537
considerably from year to year but no definite trend emerged. Rodin’s dictum’ that modern drug therapy has not seriously affected the incidence of epileptic control was, unfortunately, confirmed. I report this not as a negative observation but to draw attention to the effect of ageing on seizure frequency; for in any study of the positive aspects of long-term anticonvulsant therapy we must be aware of the natural history of chronic epilepsy. In the randomised sample (group 2) the effect of ageing on seizure frequency was clearly seen. Between the 20-29 year decade, and the 30-39 decade the fall was approximately 38%. Over the next two decades the frequency fell by a further 34%. When, in group 1, the same sample population was studied
than epilepsy, to show whether those with seizures fared less well in terms of health care than their non-epileptic counterparts. Measurements of outcome of health care are difficult enough without attempting to compare the management ot two totally different disorders-epilepsy and migraine, for example, or multiple sclerosis. It seems more appropriate to define a standard of acceptable care and assess how nearly.that standard is achieved. For those disabled by multiple sclerosis, the standard is physical and financial support within the community, and Dr and Mrs Johnson have lately shown (Jan. 1, p..31) how far from reaching that standard are the services in the West of Scotland. For those with epilepsy, one standard is abolition of seizures, and we showed how feeble were attempts to reach that standard. Dr Critchley’s letter (see below) shows the difficulties of controlling seizures in institutionalised patients but considerable control of seizures of those in the community is entirely possible, with only one drug properly used.I Dr Stores (Feb. 12, p. 359) argues that it is unreasonable to expect a general practitioner to cope with the psychological and social complications which people with epilepsy often experience. Our view is the reverse-the general practitioner is often the only person in possession of sufficient information about the patient and, as such, is the person most likely to help. There is no evidence that the bureaucratic organisation of psychological and social aid within an institutional framework is beneficial to those distressed.:2
tuated
Department of Neurological St Bartholomew’s Hospital, London EC1A 7BE
lacia induced by anticonvulsants. In addition she had hepatomegaly, with granulomas on biopsy; and chest X-ray revealed miliary mottling. The differential was that of sarcoid and tuberculosis, and while awaiting a Kveim test she collapsed
Sciences,
ANTHONY HOPKINS GRAHAM SCAMBLER
SIR,-Dr Hopkins and Mr Scambler (Jan. 22, p. 183)
state
that all too often a physician’s honour is satisfied so long as some tablets are taken. Unfortunately it cannot be claimed that we can always control epilepsy by properly monitored modern drug therapy. Using the criteria of complete seizure cessation, the 2 year, 5 year, and 10 year terminal remissionrate has hardly altered since the beginning of the century. Modern drug therapy is kinder, with fewer side-effects and less damage to the intellect, but it is not yet more effective. An attempt was made to show trends in the treatment of chronic epilepsy at an epileptic centre by a retrospective study of the number of recorded seizures. It was hoped to show the influence of regular sessions by interested neurologists, the introduction of new drugs, the monitoring of anticonvulsant levels, the correction of side-effects and the performance of drug trials on the seizure-frequency pattern of the residents over the past 10 years (1967-76). Such patients pose different problems to those living in the community who were the subject of Dr Hopkins and Mr Scambler’s report. In 10 years the number of residents has dwindled from over 400 to 360 and many are now in their 60s or 70s, The average intelligence of newcomers to the centre has possibly fallen, but the problem of epileptic control has not altered essentially. Two groups of residents were studied. The first group consisted of 80 residents (40 males and 40 females) equally divided into age decades 20-29, 30-39, 40-49, and 50-59-10 males and 10 females in each decade-and followed through, noting their seizure frequency in 1967, 1972, and 1976. To eliminate the factor of an ageing population, a second ’group comprised of 40 residents for each of the 10 years, similarly divided with 5 males and 5 females in each age range, and selected by a randomised rotation through the whole population, were also examined. There were rather fewer females than males, and in certain age-ranges a resident might be picked twice or possibly three times. In the comparison of the same population (group 1) in 1967, 1972, and 1976, there was a decrease in the number of seizures, but in the second group the seizure-frequency rate ftuc1.Reynolds, E H., Chadwick, D., Galbraith, A. W. Lancet, 1976, 2 Mayer, J E., Timms, N. The Client Speaks. London, 1970.
i, 923.
