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GENTAMICIN PLUS CARBENICILLIN
864 pregnancy and therefore included the third trimester in each instance. We have shown there is the greatest incidence of second morning fasting glycosuria after the 34th week of pregnancy and the incidence of fasting glycosuria in completed pregnancies is 7%, which agrees with their incidence of 8%. We concluded from our work that it was possible to simplify the detection of chemical gestational diabetes on a basis of glycosuria if only the second fasting variety was used as an index to test for diabetes. One such finding of second fasting glycosuria was sufficient. This indication alone produced a 15% incidence of abnormal intravenous glucose-tolerance tests, whereas random, but not fasting, glycosuria gave no abnormal result in 50 consecutive pregnant women. In relation to another of our papers2 they have cited our findings regarding the effect of ascorbic acid on glucose testing. They omit to state that ascorbic acid can give a false-positive ’Clinitest ’, in addition to the effect they mention of inhibition of clinistix. The final point concerns what surely must be a misprint, where they mention " the carbohydrate content of breakfast was meagre, averaging 290 g., the carbohydrate contents of midday and evening meals averaged 650 g." Department of Obstetrics and Gynæcology, University of Aberdeen.
HAMISH W. SUTHERLAND
JOHN M. STOWERS.
BLOOD-PRESSURE AND PEPTIC ULCER SiR,-Professor Medalie and his co-workers3 state: "The finding that the incidence of peptic ulcer and blood-pressure are inversely related is new and not previously reported so far as we have been able to determine." This prompts me to draw attention to a paper published in 1929 in Archives des Maladies de l’Appareil Digestif (vol. 19, p. 948) by Dr. A. Landau and myself, which could perhaps be considered as the first disclosure of the frequent occurrence of low systolic blood-pressure in peptic ulcer. The clinical gastroenterological information in this article is simple and sometimes naive by present-day standards, but the report contains data which corroborate the findings of Professor Medalie and his co-workers. The following figures abstracted from the article simply indicate that, in a certain number of patients with peptic ulcer of stomach and
duodenum, derived from the same hospital and in whom blood-pressures were taken under similar conditions, low systolic blood-pressure (below 100 mm. Hg) was more than 2} times more frequent than in a similarly sized group of some 60 cases of gallbladder disease and functional gastric disorders. Systolic B.P. (mm. Hg) 70-100 100-150 150-170
Ulcer patients No. % 25 35 1
41 57-4 1-6
No-ulcer patients No. % 10 49 4
15-9 77-7 6-4
After 40 years I look at the rest of this paper, written after graduation, with some scepticism-especially the speculations on the possible significance of arterial hypotension in the pathogenesis of peptic ulcer. Yet, the basic finding of frequent low arterial blood-pressure in peptic ulcer stands well. The old data of ours, collected in Warsaw, Poland, probably also have a bearing on the question which Professor Medalie and his co-workers, and the accompanying editorial, raise about the geographic distribution of this phenomenon and its general significance. New York Medical College, GEORGE B. JERZY GLASS. New York, N.Y. soon
2. 3.
Sutherland, H. W., Stowers, J. M., Christie, R. J. ibid. p. 1071. Medalie, J. H., Kahn, H. A., Neufeld, H. N., Riss, E., Goldbourt, U., Oron, D. ibid, 1970, ii, 1225.
