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Vancomycin
85 pressure did not lead to further deterioration of renal function unless considerable impairment was initially present-i.e., blood-urea over 70 mg. per 100 ml. and creatinine clearance less than 30%. They emphasise, however, the need for accurate diagnosis of the underlying renal disease ; for reduction in blood-pressure is
more likely to precipitate uraemia than in patients with a progressive active nephritis (e.g., chronic type-ll nephritis) in patients with a relatively inactive inflammatory lesion, such as chronic type-i nephritis or chronic pyelonephritis, in which hypertensive renal damage is now thought to be the dominant cause of renal failure. ABRAHAMS and WILSON point out that in many patients with chronic renal disease the sudden deterioration of renal function in the late stages is preceded by a relatively abrupt rise in blood-pressure. If therapy is introduced at this point, and the hypertension is well controlled, there is evidence that the onset of renal failure may be delayed. In those who patients persevered with treatment, the malignant form of hypertension, so common in renal disease, was not observed. These clinical results lend support to the conclusions derived from experimental studies in animals-namely, that, in certain forms of chronic renal disease, hypertension leads to renal vascular damage and accelerates renal failure. Nevertheless, when renal disease has progressed to the stage of nitrogen retention, hypotensive therapy can lead to only a limited increase in the expectation of life-a few years at the most. As in essential hypertension, cerebral vascular accidents remain
a
maior hazard.
Vancomycin THE present-day pharmaceutical equivalent of the Gold Rush is the intensive and systematic screening of soil samples for new antibiotics. Thousands of soil samples are being collected by amateur and professional mycologists all over the world, and submitted to various industrial and university laboratories. Aqueous extracts are prepared and analysed for their microbe content, and these organisms are then screened for possible antibiotic activity. Many samples may seem promising at first, but only a few satisfy the rigid criteria demanded for clinical trial. To the investigators’ chagrin, some promising antibiotics turn out to be identical with those already in clinical use ; and others become discredited by their toxicity. Finally, one out of the thousands of soil samples survives the stiffest of hurdles, clinical evaluation, and is acclaimed on an Olympic pedestal alongside its predecessors. Various species of the genus streptomyces have so far produced strepto-
mycin, chloramphenicol, neomycin, chlortetracycline (aur.eomycin), oxytetracycline (terramycin), nystatin, ’erythromycin, carbomycin, novobiocin, and oleandomycin. A recent addition is vancomycin, isolated from soil obtained in Borneo and India. Although vancomycinproducing strains were subsequently found in soil from other parts of the world, including North America, the species has been designated Streptomyces orientalis.l Vancomycin hydrochloride is a white solid, very soluble in water, and
relatively
stable.2
It is
Pitteriger, R. C., Brigham, R. B. Antibiot. Chemother. 1956, 6, 642. 2. Geraci, J. E., Heilman, F. R., Nichols, D. R., Wellman, W. E., Ross, G. T. Proc. Mayo Clin. 1956, 31, 564. 1.
bactericidal, and, like that of penicillin, its principal action is against gram-positive bacteria, particularly when they are multiplying. Organisms sensitive to it include pneumococci, streptococci, staphylococci, and FAIRBROTHER and WILL-IAMS3 recently clostridia. reported that, in vitro, the gram-negative gonococcus was also highly susceptible. The main indication for the use of vancomycin, however, is an infection due to strains of Staphylococcus aureU8 resistant to other antibiotics. This usually implies a strain found in hospitals, where the wide use of antibiotics has encouraged the emergence of drug-resistant organisms. It is fortunate that such strains are at present rarely encountered in infections outside hospitals; but how long they will remain thus confined no-one ean say. In-vitro sensitivity tests must be performed before the most potent antibiotic can be chosen to deal with a serious staphylococcal infection. Until the results are available, the clinician must in an emergency decide which agent is most likely to be successful. If the infection has been contracted outside a hospital, penicillin will probably and tetracycline will almost certainly be effective. On the other hand, serious infections contracted in hospital should be treated at the outset with an antibiotic which is in least current use in that particular hospital. This will do much to ensure early control of the organism and may prevent an outbreak of cross-infection in the ward. As we have often declared, the wisest course is to hold in reserve an antibiotic which will subdue staphylococci that are resistant to other forms of attack ; erythromycin has been the one most often held back in this way, and there have been signs that
chloramphenicol
was
returning
to
popularity, despite
its occasional association with blood disorders.
