Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2017

Open Access 01-12-2017 | Research

Ivermectin susceptibility, sporontocidal effect, and inhibition of time to re-feed in the Amazonian malaria vector Anopheles darlingi

Authors: Kevin C. Kobylinski, Karín S. Escobedo-Vargas, Victor M. López-Sifuentes, Salomón Durand, Edward S. Smith, G. Christian Baldeviano, Robert V. Gerbasi, Sara-Blythe Ballard, Craig A. Stoops, Gissella M. Vásquez

Published in: Malaria Journal | Issue 1/2017

Login to get access

Abstract

Background

Outdoor malaria transmission hinders malaria elimination efforts in the Amazon region and novel vector control tools are needed. Ivermectin mass drug administration (MDA) to humans kills wild Anopheles, targets outdoor-feeding vectors, and can suppress malaria parasite transmission. Laboratory investigations were performed to determine ivermectin susceptibility, sporontocidal effect and inhibition of time to re-feed for the primary Amazonian malaria vector, Anopheles darlingi.

Methods

To assess ivermectin susceptibility, various concentrations of ivermectin were mixed in human blood and fed to An. darlingi. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with Probit analysis was used to calculate lethal concentrations of ivermectin that killed 50% (LC50), 25% (LC25) and 5% (LC5) of mosquitoes. To examine ivermectin sporonticidal effect, Plasmodium vivax blood samples were collected from malaria patients and offered to mosquitoes without or with ivermectin at the LC50, LC25 or LC5. To assess ivermectin inhibition of mosquito time to re-feed, concentrations of ivermectin predicted to occur after a single oral dose of 200 μg/kg ivermectin were fed to An. darlingi. Every day for 12 days thereafter, individual mosquitoes were given the opportunity to re-feed on a volunteer. Any mosquitoes that re-blood fed or died were removed from the study.

Results

Ivermectin significantly reduced An. darlingi survivorship: 7-day-LC50 = 43.2 ng/ml [37.5, 48.6], -LC25 = 27.8 ng/ml [20.4, 32.9] and -LC5 = 14.8 ng/ml [7.9, 20.2]. Ivermectin compound was sporontocidal to P. vivax in An. darlingi at the LC50 and LC25 concentrations reducing prevalence by 22.6 and 17.1%, respectively, but not at the LC5. Oocyst intensity was not altered at any concentration. Ivermectin significantly delayed time to re-feed at the 4-h (48.7 ng/ml) and 12-h (26.9 ng/ml) concentrations but not 36-h (10.6 ng/ml) or 60-h (6.3 ng/ml).