10 years, the percentage decrease in seizures was even greater but these residents can be regarded as survivors and,
over
ideally, the figures should be corrected for mortality. Department of Neurology, Royal Infirmary,
E. M. R. CRITCHLEY
Preston PRI 6PS
AMIKACIN RESISTANCE DEVELOPING IN PATIENT WITH PSEUDOMONAS ÆRUGINOSA BRONCHOPNEUMONIA
SIR,-A 57-year-old woman was admitted in November, 1976, with a history of bone pain found to be due to osteoma-
admitted to intensive care on Dec. 21. She was put and isoniazid, but liver failure prompted the withdrawal of isoniazid, which was later replaced by ethambutol. Acid-fast bacilli were isolated after 3-4 weeks’ incubation from gastric aspirate, sputum, and urine obtained during the November admission. The miliary mottling had faded from the chest radiograph after 2-3 weeks’ treatment. At the beginning of the third week after her admission an acute abdomen developed, and perforated bowel was suspected. Metronidazole therapy was started and Jan. 9 a laparotomy was performed. A perforated colonic ulcer was found but and
on
was
streptomycin
M.I.C.S OF AMINOGLYCOSIDE ANTIBIOTICS AGAINST PS. AERUGINOSA ISOLATED FROM SPUTUM* BEFORE AND AFTER DEVELOPMENT OF PYOGENIC PNEUMONIA ON
JAN. 12
*Similar M.r.c. patterns were obtained for 1’s. aeruginosa isolated from rectal and tracheal swabs (Jan. 10) and abdominal drain (Jan. 13). j2 days later the M.i.C. pattern for S. marcescens was 12.5, 0.78, 25,
12.5, 25,50. $Amikacin was started on Jan. 13, 500mg immediately, then 2x250 mg/day. A=amikacin; G=gentamicin; T=tobramycin; S=srsomycin; N=netilmicin ; K=kanamycin.
peritonitis. The peritoneum was washed out with saline and colostomy was fashioned. The patient showed a slight improvement postoperatively but on the third postoperative day she appeared septicmmic and had fresh signs of chest infection with consolidation in the no
a
1. Rodin, E. A. Epilepsia,
1972, 18,
121.
538
and sensitive to amikacin,’ this is the first report of Ps, resistant to amikacin while remaining sensitive to the other aminoglycosides, although strains of S. marcescens have been recognised to be more sensitive to gentamicin and sisomicin than to other aminoglycosides.6 This suggests that mechanisms of resistance other than those already described’ may be operating and emphasises the importance of testing all available aminoglycosides against hospital coliforms and Ps. œruginosa causing life-threatening infection. Only in this way can one be sure of selecting the most suitable aminoglycoside. Antibiotic diffusion problems in vivo may have contributed to the failure of treatment with amikacin. It is important to in. vestigate possible pharmacological differences between the various systemic aminoglycosides. In-vitro studies are useful but should not be the sole criteria for selecting these antibiotics. I. D. AMIRAK Microbiology Department, ROSAMUND J. WILLIAMS Royal Free Hospital,
œruginosa
London NW3
2QG
Metabolic Unit, Royal Free Hospital ..."
...
m
14
Development of resistance to
M. R. WILLS
15
--17 aminoglycosides 16œruginosa. by Fs.
right
.