GENTAMICIN PLUS CARBENICILLIN SiR,-We should like to reply to your correspondents’ D 1-4 on our article. Your correspondents feel that our paper may lead to the abandonment of combined gentamicin/carbenicillin therapy. It was not our intention to imply such a general conclusion-what we said was that " in certain circumstances " (i.e., during combined therapy in the presence of renal failure or with very high doses of carbenicillin) gentamicin blood-levels may be lower than those anticipated from dosage calculated on a body-weight basis. We suggested that this might lead to inadequate treatment and that serum-gentamicin estimations would be essential in these circumstances. We do not deny that synergistic activity occurs between carbenicillin and gentamicin in vitro. We quoted only two original references to support this view because it was already our conviction and we wished to save space. That antagonism cannot be demonstrated in vitro is not surprising because of the rapidity of gentamicin action. We cannot understand Dr. Klastersky’s point 3 about other antagonistic substances since, as our paper stated, the inactivation of gentamicin by carbenicillin can be demonstrated when the drugs are dissolved in distilled water. Dr. Klastersky also quotes the well known beneficial effects of synergistic antibiotic activity in enterococcal infections using penicillin and an aminoglycoside. We fail to see what this has to do with the use of carbenicillin and gentamicin in pseudomonas infections, especially as the typical serum levels of carbenicillin (200-1000 {jt.g. per ml.) are so much higher than those of penicillin (1-5 µg. per ml.). As stated by ourselves (and confirmed by Dr. Riff and Dr. Jackson 2) the degree of inactivation of aminoglycoside depends on the ratio of aminoglycoside to penicillin concentration, and does not only occur at high concentrations (as suggested by Mr. Lynn 4). In the case of enterococcal infection the serum levels of penicillin G are usually lower than those of, say, streptomycin. During combined for the carbenicillin coninfection therapy pseudomonas centration is usually at least 40 times higher than that of
comments
gentamicin. In further experiments carried out since February, using the technique of measuring gentamicin activity after destroying carbenicillin with a P-lactamase, we have tried the effect of incubating 5 µg. per ml. gentamicin with varying concentrations of carbenicillin. The results show once again the adverse effect of carbenicillin on gentamicin. Gentamicin activity (µg./ml.) Incubation Incubation atat35°C 350C with: with:
250 tg./ml. carbenicillin..
7t!!t:’ay Initial
5
At At 44 hr. hr. *
N.D.C.
At 88 hr. At hr.
N.D.C.
500 g./ml. carbenicillin 5 2’8 N.D.C. 1000 v.g./ml. carbenicillin.. 5 1.7 2.9 *N.D.C. no detectable change-i.e., result within limits of error of assay. =
The half-life of gentamicin at 35 °C in the presence of carbenicillin quoted by correspondents from our paper was 40 hours, but this was for a gentamicin/carbenicillin ratio of 1/40 (5 .g, per ml./200 g. per ml.). In our second patient and in the rabbits the serum concentrations of carbenicillin were high (500 to > 1000 g. per ml.) and the loss of gentamicin activity observed is compatible with the results of our experiment described above. The latest recommended dosage regimen for carbenicillin (4-5 g. intravenously every 4 hours) must surely produce high ratios of carbenicillin to gentamicin for at least some time, so that significant inactivation of gentamicin is by no means impossible. We agree with your correspondents that the method of antibiotic administration used in our first patient was far from ideal and may have contributed to the low serum level 1. 2. 3. 4. 5.
Eykyn, S., Phillips, I., Ridley, M. Lancet, March 13, 1971, p. 545. Riff, L., Jackson, G. G. ibid. March 20, 1971, p. 592. Klastersky, J. ibid. March 27, 1971, p. 653. Lynn, B. ibid, p. 654. McLaughlin, J. E., Reeves, D. S. ibid. Feb. 6, 1971, p. 261.
865
though it was given in extraordinarily high dosage. He was, however, treated two years ago, before the unfavourable pharmacodynamics of continuous antibiotic infusion or the problems of incompatibilities were widely appreciated. Gentamicin was given to our second patient by daily intramuscular injections. Nevertheless, we wish to re-emphasise that if drugs are incompatible in the infusion bottle why should they not also be incompatible in the body, where they are mixed and incubated, particularly if excretion is delayed ? A point not made by your correspondents is that, although gentamicin action is rapid, the bacteria to be eradicated are often found in the tissues, not in the blood. Surely a good, maintained serum level of active gentamicin is necessary to cause diffusion in adequate amounts into infected sites, in view of the fact that only 70-80% of the total serum concentration is non-protein-bound and available for immediate diffusion ? Finally, we wish to make it clear that we do not oppose the combined use of gentamicin and carbenicillin, provided adequate serum levels of gentamicin are confirmed by measurement, although we feel we have demonstrated a positive reason why such a treatment may not always be better than the use of a single agent. While we agree with your correspondents that proving the combination clinically more effective is difficult, if not impossible, the onus to justify routine combined therapy still rests on those who advocate it-especially in the light of our findings. The other practical argument advanced to justify this particular combination is to prevent the development of resistance. This is a theoretical concept and one for which we have no knowledge of specific evidence. Department of Pathology, Royal Free Hospital,
of gentamicin,
even
London W.C.1.
