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To evaluate if cost and availability of antimalarials are barriers to malaria chemoprophylaxis and treatment, we surveyed retail pharmacies in Minneapolis/Saint Paul and New York City on the price and stocking of antimalarials. We demonstrated extreme price variability among pharmacies and limited availability for some recommended antimalarials.

A case report of atovaquone/proguanil esophageal ulcer.

We present a returning traveler with acute generalized exanthematous pustulosis after atovaquone/proguanil prophylaxis. Diagnosis was confirmed with biopsy and allergy testing, symptoms resolved after steroid treatment. Atovaquone/proguanil prophylaxis is generally well tolerated, however, some patients may present severe adverse events that require prompt medical evaluation and treatment.

BACKGROUND: Malaria during pregnancy increases the risk of maternal and foetal complications. There are very limited options for prophylaxis in pregnant travellers. Atovaquone-Proguanil (AP or Malarone®) is an effective and well-tolerated antimalarial medication, but is not recommended for use in pregnancy due to limited data on safety. Passively reported adverse event data may provide additional information on the safety of AP during pregnancy. METHODS: We analysed adverse event data on pregnancy and birth outcomes following accidental exposures to AP during pregnancy, which were passively reported to GlaxoSmithKline LLC (GSK) between 13 May 1997 and 15 August 2017. Birth outcomes of interest included live birth, miscarriage, and stillbirth. Adverse outcomes of interest were defined as any of the following: small for gestational age (SGA), low birth weight (LBW

As in any other field of medicine, how much evidence do we need in travel medicine before we change daily practice and adapt guidelines and recommendations for prophylaxis or treatment, for example regarding malaria? Leshem and colleagues, rightfully stating that adherence to antimalarial chemoprophylaxis (in this case to atovaquone‐proguanil—AP) may leave room for improvement, and that findings (evidence!) from clinical and pharmacokinetic studies informed such a bold move, put a shortened AP oral chemoprophylactic scheme to the test. Following intake of this regimen—in standard dosage, but only administered from the day before departure up to the day after return—outcomes were surveyed at 6 months post‐travel, resulting in the conclusion that cessation of drug intake straight after return may convey full protection compared to a standard +7 days post‐exposure regimen.1 Correctly taken for the purpose of chemoprophylaxis, suitable antimalarials are considered as being of high efficacy. The problem, however, often is a reduced effectiveness, to which noncompliance (the definition in my view encompassing also not even embarking on a recommended regimen) or nonadherence (not appropriately seeing through the intake of a begun regimen) is a major contributor, as pointed out by Rombo and colleagues in this issue.2 Leshem and colleagues assume a high level of adherence, although their study was not designed to assess it systematically.1 While the authors acknowledge several of the methodological shortcomings (possibly problematic choice of region with limited risk of exposure, insufficient level of evidence that the drugs were taken appropriately, possible recall bias), they suggest that travelers may discontinue AP prophylaxis 1 day after leaving endemic areas, and recommend their approach for further evaluation. In earlier days, what we would now consider as limited evidence may have led to major practice change, as exemplified by the introduction of primaquine for treatment and prophylaxis of vivax … Corresponding Author: Professor Martin P. Grobusch, MD, PhD, Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, PO Box 22600 1100 DD Amsterdam, The Netherlands. E‐mail: m.p.grobusch{at}amc.uva.nl

Background. Malaria continues to be a serious, world-wide infection. Atovaquone-proguanil is one of the prophylactic agents recommended for travelers to endemic regions. However, little information is available regarding adherence with this medication. A large proportion of malaria cases reported from travelers is due to non-adherence to prescribed regimens. This study was undertaken to analyze adherence with atovaquone-proguanil prophylaxis and specific factors contributing to non-adherence. Methods. Men and non-pregnant women ≥18 years of age were eligible for inclusion. Enrolled travelers received a prescription for atovaquone-proguanil prophylaxis and were contacted by telephone within 3 weeks of return to the United States. A questionnaire was prepared by the authors to determine if subjects were adherent with the medication. Additional data included demographics, duration of malarious travel, previous use of prophylactic agents, underlying medical conditions, concurrent medications, and reasons for non-adherence. Results. Complete data were available for 104/124 (84%) participants: 49 (47%) men, 55 (53%) women. Average duration of malarious travel was 12 days, and 19 (18%) travelers reported previous travel to a malarious region. Ninety-two (89%) subjects were completely adherent with their prophylactic atovaquone-proguanil course. Adverse effects were seen in 6 (5%) travelers. Conclusions. Adherence with atovaquone-proguanil malaria prophylaxis is high among travelers from a non-endemic region. Adverse effects are minimal. Non-adherence was primarily attributable to travelers' perception of need.

