Plasmodium ovale Infection After One Year Mefloquine Prophylaxis in A Young Indonesian Soldier: A Case Report.

Malaria chemoprevention using mefloquine has become the WHO standard regimen for military personnel who stay in the endemic area for an extended period of time. We reported a case of Plasmodium ovale infection in a young Indonesian Soldier following one year mefloquine prophylaxis 250 mg weekly. Typical fever and chills were experienced two weeks after returning from one year duty in Congo, West-Central Africa. The diagnosis of ovale malaria was made by peripheral blood smear, and 35/250 parasites in small microscopic view was found. Then, he recovered after dihydroartemisin and primaquine combination therapy. This was an unusual case of long-term prophylaxis failure since mefloquine has been recognized as the agent for malaria prevention, even multi-drug-resistance Plasmodium. Dormant stage of Plasmodium ovale, quinoline-resistance potential, and the efficacy of mefloquine itself are discussed as the cause of that phenomenon.

Knowledge, attitudes, and practices regarding antimalarial chemoprophylaxis in U.S. Peace Corps Volunteers--Africa, 2013.

Long-term travelers to areas where malaria is endemic are at risk for this potentially fatal disease; however, malaria can be prevented through the use of insecticide-treated bednets, mosquito repellents, and chemoprophylaxis. Three options for chemoprophylaxis are available in the Africa region: mefloquine, doxycycline, and atovaquone-proguanil. These options differ by dosing regimen, cost, and side effect profile. Long-term adverse effects of these drugs have been reported rarely.

Mefloquine safety and tolerability in pregnancy: a systematic literature review.

BACKGROUND: Control of malaria in pregnant women is still a major challenge as it constitutes an important cause of maternal and neonatal mortality. Mefloquine (MQ) has been used for malaria chemoprophylaxis in non-immune travellers for several decades and it constitutes a potential candidate for intermittent preventive treatment in pregnant women (IPTp). METHODS: The safety of MQ, including its safety in pregnancy, is controversial and a continuing subject of debate. Published studies which evaluated the use of MQ for malaria prevention or treatment in pregnant women and which reported data on drug tolerability and/or pregnancy outcomes have been reviewed systematically. RESULTS: Eighteen articles fitted the inclusion criteria, only one study was double-blind and placebo controlled. No differences were found in the risk of adverse pregnancy outcomes in women exposed to MQ compared to those exposed to other anti-malarials or to the general population. MQ combined with artesunate seems to be better tolerated than standard quinine therapy for treatment of non-severe falciparum malaria, but a MQ loading dose (10 mg/kg) is associated with more dizziness compared with placebo. When used for IPTp, MQ (15 mg/kg) may have more side effects than sulphadoxine- pyrimethamine. CONCLUSIONS: In the published literature there are no indications that MQ use during pregnancy carries an increased risk for the foetus. Ideally, the use of MQ to prevent malaria should be based on a risk-benefit analysis of adverse effects against the risk of acquiring the infection. For this purpose double-blinded randomized controlled trials in African pregnant women are much needed.

Mass administration of the antimalarial drug mefloquine to Guantánamo detainees: a critical analysis.

Recently, evidence has emerged from an unusual form of mass drug administration practised among detainees held at US Naval Station Guantánamo Bay, Cuba ('Guantánamo'), ostensibly as a public health measure. Mefloquine, an antimalarial drug originally developed by the US military, whose use is associated with a range of severe neuropsychiatric adverse effects, was administered at treatment doses to detainees immediately upon their arrival at Guantánamo, prior to laboratory testing for malaria and irrespective of symptoms of disease. In this analysis, the history of mefloquine's development is reviewed and the indications for its administration at treatment doses are discussed. The stated rationale for the use of mefloquine among Guantánamo detainees is then evaluated in the context of accepted forms of population-based malaria control. It is concluded that there was no plausible public health indication for the use of mefloquine at Guantánamo and that based on prevailing standards of care, the clinical indications for its use are decidedly unclear. This analysis suggests the troubling possibility that the use of mefloquine at Guantánamo may have been motivated in part by knowledge of the drug's adverse effects, and points to a critical need for further investigation to resolve unanswered questions regarding the drug's potentially inappropriate use.

Anti-malarial chemoprophylaxis following evacuation from Afghanistan.

