scholarly journals Environmental, pharmacological and genetic influences on the spread of drug-resistant malaria

2010 ◽  
Vol 278 (1712) ◽  
pp. 1705-1712 ◽  
Author(s):  
Tiago Antao ◽  
Ian M. Hastings
Keyword(s):  
Plasmodium Falciparum ◽  
Linkage Disequilibrium ◽  
Malaria Transmission ◽  
Clinical Outcomes ◽  
Artificial Selection ◽  
Genetic Interactions ◽  
Genetic Influences ◽  
Drug Resistant ◽  
New Approach ◽  
Rate Of Spread

Plasmodium falciparum malaria is subject to artificial selection from antimalarial drugs that select for drug-resistant parasites. We describe and apply a flexible new approach to investigate how epistasis, inbreeding, selection heterogeneity and multiple simultaneous drug deployments interact to influence the spread of drug-resistant malaria. This framework recognizes that different human ‘environments’ within which treatment may occur (such as semi- and non-immune humans taking full or partial drug courses) influence the genetic interactions between parasite loci involved in resistance. Our model provides an explanation for how the rate of spread varies according to different malaria transmission intensities, why resistance might stabilize at intermediate frequencies and also identifies several factors that influence the decline of resistance after a drug is removed. Results suggest that studies based on clinical outcomes might overestimate the spread of resistant parasites, especially in high-transmission areas. We show that when transmission decreases, prevalence might decrease without a corresponding change in frequency of resistance and that this relationship is heavily influenced by the extent of linkage disequilibrium between loci. This has important consequences on the interpretation of data from areas where control is being successful and suggests that reducing transmission might have less impact on the spread of resistance than previously expected.

scholarly journals Revisiting the effect of pharmaceuticals on transmission stage formation in the malaria parasite Plasmodium falciparum

2021 ◽  
Author(s):  
Basil T Thommen ◽  
Armin Passecker ◽  
Tamara Buser ◽  
Eva Hitz ◽  
Till S Voss ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Stress Responses ◽  
Nutrient Sensing ◽  
Therapeutic Interventions ◽  
Drug Resistant ◽  
Promoting Effect ◽  
Reporter Line ◽  
Drug Concentrations

Malaria parasites rely on specialized stages, called gametocytes, to ensure human-to-human transmission. The formation of these sexual precursor cells is initiated by commitment of blood stage parasites to the sexual differentiation pathway. Plasmodium falciparum, the most virulent of six parasite species infecting humans, employs nutrient sensing to control the rate at which sexual commitment is initiated, and the presence of stress-inducing factors, including antimalarial drugs, has been linked to increased gametocyte production in vitro and in vivo. These observations suggest that therapeutic interventions may promote gametocytogenesis and malaria transmission. Here, we engineered a P. falciparum reporter line to quantify sexual commitment rates after exposure to antimalarials and other pharmaceuticals commonly prescribed in malaria-endemic regions. Our data reveal that some of the tested drugs indeed have the capacity to elevate sexual commitment rates in vitro. Importantly, however, these effects are only observed at drug concentrations that inhibit parasite survival and only rarely result in a net increase of gametocyte production. Using a drug-resistant parasite reporter line, we further show that the gametocytogenesis-promoting effect of drugs is linked to general stress responses rather than to compound-specific activities. Altogether, we provide conclusive evidence for the absence of mechanistic links between the regulation of sexual commitment and the activity of commonly used pharmaceuticals in vitro. Our data hence contradict scenarios in which therapeutic interventions would promote the spread of drug-resistant parasites or malaria transmission in general.

scholarly journals Fungal Metabolite Asperaculane B Inhibits Malaria Infection and Transmission

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3018 ◽  
Author(s):  
Guodong Niu ◽  
Yue Hao ◽  
Xiaohong Wang ◽  
Jin-Ming Gao ◽  
Jun Li
Keyword(s):  
Plasmodium Falciparum ◽  
Anopheles Gambiae ◽  
Malaria Transmission ◽  
Malaria Infection ◽  
Bioactive Compound ◽  
Fungal Strain ◽  
Drug Resistant ◽  
Fungal Metabolite ◽  
Aspergillus Aculeatus ◽  
Dual Functional