PAUL NOONE
upper lobe. Copious green sputum yielded a heavy pure: growth of Pseudomonas aeruginosa resistant to carbenicillin. Amikacin was substituted for streptomycin in an effort to treat Ps. aeruginosa and miliary tuberculosis simultaneously and serum concentrations of the antibiotic (assayed by the urease method’) were adequate, being in the range 24-54 g/ml after a dose and about 8 g/ml just before a dose. Metronidazole was continued. therapy After an initial improvement she began to deteriorate, and chest X-ray showed cavitation in the right upper lobe and spread of consolidation to the left upper lobe. Sputum specimens were negative for acid-fast bacilli but Ps. ceruginosa was repeatedly isolated (all isolates belonging to pyocine type 5, method of Gillies and Govan2) and Serratia marcescens was isolated from tracheostomy swabs and later in a heavy growth from the sputum. Fungi and anaerobes were not isolated. The Ps. aeruginosa was at first fully sensitive to amikacin by the disc-diffusion method,’ but by the fourth day of treatment, sensitivity testing revealed diminished zones of inhibition. This was supported by subsequent M.i.c. estimations for all strains (see table). Since the organism remained fully sensitive to other aminoglycosides, amikacin was replaced by tobramycin. Liver function having improved isoniazid was restarted to supplement ethambutol. Although adequate post-dose serum concentrations of tobramycin were achieved (9-6and 5.88 g/ml) the patient continued to deteriorate, and she died on the 12th postoperative day. Necropsy revealed gross bronchopneumonia and cavitation. Ps. aeruginosa and S. marcescens were cultured from lung lesions. There was no microscopic evidence of acid-fast bacilli. Although the tuberculosis was, apparently successfully treated with streptomycin, ethambutol, and, probably, amikacin, the patient died of a fulminating secondary gram-negative infection with failure of aminoglycoside therapy. Resistance to amikacin developed within 4 days despite adequate serum concentrations but the Ps. aeruginosa remained fully sensitive to tobramycin and moderately sensitive to gentamicin (see figure). Matthias et al.4 reported four patients treated with amikacin for Ps. œruginosa urinary-tract infection where the organism became resistant not only to amikacin but also to the other aminoglycosides. Although there are several reports of organisms resistant to gentamicin, tobramycin, and sisomicin Noone, P., Pattison, J. R., Garfield Davies, D. Postgrad. med. J. 1974, 50, suppl. 7, p. 9. 2. Gillies, R. R., Govan, J. R. W. J. Part. Bact. 1966, 91, 339. 3. Stokes, E. J. Clinical Bacteriology; p. 179. London, 1968. 4. Matthias, R. G. et al. J. infect. Dis. 1976, 134, suppl. s394.
SERRATIA MARCESCENS IN HOSPITAL PRACTICE
SIR,-We read with interest the letter about Serratia
Mar-
from Dr Tabaqchali and her colleagues (Feb. 5, p. 306). Since 1970, we have identified all Enterobacteriacæ from our intensive-care unit. Among some 4500 organisms we found 28 S. marcescens, all non-pigmented—1 each in 1970 and 1971, none in 1972, 3 in 1973, 7 in 1974, 13 in 1975, and 3 in 1976. Most were isolated from respiratory-tract secretions or from dialysis fluid: two patients also had the organism in their urine. The most likely explanation of the increase in 1973--1975 was an episode of cross-infection, since all 23 isolates were found to be of serotype 014 in the Cross-Infection Laboratory, Colindale. Since early 1975 we have used techniques appropriate to the identification of S. marcescens in all our other routine diagnostic work. We isolated 5 strains in 1975 and 10 strains in 1976, mostly from sputum or wound swabs. All our isolates have been sensitive on disc-testing to chlorcescens
amphenicol, sulphonamides, neomycin, and gentamicin; some resistant to tetracycline; many were resistant to ampicilall were resistant to cephaloridine and polymyxin. and lin; Our organisms differ from those isolated from St. Bartholomew’s Hospital in that they are rarely isolated from urine and are more susceptible to antibiotics. The pattern of isolations since 1970 suggests that the organism is occasionally acquired by patients from an unidentified source, and it may, under appropriate (but as yet obscure) conditions, cause low level but long-lasting outbreaks of cross-infection. This, rather than any true increase of isolation or identification, could account for its prevalence in our hospitals. were
Department of Microbiology, St Thomas’ Hospital Medical School, London SE1 7EH
IAN PHILLIPS ANNA KING
INVERSE RELATION OF SILICON IN DRINKING WATER AND ATHEROSCLEROSIS IN FINLAND
SIR,-A good case can be made for the possible involvement of silicon, in the form of nutritionally available silicic acid and its derivatives, in atherosclerosis. Lack of silicate-silicon in diet and drinking water may contribute to the aetiology of the disease, and sufficiency or excess may inhibit its development. The evidence which speaks for this concept has been presented elsewhere.In view of the facts which support the involvement
1.
DeFuria, M. D., Pursiano, T. A. ibid. s249. J., Moss, E. L., Drube, C. G., Weinstein, M. J. Antimicrob. Ag. Chemother. 1972, 2, 431. Schwarz, K. Lancet, 1977, i, 454.
