Drug Resistance in Protozoa

Bishop, Ann

doi:10.1111/j.1469-185x.1959.tb01456.x

Cited by 3 publications

(3 citation statements)

References 188 publications

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“…Resistance to isometamidium is not yet a major problem, but its incidence appears to be increasing (Pinder & Authie, 1984;Rottcher & Schillinger, 1985). Unlike the situation in a range of organisms, such as arthropods (Beranek, 1974), Plasmodium species (Bishop, 1959) and trichostrongylid nematodes (Sutherland, Lee & Lewis, 1988), where resistance to chemotherapeutic agents is already a problem, the opportunity exists with T. congolense and other trypanosome species to elucidate the mechanism/s responsible for resistance and, perhaps, to control the onset of resistance before widespread treatment breakdown. Firstly, however, suitable methods for the detection of drug-resistant populations of trypanosomes have to be developed.…”

Section: Discussionmentioning

confidence: 99%

Reduced accumulation of isometamidium by drug-resistant Trypanosoma congolense

et al. 1991

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The accumulation of the trypanocide isometamidium chloride (Samorin, RMB Animal Health Ltd., UK) by a range of clones of Trypanosoma congolense with varying sensitivity to the drug, was measured by methods based on the fluorescence of isometamidium. Fluorescence microscopy and flow cytometry showed a reduction in drug accumulation by resistant clones. Fluorescence spectrophotometry demonstrated an inverse correlation between the intensity of cell-associated fluorescence and the level of resistance of the clones expressed in vivo. The addition of the metabolic inhibitor SHAM/glycerol to the incubation medium resulted in a reduction of this apparent difference in drug accumulation between the clones; those clones which were sensitive to isometamidium showed a reduction in fluorescence while a percentage increase in fluorescence was observed as clones became more resistant to the trypanocide. These observations may be of value for the in vitro detection of resistant T. congolense populations and may also be used to estimate the mean level of resistance in a given sample. The results also imply that decreased accumulation of isometamidium by drug-resistant clones of the parasite may be responsible for the reduction in sensitivity.

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Section: Discussionmentioning

confidence: 99%

Reduced accumulation of isometamidium by drug-resistant Trypanosoma congolense

et al. 1991

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“…The form of the experiments was similar to that of the previous experiments on proguanil resistance. Several workers have shown that strains resistant to pyrimethamine are likewise resistant to proguanil, though proguanilresistant strains are not always resistant to pyrimethamine (see Bishop, 1959); in some of the strains treated with pyrimethamine tests were therefore made for resistance to both proguanil and pyrimethamine.…”

Section: The Effect Of the Size Of The Inoculum And The Dose Of Drmentioning

confidence: 99%

An analysis of the development of resistance to proguanil and pyrimethamine in Plasmodium gallinaceum

Bishop

1962

Parasitology

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1. The development of resistance to proguanil and pyrimethamine was studied in a clone of Plasmodium gallinaceum (strain A) derived from a single erythrocytic parasite and maintained by a standard method of serial inoculations in young chicks.2. The rate of the development of resistance to 0·05 mg./20 g. doses of proguanil was compared in strains maintained by inocula of 5 × 107, 108 and 109 parasites. Some evidence was obtained that the rate of the development of resistance to the drug was related to the numbers of parasites in the inocula.3. No correlation was observed between the rate of the development of resistance to pyrimethamine and the size of the population of parasites exposed to its action in strains treated with 0·001 g./20 g. doses of the drug and maintained by inocula of 5 × 107 parasites or 109 parasites; but a greater variability was observed in the rate in the strains maintained by the small inocula than in the strains maintained by the large inocula. Resistance appeared to develop sporadically.4. Some evidence was obtained that strains treated with a high dose of pyrimethamine (0·05 mg./20 g.) might become more sensitive to the drug as a result of treatment. In three experiments the infections were eradicated by the second or third course of treatment with the drug. However, strains which withstood this dose, developed resistance as rapidly, or more rapidly than those treated with 0·001 mg./20 g. doses. There was therefore no evidence from these experiments with pyrimethamine that resistance to the drug could be produced more readily with small than with large doses of the drug.5. Except for slight variations, resistance to proguanil developed concurrently with resistance to pyrimethamine in strains treated with that drug.6. In many of the strains, whether treated with proguanil or with pyrimethamine, resistance appeared to develop quite suddenly, but in others it developed more gradually. The pattern of the development of resistance in strains treated with either of these drugs could be explained by the selection of spontaneously occurring mutants, though some of the data suggested that the mutants differed in degree of resistance to the drug.7. The rate of development of resistance to pyrimethamine was studied in strains derived from primary inocula composed of known numbers of pyrimethamine resistant parasites and 5 × 107 parasites of the untreated strain A. The addition of at least 106 resistant parasites to the inoculum was required to produce an increase in parasitaemia during the subsequent course of treatment with the drug, but the addition of 102 resistant parasites or, in some experiments, fewer than 102 resistant parasites to the primary inoculum was sufficient to produce a heavy parasitaemia during the second serial course of treatment if the strain was maintained by the standard method (p. 496). When these results are compared with the pattern of the development of resistance to pyrimethamine in the strains treated with that drug, it can be concluded that only in one strain was there any evidence that resistant parasites were present in the primary inoculum when it consisted only of parasites of the untreated parent strain. The rate of development of resistance in many of the strains treated with either proguanil or pyrimethamine suggested a mutation rate of a low frequency.

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“…There was thus no evidence that the strain had become resistant to the drug as a result of its prolonged contact with it. It has, however, been known for many years that resistance to proguanil can be developed relatively easily in avian, monkey and human malaria (Bishop, 1959), and Davey (personal communication) was able to make a strain of P. gallinaceum resistant to 4,6:diamino-l-(p-chlorophenyl)-l,2dihydro-2,2-dimethyl-s-triazine, which forms the active moiety of cycloguanil, by passing a strain through chicks which received repeated doses of the drug, an observation also made by Benazet (1964). A strain of P. berghei also has been made resistant to this compound (Thompson, Bayles, Olszewski & Waitz, 1965).…”

Section: Introductionmentioning

confidence: 99%

A study of resistance to cycloguanil in Plasmodium gallinaceum in chicks

Bishop

1966

Parasitology

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A cycloguanil-resistant strain of Plasmodium gallinaceum was produced relatively rapidly by passage through chicks treated with low but effective doses of the drug, the dose being increased as resistance developed.The strain was cross-resistant to proguanil but not to pyrimethamine or chloroquine.A strain highly resistant to proguanil was resistant to cycloguanil but only slightly resistant to pyrimethamine.A strain highly resistant to pyrimethamine was resistant to proguanil and cycloguanil.Passage for 20 months through birds treated with doses of cycloguanil which suppressed infection for relatively long periods failed to change the sensitivity of the strain to this drug or to proguanil. Although the relatively large dose did not eradicate the infection in any of the birds, subinoculations demonstrated that parasites were absent from the blood for a period in some of the birds, though infections finally developed.I am indebted to Parke Davis and Company for the supply of cycloguanil, to Imperial Chemical Industries Ltd. for the proguanil hydrochloride and chloroquine phosphate and to Burroughs Wellcome and Company for the pyrimethamine base.

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Drug Resistance in Protozoa

Cited by 3 publications

References 188 publications

Reduced accumulation of isometamidium by drug-resistant Trypanosoma congolense

Reduced accumulation of isometamidium by drug-resistant Trypanosoma congolense

An analysis of the development of resistance to proguanil and pyrimethamine in Plasmodium gallinaceum

A study of resistance to cycloguanil in Plasmodium gallinaceum in chicks

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