Background To objectively compare the mood profiles of users of malaria chemoprophylaxis regimens (atovaquone–proguanil, chloroquine–proguanil, doxycycline, or mefloquine) in a group of nonimmune tourists to sub-Saharan Africa. Methods In a randomized, double-blind, four-arm study with placebo run-in phase conducted at travel clinics in Switzerland, Germany, and Israel, we compared moods and feelings in chemoprophylaxis users (n= 547) by administering the standardized “Profile of Mood States” (POMS) questionnaire. This is designed to provide data on six categories of feelings: tension, depression, anger, vigor, fatigue, and confusion. The questionnaire was administered at four time points: recruitment (T1), 13 to 11 days before departure (T2), 6 to 4 days before departure (T3), and 7 to 14 days after return from Africa (T4). Results There were no significant differences with respect to overall mood impact between the medication arms. All scores were in the normal range, and no means were more than 1 SD from the norm. The POMS data were reanalyzed with respect to sex, age, medication group, and control time points (T1–T4). There were significant interaction effects between sex and medication group—women in the mefloquine group showed more “fatigue” (p= .011) and “confusion” (p= .011) than men. Significant effects of age group (below median age 34 y vs median age and above) were noted on the “tension” and “fatigue” scales in that less “tension” (p= .045) and less “fatigue” (p= .000) were noted in those aged 34 years and older. Younger participants, aged

A 22-year-old soldier presented with vivax malaria after extended travel in Afghanistan. Compliant with atovaquone/proguanil in country, he discontinued prophylaxis immediately upon departure. This case raises important issues regarding prophylactic choice and compliance during travel to Plasmodium vivax endemic locations and primaquine's registration status for prophylaxis and use by practitioners.

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

The resurgence of malaria in areas where it had been controlled previously and the concurrent emergence of drug-resistant malaria strains contribute to the current recommendations concerning malaria chemoprophylaxis. Chloroquine (e.g., Aralen), the former standard for malaria prevention and treatment,is now effective only in limited areas, and multidrug resistance has made chemoprophylaxis with mefloquine (e.g., Lariam) less effective in some regions. This has complicated the decision-making process with regard to selection of optimal antimalarial drug regimens for international travelers. Guidelines from the Centers for Disease Control and Prevention (CDC) provide recommendations for the use of three currently available drugs for malaria prophylaxis in chloroquine-resistant areas: mefloquine, doxycycline (e.g., Vibramycin, Doryx), and atovaquone/proguanil (e.g., Malarone). Guidelines from the World Health Organization (WHO) include the three drugs above, and in addition, consider proguanil (e.g., Paludrine) coadministered or in fixed-dose combination with chloroquine, and also primaquine among current choices for malaria prophylaxis. This article presents a concise review of current knowledge about use of these drug regimens for prophylaxis against malaria. Given the increase in international travel and the spread of malaria into previously disease-free areas,growing numbers of travelers now face the risk of contracting this disease. 1 The number of cases of imported malaria has been rising in the United States,Canada,and other developed countries since the 1970s. In 1997, over 1,500 cases of imported malaria, including 6 fatalities, were reported in the United States, whereas in Canada, 1,036 cases of imported malaria were reported that year. 2‐5 Compounding the problem of increased incidence of malaria,parasite resis

The World Health Organization estimates that there are more than 300 million cases of malaria world-wide each year, resulting in more than 3 million deaths.¹ New Zealand is malaria free; however, 340 cases of imported malaria were notified in New Zealand over a 10 year period from 1983 to 1992 alone.² The incidence of malaria due to Plasmodium falciparum in New Zealand has been increasing during this period.³ Taking chemprophylaxis decreases the severity and frequency of death from malaria due to P. falciparum compared with those who take no prophylaxis.⁴⁻⁵ In New Zealand, fatalities have been reported in cases where travelers have taken no prophylaxis.⁶⁻⁷

Background The use of preventive measures, including effective chemoprophylaxis, is essential for protection against malaria among travelers. However, data have shown that travelers and medical advisors are confused by the lack of uniform recommendations and numerous prophylactic regimens of varying effectiveness that are used. Methods To assess the use and type of preventive measures against malaria, we conducted a cross‐sectional study in 1997 among travelers departing from the Nairobi and Mombasa airports in Kenya with European destinations. Results Seventy‐five percent of the travelers studied were residents of Europe and 25% were residents of North America; all stayed less than 1 year, and visited malarious areas. Most travelers, 97.1%, were aware of the risk and 91.3% sought pretravel medical advice. Although 95.4% used chemoprophylaxis and/or antimosquito measures, only 61.7% used both regular chemoprophylaxis and two or more antimosquito measures. Compliance with chemoprophylaxis was lowest amongst those who used a drug with a daily, as opposed to, a weekly dosing schedule, stayed more than 1 month, attributed an adverse health event to the chemoprophylaxis, and were less than 40 years of age. Among US travelers, 94.6% of those taking chemoprophylaxis were taking an effective regimen, that is, mefloquine or doxycycline. Only 1.9% used a suboptimal drug regimen, such as chloroquine/proguanil. Among European travelers, 69% used mefloquine or doxycycline, and 25% used chloroquine/proguanil. Notably, 45.3% of travelers from the UK used chloroquine/proguanil. Adverse events were noted by 19.7% of mefloquine users and 16.4% of travelers taking chloroquine/proguanil. Neuropsychologic adverse events were reported by 7.8% of users of mefloquine and 1.9% of those taking chloroquine/proguanil. The adverse events, however, had a lesser impact on compliance than frequent dosing schedule. Conclusions Health information should be targeted to travelers who are likely to use suboptimal chemoprophylaxis or may be noncompliant with prophylaxis. Uniform recommendations for effective chemoprophylaxis with simple dosing schedules are necessary to reduce rates of malaria among travelers to Africa.

