- Email: [email protected]
The challenge of antiparasitic resistance
Journal of Global Antimicrobial Resistance 2 (2014) 131–132
Contents lists available at ScienceDirect
Journal of Global Antimicrobial Resistance journal homepage: www.elsevier.com/locate/jgar
Editorial
The challenge of antiparasitic resistance
Antiparasitic resistance is a global issue, representing an emerging problem in the treatment both of human and animal parasitic diseases. JGAR’s new section entitled ‘Antiparasitic resistance’ aims to diffuse knowledge in this field, monitoring the occurrence and tracking the molecular mechanisms of resistance to antiparasitic drugs. The journal is now open to receive contributions in this important research area. A high priority has, of course, been control of the spread of antimalarial drug resistance. Plasmodium falciparum has developed clinically significant resistance to all classes of antimalarial drugs, including artemisinin and its derivatives, as occurred in Cambodia and the border areas of Thailand [1]. Plasmodium vivax has also developed resistance following the introduction of antimalarial drugs, especially in areas where it is endemic, and resistance emergence usually reflects the extent of use of the antimalarial drugs [2]. Information regarding intestinal protozoa resistance to nitroimidazoles or other antiprotozoan drugs is scarce. In giardiasis, for example, treatment failures have been attributed to a number of causes, including resistance to nitroimidazoles [3]. More information is available on anthelmintic drugs owing to the fact they have been distributed in community campaigns in the last decade in millions of doses with the main intention to control soil-transmitted helminthiasis (STH), schistosomiasis and onchocerciasis and to progress towards the elimination of lymphatic filariasis [4]. This massive use of drugs has produced a relevant drug pressure on the parasite population, increasing the occurrence of resistant isolates, as already occurred in nematode populations of livestock, resulting in a reduction in the efficacy of treatment both at the individual and community level [5]. However, not all unsuccessful treatments must be ascribed to the occurrence of drug resistance; in fact, other factors are involved. Regarding soil-transmitted helminths, Ascaris lumbricoides, Trichuris trichiura and hookworms are the most widespread STH infections. For these, benzimidazole drugs (albendazole and mebendazole) and, to a lesser extent, pyrantel and levamisole are the World Health Organization (WHO)-recommended drugs for preventive chemotherapy [6]. Four factors have been identified as contributing to the development of anthelmintic drug 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) underdosing [7]. Some molecular studies have analysed the mechanisms of resistance, indicating the b-tubulin codon 200 polymorphism as
linked to benzimidazole resistance [8]; however, the molecular mechanism(s) of drug resistance in human STH has not yet been fully demonstrated. For schistosomiasis, there is currently no effective vaccine and the disease can be treated only by chemotherapy. Praziquantel (PZQ), a drug developed in the 1970s and known for its safety and reliance, has been identified by the WHO as the drug of choice [9]. Until now, no significant decreases in drug effectiveness have been observed at the population level in endemic regions, as shown in a study carried out on Pemba Island (Tanzania) [10]. However, some reports have described schistosomes with decreased PZQ sensitivity [11] or individual PZQ failures in treated patients [12], and such a decreased sensitivity appears to be inherited as a partially dominant trait [13]. A number of treatment failures, especially against Schistosoma haematobium, have been described in travellers returning to non-endemic areas, which rules out the possibility of re-infection [14,15]. For all these reasons, there is an ongoing need to develop new antischistosomal drugs. At present, some antimalarial drugs and new products are being evaluated for their introduction into the clinic [16,17]. Moreover, thanks to the publication of complete genomes and transcriptomes of Schistosoma mansoni, Schistosoma japonicum and S. haematobium, identification of new drug targets will be possible [18]. Regarding onchocerciasis, ivermectin (IVM) has been used for the management of this disease in several control programmes, 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, envisaging the development of IVM resistance where P-glycoproteins and other multidrug resistance transporters might be involved [19–22]. In the near future, high-throughput genetic and genomic approaches will elucidate the drug resistance mechanisms that make treatment of both malaria and helminth infections unsuccessful. The setting up of more reliable and hopefully reasonably priced tools will simplify and improve the accuracy of locating parasite genes involved in the modulation of drug responses. All these data will be extremely useful to formulate better drugs for future usage. References [1] Na-Bangchang K, Karbwang J. Emerging artemisinin resistance in the border areas of Thailand. Expert Rev Clin Pharmacol 2013;6:307–22.
http://dx.doi.org/10.1016/j.jgar.2014.06.002 2213-7165/ß 2014 Published by Elsevier Ltd on behalf of International Society for Chemotherapy of Infection and Cancer.
