Throat and rectal swabs may have an important role in MRSA screening of critically ill patients.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is a major problem in intensive care units (ICU). International guidelines recommend screening patients for MRSA on admission, although consensus on sites required for optimum detection has not been reached. Our aim was to determine whether throat and rectal swabs identified a significant number of additional MRSA-colonised patients not captured by swabbing at keratinized skin carriage sites (anterior nares, perineum and axillae). DESIGN: Prospective cohort study. SETTING: 30-Bed medical and surgical ICU in a tertiary teaching hospital. PATIENTS: One thousand four hundred and eighty adult patients consecutively admitted over 15 months. MEASUREMENTS AND RESULTS: Swabs from carriage sites (anterior nares, perineum, axillae, throat and rectum), wounds and clinical samples taken within 48 h of ICU admission were analysed to identify patients admitted with MRSA. A complete set of carriage swabs were received from 1,470 patients. 105 (7%) patients were admitted with MRSA of which 63 (60%) were detected by a pooled keratinized skin swab (anterior nares, perineum, axillae). A further 36 (34%) patients were detected only by throat or rectal swabs. Indeed, throat and rectal swabs combined had a higher sensitivity than pooled keratinised skin swabs (76 vs. 60% P = 0.0247). Swabs from all carriage sites together detected 95% (100) of MRSA positive patients, with five patients being positive at wound sites only. CONCLUSIONS: The throat and rectum are important and potentially hidden sites of MRSA carriage in critically ill patients. These findings prompt the need for larger studies to determine the most cost-effective screening strategy for MRSA detection. DESCRIPTOR: Non-pulmonary nosocomial infections

Evaluation of the efficacy and safety of primaquine for clearance of gametocytes in uncomplicated falciparum malaria in Uganda

Background: After standard effective antimalarial treatment with artemisinin-based combination therapy (ACT), a proportion of individuals remain infectious to mosquitoes, enabling onward transmission. This is due to persisting gametocytes, the sexual stage of the malaria parasite. Primaquine, an 8-aminoquinoline drug, sterilizes and clears gametocytes. The World Health Organization recommends that, in areas where malaria elimination is targeted, a single dose of primaquine should be given in addition to standard antimalarial treatment. Despite its recommendation in WHO guidelines since the 1970s, the optimal dose of primaquine for this purpose had not been determined. Primaquine is associated with haemolytic toxicity in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition that is prevalent in malaria-endemic regions. This thesis presents the first dose ranging trial to assess the safety and efficacy of reducing doses of primaquine in combination with ACT to treat children with uncomplicated falciparum malaria infection. Methods: A literature review was conducted to inform a novel, evidence-based trial design. Based in Jinja, Uganda, this randomised, double-blind, and placebo-controlled trial had four parallel treatment groups of reducing doses of primaquine plus ACT. Results: For trial participants, a single dose of 0.4mg/kg primaquine base had non-inferior efficacy (measured by gametocyte clearance) to the WHO-recommended dose of 0.75mg/kg, whereas a dose of 0.1mg/kg was not non-inferior. There was no significant haemolysis in any of the treatment arms and the fall in haemoglobin was not associated with the dose of primaquine. However, a sub-analysis showed a dose-dependent reduction in haemoglobin in participants who were G6PD deficient (heterozygous or hemi-/homozygous genotype). Subsequently, the WHO reduced the recommended dose to 0.25mg/kg primaquine bas

Low-dose primaquine for falciparum malaria

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Artesunate–mefloquine: a malaria treatment for African children?

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Glucose-6-phosphate dehydrogenase status and risk of hemolysis in Plasmodium falciparum-infected African children receiving single-dose primaquine.

Glucose-6-phosphate dehydrogenase (G6PD) enzyme function and genotype were determined in Ugandan children with uncomplicated falciparum malaria enrolled in a primaquine trial after exclusion of severe G6PD deficiency by fluorescent spot test. G6PD A- heterozygotes and hemizygotes/homozygotes experienced dose-dependent lower hemoglobin concentrations after treatment. No severe anemia was observed

Measuring the efficacy of anti-malarial drugs in vivo: quantitative PCR measurement of parasite clearance

BACKGROUND: Artemisinin-based combination therapy, currently considered the therapy of choice for uncomplicated Plasmodium falciparum malaria in endemic countries, may be under threat from newly emerging parasite resistance to the artemisinin family of drugs. Studies in Southeast Asia suggest some patients exhibit an extended parasite clearance time in the three days immediately following treatment with artesunate monotherapy. This phenotype is likely to become a more important trial endpoint in studies of anti-malarial drug efficacy, but currently requires frequent, closely spaced blood sampling in hospitalized study participants, followed by quantitation of parasite density by microscopy. METHODS: A simple duplex quantitative PCR method was developed in which distinct fluorescent signals are generated from the human and parasite DNA components in each blood sample. The human amplification target in this assay is the β tubulin gene, and the parasite target is the unique methionine tRNA gene (pgmet), which exhibits perfect sequence identity in all six Plasmodium species that naturally infect humans. In a small series of malaria cases treated as hospital in-patients, the abundance of pgmet DNA was estimated relative to the human DNA target in daily peripheral blood samples, and parasite clearance times calculated. RESULTS: The qPCR assay was reproducibly able to replicate parasite density estimates derived from microscopy, but provided additional data by quantification of parasite density 24 hours after the last positive blood film. Robust estimates of parasite clearance times were produced for a series of patients with clinical malaria. CONCLUSIONS: Large studies, particularly in Africa where children represent a major proportion of treated cases, will require a simpler blood sample collection regime, and a method capable of high throughput. The duplex qPCR method tested may fulfil these criteria, and should now be evaluated in such field studies

The gametocytocidal efficacy of primaquine in malaria asymptomatic carriers treated with dihydroartemisinin piperaquine in The Gambia (PRINOGAM): study protocol for a randomised controlled trial

Background: Finding efficacious tools to decrease and interrupt malaria transmission is essential to sustain the gains in malaria control and contain the emergence of artemisinin resistance. Primaquine is effective against Plasmodium falciparum gametocytes and recommended for treatment campaigns in (pre-)elimination settings. Safety concerns preclude its use in endemic African countries with variable proportions of glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The efficacy of the current recommended dose needs to be evaluated, particularly in individuals with an asymptomatic malaria infection. Methods/design: This is a four-arm, open label, randomized controlled trial that aims to determine and compare the effect of three different single doses of primaquine combined with dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, on gametocyte carriage in asymptomatic, malaria infected, G6PD-normal individuals. Approximately 1,200 participants are enrolled and followed for 42 days, with the primary endpoint being the prevalence of Plasmodium falciparum gametocyte carriage at day 7 of follow-up determined by quantitative nucleic acid sequence based amplification assay. Direct membrane feeding experiments to determine infectiousness to mosquitoes are conducted as a biological secondary endpoint. Discussion: Sub-Saharan Africa, with a relatively high but poorly characterized G6PD prevalence, could potentially benefit from the use of primaquine to further reduce or interrupt malaria transmission. However, G6PD screening may not be feasible given the cost and difficulties in interpreting test results in terms of risk of haemolysis. Because the haemolytic effect of primaquine is dose-dependent, determining the minimal gametocytocidal and transmission-blocking dose of primaquine is extremely important to help address public health concerns over its safety and validate the efficacy of lower than recommended dosages. By including infectiousness to mosquitoes, the trial provides complementary evidence for the potential of the drug to interrupt transmission to mosquitoes