Background: previous research in a number of countries has suggested considerable variability in prescribing patterns of antimalarial drugs. The aim of this study was to investigate the trends in prescription of antimalarial drugs recommended for chemoprophylaxis in Australia from 1998 to 2002. Methods: in 2005 data was extracted from the online Australian Statistics on Medicines reports published by the Pharmaceutical Benefits Advisory Committee, Drug Utilization Sub-committee, on antimalarials used in Australia from 1998 to 2002. Results: Doxycycline probably remains the malaria chemoprophylaxis of choice prescribed for Australians visiting multiple drug–resistant malarious areas. Over the past 10 years, there has been marked drop in the prescription of less useful antifolate drugs such as pyrimethamine combination antimalarial drugs, especially pyrimethamine plus dapsone, which was withdrawn by 1999. There has also been a reduction in the number of prescriptions for chloroquine, mefloquine, and proguanil. The number of prescriptions for atovaquone and proguanil remain small, although they have increased steadily since its introduction in 2000, in the absence of a recommendation in the prevailing Australian guidelines. Conclusions: the prescription of antimalarials such as proguanil, chloroquine, mefloquine, and the pyrimethamine-containing compounds reduced considerably between 1998 and 2002. This was probably largely influenced by the availability of antimalarials, increasing resistance, the issuing of updated guidelines for malaria chemoprophylaxis, and continuing education. Newer drugs such as atovaquone plus proguanil may displace older antimalarials, particularly in the prevention of Plasmodium falciparum infection.

Background France is the European country with the highest number of imported malaria cases (7,500 in 2000). The aim of this prospective study was to evaluate the nature and efficacy of prophylactic measures in children under 15 years of age referred for malaria. Methods Posttravel questionnaires were given to the parents of malarial children in the emergency room. The study took place in two university hospitals in Marseilles, southern France, from August to October 2001. Results Eighty-eight children under 15 years of age were included in this 3-month period. Most of them had been infected in Comoro archipelago. Almost two-thirds used bed nets, but only 47% did so every night. Sprayed bed nets were used by 23%. Average compliances with cutaneous repellents, bedroom repellents and long-sleeved clothing were 32%, 24% and 26%, respectively. Airconditioners were uncommon. Only 22% of the children used chemoprophylaxis correctly, according to French recommendations. Five percent did not use any chemoprophylaxis, and 61% reported nonrecommended drug use. Although all the children traveled to chloroquine-resistant areas, chemoprophylaxis with mefloquine was less common than that with chloroquine + proguanil. No child fully complied with French recommendations concerning both antimosquito measures and chemoprophylaxis. Conclusions Insufficient use of antimalaria precautions by traveling families is associated with the high incidence of pediatric imported malaria in southern France. Travelers' education should be increased to allow the optimization of malaria prophylaxis.

Background Previous experience with unacceptable adverse effects with mefloquine as treatment for uncomplicated Plasmodium falciparum malaria prompted an evaluation of the effectiveness and side effects of atovaquone–proguanil (Malarone) in a hospital setting. Methods Atovaquone–proguanil was given as standard treatment (1,000/400mgq.d. for 3 days) to 50 adults who had traveled in Africa and returned with uncomplicated Plasmodium falciparum malaria. Half of the treated patients were African and had lived outside Africa for varying periods of time; the other half were Danish-born persons without any previous immunity towards malaria. Results All patients treated with Malarone were cured without complications. The mean fever clearance times differed among the groups and according to various degrees of prior exposure to malaria and ranged from 1.3 to 2.2 days. Adverse effects during treatment were mild, and were likely to be due to the malaria itself. Fourteen people who had acquired falciparum malaria in spite of taking proguanil–chloroquine prophylaxis were also cured uneventfully without recrudescence. Conclusions Malarone appears to be an effective, safe and acceptable oral treatment for uncomplicated malaria.

An increasing number of families, including children and the elderly, are seeking more adventurous travel in exotic parts of the world. Holiday destinations now include once-remote regions such as subSaharan Africa and New Guinea. This increase in visits to tropical and subtropical regions, combined with widespread chloroquine-resistant malaria, now places millions of Western travelers at risk of infection annually. At least 30,000 travelers from industrialized countries are reported to contract malaria each year and approximately 1 in 100 travelers who acquire Plasmodium falciparum malaria will die.

Background: Atovaquone/proguanil in Europe is only licensed for 4 weeks of travel. Data on its long-term tolerability in nonimmune travelers are scarce. Methods: We prospectively studied adverse reactions reported by long-term travelers using atovaquone/proguanil among a population intolerant to mefloquine. The average length of atovaquone/proguanil use was 9 weeks (4.5 to 34 weeks). Adverse events were recorded on a regular questionnaire. Travelers rated complaints as: (1) mild, not interfering with their daily activities; (2) moderate, causing interference, such as canceling a trip or being confined to the hotel; or (3) severe, causing a visit to a doctor or clinic. Hospital admission was classified as category 3 and specified. We then compared our data with those on adverse reactions from 2 large multicenter studies of atovaquone/proguanil in nonimmune travelers. Results: One hundred and fifty-four subjects used atovaquone/proguanil for a total of 1538 weeks. Diarrhea was the most common ailment (18%). Further complaints were abdominal pain (mild 4%, moderate 5%, severe 2%), headache (mild 4%, moderate 4%, severe 1%), dizziness (mild 3%, moderate 1%, severe 1%), and insomnia (mild 6%, moderate 0%, severe 0%). Two subjects of 154 (1%) discontinued prophylaxis, both due to diarrhea. Nobody was admitted to hospital. No case of malaria was reported. Comparison with data from previous, larger atovaquone/proguanil studies shows that the adverse events reported by the long-term atovaquone/proguanil users are no different in type and frequency of occurrence to those travel-related health problems normally encountered in the Tropics. Conclusions: Atovaquone/proguanil was well tolerated by these long-term travelers. Long-term users of atovaquone/ proguanil antimalarial prophylaxis suffer no more ailments than normally occur to travelers in tropical regions.