UK forces deployed to Afghanistan between March and November are prescribed anti-malarial chemoprophylaxis (AMC). In 2007 an audit showed poor pre-injury AMC compliance and a prescription rate of 50% amongst those casualties evacuated to Role 4. We re-audited the post-deployment AMC prescribing practice for casualties from Afghanistan for the 2008 and half of the 2009 malaria season. Using the Role 4 prescribing information and communication system (PICS), a retrospective AMC search for Proguanil, Chloroquine, Doxycycline, Mefloquine and Malarone was performed on these casualties. Only five out of 305 (1.64%) inpatients were prescribed appropriate post-deployment AMC medication. Awareness of the need to prescribe AMC following evacuation remains poor, and may be improved by recording AMC compliance in field medical records and modifying the PICS software.

Prophylactic use of antimalarials during pregnancy.

QUESTION: Some of my pregnant patients wish to travel to malaria-endemic regions. Are there medications that can be used safely during pregnancy for malaria prophylaxis? ANSWER: Pregnant women should avoid travel to malaria-endemic areas if possible. However, if travel cannot be avoided, measures to prevent mosquito bites, along with an effective chemoprophylaxis regimen, should be implemented. Chloroquine or hydroxychloroquine are considered safe to use in all trimesters of pregnancy. Mefloquine is the agent of choice for chloroquine-resistant areas, and evidence suggests it is not associated with an increased risk to the fetus. Although the atovaquone-proguanil drug combination is not currently recommended for use during pregnancy, limited data suggest that it is not harmful to the fetus. Doxycycline and primaquine are not recommended during pregnancy.

Structure-switching aptamer sensors for the specific detection of piperaquine and mefloquine.

Tracking antimalarial drug use and efficacy is essential for monitoring the current spread of antimalarial drug resistance. However, available methods for determining tablet quality and patient drug use are often inaccessible, requiring well-equipped laboratories capable of performing liquid chromatography-mass spectrometry (LC-MS). Here, we report the development of aptamer-based fluorescent sensors for the rapid, specific detection of the antimalarial compounds piperaquine and mefloquine-two slow-clearing partner drugs in current first-line artemisinin-based combination therapies (ACTs). Highly selective DNA aptamers were identified that bind piperaquine and mefloquine with dissociation constants (K d's) measured in the low nanomolar range via two independent methods. The aptamers were isolated from a library of single-stranded DNA molecules using a capture-systematic evolution of ligands by exponential enrichment (SELEX) technique and then adapted into structure-switching aptamer fluorescent sensors. Sensor performance was optimized for the detection of drug from human serum and crushed tablets, resulting in two sensing platforms. The patient sample platform was validated against an LC-MS standard drug detection method in samples from healthy volunteers and patients with malaria. This assay provides a rapid and inexpensive method for tracking antimalarial drug use and quality for the containment and study of parasite resistance, a major priority for malaria elimination campaigns. This sensor platform allows for flexibility of sample matrix and can be easily adapted to detect other small-molecule drugs.

Deployment and Travel Medicine Knowledge, Attitudes, Practices, and Outcomes Study (KAPOS): Malaria Chemoprophylaxis Prescription Patterns in the Military Health System.

The Deployment and Travel Medicine Knowledge, Attitudes, Practices, and Outcomes Study (KAPOS) examines the integrated relationship between provider and patient inputs and health outcomes associated with travel and deployments. This study describes malaria chemoprophylaxis prescribing patterns by medical providers within the U.S. Department of Defense's Military Health System and its network of civilian healthcare providers during a 5-year period. Chemoprophylaxis varied by practice setting, beneficiary status, and providers' travel medicine expertise. Whereas both civilian and military facilities prescribe an increasing proportion of atovaquone-proguanil, doxycycline remains the most prevalent antimalarial at military facility based practices. Civilian providers dispense higher rates of mefloquine than their military counterparts. Within military treatment facilities, travel medicine specialists vary their prescribing pattern based on service member versus beneficiary status of the patient, both in regards to primary prophylaxis, and use of presumptive anti-relapse therapy (PQ-PART). By contrast, nonspecialists appear to carry over practice patterns developed under force health protection (FHP) policy for service members, into the care of beneficiaries, particularly in high rates of prescribing doxycycline and PQ-PART compared with both military travel medicine specialists and civilian comparators. Force health protection policy plays an important role in standardizing and improving the quality of care for deployed service members, but this may not be the perfect solution outside of the deployment context. Solutions that broaden both utilization of decision support tools and travel medicine specialty care are necessary.

