Long-Term Malaria Chemoprophylaxis with Meftoquine in Dutch Marines in Cambodia

Burna, Adriaan P. C. C. Hopperus; Thiel, Pieter P. A. M. van; Lobel, Hans O.; Ohrt, Colin; Ameijden, Eric J. C. van; Veltink, Ron L.; Tendeloo, Dick C. H.; Gool, Tom van; Green, Mark D.; Todd, G D; Kyle, Dennis E.; Kager, Piet A.

doi:10.1093/infdis/173.6.1506

Cited by 44 publications

(17 citation statements)

References 7 publications

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“…When these five symptoms were cited as feared LTAEs, over 80% of the time it was by Volunteers prescribed mefloquine. Although mefloquine is known to cause neuropsychiatric effects in 10–15% of people while it is being taken [9,10], published data demonstrating mefloquine side effects presenting or persisting after discontinuation of the medication are limited to several case reports of ototoxicity [11]. Serious adverse events due to mefloquine are rare [12].…”

Section: Discussionmentioning

confidence: 99%

Adherence to malaria prophylaxis among Peace Corps Volunteers in the Africa region, 2013

Landman

Tan

Arguin

2015

Travel Medicine and Infectious Disease

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Background Although malaria can be prevented with prophylaxis, it is diagnosed in over 100 Africa-region Peace Corps Volunteers annually. This suggests that prophylaxis non-adherence is a problem in these non-immune travelers. Methods We investigated Volunteers’ knowledge, attitudes, and practices regarding prophylaxis using an internet-based survey during August 19–September 30, 2013. Adherence was defined as taking doxycycline or atovaquone-proguanil daily, or taking mefloquine doses no more than 8 days apart. Results The survey was sent to 3,248 Volunteers. Of 781 whose responses were analyzed, 514 (73%) reported adherence to prophylaxis. The most common reasons for non-adherence were forgetting (n=530, 90%); fear of long-term adverse effects (LTAEs; n=316, 54%); and experiencing adverse events that Volunteers attributed to prophylaxis (n=297, 51%). Two hundred fourteen (27%) Volunteers reported not worrying about malaria. On multivariate analysis controlling for sex and experiencing adverse events Volunteers attributed to prophylaxis, the factor most strongly associated with non-adherence was being prescribed mefloquine (OR 5.4, 95% confidence interval 3.2–9.0). Conclusions We found moderate adherence and a prevailing fear of LTAEs among Volunteers. Strategies to improve prophylaxis adherence may include medication reminders, increasing education about prophylaxis safety and malaria risk, and promoting prompt management of prophylaxis side effects.

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Section: Discussionmentioning

confidence: 99%

Adherence to malaria prophylaxis among Peace Corps Volunteers in the Africa region, 2013

Landman

Tan

Arguin

2015

Travel Medicine and Infectious Disease

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“…1), there was an inverse correlation between mefloquine resistance and the delayed clearance phenotype in vitro (PRR 1-12 h ). Color symbols in each panel correspond to the absence or presence of Pf3D7_1343700 (K13) mutations as annotated in panel B. used W2 and CB132, an artemisinin-susceptible isolate collected from Pailin, Cambodia, in 1991 (21). In the first few hours of ring-stage development, there were no differences in viability of artemisinin-resistant or -susceptible parasites following exposure to drug, and between hours 3 and 9 of development we observed hypersusceptibility to drug in both artemisinin-resistant and -susceptible clones, as previously demonstrated (22), whereas from hours 9 through 20 there was a log increase in viability of artemisinin-resistant ring-stage parasites compared to the level for CB132 (Fig.…”

Section: Figmentioning

confidence: 99%

Artemisinin-Resistant Plasmodium falciparum Parasites Exhibit Altered Patterns of Development in Infected Erythrocytes

Hott

Casandra

Sparks

et al. 2015

Antimicrob Agents Chemother

107

120

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bArtemisinin derivatives are used in combination with other antimalarial drugs for treatment of multidrug-resistant malaria worldwide. Clinical resistance to artemisinin recently emerged in southeast Asia, yet in vitro phenotypes for discerning mechanism(s) of resistance remain elusive. Here, we describe novel phenotypic resistance traits expressed by artemisinin-resistant Plasmodium falciparum. The resistant parasites exhibit altered patterns of development that result in reduced exposure to drug at the most susceptible stage of development in erythrocytes (trophozoites) and increased exposure in the most resistant stage (rings). In addition, a novel in vitro delayed clearance assay (DCA) that assesses drug effects on asexual stages was found to correlate with parasite clearance half-life in vivo as well as with mutations in the Kelch domain gene associated with resistance (Pf3D7_1343700). Importantly, all of the resistance phenotypes were stable in cloned parasites for more than 2 years without drug pressure. The results demonstrate artemisinin-resistant P. falciparum has evolved a novel mechanism of phenotypic resistance to artemisinin drugs linked to abnormal cell cycle regulation. These results offer insights into a novel mechanism of drug resistance in P. falciparum and new tools for monitoring the spread of artemisinin resistance.A rtemisinin combination therapy (ACT) is the recommended treatment for multidrug-resistant malaria by the World Health Organization. These combinations rely on the fast-acting properties of the artemisinin derivative to rapidly clear parasites with the longer-acting partner drug clearing residual parasites, reducing the frequent observation of recrudescent infections when artemisinin drugs are used alone. Unfortunately, resistance to artemisinin derivatives has emerged in southeast Asia and now threatens the utility of the most important treatment options for Plasmodium falciparum malaria that is resistant to most antimalarial drugs. Clinical resistance to artemisinin is expressed as a reduced rate of parasite clearance from peripheral blood, resulting in a parasite clearance half-life of Ͼ5 h (1). Resistance to artemisinin is a heritable trait, linked to mutations in the Kelch propeller domains of Pf3D7_1343700, and it appears to be spreading in southeast Asia (1-3). Clearly, a public health disaster is looming if artemisinin resistance spreads globally, like the selective sweeps previously observed for chloroquine and pyrimethamine resistance (4-6).Despite the well-characterized phenotype of clinical resistance to artemisinin, resistance phenotypes in classical in vitro drug susceptibility assays, used successfully for other antimalarial drugs, have not been useful for detecting artemisinin resistance (7). Two modified in vitro assays have been used to assess resistance with some success (8, 9), with both assessing reduced susceptibility in the ring stage of development in erythrocytes; however, stable in vitro phenotypes in culture-adapted parasites remain elusive. Given the ...