J. E. MCLAUGHLIN.
Department of Pathology, Southmead Hospital, Bristol BS10 5NB.
D. S. REEVES.
(EXCLUSIVE
RECORDED SINGLE WHITE LIVE BIRTHS NEW YORK STATE OF NEW YORK 1964-66, BY SEX AND MONTH OF BIRTH
CITY),
*
Average daily number of births-both
sexes.
which to test any hypothesis of this type. It has been noted that the seasonal distribution of late fetal deaths and live births with congenital malformations does not follow the seasonal distribution of all births, and in some respects these distributions have an inverse relationship.3,4 This suggests that the seasonal distribution of live births is affected by prenatal disease and selected survival. Further, if early unrecorded or unobserved embryonic and fetal loss is seasonally related to late fetal loss, and if this loss is as large as some current estimates, the seasonal distribution of live births could be significantly affected, thus obscuring any real seasonal variability in the frequency of coitus or anovulatory cycles. In addition, the sex ratio of prenatal loss does not appear to be the same as the sex ratio of live births, therefore the sex ratio of seasonal birth cohorts may not be a good estimate of the sex ratio of these cohorts at
conception. These observations point to a noteworthy deficiency in knowledge of human population development-epidemiology of human embryonic loss-an area which holds the promise for a better understanding of population genetics, and of the xtiology of congenital defects. Epidemiology and Population Genetics Birth Defects Institute, New York State Department of Health, DWIGHT T. JANERICH. Albany, N.Y. 12208. our
SEX RATIO AND SEASON OF BIRTH SIR,-Jean McLung Goodwin (March 27, p. 652) notes the possibility of examining the seasonal distribution of live births to test the hypothesis proposed by Jamesthat the frequency of coitus is related to the sex of the offspring. It has been suggested that the bimodal peaking of births seen in most populations is related to coital frequency, and therefore should affect sex ratio. Jean Goodwin also notes that J ongbloet, conversely, has suggested that the seasonal variability in births was related to the seasonal variability in
anovulatory cycles. Data in our possession allowed us to examine the seasonal relationship between the frequency of live births and sex ratio, and these data are shown in the accompanying table. During the three-year period 1964-66, in only one year did the highest proportion of males occur in the month with the highest average number of daily births-September, 1965. During 1964 and 1966, April and July respectively had the highest sex ratio for the year. These months were in the low point or troughs between seasonal peaks in births. Dr. James suggested that relevant parental and cultural factors should be considered when examining data in the light of his hypothesis. Although these data could be adjusted for known parental factors such as age, it is difficult to see how one can objectively adjust for all relevant cultural variants. However, the use of the seasonal distribution (rate) of live births as an estimate of the seasonal distribution (rate) of coitus, ovulation, or conception may be poor data with 1. James, W. H. Lancet, Jan. 2. Jongbloet, P. H. ibid. 1970,
16, 1971, p. 112. ii, 1317.
PAIN IN HOSPITAL
SiR,ňThe question of pain in hospital has lately been aired again, and I hope it has done us all good to hear something from the patient’s point of view of the present generally unsatisfactory state of affairs. Having listened sympathetically, and conceded our rather shamefaced agreement with at least some of what has been said, the question is what do we propose doing about it. Mr. Bond’s comments emphasised the wide variations between individual requirements which has been noted before-for example in my study with Lambrechtson the use of analgesics after various forms of surgery. Yet there is still a tendency to think in averages, to assume that because simple mastectomy is not generally a painful procedure the occasional patient who complains bitterly must be, so to speak, a liar or a fool. Thus, severe pain and discomfort sometimes do, regrettably, pass unheeded. There is also the other side of the story: I well remember anaesthetising a young woman for a simple operation on the groin, an hour or two after which she was sitting up con3. 4. 5.
