosis for the cardiac condition. Experimental work on heparin encourages the view that this should be the treatment of choice, since it has been shown by Rabinowitch and Pines2 and confirmed by Loewe et al. 3 that heparin not only prevents thrombosis but also assists in the resolution of clot already formed. The secondary coagulation 1. 2. 3.
Warren, R., Linton, R. R. New Engl. J. Med. 1948, 238, 421. Rabinowitch, I., Pines, B. Surgery, 1943, 14, 669. Loewe, L., Hirsch, E., Grayzel, D.M. Ibid, 1947, 22, 746.
febrile period 7.5 days ; one man, treated on the 3rd day of the disease, was discharged for light work on the 9th day after onset. In the untreated group of 12, 2 patients developed serious complications and 1 of these died, while the mean duration of fever was 18-1 days. The chloromycetin was given by mouth, initially in large doses; but these were gradually reduced, and the last 7 cases were given the drug for only 24 hours, receiving a total of 6 g., with an equally satisfactory response. Half the patients were treated on estate hospitals where nursing conditions are necessarily somewhat primitive. To those who have had experience of scrub typhus in the Burma campaign these results will be more than striking ; they will alter the whole picture of a disease. From the laboratory work it is not too much to hope that this new antibiotic will prove equally effective against other rickettsial diseases. If so, the future history of the typhus group of diseases will depend on how far the demand for chloromycetin can be met. thrombosis extending peripherally after embolism is the chief obstacle to the success of embolectomy. The combination of surgery and heparin is attractive in theory but hazardous in practice. The patient naturally abhors amputation, but this may sometimes be the most humane treatment even when there is a chance that the limb can be saved. There have been very few long survivals of an affected limb after embolectomy, and still fewer with a symptomless limb. The embolism itself carries a risk to life because of the poor state of the patient. Warren and Linton report a case-mortality of 38-7% (but this includes embolism in sites other than limbs) and quote other rates of 50% and over. Whatever pleas are made for special forms of treatment it is clear that none has any outstanding advantage over the others. The choice of treatment at present must be an individual one, and it must depend on the prognosis of the cardiac disease and on the prospect of the future usefulness of the limb. CANCER IN CHILDREN
CANCER, in general, is a disease of the elderly, but it sometimes appears in a child, and the doctor’s philosophy and understanding may then be strained to the utmost. Often no cure is possible from the first, the miseries of the child are hard for parents to bear, and symptomatic relief may be temporary and incomplete. A small gleam of light is provided by Dargeon, of New York, in a paper sponsored by the American Medical Association and the American Cancer Society. The importance of the subject can be gauged by the fact that in New York, in the three years 1942-44, " cancer and other tumours " accounted for 215 deaths in children, against 291 for tuberculosis, and in the U.S.A. as a whole " cancer and allied diseases" was the third highest cause of death between 3 and 10 years, and the sixth at 10-14 years. The commonest sites for juvenile cancer are the bones, kidneys, eye and orbit, and the lymphatic and blood-forming organs; tumours may also arise in the nervous system, muscle, and other connective tissues. The detailed recognition and management of these different kinds of new growth are systematically described by Dargeon, and he emphasises the fact that although many of the tumours have an unfavourable prognosis from the beginning, this is not an invariable rule-for example, osteochondromas and giant-cell tumours of bone only become malignant with the advance of time ; there have been several instances 1.
Dargcon, H. W.
J. Amer. med. Ass. 1948, 136, 459.
Shigella.
Other
coliforms
and related organisms Bacterium, though groups within the genus are recognised without being accorded generic rank. Thus Escherichia, Aerobacter, Citrobacter, Eberthella, Erwinia, Alcaligenes, and Klebsiella, to mention some of the generic names found in American literature, are not used, and sound arguments against their adoption are given. The separation of some of these so-called genera-Klebsiella from Aerobacter, for example-is so ill defined that the site of origin, above or below the umbilicus, is often the deciding factor. British bacteriologists may think that some of these groups deserve generic rank but believe that recognition would be premature until we know better how to distinguish them. The sixth edition of Bergey’s Manual is not yet obtainable in this country, but earlier editions have each involved shifting many species from one genus to another, and we are told that the American Type Culture Collection, which adheres to Bergey’s nomenclature, has had to change the names of nearly all its cultures to conform with the 1948 edition of - the Manual. Unstable nomenclature of this kind does not appeal to bacteriologists here, and the only consistent users of Bergey names are biochemists, who must abide by the editorial policy of the Biochemical Journal. Names of species present a different problem ; confusion from synonyms (different names for the same organism) is greater than from homonyms (the same name given to different organisms). Some bacteria under the masquerade many names ; organisms themselves may be well known (Pseudomonas pyocyanea, Ps. aeruginosa) and the synonymy easily checked, or they may be less common (Bacillus polymyxa, B. aerosporus) when the multiple names will be more confusing. In many examples of synonymy the description appended to the first and legitimate specific name was vague or insufficient for a subsequent worker to identify the organism ; in others the second or subsequent name was bestowed because the author either did not know of the earlier name, or thought that the organisms were sufficiently different to justify distinct specific names. Homonymy is uncommon ; an example is Actinomyces bovis, which has been applied to both an aerobic and an anaerobic species, the former being regarded as a harmless saprophyte, the latter as the probable cause of actinomycosis. To avoid confusion the specific name israelii has been proposed for the anaerobe. What can be done to put matters straight ? Bacteriologists themselves, through the International Association of Microbiologists, have drawn up a code governing the acceptance of names already given and rules and recommendations for new names. This Bacteriological Code was approved by the fourth congress of the association at Copenhagen in 1947, and has recently been published.l The association also established a Nomenclature Committee which from its members elected a judicial commission to give " opinions " on the validity of proposed names of genera and species. The commission will draw up lists of proposed names so that homonyms may be avoided in choosing new names. Some names, invalid by strict application of the rules but sanctioned by common usage, may be allowed to stand and will be remain