introduction
The
of
other aritistaphylococcal drugs, including vancomycin, novobiocin, and oleandomycin, now permits a wider choice for the strategic reserve. If the laboratory report subsequently shows that the reserved drug is not the only one to which the infecting organism is responsive, then the erythromicin (or whichever drug it is) can go back into reserve. The actual reserve drug for each hospital should be changed from time to time in the light of laboratory reports. Whereas novobiocin and oleandomycin are well absorbed from the intestine, vancomycin must be given intravenously to produce any action other than in the intestine. After either oral or intravenous the faeces become odourless and strains vancomycin, and clostridium of Streptococcus fcccali,3 disappear or much become fewer, but the gram-negative flora persists. The persistence of the gram-negative organisms in the intestine should prevent the emergence of yeasts, and mucocutaneous moniliasis has not so far been reported after the administration of vancomycin. When vancomycin is taken by mouth most of it is excreted in the faeces and only negligible amounts can be detected in the blood or urine. After intravenous injection, it is rapidly excreted in high concentration by the kidneys. As only small reach the it seems that bile, quantities vancomycin, unlike many other antibiotics, is not concentrated and excreted by the biliary system. It is detectable in pleural, pericardial, synovial, and ascitic fluids after intravenous injection. It does not diffuse into spinal fluid, which is not unexpected in view of the 3.
Fairbrother, R, W., Williams, B,
L.
Lancet, 1956, ii, 1177.
86
relatively large size of the vancomycin molecule. The only toxic reactions observed by GERACi and his co-workers2 at the Mayo Clinic were occasional rigors, erythematous or morbilliform rashes, and phlebitis at the site of repeated intravenous injections. The dose of oral or intravenous vancomycin is 0’5 g. six-hourly, continued for about one week, depending upon the severity of the infection and the response to treatment. Such doses have produced good results by mouth in staphylococcal enterocolitis and intravenously in staphylococcal septicaemias and osteomyelitis. It remains to be seen whether vancomycin is best used alone or in combination with another antibiotic. It is even more important for the community’s sake to decide whether a combination of antistaphylococcal drugs is more likely to delay the emergence of resistant organisms, as it does in the chemotherapy of tuberculosis. Strains of staphylococci made resistant to vancomycin in vitro retained their sensitivity to other antibiotics, suggesting that so far there seems to be no cross-resistance between it and other antibiotics. This is a point of some importance ; for new antibiotics are not really welcome unless they remain therapeutically distinctive. Chemically similar analogues of antibiotics tend to have the same disadvantage of cross-resistance, and they are no more helpful when given in combination.
Annotations WELCOME TO A CENTENARIAN AMONG the long-established medical weeklies of the world, the N ederlands Tijdschrift voor Geneeskunde is individual alike in character and in the way it is managed. Formerly the journal of the Netherlands medical association, it became after the war a purely scientific weekly, and its ownership passed to a separate society, of some sixty members, who produce it for the benefit of the medical profession. Both the editor and the assistant editor hold university chairs (Dr. J. R. Prakken in dermatology at Amsterdam and Dr. J. W. Duyff in physiology at Leiden), and the only full-time medical member of the staff is the secretary (Dr. M. M. Hilfman) ; but they have the help of a small board, consisting mostly of professors, who serve for three years and afterwards become members of the society. Last week, when the journal started on its second hundred years, it changed its familiar small format for a larger one with double columns, which its friends will come to like even better. Normally there are English summaries of all the articles ; but the century opens with a special issue composed of some of the best contributions previously published. The story of the last fifty years is told in a commemorative volume, by Dr. C. T. van Valkenburg. At the decorous but cheerful celebrations in Amsterdam last Saturday, the other centenarian medical weeklies were represented by the editors of the British .11’Iedical Journal, the Ugeskrift for Laeger, and The Lancet. HUMAN RELATIONS
THE Tavistock Institute of Human Relations has the responsible and exacting task of providing training and conducting research in the social sciences related to
psychological medicine, and acting as consultant to industrial organisations, Government departments, and community services. It is heartening to learn that, thanks to the support of American foundations, its annual budget for this work in the coming years will be of the order of £100,000.