132
Editorial / Journal of Global Antimicrobial Resistance 2 (2014) 131–132
[2] Mwangi JM, Ranford-Cartwright LC. Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance. Parasitology 2013;140:1455–67. [3] Lopez-Velez R, Batlle C, Jime´nez C, Navarro M, Norman F, Perez-Molina J. Short course combination therapy for giardiasis after nitroimidazole failure. Am J Trop Med Hyg 2010;83:171–3. [4] Albonico M, Cioli D, Prichard RK. Anthelmintic resistance in humans: what’s new. Parassitologia 2010;52:75–8. [5] Albonico M, Engels D, Savioli L. Monitoring drug efficacy and early detection of drug resistance in human soil-transmitted nematodes: a pressing public health agenda for helminth control. Int J Parasitol 2004;34:1205–10. [6] World Health Organization. Preventive chemotherapy for human helminthiasis. Geneva, Switzerland: WHO; 2006. [7] Vercruysse J, Albonico M, Behnke JM, Kotze AC, Prichard RK, McCarthy JS, et al. Is anthelmintic resistance a concern for the control of human soil-transmitted helminths? Int J Parasitol Drugs Drug Resist 2011;1:14–27. [8] Diawara A, Drake LJ, Suswillo RR, Kihara J, Bundy DA, Scott ME, et al. Assays to detect b tubulin codon 200 polymorphisms in Trichuris trichiura and Ascaris lumbricoides. PLoS Negl Trop Dis 2009;3:e397. [9] Greenberg RM. New approaches for understanding mechanisms of drug resistance in schistosomes. Parasitology 2013;140:1534–46. [10] Guidi A, Andolina C, Makame Ame S, Albonico M, Cioli D, Juma Haji H. Praziquantel efficacy and long-term appraisal of schistosomiasis control in Pemba Island. Trop Med Int Health 2010;15:614–8. [11] Botros S, Pica-Mattoccia L, William S, El-Lakkani N, Cioli D. Effect of praziquantel on the immature stages of Schistosoma haematobium. Int J Parasitol 2005;35:1453–7. [12] Ismail M, Metwally A, Farghaly A, Bruce J, Tao LF, Bennett JL. Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel. Am J Trop Med Hyg 1996;55:214–8. [13] Pica-Mattoccia L, Doenhoff MJ, Valle C, Basso A, Troiani AR, Liberti P, et al. Genetic analysis of decreased praziquantel sensitivity in a laboratory strain of Schistosoma mansoni. Acta Trop 2009;111:82–5. [14] Silva IM, Thiengo R, Conceic¸a˜o MJ, Rey L, Lenzi HL, Pereira Filho E, et al. Therapeutic failure of praziquantel in the treatment of Schistosoma haematobium infection in Brazilians returning from Africa. Mem Inst Oswaldo Cruz 2005;100:445–9. ˜ oz J, Gasco´n J, Valls ME, Corachan M. Failure of standard [15] Alonso D, Mun treatment with praziquantel in two returned travelers with Schistosoma haematobium infection. Am J Trop Med Hyg 2006;74:342–4.
[16] Keiser J, N’Guessan NA, Adoubryn KD, Silue´ KD, Vounatsou P, Hatz C, et al. Efficacy and safety of mefloquine, artesunate, mefloquine–artesunate, and praziquantel against Schistosoma haematobium: randomized, exploratory open-label trial. Clin Infect Dis 2010;50:1205–13. [17] Abdulla MH, Ruelas DS, Wolff B, Snedecor J, Lim KC, Xu F, et al. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. PLoS Negl Trop Dis 2009;3:e478. [18] Lee EF, Young ND, Lim NTY, Gasser RB, Fairlie WD. Apoptosis in schistosomes: toward novel targets for the treatment of schistosomiasis. Trends Parasitol 2014;30:75–84. [19] Eng JK, Blackhall WJ, Osei-Atweneboana MY, Bourguinat C, Galazzo D, Beech RN, et al. Ivermectin selection on b-tubulin: evidence in Onchocerca volvulus and Haemonchus contortus. Mol Biochem Parasitol 2006;50:229–35. [20] Bourguinat C, Pion SD, Kamgno J, Gardon J, Duke BO, Boussinesq M, et al. Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment. PLoS Negl Trop Dis 2007;1:12–22. [21] Osei-Atweneboana MY, Awadzi K, Attah SK, Boakye DA, Gyapong JO, Prichard RK. Phenotypic evidence of emerging ivermectin resistance in Onchocerca volvulus. PLoS Negl Trop Dis 2011;5:e998. [22] Lespine A, Me´nez C, Bourguinat C, Prichard RK. P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: prospects for reversing transport-dependent anthelmintic resistance. Int J Parasitol Drugs Drug Resist 2012;2:58–75.
Fabrizio Bruschi Department of Translational Research, Universita` di Pisa, School of Medicine, Pisa, Italy
E-mail address: [email protected] (F. Bruschi).