Mosquito-transmitted Plasmodium parasites cause millions of people worldwide to suffer malaria every year. Drug-resistant Plasmodium parasites and insecticide-resistant mosquitoes make malaria hard to control. Thus, the next generation of antimalarial drugs that inhibit malaria infection and transmission are needed. We screened our Global Fungal Extract Library (GFEL) and obtained a candidate that completely inhibited Plasmodium falciparum transmission to Anopheles gambiae. The candidate fungal strain was determined as Aspergillus aculeatus. The bioactive compound was purified and identified as asperaculane B. The concentration of 50% inhibition on P. falciparum transmission (IC50) is 7.89 µM. Notably, asperaculane B also inhibited the development of asexual P. falciparum with IC50 of 3 µM, and it is nontoxic to human cells. Therefore, asperaculane B is a new dual-functional antimalarial lead that has the potential to treat malaria and block malaria transmission.

scholarly journals Predictors of treatment failures of plasmodium falciparum malaria in Vietnam: a 4-year single‐centre retrospective study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Minh Cuong Duong ◽  
Oanh Kieu Nguyet Pham ◽  
Phong Thanh Nguyen ◽  
Van Vinh Chau Nguyen ◽  
Phu Hoan Nguyen
Keyword(s):  
Plasmodium Falciparum ◽  
Treatment Failure ◽  
Severe Malaria ◽  
Falciparum Malaria ◽  
Control Strategies ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Molecular Technique ◽  
Drug Resistant ◽  
Public Health Burden

Abstract Background Drug-resistant falciparum malaria is an increasing public health burden. This study examined the magnitude of Plasmodium falciparum infection and the patterns and predictors of treatment failure in Vietnam. Methods Medical records of all 443 patients with malaria infection admitted to the Hospital for Tropical Diseases between January 2015 and December 2018 were used to extract information on demographics, risk factors, symptoms, laboratory tests, treatment, and outcome. Results More than half (59.8%, 265/443, CI 55.1–64.4%) of patients acquired Plasmodium falciparum infection of whom 21.9% (58/265, CI 17.1–27.4%) had severe malaria, while 7.2% (19/265, CI 4.6–10.9%) and 19.2% (51/265, CI 14.7–24.5%) developed early treatment failure (ETF) and late treatment failure (LTF) respectively. Among 58 patients with severe malaria, 14 (24.1%) acquired infection in regions where artemisinin resistance has been documented including Binh Phuoc (11 patients), Dak Nong (2 patients) and Gia Lai (1 patient). Under treatment with intravenous artesunate, the median (IQR) parasite half-life of 11 patients coming from Binh Phuoc was 3 h (2.3 to 8.3 h), two patients coming from Dak Nong was 2.8 and 5.7 h, and a patient coming from Gia Lai was 6.5 h. Most patients (98.5%, 261/265) recovered completely. Four patients with severe malaria died. Severe malaria was statistically associated with receiving treatment at previous hospitals (P < 0.001), hepatomegaly (P < 0.001) and number of inpatient days (P < 0.001). Having severe malaria was a predictor of ETF (AOR 6.96, CI 2.55–19.02, P < 0.001). No predictor of LTF was identified. Conclusions Plasmodium falciparum remains the prevalent malaria parasite. Despite low mortality rate, severe malaria is not rare and is a significant predictor of ETF. To reduce the risk for ETF, studies are needed to examine the effectiveness of combination therapy including parenteral artesunate and a parenteral partner drug for severe malaria. The study alerts the possibility of drug-resistant malaria in Africa and other areas in Vietnam, which are known as non-endemic areas of anti-malarial drug resistance. A more comprehensive study using molecular technique in these regions is required to completely understand the magnitude of drug-resistant malaria and to design appropriate control strategies.

scholarly journals Effect of seasonal malaria chemoprevention plus azithromycin on Plasmodium falciparum transmission: gametocyte infectivity and mosquito fitness

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Koudraogo Bienvenue Yaméogo ◽  
Rakiswendé Serge Yerbanga ◽  
Seydou Bienvenu Ouattara ◽  
Franck A. Yao ◽  
Thierry Lefèvre ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Life History Traits ◽  
Controlled Trial ◽  
Double Blind ◽  
Membrane Feeding ◽  
Seasonal Malaria Chemoprevention ◽  
Negative Effect ◽  
Transmission Period ◽  
Membrane Feeding Assay

