740
integrated into coherent descriptions of pathophysiological mechanisms in patients with psychiatric disorders. The approach suggested in this paper is in essence a restatement of Claude Bernard’s proposals for an "experimental medicine", phrased in more modern terminology and in relation specifically to psychiatry.22 It implies the division of patients with similar behavioural disorders into biological subgroups and explicitly rejects a search for single causes or mechanisms for such complex clinical phenomena as "schizophrenia" or "depression". Analogous studies have given very useful information in other areas of medicine. The usefulness of this approach in neuropsychiatry can be determined only by further observations. This research was supported in part by grants NF 6-76-50 from the National Foundation March of Dimes and HD-06576 from the N.I.C.H.D.
Requests for reprints should be addressed to J. P. B., Mental Retardation Research Center, U.C.L.A. School of Medicine, Los Angeles, California 90024, U.S.A.
REFERENCES 1. 2. 3. 4. 5.
Slater, E., Cowie, V. Genetics of Mental Disorders. London, 1971. Rodnight, R. Psychol. Med. 1971, 1, 353. Bloom, F., Segal, D., Ling, N., Guillemin, R. Science, 1976, 194, 632. Jacquet, Y., Marks, N. ibid. p. 634. Weil-Malherbe, H., Szara, S. I. Biochemistry of Functional and Experimental Psychoses. Springfield, Illinois, 1971. 6. Kendell, R. E. Role of Diagnosis in Psychiatry. Oxford, 1975. 7. Scadding, J. G. Lancet, 1967, ii, 877. 8. Burrows, B. Ann. intern. Med. 1975, 83, 419. 9. Ritvo, E. R., Ornitz, M., LaFranchi, S. Archs gen. Psychiat. 1968, 19, 341. 10. Brown, E. S., Waisman, H. A. Pediatrics, Springfield, 1967, 40, 247. 11. Müller, D., Pilz, H., Meulen, V. T. J. neurol. Sci. 1969, 9, 567. 12. Kaebling, R., Craig, J., Pasamanik, B. Archs gen. Psychiat. 1961, 5, 494. 13. Kappas, A., Sassa, A., Granick, S., Bradlow, H. L. in Brain Dysfunction in Metabolic Disorders (edited by F. Plum); p. 225. New York, 1974. 14. Slater, E., Roth, M. Clinical Psychiatry; p. 483. Baltimore, 1969. 15. International Statistical Classification of Diseases, Injury, and Death. W.H.O., 1967. 16. Baldwin, M., Bailey, P. (editors) Temporal Lobe Epilepsy. Springfield, Illinois, 1958. 17. Hillbom, E. Acta psychiat. neurol. scand. 1960, 35, suppl. 142, 128. 18. Graham, P., Rutter, M. Br. med. J. 1968, iii, 698. 19. Blass, J. P., Steinberg, D. in Biology of Brain Dysfunction (edited by G. Gaull); vol. 2, p. 239. New York, 1973. 20. Sandier, M., Reynolds, G. P. Lancet, 1976, i, 70. 21. Giardina, W. J., Pedemonte, W. A., Sabelli, H. C. Life Sci. 1973, 12, 153. 22. Bernard, C. Introduction à l’étude de la médicine experimentale. Pans, 1952.
Occasional
Survey
CAN RIFAMPICIN USE BE SAFELY EXTENDED?
Evidence for Non-emergence of Resistant Strains of Mycobacterium tuberculosis G. ACOCELLA*
J. M. T. HAMILTON-MILLER W. BRUMFITT
Royal Free Hospital,
Pond Street, London NW3 2QG
the incidence of primary resisrifampicin in Mycobacterium strains have been collected from various tuberculosis countries. Strains isolated from those countries where rifampicin is used for both tuberculous and non-tuberculous conditions (Italy, Argentina, Brazil, and Spain) did not show a higher incidence of primary resistance than did strains from other countries (France, U.K., and U.S.A.) where rifampicin use is confined to tuberculosis. It is concluded that there is no evidence to justify fears of an increased incidence of resistance to rifampicin in M. tuberculosis if rifampicin were used discreetly for treating non-tuberculous infections.