5. Price, K. E., 6. Allan Waitz,
1.
considerably from year to year but no definite trend emerged. Rodin’s dictum’ that modern drug therapy has not seriously affected the incidence of epileptic control was, unfortunately, confirmed. I report this not as a negative observation but to draw attention to the effect of ageing on seizure frequency; for in any study of the positive aspects of long-term anticonvulsant therapy we must be aware of the natural history of chronic epilepsy. In the randomised sample (group 2) the effect of ageing on seizure frequency was clearly seen. Between the 20-29 year decade, and the 30-39 decade the fall was approximately 38%. Over the next two decades the frequency fell by a further 34%. When, in group 1, the same sample population was studied
than epilepsy, to show whether those with seizures fared less well in terms of health care than their non-epileptic counterparts. Measurements of outcome of health care are difficult enough without attempting to compare the management ot two totally different disorders-epilepsy and migraine, for example, or multiple sclerosis. It seems more appropriate to define a standard of acceptable care and assess how nearly.that standard is achieved. For those disabled by multiple sclerosis, the standard is physical and financial support within the community, and Dr and Mrs Johnson have lately shown (Jan. 1, p..31) how far from reaching that standard are the services in the West of Scotland. For those with epilepsy, one standard is abolition of seizures, and we showed how feeble were attempts to reach that standard. Dr Critchley’s letter (see below) shows the difficulties of controlling seizures in institutionalised patients but considerable control of seizures of those in the community is entirely possible, with only one drug properly used.I Dr Stores (Feb. 12, p. 359) argues that it is unreasonable to expect a general practitioner to cope with the psychological and social complications which people with epilepsy often experience. Our view is the reverse-the general practitioner is often the only person in possession of sufficient information about the patient and, as such, is the person most likely to help. There is no evidence that the bureaucratic organisation of psychological and social aid within an institutional framework is beneficial to those distressed.:2
tuated
Department of Neurological St Bartholomew’s Hospital, London EC1A 7BE
lacia induced by anticonvulsants. In addition she had hepatomegaly, with granulomas on biopsy; and chest X-ray revealed miliary mottling. The differential was that of sarcoid and tuberculosis, and while awaiting a Kveim test she collapsed
Sciences,
ANTHONY HOPKINS GRAHAM SCAMBLER
SIR,-Dr Hopkins and Mr Scambler (Jan. 22, p. 183)
state
that all too often a physician’s honour is satisfied so long as some tablets are taken. Unfortunately it cannot be claimed that we can always control epilepsy by properly monitored modern drug therapy. Using the criteria of complete seizure cessation, the 2 year, 5 year, and 10 year terminal remissionrate has hardly altered since the beginning of the century. Modern drug therapy is kinder, with fewer side-effects and less damage to the intellect, but it is not yet more effective. An attempt was made to show trends in the treatment of chronic epilepsy at an epileptic centre by a retrospective study of the number of recorded seizures. It was hoped to show the influence of regular sessions by interested neurologists, the introduction of new drugs, the monitoring of anticonvulsant levels, the correction of side-effects and the performance of drug trials on the seizure-frequency pattern of the residents over the past 10 years (1967-76). Such patients pose different problems to those living in the community who were the subject of Dr Hopkins and Mr Scambler’s report. In 10 years the number of residents has dwindled from over 400 to 360 and many are now in their 60s or 70s, The average intelligence of newcomers to the centre has possibly fallen, but the problem of epileptic control has not altered essentially. Two groups of residents were studied. The first group consisted of 80 residents (40 males and 40 females) equally divided into age decades 20-29, 30-39, 40-49, and 50-59-10 males and 10 females in each decade-and followed through, noting their seizure frequency in 1967, 1972, and 1976. To eliminate the factor of an ageing population, a second ’group comprised of 40 residents for each of the 10 years, similarly divided with 5 males and 5 females in each age range, and selected by a randomised rotation through the whole population, were also examined. There were rather fewer females than males, and in certain age-ranges a resident might be picked twice or possibly three times. In the comparison of the same population (group 1) in 1967, 1972, and 1976, there was a decrease in the number of seizures, but in the second group the seizure-frequency rate ftuc1.Reynolds, E H., Chadwick, D., Galbraith, A. W. Lancet, 1976, 2 Mayer, J E., Timms, N. The Client Speaks. London, 1970.
i, 923.