Contents lists available at ScienceDirect
Journal of Global Antimicrobial Resistance journal homepage: www.elsevier.com/locate/jgar
Editorial
The challenge of antiparasitic resistance
Antiparasitic resistance is a global issue, representing an emerging problem in the treatment both of human and animal parasitic diseases. JGAR’s new section entitled ‘Antiparasitic resistance’ aims to diffuse knowledge in this field, monitoring the occurrence and tracking the molecular mechanisms of resistance to antiparasitic drugs. The journal is now open to receive contributions in this important research area. A high priority has, of course, been control of the spread of antimalarial drug resistance. Plasmodium falciparum has developed clinically significant resistance to all classes of antimalarial drugs, including artemisinin and its derivatives, as occurred in Cambodia and the border areas of Thailand [1]. Plasmodium vivax has also developed resistance following the introduction of antimalarial drugs, especially in areas where it is endemic, and resistance emergence usually reflects the extent of use of the antimalarial drugs [2]. Information regarding intestinal protozoa resistance to nitroimidazoles or other antiprotozoan drugs is scarce. In giardiasis, for example, treatment failures have been attributed to a number of causes, including resistance to nitroimidazoles [3]. More information is available on anthelmintic drugs owing to the fact they have been distributed in community campaigns in the last decade in millions of doses with the main intention to control soil-transmitted helminthiasis (STH), schistosomiasis and onchocerciasis and to progress towards the elimination of lymphatic filariasis [4]. This massive use of drugs has produced a relevant drug pressure on the parasite population, increasing the occurrence of resistant isolates, as already occurred in nematode populations of livestock, resulting in a reduction in the efficacy of treatment both at the individual and community level [5]. However, not all unsuccessful treatments must be ascribed to the occurrence of drug resistance; in fact, other factors are involved. Regarding soil-transmitted helminths, Ascaris lumbricoides, Trichuris trichiura and hookworms are the most widespread STH infections. For these, benzimidazole drugs (albendazole and mebendazole) and, to a lesser extent, pyrantel and levamisole are the World Health Organization (WHO)-recommended drugs for preventive chemotherapy [6]. Four factors have been identified as contributing to the development of anthelmintic drug 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) underdosing [7]. Some molecular studies have analysed the mechanisms of resistance, indicating the b-tubulin codon 200 polymorphism as
linked to benzimidazole resistance [8]; however, the molecular mechanism(s) of drug resistance in human STH has not yet been fully demonstrated. For schistosomiasis, there is currently no effective vaccine and the disease can be treated only by chemotherapy. Praziquantel (PZQ), a drug developed in the 1970s and known for its safety and reliance, has been identified by the WHO as the drug of choice [9]. Until now, no significant decreases in drug effectiveness have been observed at the population level in endemic regions, as shown in a study carried out on Pemba Island (Tanzania) [10]. However, some reports have described schistosomes with decreased PZQ sensitivity [11] or individual PZQ failures in treated patients [12], and such a decreased sensitivity appears to be inherited as a partially dominant trait [13]. A number of treatment failures, especially against Schistosoma haematobium, have been described in travellers returning to non-endemic areas, which rules out the possibility of re-infection [14,15]. For all these reasons, there is an ongoing need to develop new antischistosomal drugs. At present, some antimalarial drugs and new products are being evaluated for their introduction into the clinic [16,17]. Moreover, thanks to the publication of complete genomes and transcriptomes of Schistosoma mansoni, Schistosoma japonicum and S. haematobium, identification of new drug targets will be possible [18]. Regarding onchocerciasis, ivermectin (IVM) has been used for the management of this disease in several control programmes, 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, envisaging the development of IVM resistance where P-glycoproteins and other multidrug resistance transporters might be involved [19–22]. In the near future, high-throughput genetic and genomic approaches will elucidate the drug resistance mechanisms that make treatment of both malaria and helminth infections unsuccessful. The setting up of more reliable and hopefully reasonably priced tools will simplify and improve the accuracy of locating parasite genes involved in the modulation of drug responses. All these data will be extremely useful to formulate better drugs for future usage. References [1] Na-Bangchang K, Karbwang J. Emerging artemisinin resistance in the border areas of Thailand. Expert Rev Clin Pharmacol 2013;6:307–22.
http://dx.doi.org/10.1016/j.jgar.2014.06.002 2213-7165/ß 2014 Published by Elsevier Ltd on behalf of International Society for Chemotherapy of Infection and Cancer.