Background. In the Netherlands, cases of imported malaria peaked in the late 1990s to around 500 (60% Plasmodium falciparum) annually. About 30% to 40% of all cases and 57% to 69% of the falciparum cases presented in the Academic Medical Center, Amsterdam. In 1991 to 1994, a shift in population groups to more semi-immune patients, mostly settled immigrants visiting friends and relatives (VFRs), was noticed, when compared to 1979 to 1988. This study shows the ongoing trend in 2000 to 2002. Methods. All the patients diagnosed with malaria in the Academic Medical Center, Amsterdam, during 2000 to 2002 were analyzed. Nonimmune and semi-immune patients were analyzed separately. Results. A total of 302 patients were diagnosed with malaria: 207 (69%) were male; mean age was 34.0 years (range 1–74 years). Of the 302 patients, 105 (35%) were nonimmune travelers and 197 (65%) were considered semi-immune. In 248 (82%) patients, P falciparum was found. In 28 (9.3%), 15 (5.0%), and 6 (2.0%) cases, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae were diagnosed, respectively. Of the 248 falciparum cases, 233 (94%) were infected in sub-Saharan Africa; 90% of them had a parasitemia and

Alternatives for Malaria Prophylaxis During the First Trimester of Pregnancy : Our Personal View

Malaria prevention in travelers depends upon dissemination of accurate information about malaria risk, prevention of mosquito bites, appropriate chemoprophylaxis use and knowledge of the symptoms of malaria. A study was undertaken of travelers to the Kruger National Park and private game parks in Mpumalanga Province, South Africa to investigate travelers knowledge, of malaria, chemoprophylaxis use, and experience of adverse events. In-flight self administered questionnaires were distributed and completed by travelers on flights returning to Johannesburg International Airport, from the malaria areas. The study was conducted during the highest malaria risk period during 1996. The Mpumalanga game parks are those most visited in South Africa and are found in the extreme northeast of the country, which adjoins Mozambique in the east and Zimbabwe in the north. This area is classified by the South African health authorities as being a high risk Malaria area.10 Chloroquine-resistant Plasmodium falciparum malaria has been described in this area.2,3 The Department of Health in South Africa recommends the use of mefloquine alone or the combination of chloroquine and proguanil, (doxycycline is prescribed for travelers in which the former antimalarials cannot be utilized), for visitors to this area during the high risk period for malaria, which extends from October to May.4 For the remainder of the year mosquito avoidance measures are recommended. Little is known about travelers' compliance with these recommendations and their knowledge of malaria. A study to explore these factors was undertaken as a joint initiative between the SAIMR travel clinic, Mpumalanga Department of Health, and the South African National Parks.

Background: Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new antimalarial drug combination that has recently become available in many countries. Methods: Data were reviewed from nonclinical studies evaluating the microbiology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquone and proguanil hydrochloride. Results: Atovaquone is highly active against asexual erythrocytic stages of Plasmodium falciparum in vitro (IC60 0.7-6 nM) and in animal models. Proguanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 p.M), and its effectiveness depends on the active metabolite cycloguanil (IC60 0.5-2.5 nM). The combination of atovaquone and proguanil is synergistic in vitro. Both drugs also have activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites. Atovaquone is a ubiquinone antagonist that inhibits mitochondrial electron transport and collapses mitochondrial membrane potential. The proguanil metabolite cycloguanil is a dihydrofolate reductase inhibitor, but the mode of action of proguanil is unknown. In screening evaluations of secondary pharmacology, neither atovaquone nor proguanil had activity that adversely affected gastrointestinal, cardiovascular, or central or autonomic nervous system functions at clinically relevant concentrations. After oral administration, atovaquone exposure is extensive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but limited in rats. In both species, toxicity was related to proguanil exposure, the principal manifestations being salivation, emesis, and loss of body weight. Neither atovaquone nor proguanil was teratogenic or mutagenic. An increased incidence of hepatic adenomas and adenocarcinomas was seen in mice, but not rats, after lifetime exposure to atovaquone, and appears to be related to species-specific differences in hepatic enzymatic activity. No additional toxicity was evident in animals treated with the combination of atovaquone and proguanil hydrochloride compared to those treated with either drug alone. Conclusion: Nonclinical studies of atovaquone and proguanil hydrochloride supported the clinical development of this combination for treatment and prophylaxis of malaria.

Background: Atovaquone and proguanil hydrochloride is a new antimalarial combination that is used for treatment and prophylaxis of malaria. Methods: The clinical pharmacology of atovaquone and proguanil was reviewed. Results: Atovaquone is a highly lipophilic compound with low aqueous solubility, the absorption of which is limited by the rate and extent of dissolution. Dietary fat increases the rate and extent of atovaquone absorption, increasing AUC two- to threefold and C fivefold over fasting. Proguanil is rapidly and extensively absorbed regardless of food intake. Atovaquone is highly protein bound (> 99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely. Atovaquone is predominantly eliminated unchanged in feces, with negligible excretion in urine. Proguanil is partially metabolized and partially excreted unchanged in urine. Its principal metabolite, cycloguanil, is also excreted in urine. Metabolism of proguanil is mediated in the liver by the cytochrome P450 3A and 2C subfamilies.The elimination half-life of atovaquone is 2 to 3 days in adults and 1 to 2 days in children.The elimination half-lives of proguanil and cycloguanil are 12 to 15 hours in adults and children. Dosage adjustments based on body weight categories in children (Vi dose for 11-20 kg, h dose for >20-30 kg, 3/4 dose for >30-40 kg, and full dose for >40 kg) achieve plasma concentrations that are safe and effective during prophylaxis and treatment of malaria. No dose adjustments for race, proguanil metabolizer status, gender, or elderly patients are needed, or for patients with mild to moderately impaired renal or hepatic function. Conclusion: The clinical pharmacology of atovaquone and proguanil provides a rationale for the dosing regimens recommended for treatment and prophylaxis of malaria.

