SHIGELLOSIS AND SULPHONAMIDES

460

SHIGELLOSIS AND SULPHONAMIDES D. C. TURK Oxon., M.R.C.P.

B.M. LECTURER IN

BACTERIOLOGY, UNIVERSITY COLLEGE OF KINGSTON, JAMAICA, WEST INDIES

THE WEST

INDIES,

SHIGELLOSIS, even when it occurs as epidemic acute dysentery, is not a disease in which clinical assessment of treatments is easy. Many of the problems are illustrated in papers

with heavier inocula, not exceeding 1 drop of a 1/10 dilution of the tryptose broth culture. Absence of visible growth in a sulphonamide-containing tube after eighteen hours’ incubation at 37°C was taken as indicating sensitivity of the organism, provided that growth had occurred in the control tube.

Laboratory Results sonnei.-22 of the 24 strains were resistant to sulphadimidine per ml.ņwhich is higher than levels usually obtained in blood-and 16 of these were resistant to 500 (ig. Only 2 strains, therefore, were found to be sensitive to a level suggesting the possibility of

Shigella

100 -g. of

by Taylor (1959) and by Falisevac et al. (1959) concerning streptomycin-sulphonamide combinations. Varying bacterial species or types; varying intervals from onset of illness to beginning of treatment; varying successful sulphonamide therapy. Shigella flexneri.-All 16 strains were sensitive to kinds of patients (e.g., from healthy adults to mal100 {-g. of sulphadimidine per ml. nourished infants); and the frequency of rapid spontaneous cure-all these combine to confuse the analysis of Clinical Histories figures. The situation is further obscured when, as in Hospital notes were available for all the patients Jamaica, sporadic rather than epidemic incidence makes 2 of those with Sh. flexneri infections. Because of except consistent therapy hard to organise; the presenting sympthe strikingly different in-vitro sulphonamide sensitivities tom is not always dysentery; and bacteriological follow-up of the Sh. sonnei and the Sh. flexneri strains, the two is impaired by the impossibility of retaining symptomless of will be reviewed separately. patients in urgently needed beds, and by the near- groups patients Sonne infections (24) impossibility of persuading these same patients or their to to the once have Of 4 infants desperately ill on admission, 3 died within a bring specimens hospital they parents few hours. The 4th made a dramatic recovery on treatment been discharged. In the absence of an adequately controlled trial in his with tetracycline and cortisone. They can therefore be ignored in assessing the value of sulphonamide therapy. own land, the clinician must rely upon his own and his 12 of the 20 mild cases were treated with colleagues’ impressions, or upon laboratory findings, to 9 of them, so treated before the bacteriologicalsulphonamides. findings were indicate whether changes noted elsewhere are occurring known, made rapid recoveries. The 10th received sulphonaround him. The general clinical impression prevailing amide therapy for a week with good clinical response, but was in the University College Hospital of the West Indies in still excreting Sh. sonnei until she was given a course of tetra1958 was that sulphonamides were still effective against cycline. Her strain was sensitive to 500 -g. of sulphadimidine shigellosis here. I decided to check this impression by per ml. but not to 100 {jLg. One adult developed dysentery in in-vitro studies of the shigella strains which had been hospital, made a spontaneous recovery in twenty-four hours, and only received sulphonamide after isolation of the organism isolated during that year. had been reported. The remaining sulphonamide-treatedi Bacteriological Investigation isolated from 44 patients. No patient Shigellae was found to have more than one strain. 40 strains were available for study (24 of Sh. sonnei, 2 of Sh. flexneri 1, 9 of Sh. flexneri 3, and 5 of Sh. flexneri 6). In each case, the isolate studied was obtained from a specimen passed before any specific therapy had been given in hospital, except that one patient was already receiving streptomycin for a tuberculous infection. So far as could be determined, no patient had received antibacterial drugs for the illness in question before reporting to the hospital. An unexplained feature of the cases studied here is their age-distribution-23 under 5 years of age (16 Sh. sonnei and 7 Sh. flexneri) and 15 over the age of 18 (8 Sh. sonnei and 7 Sh. flexneri) but none between the ages of 5 and 18. were