Conclusions

Ivermectin is lethal to An. darlingi, modestly inhibits sporogony of P. vivax, and delays time to re-feed at concentrations found in humans up to 12 h post drug ingestion. The LC50 value suggests that a higher than standard dose (400-μg/kg) is necessary to target An. darlingi. These results suggest that ivermectin MDA has potential in the Amazon region to aid malaria elimination efforts.
Literature
1.
Vitor-Silva S, Siqueira A, Sampaio V, Guinovart C, Reyes-Lecca R, Melo G, et al. Declining malaria transmission in rural Amazon: changing epidemiology and challenges to achieve elimination. Malar J. 2016;15:266.CrossRefPubMedPubMedCentral
2.
WHO. World malaria report 2016. Geneva: World Health Organization; 2016.
3.
Sinka M, Rubio-Palis Y, Manguin S, Patil A, Temperley W, Gething P, et al. The dominant Anopheles vectors of human malaria in the Americas: occurence data, distribution maps and bionomic précis. Parasites Vectors. 2010;3:72.CrossRefPubMedPubMedCentral
4.
Girod R, Gaborit P, Carinci R, Issaly J, Fouque F. Anopheles darlingi bionomics and transmission of Plasmodium falciparum, Plasmodium vivax and Plasmodium malariae in Amerindian villages of the Upper-Maroni Amazonian forest, French Guiana. Mem Inst Oswaldo Cruz. 2008;103:702–10.CrossRefPubMed
5.
Moreno J, Rubio-Palis Y, Páez E, Pérez E, Sánchez V. Abundance, biting behaviour and parous rate of anopheline mosquito species in relation to malaria incidence in gold-mining areas of southern Venezuela. Med Vet Entomol. 2007;21:339–49.CrossRefPubMed
6.
7.
Moutinho P, Gil L, Cruz R, Ribolla P. Population dynamics, structure and behavior of Anopheles darlingi in a rural settlement in the Amazon rainforest of Acre, Brazil. Malar J. 2011;10:174.CrossRefPubMedPubMedCentral
8.
Gil L, Alves F, Zieler H, Salcedo J, Durlacher R, Cunha R, et al. Seasonal malaria transmission and variation of anopheline density in two distinct endemic areas in Brazilian Amazonia. J Med Entomol. 2003;40:636–41.CrossRefPubMed
9.
Kobylinski K, Ubalee R, Ponlawat A, Nitatsukprasert C, Phasomkulsolsil S, Wattanakul T, et al. Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles. Malar J. 2017;16:280.CrossRefPubMedPubMedCentral
10.
Sampaio V, Beltrán T, Kobylinski K, Melo G, Lima J, Silva S, et al. Filling gaps on ivermectin knowledge: effects on the survival and reproduction of Anopheles aquasalis, a Latin American malaria vector. Malar J. 2016;15:491.CrossRefPubMedPubMedCentral
11.
Chaccour C, Rabinovich N, Slater H, Canavati S, Bousema T, Lacerda M, et al. Establishment of the ivermectin research for malaria elimination network: updating the research agenda. Malar J. 2015;14:243.CrossRefPubMedPubMedCentral
12.
Chaccour C, Kobylinski K, Bassat Q, Bousema T, Drakeley C, Alonso P, et al. Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination. Malar J. 2013;12:153.CrossRefPubMedPubMedCentral
13.
Sylla M, Kobylinski K, Gray M, Chapman P, Sarr M, Rasgon J, et al. Mass drug administration of ivermectin in south-eastern Senegal reduces the survivorship of wild-caught, blood fed malaria vectors. Malar J. 2010;9:365.CrossRefPubMedPubMedCentral
14.
Alout H, Krajacich B, Meyers J, Grubaugh N, Brackney D, Kobylinski K, et al. Evaluation of ivermectin mass drug administration for malaria transmission control across different West African environments. Malar J. 2014;13:417.CrossRefPubMedPubMedCentral
15.
Bockarie M, Hii J, Alexander N, Bockarie F, Dagoro H, Kazura J, et al. Mass treatment with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival. Med Vet Entomol. 1999;13:120–3.CrossRefPubMed
16.
Kositz C, Talina J, Diau J, Asugeni R, Whitehorn C, Mabey D, et al. Incidental mosquitocidal effect of an ivermectin mass drug administration on Anopheles farauti conducted for scabies control in the Solomon Islands. Trans R Soc Trop Med Hyg. 2017;111:97–101.CrossRefPubMed