6ackground:Safe and effective antimalarials are required to protect pregnant women from the harmful effects of malaria. Methods: Data were collected from two separate prospective cohorts to ascertain the safety of chloroquine-proguanil, sulfadoxine-pyrimethamine (SP), and mefloquine taken in the first trimester of pregnancy. Results: In a traveler cohort of 236 pregnant women, spontaneous abortions were reported in 7.6% of 99 women taklng chloroquine-proquanil, 0% of 19 taking sulfadoxine-pyrimethamine, and 9.1% of 118 women taking mefloquine. Anomalies were identified in 1.7%, 0% and 0% of the same cohort, respectively. Differences in rates of adverse outcomes between the three groups were not statistically significant. In a pharmaceutical database of 331 and 153 women exposed to mefloquine and SP, respectively, the overall rate of abnormal outcomes (spontaneous abortions plus fetal anomalies) was not significantly different (p=.29). Spontaneous abortions were significantly higher with mefloquine than SP (9.1% and 2.6%, respectively; p=.Ol), but the higher rate was comparable to background rates (7%-11%). Fetal anomalies in the mefloquine group (4.8%) were lower than the SP group (7.8%), but this was statistically not significant (p=.19), and was comparable with the background rate of 4.6% (p=.84). However, mefloquine exposure resulted in a significantly higher rate of therapeutically induced abortions, undertaken for perceived risk to the fetus, compared with SP (pe.0001). Conclusion: From the clinical data available, there is no indication that the risk of taking mefloquine in the first trimester of pregnancy is greater than that from any of the other antimalarials studied and the risk is considerably lower than that associated with falciparum malaria. Malaria infection in nonimniune pregnant women carries a poor prognosis, including spontaneous abortion in up to 60% of cases, fetal loss, and a maternal mortality rate of up to lo%." Women are advised to abstain from travel to highly malarious areas while pregnant or to avoid getting pregnant during travel to those areas.2 If travel is unavoidable, malaria chemoprophylaxis is required, and has been limited to chloroquine alone or in combination with proguanil. Surveys have shown that this coinbination is less effective than other antimalarial^.',^ Studies have now shown that fortnightly dapsonepyrimethamine prophylaxis,' niefloquine pro phyla xi^,',^ and two separate treatment doses of sulfadoxinepyrimethamine (SP) are effective against the deleterious etrects of malaria in the second/third trimester of pregnancy.' Significant adverse outcomes were not reported

Background: Data on the long-term safety of atovaquone/proguanil in nonimmune travelers are limited. Methods: An open-label study, involving 300 Danish soldiers stationed in Eritrea for 6 months was initiated. The subjects self-reported their symptoms on a post-travel questionnaire. The study compared the symptoms of compliers and noncompliers. Results: No serious adverse events occurred. Diarrhea, stomach pain, headache, cough, and loss of appetite were the most common symptoms reported. No case of Plasmodium falciparum malaria occurred. Conclusions: Atovaquone/proguanil was safe and well tolerated in this group of long-term nonimmune travelers.

The use of chemoprophylaxis decreases the severity and frequency of death from malaria due to Plasmodium falciparum compared with those who take no prophylaxis. Advice on the prevention of malaria has been deemed as among the most important to give travelers in Australia. Geographic knowledge of the distribution and prevalence of malaria and drug-resistant malaria should be used to base decisions concerning whether or not to give malaria chemoprophlaxis. Therapeutic guidelines, which include guidelines on malaria chemoprophylaxis, assist travel health advisers in their selection of antimalarials. Previous studies have suggested that considerable variation exists in patterns of antimalarials used in relation to the prevailing antimalarial guidelines in Australia.

Current guidelines recommend continuation of atovaquone-proguanil (AP) malaria prophylaxis for 7 days after leaving Plasmodium falciparum endemic areas. Evidence from clinical studies suggests that discontinuation of AP 1 day after exposure ends may be safe and effective. Our objective was to assess the effectiveness of short-course AP prophylaxis among travelers to sub-Saharan Africa.To detect prophylactic failures associated with short-course AP prophylaxis discontinued 1 day after return, we conducted active surveillance during the years 2010 and 2011, by a retrospective telephone survey 1 to 6 months after travelers' return. Passive surveillance data were obtained from the Israel Ministry of Health (MOH) malaria registry.Among 485 travelers to sub-Saharan Africa (cumulative exposure of 4,979 days), 421 (87%) discontinued AP 1 day after leaving the endemic region (cumulative exposure of 4,337 days). None of the 485 travelers reported malaria infection. The MOH malaria registry survey included 363 P. falciparum-infected patients during the years 2003 to 2011. The majority (n = 305; 84%) did not use any malaria prophylaxis. None of the patients had used AP (neither regular nor short course AP) for malaria prophylaxis.We did not detect prophylaxis failures among a group of travelers who discontinued AP prophylaxis 1 day after leaving malaria-endemic areas. Passive surveillance in Israel did not detect any P. falciparum cases among AP users. We recommend further validation of our findings by clinical trials, prospective studies, and active surveillance in larger cohorts to assess the effectiveness of short-course AP prophylaxis in travelers.