10 years, the percentage decrease in seizures was even greater but these residents can be regarded as survivors and,
over
ideally, the figures should be corrected for mortality. Department of Neurology, Royal Infirmary,
E. M. R. CRITCHLEY
Preston PRI 6PS
AMIKACIN RESISTANCE DEVELOPING IN PATIENT WITH PSEUDOMONAS ÆRUGINOSA BRONCHOPNEUMONIA
SIR,-A 57-year-old woman was admitted in November, 1976, with a history of bone pain found to be due to osteoma-
admitted to intensive care on Dec. 21. She was put and isoniazid, but liver failure prompted the withdrawal of isoniazid, which was later replaced by ethambutol. Acid-fast bacilli were isolated after 3-4 weeks’ incubation from gastric aspirate, sputum, and urine obtained during the November admission. The miliary mottling had faded from the chest radiograph after 2-3 weeks’ treatment. At the beginning of the third week after her admission an acute abdomen developed, and perforated bowel was suspected. Metronidazole therapy was started and Jan. 9 a laparotomy was performed. A perforated colonic ulcer was found but and
on
was
streptomycin
M.I.C.S OF AMINOGLYCOSIDE ANTIBIOTICS AGAINST PS. AERUGINOSA ISOLATED FROM SPUTUM* BEFORE AND AFTER DEVELOPMENT OF PYOGENIC PNEUMONIA ON
JAN. 12
*Similar M.r.c. patterns were obtained for 1’s. aeruginosa isolated from rectal and tracheal swabs (Jan. 10) and abdominal drain (Jan. 13). j2 days later the M.i.C. pattern for S. marcescens was 12.5, 0.78, 25,
12.5, 25,50. $Amikacin was started on Jan. 13, 500mg immediately, then 2x250 mg/day. A=amikacin; G=gentamicin; T=tobramycin; S=srsomycin; N=netilmicin ; K=kanamycin.
peritonitis. The peritoneum was washed out with saline and colostomy was fashioned. The patient showed a slight improvement postoperatively but on the third postoperative day she appeared septicmmic and had fresh signs of chest infection with consolidation in the no
a
1. Rodin, E. A. Epilepsia,
1972, 18,
121.
538
and sensitive to amikacin,’ this is the first report of Ps, resistant to amikacin while remaining sensitive to the other aminoglycosides, although strains of S. marcescens have been recognised to be more sensitive to gentamicin and sisomicin than to other aminoglycosides.6 This suggests that mechanisms of resistance other than those already described’ may be operating and emphasises the importance of testing all available aminoglycosides against hospital coliforms and Ps. œruginosa causing life-threatening infection. Only in this way can one be sure of selecting the most suitable aminoglycoside. Antibiotic diffusion problems in vivo may have contributed to the failure of treatment with amikacin. It is important to in. vestigate possible pharmacological differences between the various systemic aminoglycosides. In-vitro studies are useful but should not be the sole criteria for selecting these antibiotics. I. D. AMIRAK Microbiology Department, ROSAMUND J. WILLIAMS Royal Free Hospital,
œruginosa
London NW3
2QG
Metabolic Unit, Royal Free Hospital ..."
...
m
14
Development of resistance to
M. R. WILLS
15
--17 aminoglycosides 16œruginosa. by Fs.
right
.