Abstract Background Seasonal malaria chemoprevention (SMC) consists of administration of sulfadoxine-pyrimethamine (SP) + amodiaquine (AQ) at monthly intervals to children during the malaria transmission period. Whether the addition of azithromycin (AZ) to SMC could potentiate the benefit of the intervention was tested through a double-blind, randomized, placebo-controlled trial. The effect of SMC and the addition of AZ, on malaria transmission and on the life history traits of Anopheles gambiae mosquitoes have been investigated. Methods The study included 438 children randomly selected from among participants in the SMC + AZ trial and 198 children from the same area who did not receive chemoprevention. For each participant in the SMC + AZ trial, blood was collected 14 to 21 days post treatment, examined for the presence of malaria sexual and asexual stages and provided as a blood meal to An. gambiae females using a direct membrane-feeding assay. Results The SMC treatment, with or without AZ, significantly reduced the prevalence of asexual Plasmodium falciparum (LRT X22 = 69, P < 0.0001) and the gametocyte prevalence (LRT X22 = 54, P < 0.0001). In addition, the proportion of infectious feeds (LRT X22 = 61, P < 0.0001) and the prevalence of oocysts among exposed mosquitoes (LRT X22 = 22.8, P < 0.001) was reduced when mosquitoes were fed on blood from treated children compared to untreated controls. The addition of AZ to SPAQ was associated with an increased proportion of infectious feeds (LRT X21 = 5.2, P = 0.02), suggesting a significant effect of AZ on gametocyte infectivity. There was a slight negative effect of SPAQ and SPAQ + AZ on mosquito survival compared to mosquitoes fed with blood from control children (LRTX22 = 330, P < 0.0001). Conclusion This study demonstrates that SMC may contribute to a reduction in human to mosquito transmission of P. falciparum, and the reduced mosquito longevity observed for females fed on treated blood may increase the benefit of this intervention in control of malaria. The addition of AZ to SPAQ in SMC appeared to enhance the infectivity of gametocytes providing further evidence that this combination is not an appropriate intervention.

scholarly journals 110. Impact of Diagnostic and Antimicrobial Stewardship on Time-to-Appropriate Therapy and Clinical Outcomes in Multi-Drug Resistant Pseudomonas Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S69-S70
Author(s):  
Katie A McCrink ◽  
Kailynn DeRonde ◽  
Adriana Jimenez ◽  
Gemma Rosello ◽  
Yoichiro Natori ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Antimicrobial Stewardship ◽  
Patient Survival ◽  
Intervention Group ◽  
Culture Collection ◽  
Drug Resistant ◽  
Intervention Period ◽  
Post Intervention ◽  
Appropriate Therapy ◽  
Post Intervention Group

Abstract Background Timely effective therapy in multi-drug resistant (MDR) Pseudomonas (PsA) infections has a direct impact on patient survival. We aimed to determine the impact of diagnostic and antimicrobial stewardship (AMS) on time-to-appropriate therapy (TAP) and clinical outcomes of patients with MDR PsA infections utilizing novel beta-lactam/beta-lactamase inhibitors (BL/BLIs). Methods Retrospective cohort study of adult patients with MDR PsA infections at a 1,500-bed University-affiliated public hospital in Miami, Florida who received ≥72 hours of ceftazidime-avibactam (C/A) or ceftolozane-tazobactam (C/T). During the pre-intervention period (12/2017-12/2018), additional susceptibilities for C/A and C/T were performed upon providers’ request. In the post intervention period (01/2019 – 12/2019), we implemented automatic reflex algorithms (Figure 1) for faster identification and susceptibilities for MDR PsA, including carbapenemase producers. Results were communicated in real-time to the AMS team. Figure 1. Reflex Testing Algorithm for MDR Pseudomonas Isolates from Any Source Results Seventy-six patients were included; median age was 56 years (IQR 37.5–67.0), 40 (52.6%) were in an intensive care unit at time of culture collection; median APACHE II score was 20 (IQR 15.0 – 26.0). Three isolates were carbapenemase producers (VIM = 2; KPC = 1). The most common infections were pneumonia (56.6%) and bacteremia (18.4%). We found a significant decrease in median TAP (120.1 [IQR 82.5–164.6] vs 75.9 [IQR 51.3–101.7] hours, p = 0.003). Median time from culture collection to final susceptibility results was shorter in the post-intervention group (122.2 vs 90.5 hours; p &lt; 0.001). Median length-of-stay after culture collection was numerically lower in the post-intervention group (26.0 [11.6–59.4] vs 19.7 [12.9–37.8] days; p = 0.33). Controlling for ICU admission, our intervention was not associated with decreased 30-day inpatient mortality (OR = 1.62, 95% CI 0.45–5.79). Conclusion Our study identified an improvement in TAP in MDR PsA infections with implementation of diagnostic and AMS initiatives. In an adequately powered study, our intervention could potentially impact patient survival through timely initiation of effective therapy with novel BL/BLIs. Disclosures All Authors: No reported disclosures

Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum

2021 ◽  
Author(s):  
Alina Krollenbrock ◽  
Yuexin Li ◽  
Jane Xu Kelly ◽  
Michael K. Riscoe
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Resistant
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