Summary
Data
on
tance to
INTRODUCTION
Kerry, Hamilton-Miller, and Brumfittl reported on the antibacterial activity of the combination rifampicin/trimethoprim. They found at least an additive action against a wide range of pathogens, as well as suppression of the emergence of rifampicin-resistant mutants. These results, together with those obtained in pharmacokinetic experiments23 and with an animal-infection model4 suggest that this combination might be useful for treating a wide variety of infections in man. However, some authorities’6 have declared themselves against rifampicin therapy for any non-tuberculous condition, because *Visiting Milan.
research
fellow,
on
release from
Gruppo Lepetit,
of the danger that this would encourage the emergence of rifampicin-resistant strains of Mycobacterium tuberculosis. There is reason to believe that this danger may have been exaggerated; for instance, during monotherapy of tuberculosis with rifampicin, resistant variants of this organism took at least a month to arise.’ Further, there is no evidence that the use of streptomycin during the 1950s for non-tuberculous conditions caused an increase in the frequency of strains of M. tuberculosis resistant to this antibiotic. In this paper we compare the development of primary resistance to rifampicin over the past few years, in strains of M. tuberculosis isolated in countries where the antibiotic is in use for non-tuberculous conditions, with figures from other countries where rifampicin is reserved solely for tuberculous infections. We have also made an alternative approach to the problem by searching for resistance among gram-negative bacteria from a hospital where rifampicin is widely used for the treatment of tuberculosis. METHODS
Resistance in M. tuberculosis Information on the occurrence of primary resistance (as defined, diagnosed, and described by Cannetti et al. 8) was collected from Italy, Argentina, Brazil, and Spain. Clearly the amount of rifampicin used is important, and in order to assess its usage we have defined the total consumption of rifampicin as the "use ratio". This means the use in tuberculosis, divided by the use for non-tuberculous conditions. The calculation has been made from information for the individual countries.Y
Resistance in
Gram-negative Bacteria organisms isolated from the Royal .
333 such Free Hospital and 100 consecutive isolates from the Brompton Hospital were tested. The disc technique (with a 30 jj.g rifampicin disc) as well as a precise determination of minimum inhibitory concentration was used to define resistance. RESULTS
M. tuberculosis Tableshows the frequency of M. tuberculosis with primary resistance to rifampicin. The data from Italy originate from six different regions widely separated, so
741 TABLE I-PERCENTAGE OF STRAINS OF RIFAMPICIN IN THE YEARS
1969-1975
M. tuberculosis
IN CENTRES IN
FOUND PRIMARILY RESISTANT TO
ITALY, ARGENTINA, BRAZIL, AND SPAJN
TABLE II——COMPARATIVE DATA ON PERCENTAGE PRIMARY RESISTANCE OF SOME OF THE
MAJOR
M. tuberculosis TO SPAIN, AND THE U.S.A.
ANTITUBERCULOUS DRUGS IN ITALY, ARGENTINA, BRAZIL,
that each can be assumed to reflect the local situation as well as the position in the whole of Italy. Between 1970 and 1975 the total consumption of rifampicin increased by a factor of 6, and proportionately more was found to be in use for non-tuberculous conditions. Thus, the use ratio fell from 0.4 in 1970 to 0.19 in 1975. For Argentina, the data are those calculated from successive national surveys. The use of rifampicin increased three-fold and the use ratio changed from 0.4 to 0.29 between 1970 and 1975 (table i). No primary resistance was found in the strains isolated in Brazil between 1972 and 1975, where 5 times as much rifampicin was used in 1975 as in 1970. Usage of rifampicin was mainly for tuberculosis, the use ratio being 3.5 in 1970 and 5 in 1975. Two of the rifampicin-resistant strains isolated in Spain arose because of cross-infection from patients who had been treated with rifampicin in a way that most authorities would regard as incorrect. 16 17 The total consumption of rifampicin in Spain rose five-fold between 1970 and 1975, but the use ratio was approximately constant at 1 - 3. Table u compares the incidence of resistance to rifampicin with that to other antituberculous drugs. It is clear that resistance to rifampicin occurs at a frequency which is not significantly different (p>0-2) from that found to p-aminosalicylic acid or ethambutol, but significantly less than that to either streptomycin or isoniazid ,
(P
integrated into coherent descriptions of pathophysiological mechanisms in patients with psychiatric disorders. The approach suggested in this paper is in essence a restatement of Claude Bernard’s proposals for an "experimental medicine", phrased in more modern terminology and in relation specifically to psychiatry.22 It implies the division of patients with similar behavioural disorders into biological subgroups and explicitly rejects a search for single causes or mechanisms for such complex clinical phenomena as "schizophrenia" or "depression". Analogous studies have given very useful information in other areas of medicine. The usefulness of this approach in neuropsychiatry can be determined only by further observations. This research was supported in part by grants NF 6-76-50 from the National Foundation March of Dimes and HD-06576 from the N.I.C.H.D.