Slatis, H. M., DeCloux, R. J. Hum. Biol. 1967, 39, 284. Janerich, D. T., Garfrinkel J. Am. J. Epidem. 1970, 92, 351. Lambrechts, W., Parkhouse, J., Simpson, B. R. J. Br. J. Anœsth 1961, 33, 345.
HAMISH W. SUTHERLAND
JOHN M. STOWERS.
BLOOD-PRESSURE AND PEPTIC ULCER SiR,-Professor Medalie and his co-workers3 state: "The finding that the incidence of peptic ulcer and blood-pressure are inversely related is new and not previously reported so far as we have been able to determine." This prompts me to draw attention to a paper published in 1929 in Archives des Maladies de l’Appareil Digestif (vol. 19, p. 948) by Dr. A. Landau and myself, which could perhaps be considered as the first disclosure of the frequent occurrence of low systolic blood-pressure in peptic ulcer. The clinical gastroenterological information in this article is simple and sometimes naive by present-day standards, but the report contains data which corroborate the findings of Professor Medalie and his co-workers. The following figures abstracted from the article simply indicate that, in a certain number of patients with peptic ulcer of stomach and
duodenum, derived from the same hospital and in whom blood-pressures were taken under similar conditions, low systolic blood-pressure (below 100 mm. Hg) was more than 2} times more frequent than in a similarly sized group of some 60 cases of gallbladder disease and functional gastric disorders. Systolic B.P. (mm. Hg) 70-100 100-150 150-170
Ulcer patients No. % 25 35 1
41 57-4 1-6
No-ulcer patients No. % 10 49 4
15-9 77-7 6-4
After 40 years I look at the rest of this paper, written after graduation, with some scepticism-especially the speculations on the possible significance of arterial hypotension in the pathogenesis of peptic ulcer. Yet, the basic finding of frequent low arterial blood-pressure in peptic ulcer stands well. The old data of ours, collected in Warsaw, Poland, probably also have a bearing on the question which Professor Medalie and his co-workers, and the accompanying editorial, raise about the geographic distribution of this phenomenon and its general significance. New York Medical College, GEORGE B. JERZY GLASS. New York, N.Y. soon
2. 3.
Sutherland, H. W., Stowers, J. M., Christie, R. J. ibid. p. 1071. Medalie, J. H., Kahn, H. A., Neufeld, H. N., Riss, E., Goldbourt, U., Oron, D. ibid, 1970, ii, 1225.
GENTAMICIN PLUS CARBENICILLIN SiR,-We should like to reply to your correspondents’ D 1-4 on our article. Your correspondents feel that our paper may lead to the abandonment of combined gentamicin/carbenicillin therapy. It was not our intention to imply such a general conclusion-what we said was that " in certain circumstances " (i.e., during combined therapy in the presence of renal failure or with very high doses of carbenicillin) gentamicin blood-levels may be lower than those anticipated from dosage calculated on a body-weight basis. We suggested that this might lead to inadequate treatment and that serum-gentamicin estimations would be essential in these circumstances. We do not deny that synergistic activity occurs between carbenicillin and gentamicin in vitro. We quoted only two original references to support this view because it was already our conviction and we wished to save space. That antagonism cannot be demonstrated in vitro is not surprising because of the rapidity of gentamicin action. We cannot understand Dr. Klastersky’s point 3 about other antagonistic substances since, as our paper stated, the inactivation of gentamicin by carbenicillin can be demonstrated when the drugs are dissolved in distilled water. Dr. Klastersky also quotes the well known beneficial effects of synergistic antibiotic activity in enterococcal infections using penicillin and an aminoglycoside. We fail to see what this has to do with the use of carbenicillin and gentamicin in pseudomonas infections, especially as the typical serum levels of carbenicillin (200-1000 {jt.g. per ml.) are so much higher than those of penicillin (1-5 µg. per ml.). As stated by ourselves (and confirmed by Dr. Riff and Dr. Jackson 2) the degree of inactivation of aminoglycoside depends on the ratio of aminoglycoside to penicillin concentration, and does not only occur at high concentrations (as suggested by Mr. Lynn 4). In the case of enterococcal infection the serum levels of penicillin G are usually lower than those of, say, streptomycin. During combined for the carbenicillin coninfection therapy pseudomonas centration is usually at least 40 times higher than that of
comments
gentamicin. In further experiments carried out since February, using the technique of measuring gentamicin activity after destroying carbenicillin with a P-lactamase, we have tried the effect of incubating 5 µg. per ml. gentamicin with varying concentrations of carbenicillin. The results show once again the adverse effect of carbenicillin on gentamicin. Gentamicin activity (µg./ml.) Incubation Incubation atat35°C 350C with: with:
250 tg./ml. carbenicillin..