Adherence to malaria prophylaxis among travelers from a middle-income country.

INTRODUCTION: Malaria is the main cause of death by infection among travelers and is preventable through a combination of chemoprophylaxis and personal protective measures. METHODS: Travelers were interviewed by phone 28-90 days after returning, to assess adherence to pre-travel advice for malaria prevention. RESULTS: A total 57 travelers were included. Adherence to chemoprophylaxis was significantly higher among participants prescribed mefloquine (n=18; 75%) than doxycycline (n=14; 45%). Adherence to mosquito repellent and bed net use was 65% and 67%, respectively. CONCLUSIONS: Adherence to malaria prophylaxis was lower than expected. Further studies testing innovative approaches to motivate travelers' compliance are required.

Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison.

BACKGROUND: Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). METHODS: We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. FINDINGS: Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. INTERPRETATION: Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine.

Mefloquine-induced eosinophilic pneumonia.

Mefloquine has been widely used for prophylaxis and treatment of patients with chloroquine-resistant malaria; the drug is usually well tolerated. Rarely, adverse effects may be severe, including gastrointestinal disturbances, neuropsychiatric reactions, cardiovascular manifestations, skin lesions, musculoskeletal symptoms, and bone marrow toxicity. We describe a 67-year-old woman with fever, dyspnea on exertion, peripheral blood eosinophilia, and diffuse pulmonary infiltrates on chest radiography. She had taken mefloquine for malaria prophylaxis for an 8-week trip to South Africa. A thorough work-up led to the diagnosis of eosinophilic pneumonia caused by the mefloquine. Her condition improved after the drug was discontinued. To our knowledge, this is the first report of mefloquine-induced eosinophilic pneumonia. Clinicians should be aware of this rare, potential adverse effect of mefloquine.

Clinical efficacy of high dose monotherapy of oral dihydroartemisinin in uncomplicated falciparum malaria in viet nam.

The clinical efficacy of the monotherapy involving the administration of a high dose of dihydroartemisinin (DHA 900 mg) for 5 days was compared with that of the combination regimen (DHA 600 mg + mefloquine [MQ] 750 mg) in an open randomized study in 90 patients with uncomplicated falciparum malaria in the southern part of Viet Nam. Patients were randomly treated with the DHA-5 day monotherapy regimen (300, 300, 100, 100, and 100 mg given at 0, 24, 48, 72, and 96 h) or the DHA-MQ combination regimen (300 mg DHA at 0 h, then 300 mg DHA plus 750 mg MQ at 24 h). The end points for comparison were the parasite and fever clearance times (PCT and FCT) and recrudescence rates (by day 28 for DHA-5 days and day 42 for DHA-MQ). Eighty-nine patients completed the trial per protocol, including 45 cases receiving DHA-5 day and 44 receiving DHA-MQ. There was no difference in clinical manifestations, parasitemia density or other laboratory tests between the two patient groups. The PCTs were 35.3 +/- 17.4 h (mean +/- SD; range, 12-96) and 37.8 +/- 19.2 h (range, 12-96), respectively for the DHA-5 day and DHA-MQ regimens (P > 0.05). Twelve patients receiving the DHA-5 day regimen relapsed with falciparum malaria by day 28 (26.7%) and 5 patients receiving the DHA-MQ regimen relapsed by day 42 (11.4%) (P=0.07). Survival analysis showed that the DHA-5 day regimen had a radical cure rate significantly lower than that of the DHA-MQ regimen (P=0.003). The high dose of DHA in the monotherapy regimen did not increase the efficacy of the treatment of patients with uncomplicated Plasmodium falciparum malaria. The DHA combination regimens are suggested to be the better regimens for DHA.

Controversies and misconceptions in malaria chemoprophylaxis for travelers.