Requests for reprints should be addressed to J. P. B., Mental Retardation Research Center, U.C.L.A. School of Medicine, Los Angeles, California 90024, U.S.A.
REFERENCES 1. 2. 3. 4. 5.
Slater, E., Cowie, V. Genetics of Mental Disorders. London, 1971. Rodnight, R. Psychol. Med. 1971, 1, 353. Bloom, F., Segal, D., Ling, N., Guillemin, R. Science, 1976, 194, 632. Jacquet, Y., Marks, N. ibid. p. 634. Weil-Malherbe, H., Szara, S. I. Biochemistry of Functional and Experimental Psychoses. Springfield, Illinois, 1971. 6. Kendell, R. E. Role of Diagnosis in Psychiatry. Oxford, 1975. 7. Scadding, J. G. Lancet, 1967, ii, 877. 8. Burrows, B. Ann. intern. Med. 1975, 83, 419. 9. Ritvo, E. R., Ornitz, M., LaFranchi, S. Archs gen. Psychiat. 1968, 19, 341. 10. Brown, E. S., Waisman, H. A. Pediatrics, Springfield, 1967, 40, 247. 11. Müller, D., Pilz, H., Meulen, V. T. J. neurol. Sci. 1969, 9, 567. 12. Kaebling, R., Craig, J., Pasamanik, B. Archs gen. Psychiat. 1961, 5, 494. 13. Kappas, A., Sassa, A., Granick, S., Bradlow, H. L. in Brain Dysfunction in Metabolic Disorders (edited by F. Plum); p. 225. New York, 1974. 14. Slater, E., Roth, M. Clinical Psychiatry; p. 483. Baltimore, 1969. 15. International Statistical Classification of Diseases, Injury, and Death. W.H.O., 1967. 16. Baldwin, M., Bailey, P. (editors) Temporal Lobe Epilepsy. Springfield, Illinois, 1958. 17. Hillbom, E. Acta psychiat. neurol. scand. 1960, 35, suppl. 142, 128. 18. Graham, P., Rutter, M. Br. med. J. 1968, iii, 698. 19. Blass, J. P., Steinberg, D. in Biology of Brain Dysfunction (edited by G. Gaull); vol. 2, p. 239. New York, 1973. 20. Sandier, M., Reynolds, G. P. Lancet, 1976, i, 70. 21. Giardina, W. J., Pedemonte, W. A., Sabelli, H. C. Life Sci. 1973, 12, 153. 22. Bernard, C. Introduction à l’étude de la médicine experimentale. Pans, 1952.
Occasional
Survey
CAN RIFAMPICIN USE BE SAFELY EXTENDED?
Evidence for Non-emergence of Resistant Strains of Mycobacterium tuberculosis G. ACOCELLA*
J. M. T. HAMILTON-MILLER W. BRUMFITT
Royal Free Hospital,
Pond Street, London NW3 2QG
the incidence of primary resisrifampicin in Mycobacterium strains have been collected from various tuberculosis countries. Strains isolated from those countries where rifampicin is used for both tuberculous and non-tuberculous conditions (Italy, Argentina, Brazil, and Spain) did not show a higher incidence of primary resistance than did strains from other countries (France, U.K., and U.S.A.) where rifampicin use is confined to tuberculosis. It is concluded that there is no evidence to justify fears of an increased incidence of resistance to rifampicin in M. tuberculosis if rifampicin were used discreetly for treating non-tuberculous infections.