Methods

Strains, maintained on egg-medium slants, were subcultured MacConkey’s agar and purified if necessary. Tryptose-broth (‘ I7ifco ’) cultures were then set up. Sulphonamide-sensitivity determinations were carried out in the sulphonamide-antagonist-free broth described by Jewell Pearmain (1954). Each organism was inoculated into 3 ml. to

and of volumes alone,ofbroth containing inoculated ofsulphabroth containing ml. dimidine of broth dimidine ml.,and of broth containing100-g.ofsulphabroth

and of 500 -g. per per Size of inoculum is critically important in determining sulphonamide sensitivities (Fleming 1940, Colebrook and Francis of single drops from Pasteur 1941). Inocula usually consisted " pipettes (approximately 50-dropper ") of 1/100 dilutions of four-hour broth cultures. A few of the Sh. sonnei strains persistently grew poorly in the tryptose broth and failed to grow at all from such small transfers. These were retested

patient had had dysentery for six days and was already recovering before she reported sick. She continued to Improve slowly during five days of sulphonamide therapy. One adult who developed dysentery shortly after admission received no specific treatment. She recovered completely in two days. The remaining 7 patients made rapid and uneventful recoveries on streptomycin, tetracycline, or chloramphenicol. Flexner infections (14) 1 infant, seriously ill and malnourished on admission, died before adequate therapy could be given. A 2nd seriously ill infant, treated with chloramphenicol, died three days after admission from bronchopneumonia. Of 5 other children under 4 years of age, 1, given sulphonamide as an outpatient, failed to return to hospital-probably

:

’

I I

;

i

;

indication of successful treatment. 3 were treated with chloramphenicol and 1 with streptomycin. All made rapid clinical recoveries. Of 5 adults treated with sulphonamides, 4 recovered rapidly. 1, treated with sulphonamide as an outpatient, failed to return. The 2 remaining adults were treated with antibiotics. One was already improving before starting tetracycline. The other made a slow clinical recovery on chloramphenicol, but was still excreting Sh. flexneri eight days after the beginning of treatan

ment

(see below).

From this retrospective survey of the records of a small number of variously treated patients, it is clearly impossible to draw any positive conclusions as to the efficacy of sulphonamide therapy, especially as bacteriological follow-up was nearly always inadequate to prove elimination of infection. The most that can be said is that the clinical data do not give grounds for the relevance of the laboratory findings.

I

doubting -It

461 Note on Antibiotic Sensitivities At the time of sulphonamide-sensitivity testing, all strains were tested on blood-agar plates for sensitivity to discs of streptomycin (10 g.), tetracycline (5 .g.), and chloramphenicol (5 g.). 16 of the 24 Sh. sonnei strains and all the Sh. flexneri strains were fully sensitive to all three antibiotics. 7 Sh. sonnei strains showed resistance or reduced sensitivity to streptomycin or tetracycline or both. The only chloramphenicol-resistant strain, which was also streptomycin-resistant, was isolated from a patient who developed dysentery while already receiving streptomycin for a pleural effusion. No record was found of her ever having received chloramphenicol. Reading of the history of the patient who was still excreting Sh. flexneri eight days after beginning chloramphenicol treatment prompted examination of his post-treatment isolate. Plate-disc testing showed it to be sensitive to tetracycline but resistant to streptomycin and to chloramphenicol. By a brothdilution technique similar to that employed for the sulphonamide sensitivity determinations, it was found (using doubling dilutions) to be inhibited by 1 p.g. of tetracycline but only by 64 g. of streptomycin and by 128 {jLg. of chloramphenicol. Unfortunately, the pre-treatment isolate, which had shown sensitivity to all three antibiotics on plate-disc testing, was no longer available for quantitative testing. But it appears that this patient’s unsatisfactory response to chloramphenicol was associated with the emergence of the only antibiotic-resistant Sh. flexneri strain found in the present series, and that this resistance involved streptomycin, which the patient had not received, as well as chloramphenicol. Discussion

Hardy (1945) reported the ready development of sulphonamide-resistance by Sh. sonnei strains in New York State in 1943. Since then, similar reports, involving shigellae of all types, have come from many parts of the world (e.g., Cheever 1946, Philippine Islands; Tateno 1950, Japan; Garfinkel et al. 1953, Korea; Davies 1954," London; Verselder et al. 1655, Belgian Congo; Marberg et al. 1958, Israel; Stein and Schaff 1958, South Africa). It seems that the time is approaching when sulphonamides will cease to be effective against shigellosis. Yet clearly this time must be delayed as long as possible, especially as

isolation of the organism, and must therefore at first be guided by general knowledge of the strains prevailing in the area at the time. 5. The importance of public-health measures and personal hygiene is self-evident.