The spread of drug-resistant malaria and appreciation of side effects associated with existing antimalarial drugs emphasize the need for new drugs to prevent malaria. The combination of atovaquone and proguanil hydrochloride was previously shown to be safe and highly effective for treatment of malaria, including multi-drug-resistant Plasmodium falciparum.We reviewed results of clinical trials that evaluated either a fixed-dose combination of atovaquone and proguanil hydrochloride for malaria prophylaxis or atovaquone alone for causal prophylactic activity against P. falciparum.In three placebo-controlled trials, 331 subjects received 250 mg atovaquone and 100 mg proguanil hydrochloride (or an equivalent dose based on body weight in children) once daily for 10 to 12 weeks. The overall efficacy for preventing parasitemia was 98%. Among 175 nonimmune volunteers taking the same dose of atovaquone/proguanil once daily for 10 weeks while temporarily residing in a malaria-endemic area, malaria developed in one patient who was noncompliant with therapy. Results of volunteer challenge studies indicate that both atovaquone and proguanil have causal prophylactic activity directed against the liver stages of P. falciparum. Adverse events occurred with similar or lower frequencies in subjects treated with atovaquone/proguanil compared to placebo. Less than 1% of patients discontinued from these studies due to a treatment-related adverse event.A fixed-dose combination of atovaquone and proguanil hydrocloride is a promising new alternative for malaria prophylaxis.

There are currently a limited number of drugs available to prevent malaria in travelers, and new, more efficacious, and better tolerated regimens are urgently needed. Clearly, none of the available regimens are ideal for all travelers, and the travel medicine practitioner should attempt to match the individual's risk of exposure to malaria with the appropriate regimen based on drug efficacy, tolerance, and safety. To facilitate decision making, we have generated a Clinical Utility Score, in which different attributes of each drug regimen, such as efficacy, tolerance, convenience, cost, etc., are estimated based on our experience with these drugs (see Table 1). Other groups and users may weight each variable somewhat differently depending on the specific needs and risk of drug-resistant malaria. For example, a traveler to rural Irian Jaya may weight efficacy more heavily than cost or convenience. Using this scoring strategy, new agents like atovaquone/proguanil and WR 238605 compare favorably to our current options, indicating their potential to fill important holes in our chemoprophylactic arsenal.

Safe and effective new drugs are needed for treatment of malaria. Atovaquone and proguanil hydrochloride is a new antimalarial combination that has recently become available in many countries.Data from clinical trials evaluating atovaquone/proguanil for treatment of malaria were reviewed.In 10 open-label clinical trials, treatment of uncomplicated falciparum malaria with 1000 mg atovaquone and 400 mg proguanil hydrochloride (or the equivalent based on body weight in patientsor = 40 kg) once daily for 3 days achieved cure in 514 of 521 (99%) evaluable patients. Treatment-limiting adverse events occurred in1% of patients (vomiting in four, anaphylaxis in one). Atovaquone/proguanil has been used to provide radical cure of asymptomatic Plasmodium falciparum infections prior to initiation of placebo-controlled trials of malaria prophylaxis. Recurrent parasitemia occurred within 28 days in 0 of 99 subjects who subsequently received prophylaxis with atovaquone/proguanil and 1 of 81 subjects who subsequently received placebo. Atovaquone/proguanil is also effective for treatment of malaria caused by the other three Plasmodium species that cause malaria in humans. For treatment of vivax malaria, therapy with primaquine in addition to atovaquone/proguanil is needed to prevent relapse from latent hepatic hypnozoites.Atovaquone and proguanil hydrochloride is a safe and effective combination for treatment of malaria.

Background: The number of tourists visiting malaria endemic regions is continuously increasing. The risk of aquiring malaria infection can largely be prevented by the regular use of chemoprophylactic drugs combined with using protective measures against mosquito bites. In a prospective study we wished to determine the tolerability of chemoprophylactic drugs and the factors that influence compliance with malaria chemoprophylaxis and antimosquito measures. Method: German travelers (n = 6504) who attended the Berlin Institute of Tropical Medicine in Berlin for pretravel medical advice were interviewed by phone 4 weeks after their journeys about compliance with the recommended malaria chemoprophylaxis and the incidence of side effects. Results: Compliance was better with mefloquine (94.5%) than with chloroquine (85.9%) (p

Background : Current guidelines recommend daily dosing of atovaquone–proguanil (AP), beginning a day before travel to endemic areas and continuing for 7 days after departure. Adherence of long-term travellers to daily malaria chemoprophylaxis tends to be poor, even when residing in highly endemic malaria regions. Evidence from a volunteer challenging study suggests that non-daily, longer intervals dosing of AP provides effective protection against Plasmodium falciparum . This study examines the effectiveness of twice weekly AP prophylaxis in long-term travellers to highly endemic P. falciparum areas in West Africa. Methods : An observational surveillance study aimed to detect prophylactic failures associated with twice weekly AP, during the years 2013–2014, among long-term expatriates in two sites in West Africa. The expatriates were divided according to the malaria prophylaxis regimen taken: AP twice weekly; mefloquine once weekly and a group refusing to take prophylaxis. Malaria events were recorded for each group. The incidence-density of malaria was calculated by dividing malaria events per number of person-months at risk. Results : Among 122 expatriates to West Africa the malaria rates were: 11.7/1000 person-months in the group with no-prophylaxis ( n = 63); 2.06/1000 person-months in the 40 expatriates taking mefloquine ( P = 0.006) and no cases of malaria (0/391 person-months, P = 0.01) in the twice weekly AP group ( n = 33). Conclusions : No prophylaxis failures were detected among the group of expatriates taking AP prophylaxis twice weekly compared with 11.7/1000 person-months among the no-prophylaxis group. Twice weekly AP prophylaxis may be an acceptable approach for long-term travellers who are unwilling to adhere to malaria chemoprophylaxis guidelines.

