Chloramphenicol (chloromycetin) in the treatment of experimental relapsing fever

65 TRANSACTIONSOF THE ROYALSOCIETYOF TROPICAL MEDICINE AND HYGIENE. Vol. 46. No. 1. January, 1952.

C H L O R A M P H E N I C O L (CHLOROMYCETIN) IN T H E T R E A T M E N T OF E X P E R I M E N T A L RELAPSING FEVER BY R. B. HEISCH, M.D. AND A. E. C. HARVEY

From the Division of Insect-borne Diseases, Medical Research Laboratory, Kenya In 1948 SMITH and his co-workers demonstrated that chloramphenicol is active against relapsing fever spirochaetes in vitro, and in 1949 THOMPSON and DUNN found that the drug rapidly cleared spirochaetes from the blood of white mice infected with a virulent strain of Spirochaeta novyi. The present paper describes the treatment of relapsing fever infections in white rats, monkeys and patients with general paralysis. The species of monkey were Cercopithecus mitis kolbi Neumann, C. aethiops johnstonl Pocock, and Papio doguera furax Elliott. An East African strain of Spirochaeta duttoni was used, the white rats and monkeys being infected intraperitoneally and the general paralytics conjunctivally with blood from heavily infected laboratory animals. The strain had been passaged in white rats for several years and was of a rather low virulence. Treated animals and humans were not given chloramphenicol until spirochaetes had been present in their blood for 1 or 2 days; the drug was then administered orally in divided doses. Details are given in Table I. TABLE I Species infected

Nun lber infected

Number treated

Dosage of chloromycetin in 24 hours (nag. per kg.)

Number of controls

White rats . Monkeys .. Humans

20 16 4

10 7 2

500 400 150 (approx.)

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* We have to thank the Director of Medical Services, Kenya, for permission to publish this paper.

66

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R. B. HEISCH AND A. E. C. HARVEY

67

In the case of the animals each daily dose, calculated according to body weight, was divided and placed in three gelatine'capsules, the contents of which were introduced orally at 8.30 a.m., 4.30 p.m:, arrd 11 p.m. f o r 3 days. The largest dose was given at 11 p.m. in order to maintain blood concentrations during the night. Table I shows that the white rats and monkeys received much heavier doses in relation to :their body weight than the general! paralytics, who after an initial dose of gramme 3 given at 3 p.m., received g r a m m e 1"5 4-hourly for 72 hours. The dose per kg. for the general paralytics shown in Table I is an approximate one as, the Africans were not weighed. Treatment could not be given for longer than 3 days because only limited supplies of chloramphenicol were available. The course of t h e experimentally induced infections is shown in Tables II and III. Blood films (thick drops stained with Giemsa) were examined daily for spirochaetes for 3 months. Table II shows that chloramphenicol shortened the primary attack in infected rats, spirochaetes disappearing from the peripheral blood by the 4th day in treated animals, while persisting until the 5th or 6th day in controls. Relapses, although delayed, were not prevented in treated animals. Of the 10 treated rats, seven relapsed as might have two others if they had lived longer. All 10 control rats relapsed, although in one of them this was delayed until the 80th day. The other results were more encouraging. Thus only two of seven treated monkeys relapsed, as compared with five out of nine controls, and two treated general paralytics failed to relapse. The course of the experimental disease in two Africans, one of whom was treated, is shown in the Chart. However, the general paralytics were from an area where tick-borne relapsing fever is endemic, and Table III shows that at least one of them (20c) was practically immune. Several months after recovery, a few of the treated rats were tested for residual brain infections. Their brains were emulsified and inoculated into clean animals, several of which became infected, showing that residual brain infections were not prevented in white rats. These results suggest, that in the dosage given, chloramphenicol was not particularly effective against laboratory animals infected with S. duttoni. Better results might have been obtained if treatment had been continued for longer than 3 days. Although the h u m a n series was too small to be of much significance, it is thought that the drug may prove more effective in the human disease. D~scuss~oN

Although this paper is concerned with experimental infections, it is felt that a more general statement on the treatment of relapsing fever may be of interest. It is difficult to judge the value of a drug in treating relapsing fever in Africans, because many ~of them live in areas where the tick-borne disease is endemic and are partially immune. The disease in such patients, even when untreated, is

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70

CHLORAMPHENICOL IN RELAPSING FEVER

often modified with a brief initial pyrexia and indefinite relapses. Results in Europeans would be more significant, but the disease in them is now rare. A drug to be effective against tick-borne relapsing fever should not only be capable of shortening the primary attack, but must prevent relapses. The most promising results appear to have been with aureomycin in South Africa where YEO (1950) treated 25 Bantu, only three relapsing. However, some of these Africans may have been partially immune. What has been said about the tick-borne disease does not apply to the louseborne variety, and it is not generally realized how different these two forms can be. The relapsing fever of Tropical and South Africa is mostly tick-borne, and caused by S. duttoni transmitted in nature by the tick Ornithodorus moubata. Other forms of the tick-borne disease occur in various parts of the world (e.g., America, Spain, the Middle East, and Russia). All these tick-borne strains have in common a tendency to cause relapses in humans (usually three to nine) and residual brain infections in laboratory animals, whereas with the louse-borne disease, although the primary attack is often more severe, relapses are less common and limited to one or two. Also louse-borne spirochaetes only rarely cause residual brain infections in laboratory animals. It is therefore much more difficult to judge the value of drugs in the treatment of louse-borne relapsing fever. In testing drugs against patients infected with S. duttoni, it is thought essential not only to have a carefully controlled African series, which should be observed for at least 3 months after treatment, but a parallel European series infected therapeutically. However, in our opinion, the final test of efficacy is the prevention o f residual brain infections which occur in a high proportion of white rats and mice after recovery from the tick-borne disease. SUMMARY

(1) White rats, monkeys and general paralytics infected with S. duttoni were treated with chloramphenicol. In animals the primary attack was shortened but relapses were not prevented. Two treated general paralytics failed to relapse, but they may have been partially immune. (2) Treatment did not prevent residual brain infections in white rats. (3) Certain criteria are suggested for judging the value of drugs in the treatment of tick-borne relapsing fever. REFERENCES SMITH, R. M., JOSLYN, D. A., GRAZILET, O. M., MCLEAN, I. W., PENNER, M. A., &

EHRLICH, J. (1948). 57. Bact., 55, 425. THOMPSON, P. E., & DUNN, MARY C. (1949). Fed. Proc., 8, 338. YEO, R. M. (1950). S..ZJfr. med. 57, 24, 457.