PAUL NOONE
upper lobe. Copious green sputum yielded a heavy pure: growth of Pseudomonas aeruginosa resistant to carbenicillin. Amikacin was substituted for streptomycin in an effort to treat Ps. aeruginosa and miliary tuberculosis simultaneously and serum concentrations of the antibiotic (assayed by the urease method’) were adequate, being in the range 24-54 g/ml after a dose and about 8 g/ml just before a dose. Metronidazole was continued. therapy After an initial improvement she began to deteriorate, and chest X-ray showed cavitation in the right upper lobe and spread of consolidation to the left upper lobe. Sputum specimens were negative for acid-fast bacilli but Ps. ceruginosa was repeatedly isolated (all isolates belonging to pyocine type 5, method of Gillies and Govan2) and Serratia marcescens was isolated from tracheostomy swabs and later in a heavy growth from the sputum. Fungi and anaerobes were not isolated. The Ps. aeruginosa was at first fully sensitive to amikacin by the disc-diffusion method,’ but by the fourth day of treatment, sensitivity testing revealed diminished zones of inhibition. This was supported by subsequent M.i.c. estimations for all strains (see table). Since the organism remained fully sensitive to other aminoglycosides, amikacin was replaced by tobramycin. Liver function having improved isoniazid was restarted to supplement ethambutol. Although adequate post-dose serum concentrations of tobramycin were achieved (9-6and 5.88 g/ml) the patient continued to deteriorate, and she died on the 12th postoperative day. Necropsy revealed gross bronchopneumonia and cavitation. Ps. aeruginosa and S. marcescens were cultured from lung lesions. There was no microscopic evidence of acid-fast bacilli. Although the tuberculosis was, apparently successfully treated with streptomycin, ethambutol, and, probably, amikacin, the patient died of a fulminating secondary gram-negative infection with failure of aminoglycoside therapy. Resistance to amikacin developed within 4 days despite adequate serum concentrations but the Ps. aeruginosa remained fully sensitive to tobramycin and moderately sensitive to gentamicin (see figure). Matthias et al.4 reported four patients treated with amikacin for Ps. œruginosa urinary-tract infection where the organism became resistant not only to amikacin but also to the other aminoglycosides. Although there are several reports of organisms resistant to gentamicin, tobramycin, and sisomicin Noone, P., Pattison, J. R., Garfield Davies, D. Postgrad. med. J. 1974, 50, suppl. 7, p. 9. 2. Gillies, R. R., Govan, J. R. W. J. Part. Bact. 1966, 91, 339. 3. Stokes, E. J. Clinical Bacteriology; p. 179. London, 1968. 4. Matthias, R. G. et al. J. infect. Dis. 1976, 134, suppl. s394.
SERRATIA MARCESCENS IN HOSPITAL PRACTICE
SIR,-We read with interest the letter about Serratia
Mar-
from Dr Tabaqchali and her colleagues (Feb. 5, p. 306). Since 1970, we have identified all Enterobacteriacæ from our intensive-care unit. Among some 4500 organisms we found 28 S. marcescens, all non-pigmented—1 each in 1970 and 1971, none in 1972, 3 in 1973, 7 in 1974, 13 in 1975, and 3 in 1976. Most were isolated from respiratory-tract secretions or from dialysis fluid: two patients also had the organism in their urine. The most likely explanation of the increase in 1973--1975 was an episode of cross-infection, since all 23 isolates were found to be of serotype 014 in the Cross-Infection Laboratory, Colindale. Since early 1975 we have used techniques appropriate to the identification of S. marcescens in all our other routine diagnostic work. We isolated 5 strains in 1975 and 10 strains in 1976, mostly from sputum or wound swabs. All our isolates have been sensitive on disc-testing to chlorcescens
amphenicol, sulphonamides, neomycin, and gentamicin; some resistant to tetracycline; many were resistant to ampicilall were resistant to cephaloridine and polymyxin. and lin; Our organisms differ from those isolated from St. Bartholomew’s Hospital in that they are rarely isolated from urine and are more susceptible to antibiotics. The pattern of isolations since 1970 suggests that the organism is occasionally acquired by patients from an unidentified source, and it may, under appropriate (but as yet obscure) conditions, cause low level but long-lasting outbreaks of cross-infection. This, rather than any true increase of isolation or identification, could account for its prevalence in our hospitals. were
Department of Microbiology, St Thomas’ Hospital Medical School, London SE1 7EH
IAN PHILLIPS ANNA KING
INVERSE RELATION OF SILICON IN DRINKING WATER AND ATHEROSCLEROSIS IN FINLAND
SIR,-A good case can be made for the possible involvement of silicon, in the form of nutritionally available silicic acid and its derivatives, in atherosclerosis. Lack of silicate-silicon in diet and drinking water may contribute to the aetiology of the disease, and sufficiency or excess may inhibit its development. The evidence which speaks for this concept has been presented elsewhere.In view of the facts which support the involvement
1.
DeFuria, M. D., Pursiano, T. A. ibid. s249. J., Moss, E. L., Drube, C. G., Weinstein, M. J. Antimicrob. Ag. Chemother. 1972, 2, 431. Schwarz, K. Lancet, 1977, i, 454.
5. Price, K. E., 6. Allan Waitz,
1.