132
Editorial / Journal of Global Antimicrobial Resistance 2 (2014) 131–132
[2] Mwangi JM, Ranford-Cartwright LC. Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance. Parasitology 2013;140:1455–67. [3] Lopez-Velez R, Batlle C, Jime´nez C, Navarro M, Norman F, Perez-Molina J. Short course combination therapy for giardiasis after nitroimidazole failure. Am J Trop Med Hyg 2010;83:171–3. [4] Albonico M, Cioli D, Prichard RK. Anthelmintic resistance in humans: what’s new. Parassitologia 2010;52:75–8. [5] Albonico M, Engels D, Savioli L. Monitoring drug efficacy and early detection of drug resistance in human soil-transmitted nematodes: a pressing public health agenda for helminth control. Int J Parasitol 2004;34:1205–10. [6] World Health Organization. Preventive chemotherapy for human helminthiasis. Geneva, Switzerland: WHO; 2006. [7] Vercruysse J, Albonico M, Behnke JM, Kotze AC, Prichard RK, McCarthy JS, et al. Is anthelmintic resistance a concern for the control of human soil-transmitted helminths? Int J Parasitol Drugs Drug Resist 2011;1:14–27. [8] Diawara A, Drake LJ, Suswillo RR, Kihara J, Bundy DA, Scott ME, et al. Assays to detect b tubulin codon 200 polymorphisms in Trichuris trichiura and Ascaris lumbricoides. PLoS Negl Trop Dis 2009;3:e397. [9] Greenberg RM. New approaches for understanding mechanisms of drug resistance in schistosomes. Parasitology 2013;140:1534–46. [10] Guidi A, Andolina C, Makame Ame S, Albonico M, Cioli D, Juma Haji H. Praziquantel efficacy and long-term appraisal of schistosomiasis control in Pemba Island. Trop Med Int Health 2010;15:614–8. [11] Botros S, Pica-Mattoccia L, William S, El-Lakkani N, Cioli D. Effect of praziquantel on the immature stages of Schistosoma haematobium. Int J Parasitol 2005;35:1453–7. [12] Ismail M, Metwally A, Farghaly A, Bruce J, Tao LF, Bennett JL. Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel. Am J Trop Med Hyg 1996;55:214–8. [13] Pica-Mattoccia L, Doenhoff MJ, Valle C, Basso A, Troiani AR, Liberti P, et al. Genetic analysis of decreased praziquantel sensitivity in a laboratory strain of Schistosoma mansoni. Acta Trop 2009;111:82–5. [14] Silva IM, Thiengo R, Conceic¸a˜o MJ, Rey L, Lenzi HL, Pereira Filho E, et al. Therapeutic failure of praziquantel in the treatment of Schistosoma haematobium infection in Brazilians returning from Africa. Mem Inst Oswaldo Cruz 2005;100:445–9. ˜ oz J, Gasco´n J, Valls ME, Corachan M. Failure of standard [15] Alonso D, Mun treatment with praziquantel in two returned travelers with Schistosoma haematobium infection. Am J Trop Med Hyg 2006;74:342–4.
[16] Keiser J, N’Guessan NA, Adoubryn KD, Silue´ KD, Vounatsou P, Hatz C, et al. Efficacy and safety of mefloquine, artesunate, mefloquine–artesunate, and praziquantel against Schistosoma haematobium: randomized, exploratory open-label trial. Clin Infect Dis 2010;50:1205–13. [17] Abdulla MH, Ruelas DS, Wolff B, Snedecor J, Lim KC, Xu F, et al. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. PLoS Negl Trop Dis 2009;3:e478. [18] Lee EF, Young ND, Lim NTY, Gasser RB, Fairlie WD. Apoptosis in schistosomes: toward novel targets for the treatment of schistosomiasis. Trends Parasitol 2014;30:75–84. [19] Eng JK, Blackhall WJ, Osei-Atweneboana MY, Bourguinat C, Galazzo D, Beech RN, et al. Ivermectin selection on b-tubulin: evidence in Onchocerca volvulus and Haemonchus contortus. Mol Biochem Parasitol 2006;50:229–35. [20] Bourguinat C, Pion SD, Kamgno J, Gardon J, Duke BO, Boussinesq M, et al. Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment. PLoS Negl Trop Dis 2007;1:12–22. [21] Osei-Atweneboana MY, Awadzi K, Attah SK, Boakye DA, Gyapong JO, Prichard RK. Phenotypic evidence of emerging ivermectin resistance in Onchocerca volvulus. PLoS Negl Trop Dis 2011;5:e998. [22] Lespine A, Me´nez C, Bourguinat C, Prichard RK. P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: prospects for reversing transport-dependent anthelmintic resistance. Int J Parasitol Drugs Drug Resist 2012;2:58–75.
Fabrizio Bruschi Department of Translational Research, Universita` di Pisa, School of Medicine, Pisa, Italy
E-mail address: [email protected] (F. Bruschi).