Alternative approaches to malaria chemoprophylaxis are discussed in light of the difficulties of executing clinical trials within limits of infection rates and ethics.

Background: Malaria continues to represent a significant risk for some travelers and malaria chemoprophylaxis has remained an important countermeasure. Trends in antimalarial use may be influenced by a number of factors, including the availability of antimalarials, increasing resistance, the issuing of updated guidelines for malaria chemoprophylaxis, and continuing education. The aim of this study was to investigate the trends in prescription of antimalarial drugs, particularly those recommended for chemoprophylaxis in Australia, from 2005 to 2009. Methods: In 2011, data were extracted from the online Australian Statistics on Medicines reports published by the Pharmaceutical Benefits Advisory Committee, Drug Utilization Committee, on antimalarials used in Australia for the period 2005 to 2009. Results: Among the drugs solely used as antimalarial drugs from 2005 to 2009, atovaquone plus proguanil and melfloquine were the most commonly prescribed antimalarials. Mefloquine prescriptions increased by 38% from 2005 to 2008 before decreasing by 17% from 2008 to 2009. The number of prescriptions for atovaquone plus proguanil has trebled during the period. Prescriptions for proguanil have dropped over 90% from 2005 to 2009. The diaminopyrimidines, pyrimethamine-containing antimalarials, have mostly been removed from the prescription drug list. Prescriptions for chloroquine have reduced by 66% from 2005 to 2008 and chloroquine was only available on special access from 2009. Artemether plus lumefantrine combination has been used in relatively small quantities and only on special authority from 2007 to 2009. Quinine prescriptions have fallen by 60%. Although a considerable quantity of doxycycline was prescribed, it was unknown how much was intended for malaria chemoprophylaxis. Conclusions: The prescription of antimalarials in Australia was consistent with the national guidelines with the most commonly prescribed antimalarials being atovaquone plus proguanil, mefloquine, and most likely doxycycline. Other antimalarials previously used for chemoprophylaxis have continued to be removed from the prescriber list between 2005 and 2009. The prescriptions of quinine may be becoming displaced by newer antimalarial drugs for treatment, but this needs further investigation.

Malaria continues to be a serious, world-wide infection. Atovaquone-proguanil is one of the prophylactic agents recommended for travelers to endemic regions. However, little information is available regarding adherence with this medication. A large proportion of malaria cases reported from travelers is due to non-adherence to prescribed regimens. This study was undertaken to analyze adherence with atovaquone-proguanil prophylaxis and specific factors contributing to non-adherence.Men and non-pregnant womenor = 18 years of age were eligible for inclusion. Enrolled travelers received a prescription for atovaquone-proguanil prophylaxis and were contacted by telephone within 3 weeks of return to the United States. A questionnaire was prepared by the authors to determine if subjects were adherent with the medication. Additional data included demographics, duration of malarious travel, previous use of prophylactic agents, underlying medical conditions, concurrent medications, and reasons for non-adherence.Complete data were available for 104/124 (84%) participants: 49 (47%) men, 55 (53%) women. Average duration of malarious travel was 12 days, and 19 (18%) travelers reported previous travel to a malarious region. Ninety-two (89%) subjects were completely adherent with their prophylactic atovaquone-proguanil course. Adverse effects were seen in 6 (5%) travelers.Adherence with atovaquone-proguanil malaria prophylaxis is high among travelers from a non-endemic region. Adverse effects are minimal. Non-adherence was primarily attributable to travelers' perception of need.

Background Prescribing patterns of antimalarial drugs have previously been observed to vary considerably in Australia. The aim of this study was to investigate the trends in prescription of antimalarial drugs recommended for chemoprophylaxis in Australia from 2002 to 2005. Methods In 2007, data were extracted from the online Australian Statistics on Medicines reports published by the Pharmaceutical Benefits Advisory Committee, Drug Utilization Sub-Committee on antimalarials used in Australia for the period 2002 to 2005. Results Doxycycline probably remains the malaria chemoprophylaxis of choice prescribed for Australians visiting multiple drug–resistant malarious areas. Over the past 15 years, there has been a marked drop in the prescription of less useful antifolate drugs, such as pyrimethamine-containing antimalarial drugs. There has also been a reduction in the number of prescriptions of chloroquine and proguanil, although the downward trend in prescriptions of mefloquine appears to have arrested and has trended upward. The number of prescriptions of atovaquone and proguanil has been increasing dramatically, particularly since inclusion of this combination antimalarial in the prevailing Australian guidelines. Artemether plus lumefantrine combination is now available, but it is used in relatively small quantities. Conclusions The prescription of the antimalarial drugs, proguanil, chloroquine, and the pyrimethamine-containing compounds, has generally reduced in number. Prescription of mefloquine trended upward during 2002 to 2005, following a period of reducing prescriptions. The atovaquone plus proguanil combination has steadily increased in use and is presumably displacing older antimalarials. The use of quinine has halved, which might be related in part to the uptake of newer antimalarial drugs for treatment. Trends in antimalarial use may be influenced by a number of factors, including the availability of antimalarials, increasing resistance, the issuing of updated guidelines for malaria chemoprophylaxis, and continuing education.