as
1. J. Bact. 1948, 55, 287.
the commission as nomina conservanda;; others will appear on lists of nomina rejicienda. It is unlikely that these opinions and lists will be available before further confusion has arisen ; the Nomenclature Committee was first appointed in 1930 and so far only two generic names (Bacillus and Salmonella) have been approved. The committee has set up subcommittees to consider the family Enterobacteraceœ (Salmonella, Shigella, Bacterium) and the genus Streptococcus ; these subcommittees have to tackle thorny-problems and will do well if they can produce schemes acceptable to the differing viewpoints of bacteriologists. What, then, of the immediate future ? American workers, with a new edition of Bergey’s
published by
Manual as a stimulus, will presumably use new combinations and entirely new names, based on the recommendations of the Bacteriological Code. British bacteriologists are likely to remain faithful to the names they now use and to modify them when there is sufficient evidence that a change is needed. The list of species maintained- by the National Collection of Type Cultures, shortly appearing as a M.R.C. Memo, will be a valuable guide to current British practice.
Chloromycetin
in Rickettsial Infections
THE efficacy of the antibiotic, chloromycetin, in scrub typhus is likely to prove a discovery of capital importance. The first results of the Anglo-American clinical trial proceeding in Malaya suggest that we at last have a potent remedy for the rickettsial diseases. The antibiotic was isolated in 1947 by EHRLICH and colleaguesin Detroit from a soil actinomycete, and its active principle, obtained in crystalline form, was found to differ from any antibiotic so far described in containing both nitrogen and non-ionic chlorine. In laboratory infections chloromycetin, weight for weight, appeared more effective against R. prowazeki in chick embryos than any other agent tested under these experimental conditions, and large doses produced no symptoms in animals. These encouraging laboratory results demanded clinical trial in human typhus infection, and satisfactory results were claimed in a few cases of epidemic typhus in Mexico early this year. Since March, SMADEL and other researchworkers from the U.S. Army and the University of Maryland have been collaborating with LEWTHWAITE and SAvooR of Kuala Lumpur in a clinical trial in scrub typhus, and preliminary results were reported2 at the International Congress on Tropical Medicine 3 at Washington, D.C., in May. Scrub typhus, or tsutsugamushi fever, was one of the major medical problems of the Burma campaign. The disease is indigenous to a large part of tropical and. subtropical Asia, but its extent was not realised until large numbers of troops were put into jungle previously unvisited by white men. It has long been recognised in Malaya, and much work has been done on it there by LEWTHWAITE and his colleagues at the Institute for Medical Research, Kuala Lumpur; so it is fitting that this institute was chosen as the headquarters of the trial. The vector of the disease is a 1. Ehrlich, J., Bartz, Q. R., Smith, R. M., Joslyn, D. A., Burkholder, P. R. Science, 1947, 106, 417. See annotation, Lancet, 1947, ii, 952. 2. Smadel, J. E., Woodward, T. E., Ley, H. L. jun., Philip, C. B., Traub, R., Lewthwaite, R., Savoor, S. R. Released by the Department of the Army, Technical Information Office, Washington, D.C. 3. See Lancet, May 29, p. 842.