CONTEXT: Controversies in malaria prevention arise from the absence of data, conflicting data between different studies, conflicting recommendations, deviation of local practice from scientific data, and varying risk thresholds. Misconceptions about the seriousness of malaria, the tolerability of chemoprophylaxis drugs, and the efficacy and safety of repellents contribute to the controversies. OBJECTIVES: To compare several national guidelines on malaria chemoprophylaxis to identify variations in recommendations. We reviewed studies on tolerability of mefloquine with particular focus on its neuropsychiatric adverse effects and influence on performance. We also describe why most recommended chemoprophylactic regimens fail to prevent relapses of Plasmodium vivax malaria and review available options. EVIDENCE ACQUISITION: We searched scientific publications in MEDLINE via PubMED for relevant articles with a cutoff date of December 2006 using the search terms malaria, chemoprophylaxis, travel, mefloquine, neuropsychiatric adverse events, tolerability, vivax malaria, and primaquine. Additional references were obtained from bibliographies of the selected articles. There were no language restrictions. EVIDENCE SYNTHESIS: Gaps and conflicts exist among current guidelines. Health authorities vary in the chemoprophylaxis drugs they recommend, the indications for continuous prophylaxis vs no prophylaxis, and the use of standby emergency treatment. Despite widespread reports on the adverse effects of mefloquine, controlled studies found that serious neuropsychiatric adverse events occur at rates comparable with or lower than other chemoprophylaxis drugs. Moreover, mefloquine does not appear to impair performance while driving, flying, or diving. Vivax malaria causes significant illness in travelers, but current first-line chemoprophylaxis agents do not prevent relapses of vivax malaria. Although not licensed in most countries as primary prophylaxis, primaquine effectively prevents relapses of vivax malaria. CONCLUSIONS: Prevention of malaria in travelers requires detailed knowledge of malaria epidemiology and host-vector-parasite interactions. Decisions are complicated by a lack of standardized recommendations, controversies, and misconceptions. Improved international consensus is indicated to minimize conflicting guidelines, clarify controversies, and promote adherence to preventive measures.

Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report.

BACKGROUND: Convenient once-a-week dosing has made mefloquine a popular choice as malaria prophylaxis for travel to countries with chloroquine-resistant malaria. However, the increased use of mefloquine over the past decade has resulted in reports of rare, but severe, neuropsychiatric adverse reactions, such as anxiety, depression, hallucinations and psychosis. A direct causality between mefloquine and severe reactions among travelers has been partly confounded by factors associated with foreign travel and, in the case of therapeutic doses of mefloquine, the central nervous system manifestations of Plasmodium infection itself. The present case provides a unique natural history of mefloquine-induced neuropsychiatric toxicity and revisits its dose-dependent nature. CASE PRESENTATION: This report describes an acute exacerbation of neuropsychiatric symptoms after an unwarranted therapeutic dose (1250 mg) of mefloquine in a 37-year-old male previously on a once-a-week prophylactic regimen. Neuropsychiatric symptoms began as dizziness and insomnia of several days duration, which was followed by one week of escalating anxiety and subtle alterations in behaviour. The patient's anxiety culminated into a panic episode with profound sympathetic activation. One week later, he was hospitalized after developing frank psychosis with psychomotor agitation and paranoid delusions. His psychosis remitted with low-dose quetiapine. CONCLUSION: This report suggests that an overt mefloquine-induced psychosis can be preceded by a prodromal phase of moderate symptoms such as dizziness, insomnia, and generalized anxiety. It is important that physicians advise patients taking mefloquine prophylaxis and their relatives to recognize such symptoms, especially when they are accompanied by abrupt, but subtle, changes in behaviour. Patients with a history of psychiatric illness, however minor, may be at increased risk for a mefloquine-induced neuropsychiatric toxicity. Physicians must explicitly caution patients not to self-medicate with a therapeutic course of mefloquine when a malaria diagnosis has not been confirmed.

Chemoprophylaxis according to the guidelines on malaria prevention for Japanese overseas travelers.