Summary

My thanks are due to Miss Marjorie Sanguinetti, D.S.M.T., for the isolation and identification of the shigella strains studied; and to Dr. E. H. Back, consultant paediatrician to the University College Hospital of the West Indies, and to other clinical colleagues, for access to clinical records. REFERENCES med. Bull. 46, 479. Colebrook, L., Francis, A. E. (1941) J. Path. Bact. 53, 155. Davies, J. R. (1954) Mon. Bull. Min. Hlth Lab. Serv. 13, 114. Falisevac, J., Kosutic, Z., Galinovac-Weisglass, M. (1959) Brit. med. J. ii, 12. Fleming, A. (1940) J. Path. Bact. 50, 69. Garfinkel, B. T., Martin, G. M., Watt, J., Payne, F. J., Mason, R. P., Hardy, A. V. (1953) J. Amer. med. Ass. 151, 1157. Hardy, A. V. (1945) Publ. Hlth Rep., Wash. 60, 1037. Jewell, P., Pearmain, G. E. G. (1954) J. clin. Path. 7, 308. Marberg, K., Altmann, G., Eshkol-Bruck, A. (1958) Amer. J. trop. Med. Hyg. 7, 51. Olarte, J., De La Torre, J. A. (1959) ibid. 8, 324. Stein, H., Schaff, G. (1958) S. Afr. med. J. 32, 1161. Tateno, I. (1950) Jap. J. exp. Med. 20, 795. Taylor, P. J. (1959) Brit. med. J. ii, 9. Verselder, R., Courtois, G., Limbo, P. (1955) Bull. Soc. Path. exot. 48, 892.

Cheever F. S. (1946) U.S.

therapy." How

can we

make the best use of our available means ? the following lines of policy:

Possibly by adopting

Many mild cases do not need specific antibacterial therapy, and, by withholding it until it is plain that spontaneous cure is not taking place, the time may be deferred when severe cases due to untreatable organisms make their appearance. 2. While spontaneous cure is awaited, the sensitivity pattern of the infecting organism should be determined, so that, if antibacterial therapy is used, it may be well directed and 1.

adequate. 3. When such

cases are treated, it is probably preferable to sulphonamides against strains that are still sensitive to them-e.g., the Jamaican Sh. flexneri strains. This suggestion is subject to the qualification that combination-therapy may be

use

shown to prevent -the emergence of resistant strains. Even if this is so, it will presumably necessitate the use of two agents to which the infecting organism is known to be sensitive, rather than predetermined mixtures such as those employed by Taylor (1959) and by Falisevac et al. (1959). 4. Treatment of severe cases must, of course, precede

nav.

DETECTION OF PREDIABETES BY GLUCOSE-TOLERANCE TEST SENSITISED BY PREDNISOLONE *

many recent reports also refer to the emergence of anti-

biotic-resistant shigella strains. Both Marberg et al. (1958) from Israel, and Olarte and De La Torre (1959) from Mexico, provide evidence of disturbingly rapid adaptation of shigella populations to"changes in prevailing therapy. Marberg et al. comment: Bacillary dysentery, after having been almost deleted as a problem with important clinical implications, may revert to its former clinical severity, thus demanding again new means of

in

Jamaica as a sporadic endemic Shigellosis infection of varied presentation and severity, and thus does not lend itself to controlled trials of therapy. In the laboratory, 22 of 24 Sh. sonnei strains isolated at the University College Hospital of the West Indies during 1958 were sulphonamide-resistant, whereas all of 16 Sh. flexneri strains were sulphonamide-sensitive. Retrospective examination of the patients’ clinical records threw very little light upon the clinical efficacy of sulphonamides against the two types of infection. Suggestions regarding treatment are made in the light of the world-wide increase in shigella strains resistant to sulphonamides and to antibiotics. occurs

YOSHIO GOTO

JOJI KATO

M.D.

M.D.

LECTURER IN MEDICINE

AKIRA TAKANAMI

AKIRA OHNEDA

M.D.

M.D.

From the Medical Department of Prof. S. Yamagata, Tohoku University Medical Faculty, Sendai, Japan

glucose-tolerance test has proved to be the best of detecting early or mild diabetes mellitus. If the disease can be detected in an early or presymptomatic stage, it may be controllable by diet. But in borderline cases where the tolerance test reveals some abnormality yet does not satisfy all the criteria for diabetes mellitus repeated tests and observation of the clinical course are sometimes required before one can decide whether the prediabetes state exists. If a person has a latent impairment of carbohydrate metabolism, this may be made manifest by administration of diabetogenic substances. This was suggested by Zucker (1949) and its application was studied by Berger (1952) with corticotrophin, and by Fajans and Conn (1954) and others (Downie 1955, West 1957, German 1958, Goudie et al. 1958, Duncan 1956) with corticosteroids. The present studv was undertaken to ascertain THE

means

*

The data of this paper were presented to the Japanese Society of Endocrinology on April 2, 1957, and to the Japanese Diabetes Society in April, 1958.