About half of this will go to
the projects which the institute has undertaken jointly with the Tavistock Clinic and the other half to independent social-science programmes outside the medical field. From the start of the National Health Service, the North West Metropolitan Regional Hospital Board has supported the educational work of the institute, especially through the postgraduate courses offered at the Tavistock Clinic for psychiatrists, psychologists, child psychotherapists, and social workers. External courses have also been run for general practitioners, public-health .
workers, teachers, probation officers, family-care workers, and industrial personnel officers, including students from overseas. For this side of its work the institute received last year from the Old Dominion Foundation £89,000 (to be spent over seven years) and from the Grant Foundation £25,000 (to be spent over three years) which was given specially for the training of people working among children and parents. During 1956 the institute also received grants for its research. The Ford Foundation gave £80,000 (to be spent over five years) and the Josiah Macy, jun., Foundation £ 13,000 (to be spent over three years). It is planned to extend the work of the institute’s child development unit from problems arising from the deprivation of maternal care, to which it has been giving special attention, to the conditions which promote the development of a healthy personality. Another research group has been making an exploratory study of a small number of London families who have different incomes This work grew out of but are otherwise alike. in experience marriage-counselling at the clinic and at the institute’s Family Discussion Bureau, and towards it the Grant Foundation has given E5000 to be spent during 1956 and 1957. The Home Office, the London County Council, and British foundations which have aided the institute with this work in the past will share the institute’s pleasure at this international recognition of its work and practical help towards its achievement.
BODY FAT IN CHILDHOOD
" Puppy fat " is a convenient term of abuse or of defensive hope for the future : it covers, perhaps, a multitude of sins. Just what it connotes anatomically, however, is harder to say. Recently reliable growth curves for subcutaneous fatty tissue in childhood have been prepared, thanks to the efforts of those engaged in longitudinal studies here and in America. There are four methods of obtaining information about body fat: by taking soft-tissue radiographs, which enable the investigator to distinguish and measure individually the bone, muscle, and subcutaneous tissue ; by-pulling with the thumb and forefinger a fold of skin and subcutaneous tissue away from the underlying muscle and measuring its thickness with pinch-callipers; by calculation from the specific gravity of the body, itself obtained through underwater weighing and application of the principle of Archimedes ; and by calculation from the amount of body-water estimated by chemical or isotopic dilution techniques. The last two of these have not yet yielded sufficient data during childhood to warrant much discussion, though potentially they are the most valid measures of the amount of total body fat, since the other methods measure only the thickness of the subcutaneous layer. There is, however, good evidence1 that the internal fat is, under most circumstances, closely proportional in amount to the fat stored beneath the skin. The soft-tissue X-ray technique was initiated by Stuart2 and his associates at Boston, who studied the 1. 2.
Brozek, J., Keys, A. Brit. J. Nutr. 1951, 5, 194. Stuart, H. Monogr. Soc. Res. Child Develop. 1940, 5, no.3; Child Develop. 1942, 13, 195 ; J. Pediat. 1946, 28, 637 ; Child Develop. 1950, 21, 229.
more likely to precipitate uraemia than in patients with a progressive active nephritis (e.g., chronic type-ll nephritis) in patients with a relatively inactive inflammatory lesion, such as chronic type-i nephritis or chronic pyelonephritis, in which hypertensive renal damage is now thought to be the dominant cause of renal failure. ABRAHAMS and WILSON point out that in many patients with chronic renal disease the sudden deterioration of renal function in the late stages is preceded by a relatively abrupt rise in blood-pressure. If therapy is introduced at this point, and the hypertension is well controlled, there is evidence that the onset of renal failure may be delayed. In those who patients persevered with treatment, the malignant form of hypertension, so common in renal disease, was not observed. These clinical results lend support to the conclusions derived from experimental studies in animals-namely, that, in certain forms of chronic renal disease, hypertension leads to renal vascular damage and accelerates renal failure. Nevertheless, when renal disease has progressed to the stage of nitrogen retention, hypotensive therapy can lead to only a limited increase in the expectation of life-a few years at the most. As in essential hypertension, cerebral vascular accidents remain
a
maior hazard.
Vancomycin THE present-day pharmaceutical equivalent of the Gold Rush is the intensive and systematic screening of soil samples for new antibiotics. Thousands of soil samples are being collected by amateur and professional mycologists all over the world, and submitted to various industrial and university laboratories. Aqueous extracts are prepared and analysed for their microbe content, and these organisms are then screened for possible antibiotic activity. Many samples may seem promising at first, but only a few satisfy the rigid criteria demanded for clinical trial. To the investigators’ chagrin, some promising antibiotics turn out to be identical with those already in clinical use ; and others become discredited by their toxicity. Finally, one out of the thousands of soil samples survives the stiffest of hurdles, clinical evaluation, and is acclaimed on an Olympic pedestal alongside its predecessors. Various species of the genus streptomyces have so far produced strepto-
mycin, chloramphenicol, neomycin, chlortetracycline (aur.eomycin), oxytetracycline (terramycin), nystatin, ’erythromycin, carbomycin, novobiocin, and oleandomycin. A recent addition is vancomycin, isolated from soil obtained in Borneo and India. Although vancomycinproducing strains were subsequently found in soil from other parts of the world, including North America, the species has been designated Streptomyces orientalis.l Vancomycin hydrochloride is a white solid, very soluble in water, and
relatively
stable.2
It is
Pitteriger, R. C., Brigham, R. B. Antibiot. Chemother. 1956, 6, 642. 2. Geraci, J. E., Heilman, F. R., Nichols, D. R., Wellman, W. E., Ross, G. T. Proc. Mayo Clin. 1956, 31, 564. 1.
