Susceptibility of human Plasmodium knowlesi infections to anti-malarials

Fatih, Farrah A.; Staines, Henry M.; Siner, Angela; Ahmed, Atique; Woon, Lu Chan; Pasini, Erica M.; Kocken, Clemens H. M.; Singh, Balbir; Cox-Singh, Janet; Krishna, Sanjeev

doi:10.1186/1475-2875-12-425

Cited by 45 publications

(46 citation statements)

References 33 publications

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“…Chloroquine and cycloguanil are fast-acting drugs which act in the first P. falciparum asexual intraerythrocytic developmental cycle (16,17), while clindamycin is a slow-acting drug with a "delayed-death" phenotype that is not observable until after two asexual intraerythrocytic developmental cycles (16). The activity of all three drugs was assessed against P. knowlesi A1H.1 using asynchronous parasites (0.25% parasitemia and 2% hematocrit) over 24 h, 48 h, or 72 h. Three independent assays (in triplicate wells) were carried out, and the resulting 50% inhibitory concentrations (IC 50 s) determined by log-linear interpolation (18) (20). While there were significant differences in the IC 50 s for cycloguanil at 24 h versus 48 h and 72 h (Table 1) (P Ͻ 0.05), there was no significant difference between the 48-h and 72-h IC 50 s (Table 1) (P ϭ 0.540).…”

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Adaptation of the [ ³ H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

Arnold

Engel

Chua

et al. 2016

Antimicrob Agents Chemother

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The zoonotic malaria parasite Plasmodium knowlesi has recently been established in continuous in vitro culture. Here, the Plasmodium falciparum [ 3 H]hypoxanthine uptake assay was adapted for P. knowlesi and used to determine the sensitivity of this parasite to chloroquine, cycloguanil, and clindamycin. The data demonstrate that P. knowlesi is sensitive to all drugs, with 50% inhibitory concentrations (IC 50 s) consistent with those obtained with P. falciparum. This assay provides a platform to use P. knowlesi in vitro for drug discovery. In 2015, there were an estimated 214 million clinical cases of malaria which resulted in ϳ438,000 deaths (1). Substantial funds have been invested in producing a malaria vaccine; however, the efficacy of experimental vaccines has been poor (2, 3), and as a result, vector control and drugs remain the mainstays for the prevention and treatment of malaria. While there has been a significant reduction in malaria-associated mortality and morbidity in recent years (1), there is concern that lack of sustained funding, together with insecticide and antimalarial drug resistance, will affect this progress (4). To prevent backward momentum in disease control and push toward the endgame strategy of malaria elimination, new chemotherapeutics with novel modes of action and activity against multiple species and life cycle stages are needed (5).The ability to easily and rapidly assess the activity of new lead compounds against multiple Plasmodium species has been limited to date, as only Plasmodium falciparum has been amenable to routine, long-term, continuous in vitro culture (6). While there have been some recent improvements to in vitro culture techniques for Plasmodium vivax, the culture of this parasite is still limited by the requirement of reticulocytes, and the parasite density over longterm culture is low (7). However, the recent adaptation of the zoonotic malaria species Plasmodium knowlesi (8) to continuous in vitro culture in human erythrocytes (9-11) has changed this position. Although a routine drug sensitivity assay for P. knowlesi has not yet been established, the ability to culture this parasite species in vitro provides researchers with an unprecedented opportunity to rapidly test new drug leads against two human-infecting Plasmodium species.In vitro assays for assessing malaria parasite growth inhibition are indispensable tools for the screening and evaluation of potential new drug leads and, also, for the surveillance of parasite drug resistance. A "gold standard" approach for assessing P. falciparum growth inhibition is the incorporation of [ 3 H]hypoxanthine into parasite nucleic acids (12). As Plasmodium parasites are unable to synthesize purines de novo, they must scavenge these metabolic precursors for growth. Thus, supplementation of parasite cultures with [3 H]hypoxanthine results in the incorporation of this radiolabeled purine into nucleic acids, permitting growth to be quantitated using a scintillation counter. While there are a number of other methods available t...

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Adaptation of the [ ³ H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

Arnold

Engel

Chua

et al. 2016

Antimicrob Agents Chemother

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“…Previous small studies have shown the efficacy of parenteral artesunate in treating severe knowlesi malaria, likely attributed to its fast parasite clearance properties 7. A study by Fatih et al 8 has shown that Plasmodium knowlesi is highly sensitive to artemisinins compared to chloroquine and mefloquine. An randomised controlled trial carried out by Dr Matthew J Grigg and his team, published in February 2016, has shown that artesunate-mefloquine was better compared to chloroquine monotherapy in uncomplicated Plasmodium knowlesi infection 9.…”

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confidence: 99%

SeverePlasmodium knowlesiwith dengue coinfection

et al. 2017

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We report a case of severe and dengue coinfection in a previously healthy 59-year-old Malay man who presented with worsening shortness of breath, high-grade fever with chills and rigors, dry cough, myalgia, arthralgia, chest discomfort and poor appetite of 1 week duration. There was a history mosquito fogging around his neighbourhood in his hometown. Further history revealed that he went to a forest in Jeli (northern part of Kelantan) 3 weeks prior to the event. Initially he was treated as severe dengue with plasma leakage complicated with type 1 respiratory failure as evidenced by positive serum NS1-antigen and thrombocytopenia. Blood for malarial parasite (BFMP) was sent for test as there was suspicion of malaria due to persistent thrombocytopenia despite recovering from dengue infection and the presence of a risk factor. The test revealed high count of malaria parasite. Confirmatory PCR identified the parasite to be Intravenous artesunate was administered to the patient immediately after acquiring the BFMP result. Severe malaria was complicated with acute kidney injury and septicaemic shock. Fortunately the patient made full recovery and was discharged from the ward after 2 weeks of hospitalisation.

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“…3,18 Consistently, in vitro drug susceptibility study has shown that P. knowlesi exhibited high sensitivity to artemisinins, whereas sensitivities to chloroquine and mefloquine were lower. 19 Therefore, parenteral artesunate has been recommended by the World Health Organization (WHO) as the treatment of choice for severe knowlesi malaria. 20 On the other hand, delay in diagnosis and treatment could lead to high parasite density that reportedly had a strong association with disease severity.…”

Section: Discussionmentioning

confidence: 99%

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

Nakaviroj¹,

Kobasa²,

Teeranaipong³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract.A 58-year-old Thai man was infected with Plasmodium knowlesi in Chantaburi Province, eastern Thailand. In addition to pyrexia, the patient developed hypotension, renal failure, jaundice, and severe thrombocytopenia. The parasitemia at the time of admission was 16.67% or~503,400 parasites/μL. With artesunate treatment and supportive care, the patient recovered uneventfully. The occurrence of complicated knowlesi malaria in a low-endemic area underscores the risk of high morbidity from this simian malaria.

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Susceptibility of human Plasmodium knowlesi infections to anti-malarials

Cited by 45 publications

References 33 publications

Adaptation of the [ ³ H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

Adaptation of the [ ³ H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

SeverePlasmodium knowlesiwith dengue coinfection

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

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Susceptibility of human Plasmodium knowlesi infections to anti-malarials

Cited by 45 publications

References 33 publications

Adaptation of the [ 3 H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

Adaptation of the [ 3 H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

SeverePlasmodium knowlesiwith dengue coinfection

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

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Adaptation of the [ ³ H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites

Adaptation of the [ ³ H]Hypoxanthine Uptake Assay for In Vitro -Cultured Plasmodium knowlesi Malaria Parasites