Mefloquine has been licensed and registered in Japan for chemoprophylaxis against malaria since 2001. Guidelines for the prevention of malaria for Japanese overseas travelers were published by a group of malaria specialists under the auspices of the Japanese Society of Tropical Medicine and the Ministry of Health, Labor and Welfare, but not until March 2005. We implemented these guidelines in our clinic at the International Medical Center of Japan in Tokyo and, to better understand whether these guidelines are optimally useful, we conducted a study of Japanese travelers who visited our clinic seeking pertinent information and prophylaxis against malaria. The study group comprised 52 individuals who visited our clinic during the period October 2004 through June 2005 prior to travel abroad. On the basis of the above-mentioned guidelines, mefloquine was given to 27 of these individuals, 22 of whom were judged to need regular chemoprophylaxis. Mefloquine was not recommended to the other 25 individuals because their stays abroad would have been too long to avoid possible side effects or too short for symptoms to appear. In fact, some were traveling to malaria-free areas. Of the 27 individuals given mefloquine, 7 (26%) reported side effects, such as headache, vertigo, and nausea, 17 (63%) reported no side-effects, and the other 3 (11%) were unable to be followed. The diversity of destinations and accompanying malaria risks makes it very difficult for us to administer chemoprophylaxis to overseas travelers appropriately. The guidelines proved to be somewhat useful, but further experience in malaria chemoprophylaxis is needed for physicians to provide reliable pre-travel consultation.

[Atypical course of falciparum malaria in an asplenic patient]. / Paludisme à Plasmodium falciparum d'évolution atypique chez un patient splénectomisé

INTRODUCTION: The aim of treatment for falciparum malaria therapy is to achieve adequate clinical and parasitologic response within 7 days of starting treatment, with no subsequent relapse. We report and discuss the atypical course of a falciparum malaria attack observed in an asplenic patient returning from Burkina-Faso. CASE: This 34-year-old man was hospitalized for severe malaria and treated for 7 days with quinine, as an inpatient. Adequate early clinical response was observed. Twenty days after the end of the quinine course, he was readmitted for uncomplicated falciparum malaria. Inpatient treatment used mefloquine this time. Clinical response was adequate, but the blood smear was still positive 10 days later. It was decided not to administer further treatment at that time. Subsequent clinical and parasitologic assessments 1 month and 3 months later showed the patient was cured. CONCLUSION: This report illustrates the critical role played by the spleen in parasite clearance. Clinical and parasitologic assessments are essential after treatment of asplenic patients for falciparum malaria.

[Relapse of Plasmodium falciparum malaria in a patient treated with artesunate]. / Rechute d'un paludisme à Plasmodium falciparum après un traitement par artésunate.

Chemoprophylaxis and the curative treatment of malaria are well documented in France. Nevertheless this data is still not accounted for by healthcare professionals and in the global population, and no longer approved treatments may be prescribed. The authors report the case of a 24-year-old female traveler having stayed in Africa where she was used to treat fever with artesunate. Soon after her return, she presented with uncomplicated Plasmodium falciparum malaria once again treated with artesunate. The evolution was initially favorable but a relapse occurred 3 weeks later. A conventional mefloquine treatment lead to a final cure. This observation confirms that artesunate monotherapy in malaria exposes to a risk of relapse. Artesunate should not be used as monotherapy in P. falciparum malaria.

[Coartem and fansimef in the treatment of falciparum malaria].

From 2001 to 2003, anti-malarial combination coartem and fansimef, recommended by WHO, were used to treat falciparum malaria in Mali, 28 cases in each group. The mean fever clearance time, mean asexual parasite clearance time and the cure rate in 28 days were 35.3 +/- 6. 4, 34.7 +/- 6.9 hours and 100% respectively in coartem group, and 32. 6 +/- 5.8, 36.8 +/- 5.3 hours and 96.4% respectively in the fansimef group, with no significant difference between the two groups (P > 0.05).

Steroid Pulse Therapy May Mitigate Prolonged Neurological Manifestations after Eradication of Severe Plasmodium falciparum Parasitemia.

A 58-year-old Japanese man with a high parasitemia of Plasmodium falciparum, returning from Uganda, was admitted to our hospital since his consciousness level rapidly deteriorated after the initial dose of mefloquine. Despite the parasitemia was cleared by quinine by day 7, the coma remained unchanged and diffuse leukoencephalopathy was detected on magnetic resonance image. Steroid pulse therapy was initiated on day 8. Subsequently, the neurological manifestations improved and he was discharged on day 73 without any sequelae. Pathogenesis of P. falciparum causing cerebral malaria is diverse and complex. If neurological symptoms unusually prolong, steroid may be an effective treatment option.