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The management of drug resistance
Parasitology Today, vol 9, no. 5, 1993
149
The Management of Drug Resistance The occurrence and seriousness of drug resistance in parasitic diseases are of such common knowledge and concern that it is not necessary to iustify devoting an entire issue to the subject. At the planning stage, the aim was to cover as many parasitic diseases as practicable, and to present as broad a spectrum of disciplines as the relevant subject matter allowed. The resulting contributions range in emphasis, from the biochemical, genetic and molecular biological, to discussions of management, research funding and vector control. Malaria is present in 102 countries, and accounts for 100 million clinical cases and two million deaths annually. Gone is the 'heyday of funding malaria eradication'; we now find ourselves in the 'quagmire of malaria control'. Bu¢~ as Brian Schuster and Wilbur Milhous ask, why is this disease (the scale of which puts AIDS in glaring perspective) being virtually ignored by the majority of pharmaceutical companies? In the first of two papers on malaria, they plead for industrialized nations to recognize that malaria is a threat that will have a tremendous impact, economically and socially, on them, too, and that funding agencies must act with that in mind. In the second paper, Allan Schapira, Peter Beales and M, Elizabeth Halloran discuss ways of living with chloroquine resistance in Africa, and stress the importance of strengthening management of the disease, with appropriate mathematical models for analysing the long- and short-term consequences of drug policy change. They stress that the emphasis must be on setting modest, realistic targets, and on reacting in measured ways, rather than waiting for the single, simple solution. Resistance to schistosomes is (so far) restricted to the hycanthone/oxamniquine family, Donato Cioli, Livia
Pica-Mattoccia and Sydney Archer look at the genetics and biochemistry of resistance, and discuss how it is due to the loss of a drug-activating (esterifying) enzyme that is present in sensitive schistosomes. Assessing the situation in African trypanosomes, Cyrus Bacchi looks at resistance to melarsoprof and the relationship between resistance to melarsoprol and diamidine, and outlines developments in the elucidation of mechanisms of resistance to DL-e~-difluoromethylomithine, which is effective © 1993, Elsevier Science Publishers Ltd, (UK)
against West African but not East African disease, in laboratory strains of
Trypanosoma brucei rhodesiense. The first report of refractoriness of Leishmania to antimonial chemotherapy was in the 1940s. The ease with which drug-resistant strains of L. tarentolae can be maintained in the laboratory have facilitated the study of resistance mechanisms. Marc Ouellette and Barbara Papadopoulou look at mechanisms of pentavalent antimonial resistance in promastigote forms and survey the occurrence of gene amplification. They conclude that the H locus of the Leishmania genome contains several drug-resistance genes, and that gene amplification has evolved to be the preferred resistance mechanism. The selectivity of activity of metronidazole is based on biochemical mechanisms peculiar to its anaerobic targets, in that the nitro group of the inactive, administered form is reduced via metabolic pathways of low redox potential found exclusively in anaerobes. Patricia Johnson discusses how activation results in a gradient that drives more of the inactive form into the cell. Metronidazote has been used for the past 30 years, and is the only drug for the treatment of trichomoniasis, which affects 150 million women worldwide. Indeed, resistance to this drug has been best studied in Trichomonas vaginatis, but, as Jacqueline and Peter Upcroft stress, every time metronidazole is used prophylactically in a developing country, the chances are great that T. vaginatis, Entamoeba histolytica and Giardia duodenalis will be exposed. Because of this drug's efficacy, bioavailability, cost and general tolerance, the horrific consequences that are now being witnessed in Trichomonas resistance will surely be seen, with increasing frequency, in Giardia. Then what will we do? The prophylactic supplementation of poultry feed with drugs against Eimeria has been convenient and cost effective, and has facilitated intensive farming practices. But at what cost? David Chapman gives, in some detail, an account of how Eimeria is now resistant to all drugs thrown at it. The practicality of a vaccination program is questionable. Resistance to benzimidazoles is not discussed in this issue. This journal has recently featured this area (see Para-
sitotogy Today, April issue 1990) and Marlene Roos is currently preparing an update. In this issue, Wesley Shoop discusses the occurrence of resistance to ivermectin in trichostrongyles from the gastrointestinal tracts of sheep and goats, and considers a future in which resistance will spread to the filariae. He makes a powerful case for getting right our definition of drug resistance', if we do not correctly identify the point at which drug resistance occurs, we run the obvious risk of recognizing the problem when it is too late to do anything about it. Tests for earlier detection are seen to be the key to preserving the longevity of broad-spectrum anthelmintics, This is one of the points also made by Richard Roush, when he discusses resistance to insecticides. As he eloquently describes, resistance has always been seen as a business opportunity for those companies with new insecticides to market. But from 1908, when we had the first report of insecticide resistance to inorganic insecticides, we have come to a situation where we have resistance to every kind of widely used toxicant, in more than 500 species. Once resistance is recognized to have occurred, the frequencies are so high that most of the best options to manage it are ineffective. Need it always be so? In addition to insecticide resistance, there must be research into complementary, non-chemical approaches to vector control. Charles Beard, Scott O'Neill, Robert Tesh, Frank Richards and Serap Aksoy discuss work on transforming symbiotic bacteria of Rhodnius protixus (vector of Trypanosoma cruzi) and Glossina morsitans (vector of T. brucei) that would result in engineered refractoriness to infection. The message from across the board of drug resistance in parasites is loud and clear. Knowledge, and the will to apply it, must result in measured, intelligent management programs. A declaration of drug resistance that comes in time to take effective action is vital. The consequences of not doing so will surely be catastrophic. For all of us. It is appropriate for a Special Issue that special gratitude be expressed: to authors, and to the referees of their manuscripts, through whom excellence is guaranteed. Thank you. Theresa Saklatvala