17.
Kobylinski K, Sylla M, Chapman P, Sarr M, Foy B. Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages. Am J Trop Med Hyg. 2011;85:3–5.CrossRefPubMedPubMedCentral
18.
19.
Kobylinski K, Alout H, Foy B, Clements A, Adisakwattana P, Swierczewski B, et al. Rationale for the coadministration of albendazole and ivermectin to humans for malaria parasite transmission control. Am J Trop Med Hyg. 2014;91:655–62.CrossRefPubMedPubMedCentral
20.
Kobylinski K, Deus K, Butters M, Hongyu T, Gray M, da Silva I, et al. The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors. Acta Trop. 2010;116:119–25.CrossRefPubMedPubMedCentral
21.
Cupp E, Sauerbrey M, Richards F. Elimination of human onchocerciasis: history of progress and current feasibility using ivermectin (Mectizan®) monotherapy. Acta Trop. 2011;120:S100–8.CrossRefPubMed
22.
Lovato R, Guevara A, Guderian R, Proaño R, Unnasch T, Criollo H, et al. Interruption of infection transmission in the Onchocerciasis focus of Ecuador leading to the cessation of ivermectin distribution. PLoS Negl Trop Dis. 2014;5:2821.CrossRef
23.
Rodríguez-Pérez M, Fernández-Santos N, Orozco-Algarra M, Rodríguez-Atanacio J, Domínguez-Vázquez A, Rodríguez-Morales K, et al. Elimination of onchocerciasis from Mexico. PLoS Negl Trop Dis. 2015;9:0003922.CrossRef
24.
WHO. Progress towards eliminating onchocerciasis in the WHO Region of the Americas: verification by WHO of elimination of transmission in Colombia. Wkly Epidemiol Rec. 2013;88:381–5.
25.
WHO. Progress towards eliminating onchocerciasis in the WHO Region of the Americas: verification of elimination of transmission in Guatemala. Wkly Epidemiol Rec. 2016;91:501–5.
26.
Duke B, Zea-Flores G, Castro J, Cupp E, Munoz B. Effects of three-month doses of ivermectin on adult Onchocerca volvulus. Am J Trop Med Hyg. 1992;46:189–94.CrossRefPubMed
27.
Cupp E, Cupp M. Impact of ivermectin community-level treatments on elimination of adult Onchocerca volvulus when individuals receive multiple treatments per year. Am J Trop Med Hyg. 2005;73:1159–61.PubMed
28.
Slater H, Walker P, Bousema T, Okell L, Ghani A. The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: a modelling study. J Infect Dis. 2014;210:1972–80.CrossRefPubMed
29.
Villarreal-Treviño C, Vásquez G, López-Sifuentes V, Escobedo-Vargas K, Huayanay-Repetto A, Linton Y, et al. Establishment of a free-mating, long-standing and highly productive laboratory colony of Anopheles darlingi from the Peruvian Amazon. Malar J. 2015;14:227.CrossRefPubMedPubMedCentral
30.
Baldeviano G, Okoth S, Arrospide N, Gonzalez R, Sánchez J, Macedo S, et al. Molecular epidemiology of Plasmodium falciparum malaria outbreak, Tumbes, Peru, 2010–2012. Emerg Infect Dis. 2015;21:797–803.CrossRefPubMedPubMedCentral
31.
Singh B, Bobogare A, Cox-Singh J, Snounou G, Abdullah M, Rhaman H. A genus- and species-specific nested polymerase chain reaction malaria detection assay for epidemiologic studies. Am J Trop Med Hyg. 1999;60:687–92.CrossRefPubMed
32.
Na-Bangchang K, Kietinun S, Pawa K, Hanpitakpong W, Na-Bangchang C, Lazdins J. Assessments of pharmacokinetic drug interactions and tolerability of albendazole, praziquantel and ivermectin combinations. Trans R Soc Trop Med Hyg. 2006;100:335–45.CrossRefPubMed
33.
Black W, Moore C. Population biology as a tool to study vector-borne diseases. In: Marquardt W, editor. Biology of disease vectors. San Diego: Elsevier Academic Press; 2005. p. 187–206.
34.
Merck Sharp & Dohme (France): Mectizan Package Insert. 2014.
35.
Dreyer G, Addiss D, Norões J, Amaral F, Rocha A, Coutinho A. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis. Trop Med Int Health. 1996;1:427–32.CrossRefPubMed
36.