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“…To determine if cryo-preservation can support infectious cultures of other strains of P. falciparum, RBC donor number 4 (additional file 2b) used for the NF54 cultures above was used as a substrate for sexual stage cultures of a clinical isolate of Cambodian origin ( P. falciparum CB132 [30]) following storage periods of 6 (n=35 midguts and 23 salivary glands) and 8 weeks (n=49 midguts) (additional file 5). Statistical analyses were not performed due to the lack of replication in the study design.…”

Section: Resultsmentioning

confidence: 99%

“…We also addressed whether infectiousness was retained following extended periods of cryo-preservation. Lastly, although we accomplished these objectives primarily with the standard lab strain (NF54) of P. falciparum , we also tested the potential of cryo-preserved RBCs to serve as a substrate for supporting growth and differentiation of infectious stages of a Cambodian isolate of P. falciparum , CB132 [30].…”

Section: Introductionmentioning

confidence: 99%

Cryogenically preserved RBCs support gametocytogenesis ofPlasmodium falciparuminvitroand gametogenesis in mosquitoes

Pathak

Shiau

Thomas

et al. 2018

Preprint

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21Background 22 The malaria Eradication Research Agenda (malERA) has identified human-to-mosquito 23 transmission of Plasmodium falciparum as a major target for eradication. The cornerstone for 24 identifying and evaluating transmission in the laboratory is small membrane feeding assays 25(SMFAs) where mature gametocytes of P. falciparum generated in vitro are offered to 26 mosquitoes as part of a blood-meal. However, propagation of "infectious" gametocytes requires 27 10-12 days with considerable physico-chemical demands imposed on host RBCs and 28 thus, "fresh" RBCs that are ≤1-week old post-collection are generally recommended. However, 29 in addition to the costs, physico-chemical characteristics unique to RBC donors may confound 30 reproducibility and interpretation of SMFAs. Cryogenic storage of RBCs (cryo-preserved RBCs 31 herein) is approved by the European and US FDAs as an alternative to refrigeration (4°C) for 32 preserving RBC quality and while cryo-preserved RBCs have been used for in vitro cultures of 33 other Plasmodia and the asexual stages of P. falciparum, none of the studies required RBCs to 34 support parasite development for >4 days. 35 Results 36Using the standard laboratory strain, P. falciparum NF54, we first demonstrate that cryo-37 preserved RBCs preserved in the gaseous phase of liquid nitrogen and thawed after storage for 38 1, 4, 8 and 12 weeks, supported gametocytogenesis in vitro and subsequent gametogenesis 39 in Anopheles stephensi mosquitoes. Using data from 11 SMFAs and RBCs from 4 separate 40 donors with 3 donors re-tested following various periods of cryo-preservation, we show that 41 overall levels of sporogony in the mosquito, as measured by oocyst prevalence and burdens in 42 the midguts and sporozoites in salivary glands, were similar or better than using ≤1-week old 43 3 refrigerated RBCs. Additionally, the potential for cryo-preserved RBCs to serve as a universal 44 substrate for SMFAs is shown for a Cambodian isolate of P. falciparum. 45 Conclusions 46Considering the suitability of cryo-preserved RBCs for P. falciparum SMFAs, we suggest 47 guidelines for their use and how they can be integrated into an existing laboratory/insectary 48 framework with the potential to significantly reduce running costs and provide greater reliability. 49Finally, we discuss scenarios where cryo-preserved RBCs may be especially useful in 50 enhancing our understanding and/or providing novel insights into the patterns and process 51 underlying human-to-mosquito transmission. 52Background 56Incidence of malaria due to Plasmodium falciparum has seen a steady decline in the last 15-20 57 years, enabled primarily by the synergy between drug-combination therapies for case/disease 58 management and vector control programs [1, 2]. Since transmission to the mosquito is thought 59 to be a severe bottleneck in the parasite's life history, considerable effort has been channeled 60 towards identifying parasite and vector traits influencing transmission to the mosquito with the 61 aim of designing and te...

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Long-Term Malaria Chemoprophylaxis with Meftoquine in Dutch Marines in Cambodia

Cited by 44 publications

References 7 publications

Adherence to malaria prophylaxis among Peace Corps Volunteers in the Africa region, 2013

Adherence to malaria prophylaxis among Peace Corps Volunteers in the Africa region, 2013

Artemisinin-Resistant Plasmodium falciparum Parasites Exhibit Altered Patterns of Development in Infected Erythrocytes

Cryogenically preserved RBCs support gametocytogenesis ofPlasmodium falciparuminvitroand gametogenesis in mosquitoes

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