bactericidal, and, like that of penicillin, its principal action is against gram-positive bacteria, particularly when they are multiplying. Organisms sensitive to it include pneumococci, streptococci, staphylococci, and FAIRBROTHER and WILL-IAMS3 recently clostridia. reported that, in vitro, the gram-negative gonococcus was also highly susceptible. The main indication for the use of vancomycin, however, is an infection due to strains of Staphylococcus aureU8 resistant to other antibiotics. This usually implies a strain found in hospitals, where the wide use of antibiotics has encouraged the emergence of drug-resistant organisms. It is fortunate that such strains are at present rarely encountered in infections outside hospitals; but how long they will remain thus confined no-one ean say. In-vitro sensitivity tests must be performed before the most potent antibiotic can be chosen to deal with a serious staphylococcal infection. Until the results are available, the clinician must in an emergency decide which agent is most likely to be successful. If the infection has been contracted outside a hospital, penicillin will probably and tetracycline will almost certainly be effective. On the other hand, serious infections contracted in hospital should be treated at the outset with an antibiotic which is in least current use in that particular hospital. This will do much to ensure early control of the organism and may prevent an outbreak of cross-infection in the ward. As we have often declared, the wisest course is to hold in reserve an antibiotic which will subdue staphylococci that are resistant to other forms of attack ; erythromycin has been the one most often held back in this way, and there have been signs that
chloramphenicol
was
returning
to
popularity, despite
its occasional association with blood disorders.
introduction
The
of
other aritistaphylococcal drugs, including vancomycin, novobiocin, and oleandomycin, now permits a wider choice for the strategic reserve. If the laboratory report subsequently shows that the reserved drug is not the only one to which the infecting organism is responsive, then the erythromicin (or whichever drug it is) can go back into reserve. The actual reserve drug for each hospital should be changed from time to time in the light of laboratory reports. Whereas novobiocin and oleandomycin are well absorbed from the intestine, vancomycin must be given intravenously to produce any action other than in the intestine. After either oral or intravenous the faeces become odourless and strains vancomycin, and clostridium of Streptococcus fcccali,3 disappear or much become fewer, but the gram-negative flora persists. The persistence of the gram-negative organisms in the intestine should prevent the emergence of yeasts, and mucocutaneous moniliasis has not so far been reported after the administration of vancomycin. When vancomycin is taken by mouth most of it is excreted in the faeces and only negligible amounts can be detected in the blood or urine. After intravenous injection, it is rapidly excreted in high concentration by the kidneys. As only small reach the it seems that bile, quantities vancomycin, unlike many other antibiotics, is not concentrated and excreted by the biliary system. It is detectable in pleural, pericardial, synovial, and ascitic fluids after intravenous injection. It does not diffuse into spinal fluid, which is not unexpected in view of the 3.
Fairbrother, R, W., Williams, B,
L.
Lancet, 1956, ii, 1177.
86
relatively large size of the vancomycin molecule. The only toxic reactions observed by GERACi and his co-workers2 at the Mayo Clinic were occasional rigors, erythematous or morbilliform rashes, and phlebitis at the site of repeated intravenous injections. The dose of oral or intravenous vancomycin is 0’5 g. six-hourly, continued for about one week, depending upon the severity of the infection and the response to treatment. Such doses have produced good results by mouth in staphylococcal enterocolitis and intravenously in staphylococcal septicaemias and osteomyelitis. It remains to be seen whether vancomycin is best used alone or in combination with another antibiotic. It is even more important for the community’s sake to decide whether a combination of antistaphylococcal drugs is more likely to delay the emergence of resistant organisms, as it does in the chemotherapy of tuberculosis. Strains of staphylococci made resistant to vancomycin in vitro retained their sensitivity to other antibiotics, suggesting that so far there seems to be no cross-resistance between it and other antibiotics. This is a point of some importance ; for new antibiotics are not really welcome unless they remain therapeutically distinctive. Chemically similar analogues of antibiotics tend to have the same disadvantage of cross-resistance, and they are no more helpful when given in combination.