In Europe, atovaquone/proguanil (A/P) is only licensed for malaria prophylaxis for 28 days of travel. Data on the long-term safety and tolerance in nonimmune travelers are scarce.We initiated a prospective observational study on ailments reported by travelers using A/P on a long-term basis. Ailments were recorded on a regular questionnaire. Travelers rated their ailments as (1) mild, not interfering with their daily activities; (2) moderate, causing interference with daily activities; or (3) severe, resulting in a visit to a doctor or clinic.One hundred sixty-nine subjects used A/P for a total of 2.974 weeks. One hundred fifty-three (90.5%) traveled to malaria-endemic regions in Africa. Seventy-five (44%) travelers, who used A/P for 1.140 weeks, reported no ailments. Ninety-four (56%) subjects who used A/P for 1.834 weeks reported a total of 363 ailments. Diarrhea was the most common ailment (13.5%; graded as mild in 7.2%, moderate in 4.7%, severe in 1.7%). Further complaints were headache (7.4%), malaise (6.1%), insomnia (5.2%), abdominal pain (5.0%), nausea (5.0%), and oral ulcers (4.1%). Four (2.4%) subjects discontinued prophylaxis due to complaints. No patient was admitted. Five (3.0%) cases of malaria were reported.In our observational study encompassing more than 57 person-years of follow-up, A/P was tolerated well when taken longer than the current recommendation of 28 days of travel. Treatment-limiting ailments resulting in discontinuation of chemoprophylaxis were observed in 4 of 169 (2.4%) participants, whereas none of them was admitted. There were five (3.0%) cases of self-reported malaria. These observations suggest that A/P is also a safe and efficacious drug for the long-term chemoprophylaxis of falciparum malaria.

Much effort and resources have been focused on improving or evolving antimalarial prophylactic regimens in order to reduce the increasing problems of malaria infection in nonimmune travelers to malaria endemic regions. Falciparum malaria in travelers returned from Africa has been attributed to reduced efficacy of chloroquine against chloroquine-resistant strains of Plasmodium falciparum (CRPF). Reported prophylaxis use by tourists from East Africa suggests only 52% admit taking their chemoprophylaxis without any missed doses. The effect of noncompliance with chloroquine (CQ) or proguanil (PG) in East Africa has been estimated as equivalent to taking no prophylaxis at all. The influence of poor compliance and/or parasite resistance on the changing pattern of malaria among travelers needs to be understood if methods of reducing morbidity are to be identified. In a number of studies, prophylaxis compliance in travelers has been collected by self-administered questionnaires from which prophylaxis efficacy of drug regimens has been calculated. The interpretation of drug efficacy has hinged on drug compliance and is controversial. We have addressed the role of chemoprophylaxis compliance in travelers with malaria using a prospective study of 368 malaria patients attending the Hospital for Tropical Diseases by examining their travel history and reported prophylaxis compliance compared to their actual plasma drug levels. This has enabled us to characterize the role of CRPF and poor compliance in the etiology of breakthrough malaria in travelers.

There is limited data regarding the efficacy of prophylaxis with atovaquone/proguanil (A/P) against non-falciparum malaria in travelers. Two cases, one Plasmodium vivax infection and another Plasmodium ovale infection, in travelers despite A/P prophylaxis are presented.

A 31-year-old healthy man developed acute hepatitis after receiving atovaquone (250 mg) and proguanil (100 mg) for malaria prophylaxis daily for 25 days. Although atovaquone/proguanil is generally well-tolerated, this case highlights the hepatotoxic potential with considerable morbidity and should alert physicians to this harmful side effect.

Background: Because malaria in endemic areas presents a serious threat to the health of aircrew, optimal prevention is important. An effective and safe prophylactic antimalarial drug is needed. The combination of 250 mg atovaquone with 100 mg proguanil HCl (atovaquone/proguanil, or A/P) has shown good prophylactic efficacy and tolerance for prevention of falciparum malaria. However, medication for use by aircrew on duty is subject to approval by national and international aviation authorities, who require convincing evidence that the treatment has no negative effects on the flight performance of crews. The purpose of the present study was to evaluate the risk of detrimental effects of atovaquone/proguanil on flight-related performance and alertness in healthy subjects under conditions of aircraft cabin pressure. Methods: A randomized, double-blind crossover study was conducted in which 24 subjects were enrolled to use A/P and placebo, each in a 14-day prophylactic dosing regimen with a 21-day washout phase. Vigilance, alertness, complex information processing, and sleepiness were assessed in a hypobaric chamber at 75.2 kPa, which equals the lower limit of commercial aircraft cabin pressure. Furthermore, duration and quality of sleep at home were recorded during the 14 days of drug administration. Results: Twenty-two subjects completed the study. No significant differences were found between the effects of placebo and A/P on vigilance, alertness, complex information processing, sleep duration and quality, and the occurrence of adverse effects. Conclusions: In-flight performance and alertness of aircrew will not be affected by the prophylactic use of A/P during a period of 14 days