Summary
Data
on
tance to
INTRODUCTION
Kerry, Hamilton-Miller, and Brumfittl reported on the antibacterial activity of the combination rifampicin/trimethoprim. They found at least an additive action against a wide range of pathogens, as well as suppression of the emergence of rifampicin-resistant mutants. These results, together with those obtained in pharmacokinetic experiments23 and with an animal-infection model4 suggest that this combination might be useful for treating a wide variety of infections in man. However, some authorities’6 have declared themselves against rifampicin therapy for any non-tuberculous condition, because *Visiting Milan.
research
fellow,
on
release from
Gruppo Lepetit,
of the danger that this would encourage the emergence of rifampicin-resistant strains of Mycobacterium tuberculosis. There is reason to believe that this danger may have been exaggerated; for instance, during monotherapy of tuberculosis with rifampicin, resistant variants of this organism took at least a month to arise.’ Further, there is no evidence that the use of streptomycin during the 1950s for non-tuberculous conditions caused an increase in the frequency of strains of M. tuberculosis resistant to this antibiotic. In this paper we compare the development of primary resistance to rifampicin over the past few years, in strains of M. tuberculosis isolated in countries where the antibiotic is in use for non-tuberculous conditions, with figures from other countries where rifampicin is reserved solely for tuberculous infections. We have also made an alternative approach to the problem by searching for resistance among gram-negative bacteria from a hospital where rifampicin is widely used for the treatment of tuberculosis. METHODS
Resistance in M. tuberculosis Information on the occurrence of primary resistance (as defined, diagnosed, and described by Cannetti et al. 8) was collected from Italy, Argentina, Brazil, and Spain. Clearly the amount of rifampicin used is important, and in order to assess its usage we have defined the total consumption of rifampicin as the "use ratio". This means the use in tuberculosis, divided by the use for non-tuberculous conditions. The calculation has been made from information for the individual countries.Y
Resistance in
Gram-negative Bacteria organisms isolated from the Royal .
333 such Free Hospital and 100 consecutive isolates from the Brompton Hospital were tested. The disc technique (with a 30 jj.g rifampicin disc) as well as a precise determination of minimum inhibitory concentration was used to define resistance. RESULTS
M. tuberculosis Tableshows the frequency of M. tuberculosis with primary resistance to rifampicin. The data from Italy originate from six different regions widely separated, so
741 TABLE I-PERCENTAGE OF STRAINS OF RIFAMPICIN IN THE YEARS
1969-1975
M. tuberculosis
IN CENTRES IN
FOUND PRIMARILY RESISTANT TO
ITALY, ARGENTINA, BRAZIL, AND SPAJN
TABLE II——COMPARATIVE DATA ON PERCENTAGE PRIMARY RESISTANCE OF SOME OF THE
MAJOR
M. tuberculosis TO SPAIN, AND THE U.S.A.
ANTITUBERCULOUS DRUGS IN ITALY, ARGENTINA, BRAZIL,
that each can be assumed to reflect the local situation as well as the position in the whole of Italy. Between 1970 and 1975 the total consumption of rifampicin increased by a factor of 6, and proportionately more was found to be in use for non-tuberculous conditions. Thus, the use ratio fell from 0.4 in 1970 to 0.19 in 1975. For Argentina, the data are those calculated from successive national surveys. The use of rifampicin increased three-fold and the use ratio changed from 0.4 to 0.29 between 1970 and 1975 (table i). No primary resistance was found in the strains isolated in Brazil between 1972 and 1975, where 5 times as much rifampicin was used in 1975 as in 1970. Usage of rifampicin was mainly for tuberculosis, the use ratio being 3.5 in 1970 and 5 in 1975. Two of the rifampicin-resistant strains isolated in Spain arose because of cross-infection from patients who had been treated with rifampicin in a way that most authorities would regard as incorrect. 16 17 The total consumption of rifampicin in Spain rose five-fold between 1970 and 1975, but the use ratio was approximately constant at 1 - 3. Table u compares the incidence of resistance to rifampicin with that to other antituberculous drugs. It is clear that resistance to rifampicin occurs at a frequency which is not significantly different (p>0-2) from that found to p-aminosalicylic acid or ethambutol, but significantly less than that to either streptomycin or isoniazid ,
(P