954 not unlike our own " harvester " that picnic parties encounter in the September corn stubble, but
mite,
picked up in the tropics by walking through the lalang grass. The overgrown rubber plantations are now being cleared after the Japanese occupation, and the disease, always endemic, is being encountered again among the native workers. So far 25 patients have been treated with the drug, while a control
group of 12 untreated cases have been observed during the same period. The treated and untreated come from the same areas and in some cases from the same plantations, so the strains of R. tsutsugamushi are likely to be of similar virulence. The mean ages of the two groups-an important factor in any typhus infection-were the same. The diagnosis was proved in each instance, either by recovering the rickettsia from the blood or by demonstrating satisfactory titres for agglutination against an OXK strain of In the treated group nobody developed Proteus. complications or died ; the average duration of fever after the first dose was 31 hours, and the average total
Annotations TREATMENT OF ARTERIAL EMBOLISM
ARTERIAL embolism is a complication of cardiac or vascular disease, and its effects depend on the site and size of the embolus as well as on the severity of the primary disease. The variation of these three factors offers such a formidable range of combinations that any statistical analysis of the results of treatment is almost foredoomed to failure. A surgeon who is called in during the course of a disabling disease to treat a complication may be forgiven some preoccupation with that complication, but his claims for the value of treatment must be based on their effect on the patient as a whole. In the case of embolism affecting a limb artery the surgeon’s aim is usually to save the limb, and there is a tendency to assess results purely on the rate of limb survival without reference to its usefulness to the patient. Warren and Linton,l analysing experience of arterial embolism at the Massachusetts General Hospital, conclude that arterial embolectomy is the treatment of choice in embolism of a peripheral artery, mainly on the grounds that the cases operated on show a higher proportion of limb survival than those treated by conservative methods. It is difficult to judge the validity of their claim because it is not clear what determined the choice between operation and other methods, but since all surgeons insist on the importance of the time interval it is reasonable to suppose that this plays some part in selection. Apart from one case operated on at 60 hours, their longest interval between onset and operation was 11 hours. It must also be supposed that the patient’s general condition was also a criterion in selection, though it is recorded that two patients selected for surgery died on their way to the operating-theatre. If any useful comparison is to be made between surgery and conservative treatment, both should be tried in the most favourable cases-i.e., those with a brief interval since the embolism and a reasonable prognosis for the cardiac condition. Experimental work on heparin encourages the view that this should be the treatment of choice, since it has been shown by Rabinowitch and Pines2 and confirmed by Loewe et al. 3 that heparin not only prevents thrombosis but also assists in the resolution of clot already formed. The secondary coagulation 1. 2. 3.
Warren, R., Linton, R. R. New Engl. J. Med. 1948, 238, 421. Rabinowitch, I., Pines, B. Surgery, 1943, 14, 669. Loewe, L., Hirsch, E., Grayzel, D.M. Ibid, 1947, 22, 746.
febrile period 7.5 days ; one man, treated on the 3rd day of the disease, was discharged for light work on the 9th day after onset. In the untreated group of 12, 2 patients developed serious complications and 1 of these died, while the mean duration of fever was 18-1 days. The chloromycetin was given by mouth, initially in large doses; but these were gradually reduced, and the last 7 cases were given the drug for only 24 hours, receiving a total of 6 g., with an equally satisfactory response. Half the patients were treated on estate hospitals where nursing conditions are necessarily somewhat primitive. To those who have had experience of scrub typhus in the Burma campaign these results will be more than striking ; they will alter the whole picture of a disease. From the laboratory work it is not too much to hope that this new antibiotic will prove equally effective against other rickettsial diseases. If so, the future history of the typhus group of diseases will depend on how far the demand for chloromycetin can be met. thrombosis extending peripherally after embolism is the chief obstacle to the success of embolectomy. The combination of surgery and heparin is attractive in theory but hazardous in practice. The patient naturally abhors amputation, but this may sometimes be the most humane treatment even when there is a chance that the limb can be saved. There have been very few long survivals of an affected limb after embolectomy, and still fewer with a symptomless limb. The embolism itself carries a risk to life because of the poor state of the patient. Warren and Linton report a case-mortality of 38-7% (but this includes embolism in sites other than limbs) and quote other rates of 50% and over. Whatever pleas are made for special forms of treatment it is clear that none has any outstanding advantage over the others. The choice of treatment at present must be an individual one, and it must depend on the prognosis of the cardiac disease and on the prospect of the future usefulness of the limb. CANCER IN CHILDREN
CANCER, in general, is a disease of the elderly, but it sometimes appears in a child, and the doctor’s philosophy and understanding may then be strained to the utmost. Often no cure is possible from the first, the miseries of the child are hard for parents to bear, and symptomatic relief may be temporary and incomplete. A small gleam of light is provided by Dargeon, of New York, in a paper sponsored by the American Medical Association and the American Cancer Society. The importance of the subject can be gauged by the fact that in New York, in the three years 1942-44, " cancer and other tumours " accounted for 215 deaths in children, against 291 for tuberculosis, and in the U.S.A. as a whole " cancer and allied diseases" was the third highest cause of death between 3 and 10 years, and the sixth at 10-14 years. The commonest sites for juvenile cancer are the bones, kidneys, eye and orbit, and the lymphatic and blood-forming organs; tumours may also arise in the nervous system, muscle, and other connective tissues. The detailed recognition and management of these different kinds of new growth are systematically described by Dargeon, and he emphasises the fact that although many of the tumours have an unfavourable prognosis from the beginning, this is not an invariable rule-for example, osteochondromas and giant-cell tumours of bone only become malignant with the advance of time ; there have been several instances 1.
Dargcon, H. W.
J. Amer. med. Ass. 1948, 136, 459.