7t!!t:’ay Initial
5
At At 44 hr. hr. *
N.D.C.
At 88 hr. At hr.
N.D.C.
500 g./ml. carbenicillin 5 2’8 N.D.C. 1000 v.g./ml. carbenicillin.. 5 1.7 2.9 *N.D.C. no detectable change-i.e., result within limits of error of assay. =
The half-life of gentamicin at 35 °C in the presence of carbenicillin quoted by correspondents from our paper was 40 hours, but this was for a gentamicin/carbenicillin ratio of 1/40 (5 .g, per ml./200 g. per ml.). In our second patient and in the rabbits the serum concentrations of carbenicillin were high (500 to > 1000 g. per ml.) and the loss of gentamicin activity observed is compatible with the results of our experiment described above. The latest recommended dosage regimen for carbenicillin (4-5 g. intravenously every 4 hours) must surely produce high ratios of carbenicillin to gentamicin for at least some time, so that significant inactivation of gentamicin is by no means impossible. We agree with your correspondents that the method of antibiotic administration used in our first patient was far from ideal and may have contributed to the low serum level 1. 2. 3. 4. 5.
Eykyn, S., Phillips, I., Ridley, M. Lancet, March 13, 1971, p. 545. Riff, L., Jackson, G. G. ibid. March 20, 1971, p. 592. Klastersky, J. ibid. March 27, 1971, p. 653. Lynn, B. ibid, p. 654. McLaughlin, J. E., Reeves, D. S. ibid. Feb. 6, 1971, p. 261.
865
though it was given in extraordinarily high dosage. He was, however, treated two years ago, before the unfavourable pharmacodynamics of continuous antibiotic infusion or the problems of incompatibilities were widely appreciated. Gentamicin was given to our second patient by daily intramuscular injections. Nevertheless, we wish to re-emphasise that if drugs are incompatible in the infusion bottle why should they not also be incompatible in the body, where they are mixed and incubated, particularly if excretion is delayed ? A point not made by your correspondents is that, although gentamicin action is rapid, the bacteria to be eradicated are often found in the tissues, not in the blood. Surely a good, maintained serum level of active gentamicin is necessary to cause diffusion in adequate amounts into infected sites, in view of the fact that only 70-80% of the total serum concentration is non-protein-bound and available for immediate diffusion ? Finally, we wish to make it clear that we do not oppose the combined use of gentamicin and carbenicillin, provided adequate serum levels of gentamicin are confirmed by measurement, although we feel we have demonstrated a positive reason why such a treatment may not always be better than the use of a single agent. While we agree with your correspondents that proving the combination clinically more effective is difficult, if not impossible, the onus to justify routine combined therapy still rests on those who advocate it-especially in the light of our findings. The other practical argument advanced to justify this particular combination is to prevent the development of resistance. This is a theoretical concept and one for which we have no knowledge of specific evidence. Department of Pathology, Royal Free Hospital,
of gentamicin,
even
London W.C.1.
J. E. MCLAUGHLIN.
Department of Pathology, Southmead Hospital, Bristol BS10 5NB.