Annotations WELCOME TO A CENTENARIAN AMONG the long-established medical weeklies of the world, the N ederlands Tijdschrift voor Geneeskunde is individual alike in character and in the way it is managed. Formerly the journal of the Netherlands medical association, it became after the war a purely scientific weekly, and its ownership passed to a separate society, of some sixty members, who produce it for the benefit of the medical profession. Both the editor and the assistant editor hold university chairs (Dr. J. R. Prakken in dermatology at Amsterdam and Dr. J. W. Duyff in physiology at Leiden), and the only full-time medical member of the staff is the secretary (Dr. M. M. Hilfman) ; but they have the help of a small board, consisting mostly of professors, who serve for three years and afterwards become members of the society. Last week, when the journal started on its second hundred years, it changed its familiar small format for a larger one with double columns, which its friends will come to like even better. Normally there are English summaries of all the articles ; but the century opens with a special issue composed of some of the best contributions previously published. The story of the last fifty years is told in a commemorative volume, by Dr. C. T. van Valkenburg. At the decorous but cheerful celebrations in Amsterdam last Saturday, the other centenarian medical weeklies were represented by the editors of the British .11’Iedical Journal, the Ugeskrift for Laeger, and The Lancet. HUMAN RELATIONS
THE Tavistock Institute of Human Relations has the responsible and exacting task of providing training and conducting research in the social sciences related to
psychological medicine, and acting as consultant to industrial organisations, Government departments, and community services. It is heartening to learn that, thanks to the support of American foundations, its annual budget for this work in the coming years will be of the order of £100,000.
About half of this will go to
the projects which the institute has undertaken jointly with the Tavistock Clinic and the other half to independent social-science programmes outside the medical field. From the start of the National Health Service, the North West Metropolitan Regional Hospital Board has supported the educational work of the institute, especially through the postgraduate courses offered at the Tavistock Clinic for psychiatrists, psychologists, child psychotherapists, and social workers. External courses have also been run for general practitioners, public-health .
workers, teachers, probation officers, family-care workers, and industrial personnel officers, including students from overseas. For this side of its work the institute received last year from the Old Dominion Foundation £89,000 (to be spent over seven years) and from the Grant Foundation £25,000 (to be spent over three years) which was given specially for the training of people working among children and parents. During 1956 the institute also received grants for its research. The Ford Foundation gave £80,000 (to be spent over five years) and the Josiah Macy, jun., Foundation £ 13,000 (to be spent over three years). It is planned to extend the work of the institute’s child development unit from problems arising from the deprivation of maternal care, to which it has been giving special attention, to the conditions which promote the development of a healthy personality. Another research group has been making an exploratory study of a small number of London families who have different incomes This work grew out of but are otherwise alike. in experience marriage-counselling at the clinic and at the institute’s Family Discussion Bureau, and towards it the Grant Foundation has given E5000 to be spent during 1956 and 1957. The Home Office, the London County Council, and British foundations which have aided the institute with this work in the past will share the institute’s pleasure at this international recognition of its work and practical help towards its achievement.
BODY FAT IN CHILDHOOD
" Puppy fat " is a convenient term of abuse or of defensive hope for the future : it covers, perhaps, a multitude of sins. Just what it connotes anatomically, however, is harder to say. Recently reliable growth curves for subcutaneous fatty tissue in childhood have been prepared, thanks to the efforts of those engaged in longitudinal studies here and in America. There are four methods of obtaining information about body fat: by taking soft-tissue radiographs, which enable the investigator to distinguish and measure individually the bone, muscle, and subcutaneous tissue ; by-pulling with the thumb and forefinger a fold of skin and subcutaneous tissue away from the underlying muscle and measuring its thickness with pinch-callipers; by calculation from the specific gravity of the body, itself obtained through underwater weighing and application of the principle of Archimedes ; and by calculation from the amount of body-water estimated by chemical or isotopic dilution techniques. The last two of these have not yet yielded sufficient data during childhood to warrant much discussion, though potentially they are the most valid measures of the amount of total body fat, since the other methods measure only the thickness of the subcutaneous layer. There is, however, good evidence1 that the internal fat is, under most circumstances, closely proportional in amount to the fat stored beneath the skin. The soft-tissue X-ray technique was initiated by Stuart2 and his associates at Boston, who studied the 1. 2.
Brozek, J., Keys, A. Brit. J. Nutr. 1951, 5, 194. Stuart, H. Monogr. Soc. Res. Child Develop. 1940, 5, no.3; Child Develop. 1942, 13, 195 ; J. Pediat. 1946, 28, 637 ; Child Develop. 1950, 21, 229.