Editorial
Why a section of JGAR on antiparasitic resistance? Fabrizio Bruschi
Department of Translational Research, Università di Pisa School of Medicine
Pisa, Italy
The World Health Organization (WHO) defines drug resistance the ability of a parasite strain to multiply or to thrive in the presence of drug concentrations normally able to destroy parasites of the same species or to prevent their multiplication (1).
Antiparasitic resistance represents an emerging problem in the treatment of both human and animal parasitic diseases (2).
For this reason, JGAR deals with a new section entitled antiparasitic resistance, with the aim to increase the knowledge in this field and to develop this important research area.
We describe here the current situation about the occurrence of resistance to antiparasitic drugs. As regards malaria caused by Plasmodium falciparum this parasite has developed clinically significant resistance to all classes of antimalarial drugs, with the latest being reduced sensitivity to artemisinin and its derivatives (3 ), recently occurring in Cambodia and the border areas of Thailand (4).
The control of the spread of this drug resistance represents then a high priority (5).
A review on resistance to antimalaria drugs for P. falciparum malaria will appear in the next issues of the journal.
After introduction of antimalarial drugs in areas endemic for Plasmodium vivax resistance to this species is now well documented and its emergence usually reflects the extent of use of each antimalarial drug once it has been introduced (6).
As regards intestinal protozoa the informations about the resistance to nitroimidazoles or other antiprotozoan drugs are scarce. In giardiosis, just to give an example, treatment failure has been attributed to a number of causes, including parasite resistance to nitroimidazoles (7).
More informations are available on antihelmintic drugs due to the fact they have been distributed in community campaigns in the last decade in millions of doses with the main intent to control soil-transmitted helminthiasis (STH), schistosomiasis, onchocercosis and to progress towards elimination of lymphatic filariosis (8).
This massive use of drugs has produced a relevant drug pressure on the parasite population, increasing the occurrence of resistant isolates as already occurrred in nematode populations of livestock (9), resulting in the reduction of the efficacy of treatment either at the individual or community levels (10).
However, not all unsuccessful treatments must be ascribed to the occurrence of drug resistance, being other factors involved.
As regards soil-transmitted helminths, Ascaris lumbricoides, Trichuris trichiura and the hookworms are the most widespread STH infections. For these, benzimidazoles (BZ) drug (albendazole and mebendazole) and, to a lesser extent, pyrantel and levamisole are the recommended drugs by WHO for preventive chemotherapy (11). Four factors have been identified as contributing to the development of anthelmintic resistance of these parasites: (i) initial resistance allele frequency, (ii) treatment frequency, (iii) refugia (the proportion of the parasite population not exposed to drugs, thus escaping selection for resistance) and (iv) possibly underdosing (12).
Some molecular studies have analised the mechanisms of resistance, indicating the presence/absence of the-tubulin codon 200 polymorphism as linked to BZ resistance (13), however the molecular mechanism(s) of drug resistance in human STH has yet to be fully demonstrated.
In schistosomiasis there is no vaccine at present and the disease can be treated and controlled with praziquantel (PZQ), a drug developed in the 1970s and then identified as the treatment of choice by the WHO (14).
Very poor PZQ cure rates were reported in the past in Northern Senegal (15), however, no significant decreases of drug effectiveness have been observed until now at the population level in endemic regions, as shown in a study carried out in Pemba Island (Tanzania) (16). Some reports have described schistosomes with decreased PZQ sensitivity (17, 18) or individual PZQ failures in treated patients (19) and such a decreased sensitivity appears to be inherited as a partially dominant trait (20). Snails collected in the above-mentioned area of Northern Senegal carried a schistosome strain that, when tested in the laboratory, proved to have a decreased susceptibility to PZQ (21). A number of treatment failures, especially against S. haematobium, have been described in travelers returning to non-endemic areas, which rules out the possibility of reinfection (22, 23).
A well defined resistance has been described against oxamniquine (17, 24), but this drug is used in a very limited manner.
Reliance on a single drug for any disease of this magnitude is dangerous, as there are few if any alternatives should resistance arise (14).
For all these reasons, there is an increasing need to develope new antischistosomal drugs. At present, some antimalaria drugs (25) and new products (26) are evaluated for possible introduction. In onchocercosis, ivermectin (IVM) has been used for the control of this disease, in several control programs such as the Onchocerciasis Control Programme (West Africa), and it is still used for mass chemotherapy in the African Programme for Onchocerciasis Control and the Onchocerciasis Elimination Programme for the Americas, as the sole drug. This has caused the occurrence of genetic selection in Onchocerca volvulus (27, 28), envisaging the development of IVM resistance (29) where P-glycoproteins and other multidrug resistance transporters might be involved (30). Conclusions
In the near future, genetic and genomic methodologies will increase the knowledge on the drug resistance mechanisms which make both malaria and helminth infection treatment unsuccessful. The set up of more reliable and hopefully inexpensive tools, such as the recent advances in sequencing whole genomes, will simplify and ameliorate the accuracy of locating parasite genes involved in the modulation of drug responses.
This knowledge will be obviously useful to formulate better drugs for future usage. References
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