D. S. REEVES.
(EXCLUSIVE
RECORDED SINGLE WHITE LIVE BIRTHS NEW YORK STATE OF NEW YORK 1964-66, BY SEX AND MONTH OF BIRTH
CITY),
*
Average daily number of births-both
sexes.
which to test any hypothesis of this type. It has been noted that the seasonal distribution of late fetal deaths and live births with congenital malformations does not follow the seasonal distribution of all births, and in some respects these distributions have an inverse relationship.3,4 This suggests that the seasonal distribution of live births is affected by prenatal disease and selected survival. Further, if early unrecorded or unobserved embryonic and fetal loss is seasonally related to late fetal loss, and if this loss is as large as some current estimates, the seasonal distribution of live births could be significantly affected, thus obscuring any real seasonal variability in the frequency of coitus or anovulatory cycles. In addition, the sex ratio of prenatal loss does not appear to be the same as the sex ratio of live births, therefore the sex ratio of seasonal birth cohorts may not be a good estimate of the sex ratio of these cohorts at
conception. These observations point to a noteworthy deficiency in knowledge of human population development-epidemiology of human embryonic loss-an area which holds the promise for a better understanding of population genetics, and of the xtiology of congenital defects. Epidemiology and Population Genetics Birth Defects Institute, New York State Department of Health, DWIGHT T. JANERICH. Albany, N.Y. 12208. our
SEX RATIO AND SEASON OF BIRTH SIR,-Jean McLung Goodwin (March 27, p. 652) notes the possibility of examining the seasonal distribution of live births to test the hypothesis proposed by Jamesthat the frequency of coitus is related to the sex of the offspring. It has been suggested that the bimodal peaking of births seen in most populations is related to coital frequency, and therefore should affect sex ratio. Jean Goodwin also notes that J ongbloet, conversely, has suggested that the seasonal variability in births was related to the seasonal variability in
anovulatory cycles. Data in our possession allowed us to examine the seasonal relationship between the frequency of live births and sex ratio, and these data are shown in the accompanying table. During the three-year period 1964-66, in only one year did the highest proportion of males occur in the month with the highest average number of daily births-September, 1965. During 1964 and 1966, April and July respectively had the highest sex ratio for the year. These months were in the low point or troughs between seasonal peaks in births. Dr. James suggested that relevant parental and cultural factors should be considered when examining data in the light of his hypothesis. Although these data could be adjusted for known parental factors such as age, it is difficult to see how one can objectively adjust for all relevant cultural variants. However, the use of the seasonal distribution (rate) of live births as an estimate of the seasonal distribution (rate) of coitus, ovulation, or conception may be poor data with 1. James, W. H. Lancet, Jan. 2. Jongbloet, P. H. ibid. 1970,
16, 1971, p. 112. ii, 1317.
PAIN IN HOSPITAL
SiR,ňThe question of pain in hospital has lately been aired again, and I hope it has done us all good to hear something from the patient’s point of view of the present generally unsatisfactory state of affairs. Having listened sympathetically, and conceded our rather shamefaced agreement with at least some of what has been said, the question is what do we propose doing about it. Mr. Bond’s comments emphasised the wide variations between individual requirements which has been noted before-for example in my study with Lambrechtson the use of analgesics after various forms of surgery. Yet there is still a tendency to think in averages, to assume that because simple mastectomy is not generally a painful procedure the occasional patient who complains bitterly must be, so to speak, a liar or a fool. Thus, severe pain and discomfort sometimes do, regrettably, pass unheeded. There is also the other side of the story: I well remember anaesthetising a young woman for a simple operation on the groin, an hour or two after which she was sitting up con3. 4. 5.
Slatis, H. M., DeCloux, R. J. Hum. Biol. 1967, 39, 284. Janerich, D. T., Garfrinkel J. Am. J. Epidem. 1970, 92, 351. Lambrechts, W., Parkhouse, J., Simpson, B. R. J. Br. J. Anœsth 1961, 33, 345.