Ismail M, Weil G, Jayasinghe K, Premaratne U, Abeyewickreme W, Rajaratnam H, et al. Prolonged clearance of microfilaraemia in patients with bancroftian filariasis after multiple high doses of ivermectin or diethylcarbamazine. Trans R Soc Trop Med Hyg. 1996;90:684–8.CrossRefPubMed
37.
Carter R. Speculations on the origins of Plasmodium vivax malaria. Trends Parasitol. 2003;19:214–9.CrossRefPubMed
38.
Butters M, Kobylinski K, Deus K, da Silva I, Gray M, Sylla M, et al. Comparative evaluation of systemic drugs for their effects against Anopheles gambiae. Acta Trop. 2012;121:34–43.CrossRefPubMed
39.
Verdú J, Cortez V, Ortiz A, González-Rodríguez E, Martinez-Pinna J, Lumaret J-P, et al. Low doses of ivermectin cause sensory and locomotor disorders in dung beetles. Sci Rep. 2015;5:13912.CrossRefPubMedPubMedCentral
40.
Meyers J, Gray M, Kuklinski W, Johnson L, Snow C, Black W, et al. Characterization of the target of ivermectin, the glutamate-gated chloride channel, from Anopheles gambiae. J Exp Biol. 2015;218:1478–86.CrossRefPubMedPubMedCentral
41.
Sollai G, Solari P, Masala C, Crnjar R, Liscia A. Effects of avermectins on olfactory responses of Culicoides imicola (Diptera: Ceratopogonidae). J Med Entomol. 2007;44:656–9.CrossRefPubMed
42.
Botto C, Basañez M-G, Escalona M, Villamizar N, Noya-Alarcón O, Cortez J, et al. Evidence of suppression of onchocerciasis transmission in the Venezuelan Amazonian focus. Parasites Vectors. 2016;9:40.CrossRefPubMedPubMedCentral
43.
44.
Cabada M, Lopez M, Arque E, Clinton WA. Prevalence of soil-transmitted helminths after mass albendazole administration in an indigenous community of the Manu jungle in Peru. Pathog Glob Health. 2014;108:200–5.CrossRefPubMedPubMedCentral
45.
Valverde J, Gomes-Silva A, de Carvalho Moreira C, Leles de Souza D, Jaeger L, Martins P, et al. Prevalence and epidemiology of intestinal parasitism, as revealed by three distinct techniques in an endemic area in the Brazilian Amazon. Ann Trop Med Parasitol. 2011;105:413–24.CrossRefPubMedPubMedCentral
46.
Buonfrate D, Mena M, Angheben A, Requena-Mendez A, Muñoz J, Gobbi F, et al. Prevalence of strongyloidiasis in Latin America: a systematic review of the literature. Epidemiol Infect. 2015;143:452–60.CrossRefPubMed
47.
Anselmi M, Buonfrate D, Espinoza A, Prandi R, Marquez M, Gobbo M, et al. Mass administration of ivermectin for the elimination of Onchocerciasis significantly reduced and maintained low the prevalence of Strongyloides stercoralis in Esmeraldas, Ecuador. PLoS Negl Trop Dis. 2015;9:0004150.CrossRef
48.
Knudson A, Ariza Y, López M, Fajardo O, Reyes P, Moncada L, et al. The effect of ivermectin on geohelminth frequency (i.e. as used in the onchocerciasis control program in Colombia). Rev Salud Publica. 2012;14:681–94.PubMed
49.
Schuster A, Lesshafft H, Reichert F, Talhari S, de Oliveira S, Ignatius R, et al. Hookworm-related cutaneous larva migrans in Northern Brazil: resolution of clinical pathology after a single dose of ivermectin. Clin Infect Dis. 2013;57:1155–7.CrossRefPubMed
50.
Worth C, Heukelbach J, Fengler G, Walter B, Liesenfeld O, Hengge U, et al. Acute morbidity associated with scabies and other ectoparasites rapidly improves after treatment with ivermectin. Pediatr Dermatol. 2012;29:430–6.CrossRefPubMed
51.
Heukelbach J, Wilcke T, Winter B, de Oliveira F, Moura R, Harms G, et al. Efficacy of ivermectin in a patient population concomitantly infected with intestinal helminths and ectoparasites. Arzneimittelforschung. 2004;54:416–21.PubMed
52.
Heukelbach J, Winter B, Wilcke T, Muehlen M, Albrecht S, De Oliveira F, et al. Selective mass treatment with ivermectin to control intestinal helminthiases and parasitic skin diseases in a severely affected population. Bull World Health Organ. 2004;82:563–71.PubMedPubMedCentral
53.