149
The Management of Drug Resistance The occurrence and seriousness of drug resistance in parasitic diseases are of such common knowledge and concern that it is not necessary to iustify devoting an entire issue to the subject. At the planning stage, the aim was to cover as many parasitic diseases as practicable, and to present as broad a spectrum of disciplines as the relevant subject matter allowed. The resulting contributions range in emphasis, from the biochemical, genetic and molecular biological, to discussions of management, research funding and vector control. Malaria is present in 102 countries, and accounts for 100 million clinical cases and two million deaths annually. Gone is the 'heyday of funding malaria eradication'; we now find ourselves in the 'quagmire of malaria control'. Bu¢~ as Brian Schuster and Wilbur Milhous ask, why is this disease (the scale of which puts AIDS in glaring perspective) being virtually ignored by the majority of pharmaceutical companies? In the first of two papers on malaria, they plead for industrialized nations to recognize that malaria is a threat that will have a tremendous impact, economically and socially, on them, too, and that funding agencies must act with that in mind. In the second paper, Allan Schapira, Peter Beales and M, Elizabeth Halloran discuss ways of living with chloroquine resistance in Africa, and stress the importance of strengthening management of the disease, with appropriate mathematical models for analysing the long- and short-term consequences of drug policy change. They stress that the emphasis must be on setting modest, realistic targets, and on reacting in measured ways, rather than waiting for the single, simple solution. Resistance to schistosomes is (so far) restricted to the hycanthone/oxamniquine family, Donato Cioli, Livia
Pica-Mattoccia and Sydney Archer look at the genetics and biochemistry of resistance, and discuss how it is due to the loss of a drug-activating (esterifying) enzyme that is present in sensitive schistosomes. Assessing the situation in African trypanosomes, Cyrus Bacchi looks at resistance to melarsoprof and the relationship between resistance to melarsoprol and diamidine, and outlines developments in the elucidation of mechanisms of resistance to DL-e~-difluoromethylomithine, which is effective © 1993, Elsevier Science Publishers Ltd, (UK)
against West African but not East African disease, in laboratory strains of
Trypanosoma brucei rhodesiense. The first report of refractoriness of Leishmania to antimonial chemotherapy was in the 1940s. The ease with which drug-resistant strains of L. tarentolae can be maintained in the laboratory have facilitated the study of resistance mechanisms. Marc Ouellette and Barbara Papadopoulou look at mechanisms of pentavalent antimonial resistance in promastigote forms and survey the occurrence of gene amplification. They conclude that the H locus of the Leishmania genome contains several drug-resistance genes, and that gene amplification has evolved to be the preferred resistance mechanism. The selectivity of activity of metronidazole is based on biochemical mechanisms peculiar to its anaerobic targets, in that the nitro group of the inactive, administered form is reduced via metabolic pathways of low redox potential found exclusively in anaerobes. Patricia Johnson discusses how activation results in a gradient that drives more of the inactive form into the cell. Metronidazote has been used for the past 30 years, and is the only drug for the treatment of trichomoniasis, which affects 150 million women worldwide. Indeed, resistance to this drug has been best studied in Trichomonas vaginatis, but, as Jacqueline and Peter Upcroft stress, every time metronidazole is used prophylactically in a developing country, the chances are great that T. vaginatis, Entamoeba histolytica and Giardia duodenalis will be exposed. Because of this drug's efficacy, bioavailability, cost and general tolerance, the horrific consequences that are now being witnessed in Trichomonas resistance will surely be seen, with increasing frequency, in Giardia. Then what will we do? The prophylactic supplementation of poultry feed with drugs against Eimeria has been convenient and cost effective, and has facilitated intensive farming practices. But at what cost? David Chapman gives, in some detail, an account of how Eimeria is now resistant to all drugs thrown at it. The practicality of a vaccination program is questionable. Resistance to benzimidazoles is not discussed in this issue. This journal has recently featured this area (see Para-
sitotogy Today, April issue 1990) and Marlene Roos is currently preparing an update. In this issue, Wesley Shoop discusses the occurrence of resistance to ivermectin in trichostrongyles from the gastrointestinal tracts of sheep and goats, and considers a future in which resistance will spread to the filariae. He makes a powerful case for getting right our definition of drug resistance', if we do not correctly identify the point at which drug resistance occurs, we run the obvious risk of recognizing the problem when it is too late to do anything about it. Tests for earlier detection are seen to be the key to preserving the longevity of broad-spectrum anthelmintics, This is one of the points also made by Richard Roush, when he discusses resistance to insecticides. As he eloquently describes, resistance has always been seen as a business opportunity for those companies with new insecticides to market. But from 1908, when we had the first report of insecticide resistance to inorganic insecticides, we have come to a situation where we have resistance to every kind of widely used toxicant, in more than 500 species. Once resistance is recognized to have occurred, the frequencies are so high that most of the best options to manage it are ineffective. Need it always be so? In addition to insecticide resistance, there must be research into complementary, non-chemical approaches to vector control. Charles Beard, Scott O'Neill, Robert Tesh, Frank Richards and Serap Aksoy discuss work on transforming symbiotic bacteria of Rhodnius protixus (vector of Trypanosoma cruzi) and Glossina morsitans (vector of T. brucei) that would result in engineered refractoriness to infection. The message from across the board of drug resistance in parasites is loud and clear. Knowledge, and the will to apply it, must result in measured, intelligent management programs. A declaration of drug resistance that comes in time to take effective action is vital. The consequences of not doing so will surely be catastrophic. For all of us. It is appropriate for a Special Issue that special gratitude be expressed: to authors, and to the referees of their manuscripts, through whom excellence is guaranteed. Thank you. Theresa Saklatvala