von Seidlein L, Dondorp A. Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance. Expert Rev Anti Infect Ther. 2015;13:715–30.CrossRef
54.
Eisele T, Bennett A, Silumbe K, Finn T, Chalwe V, Kamuliwo M, et al. Short-term impact of mass drug administration with dihydroartemisinin plus piperaquine on malaria in Southern Province Zambia: a cluster-randomized controlled trial. J Infect Dis. 2016;214:1831–9.CrossRefPubMedPubMedCentral
55.
Lin J, Bethell D, Tyner S, Lon C, Shah N, Saunders D, et al. Plasmodium falciparum gametocyte carriage is associated with subsequent Plasmodium vivax relapse after treatment. PLoS ONE. 2011;6:18716.CrossRef
56.
Douglas N, Nosten F, Ashley E, Phaiphun L, van Vugt M, Singhasivanon P, et al. Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics. Clin Infect Dis. 2011;52:612–20.CrossRefPubMedPubMedCentral
57.
Looareesuwan S, White N, Bunnag D, Chittamas S, Harinasuta T. High-rate of Plasmodium vivax relapse following treatment of falciparum-malaria in Thailand. Lancet. 1987;2:1052–5.CrossRefPubMed
58.
Smithuis F, Kyaw M, Phe O, Win T, Aung P, Oo A, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010;10:673–81.CrossRefPubMedPubMedCentral
59.
Lwin K, Phyo A, Tarning J, Hanpitakpong W, Ashley E, Lee S, et al. Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin–piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother. 2012;56:1571–7.CrossRefPubMedPubMedCentral
60.
Kondrashin A, Baranova A, Ashley E, Recht J, White N, Sergiev V. Mass primaquine treatment to eliminate vivax malaria: lessons from the past. Malar J. 2014;13:51.CrossRefPubMedPubMedCentral
61.
62.
Kaneko A, Taleo G, Kalkoa M, Yamar S, Kobayakawa T, Björkman A. Malaria eradication on islands. Lancet. 2000;356:1560–4.CrossRefPubMed
63.
Song J, Socheat D, Tan B, Dara P, Deng C, Sokunthea S, et al. Rapid and effective malaria control in Cambodia through mass administration of artemisinin–piperaquine. Malar J. 2010;9:57.CrossRefPubMedPubMedCentral
64.
Leslie T, Mayan I, Mohammed N, Erasmus P, Kolaczinski J, Whitty C, et al. A randomised trial of an eight-week, once weekly primaquine regimen to prevent relapse of Plasmodium vivax in Northwest Frontier Province, Pakistan. PLoS ONE. 2008;3:2861.CrossRef
65.
Smit M, Ochomo E, Aljayyoussi G, Kwambai T, Abong’o B, Bayoh N, et al. Efficacy and safety of high-dose ivermectin for reducing malaria transmission (IVERMAL): protocol for a double-blind, randomized, placebo-controlled, dose-finding trial in Western Kenya. JMIR Res Protoc. 2016;5:213.CrossRef
Metadata
Title
Ivermectin susceptibility, sporontocidal effect, and inhibition of time to re-feed in the Amazonian malaria vector Anopheles darlingi
Authors
Kevin C. Kobylinski
Karín S. Escobedo-Vargas
Victor M. López-Sifuentes
Salomón Durand
Edward S. Smith
G. Christian Baldeviano
Robert V. Gerbasi
Sara-Blythe Ballard
Craig A. Stoops
Gissella M. Vásquez
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2017
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-017-2125-0

Other articles of this Issue 1/2017

Malaria Journal 1/2017 Go to the issue

Research

Describing interaction effect between lagged rainfalls on malaria: an epidemiological study in south–west China

Research

An assessment of national surveillance systems for malaria elimination in the Asia Pacific

Research

Do anti-malarials in Africa meet quality standards? The market penetration of non quality-assured artemisinin combination therapy in eight African countries

Research

Cerebral malaria induces electrophysiological and neurochemical impairment in mice retinal tissue: possible effect on glutathione and glutamatergic system

Research

Patterns of inflammatory responses and parasite tolerance vary with malaria transmission intensity

Methodology

Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits