Safety evaluation of the drugs available to prevent malaria

All drugs used for malaria prophylaxis have common adverse effects, in addition to rare and/or severe adverse effects. For many of the drugs in current use, the common adverse effects include neuropsychiatric harms. This property makes these drugs unpopular with tourists and business travellers, most of whom will be well at the start of chemoprophylaxis. Drugs available to prevent malaria have not been rigorously researched in terms of the phenomenology of their unwanted effects. Consequently, prescribers are not well placed to give useful information to travellers on the incidence, natural history and avoidability of the harms they may experience from malaria chemoprophylaxis. There is some evidence that the adverse effects of mefloquine may be a post-hepatic syndrome caused by drug-induced liver damage with, in some users, symptomatic thyroid disturbance. However, confusion in the interpretation of the scientific evidence has led to conflicting messages regarding the safety of mefloquine and other antimalaria drugs, and to incorrect self-therapy by individual travellers, sometimes with fatal outcomes. In this review, the existing knowledge base for the safety of drugs currently used to prevent malaria is described along with present designs for future studies that would allow a rigorous safety assessment of candidate chemoprophylactic agents and of new drugs introduced to prevent malaria. There is an urgent need for internationally-agreed, evidence-based malaria prevention guidelines. These guidelines should be explicitly linked to the best available research evidence (normally systematic reviews of trials and individual randomised trials) and should highlight gaps in the knowledge base as priority areas for research.     

Modern malaria chemoprophylaxis

Currently available medications for malaria chemoprophylaxis are efficacious but the problems of patient compliance, the advance of parasite drug resistance, and real or perceived serious adverse effects mean that new chemical compounds are needed.Primaquine, which has been widely used to treat relapsing malaria since the 1950s, has been shown to prevent malaria when taken daily. Tafenoquine is a new 8-aminoquinoline with a much longer half-life than primaquine. Field trials to date indicate that tafenoquine is efficacious and can be taken weekly or perhaps even less frequently. Both primaquine and tafenoquine require exact knowledge of a person's glucose 6-phosphate dehydrogenase status in order to prevent drug-induced haemolysis. Other potential malaria chemoprophylactic drugs such as third-generation antifol compounds and Mannich bases have reached advanced preclinical testing. Mefloquine has been seen to cause serious neuropsychiatric adverse effects on rare occasions. Recent public controversy regarding reputedly common serious adverse effects has made many Western travellers unwilling to take mefloquine.Special risk groups exposed to malaria, such as long-term travellers, children, pregnant women, aircrew and those requiring unimpeded psychomotor reactions, migrants returning to visit malarious countries of origin and febrile persons who have returned from malaria endemic areas, all require a nuanced approach to the use of drugs to prevent malaria. The carrying of therapeutic courses of antimalarial drugs to be taken only if febrile illness develops is indicated in very few travellers despite its appeal to some who fear adverse effects more than they fear potentially lethal malaria infection. Travellers with a significant exposure to malaria require a comprehensive plan for prevention that includes anti-mosquito measures but which is still primarily be based on the regular use of efficacious antimalarial medications.     

Prevention of malaria

With the increased spread of chloroquine-resistant Plasmodium falciparum malaria and mounting evidence of lack of efficacy and toxicity of alternative drugs, it has become extremely difficult to propose simple, widely applicable and uniformly acceptable recommendations for malaria chemoprophylaxis. With regard to specific drugs, it is clear that because of its toxicity amodiaquine should no longer be used for chemoprophylaxis, and that pyrimethamine/sulfadoxine should, for the most part, be used only as a presumptive therapy. The pyrimethamine/dapsone combination is promising, but data on its efficacy are limited. Although proguanil (chloroguanide) is recommended by several sources because of its safety, disturbing reports of chemoprophylaxis failure in Africa and a well-documented lack of efficacy in South East Asia would suggest that its usefulness may be limited. However, a recent study has documented the efficacy of a proguanil-sulphonamide combination in Thailand, an area of high grade chloroquine resistance. Although long term studies of drug safety are not yet available, doxycycline and mefloquine appear to be the drugs of choice in areas where P. falciparum shows multidrug resistance. Regardless of the drug regimen recommended for chemoprophylaxis, travellers must be informed that no present-day antimalarial agent guarantees protection against malaria.     

Malaria: still a threat to travellers

Each year, some 25-30 million international travellers from non-tropical regions visit malaria endemic countries. Up to 10,000 cases of malaria are imported into industrialised countries with an average case fatality rate of around 1%. Malaria still poses a real threat to travellers, particularly in areas with high transmission such as sub-Saharan Africa, Papua New Guinea and the South Pacific islands. The spread of malaria resistant to an increasing number of drugs forces us to adjust chemoprophylaxis regimens. Although new drugs are available and can protect travellers effectively, the number of imported cases to Europe and North America remains substantial. An increasing proportion of imported cases is seen in migrants and foreign-born residents visiting friends and relatives (VFR) in endemic countries. New easy-to-use drugs, better understanding of risk perception of travellers, finding new and innovative ways to reach at risk travellers such as VFRs are among the new challenges to improve malaria prevention for international travellers.     

Malaria Chemoprophylaxis in German Tourists: A Prospective Study on Compliance and Adverse Reactions

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<.001) or chloroquine plus proguanil (79.8%) (p<.001). Compliance was influenced by the purpose of travel, duration of stay, places of stay, and adverse reactions. Side effects occurred in 20.6% of the travelers who took chemoprophylactic drugs. There was no significant difference in the incidence of side effects between the three drug regimens, but people who took mefloquine more often reported neuropsychiatric reactions (6.5% versus 3.9% with chloroquine and 3.6% with chloroquine and proguanil; p<.001)). Side effects were usually mild to moderate and in no instance required hospitalization. People who took their drugs with meals less often reported side effects (15.2%) (p<.01).
Conclusion: The knowledge of user profiles (and particular factors that presage side effects and noncompliance) may help us to improve pretravel counseling, thereby reducing the risk that travelers may acquire malaria infection.     

Adverse effects and compliance with mefloquine or proguanil antimalarial chemoprophylaxis

Objective: We had the impression that adverse reactions to standard antimalarial prophylaxis were reported much more often than stated by the package insert and medical drug references; and that side effects adversely affected compliance. Therefore, we evaluated adverse effects and compliance of the two standard malaria prophylactic regimens (mefloquine 250 mg per week and proguanil 100 mg twice per day) among short-term travellers. We expected that travellers who had experienced possible adverse effects on previous journeys might avoid antimalarial drugs on subsequent journeys (self-selection) and we therefore looked at adverse effects dependent on prior use. Methods: The presence of neuropsychological and gastrointestinal symptoms were assessed by telephone interviewing of 300 travellers who had visited the travel vaccination service of our regional public health institute. Symptoms, prior use and non-compliance of 104 mefloquine users and 103 proguanil users were compared with 93 non-users in order to control for travel-related symptoms. Results: Mefloquine showed the following adverse effects: depression [excess risk (ER) 7.2 per 100 users], dizziness (ER 9.3) and itching (ER 12.3). Adverse effects of proguanil were dizziness (ER 7.5) and nausea (ER 12.7). Adverse effects were mostly mild to moderate and occurred mainly during the time abroad. These results did not change when adjusting for age, sex, or destination. For almost every symptom, we found a remarkable difference between the relationship of symptoms and antimalarial drugs in first-time users and that in prior users: in the first-time users the relationship was positive, while in prior users it was absent or negative. This could be due to self-selection or adaptation to adverse effects. 22% of mefloquine users were non-compliant, whereas 35% of proguanil users were non-compliant. Adverse effects (experienced or expected) were the most often reported reason for mefloquine users to stop or even not to start taking the drug (42%). For proguanil, most of the non-compliant participants saw no point in starting or continuing its use (perceived uselessness 54%). Conclusion: We can confirm the reports by users that adverse effects of mefloquine and proguanil are common and, although mostly mild, adversely affect compliance. We suggest that a longer run-in period for mefloquine as well as counselling travellers about possible adverse effects might improve compliance. Received: 24 May 1996 / Accepted in revised form: 30 January 1997     

Atovaquone + proguanil: new preparation. Second-line antimalarial combination

(1) Quinine, halofantrine and mefloquine are effective treatments for most cases of uncomplicated Plasmodium falciparum malaria. (2) The choice of drug for prevention of P. falciparum malaria in highly endemic regions depends on the risk of chloroquine resistance, and possibly mefloquine resistance. The reference treatments are the chloroquine + proguanil combination, and mefloquine. (3) Marketing authorisation has been granted in France for the atovaquone + proguanil combination, in curative and preventive treatment of P. falciparum malaria. (4) The efficacy of the atovaquone + proguanil combination in uncomplicated malaria is similar to that of other treatments. Some strains of malaria seem to have reduced sensitivity. (5) The atovaquone + proguanil combination is also effective as prophylaxis, but there are no clinical trials showing whether it is equivalent to or better than other preventive treatments in non immune travellers. (6) According to the French licensing terms, atovaquone + proguanil prophylaxis can be stopped 7 days after leaving an endemic area, rather than 3-4 weeks with other drugs. This recommendation is based on weak evidence: mainly on theoretical arguments and on the absence of clinical malaria in some patients with evidence of P. falciparum infection. (7) The atovaquone + proguanil combination is less effective against other Plasmodium species (P. malariae, P. ovale and P. vivax). Chloroquine remains the reference treatment for these forms of malaria, which do not carry a risk of serious complications. (8) There were few adverse events in people taking the atovaquone + proguanil combination during clinical trials. During curative treatment, this combination caused more nausea and vomiting than reference treatments, while, in the prophylactic setting, it had slightly fewer adverse effects than the chloroquine + proguanil combination or mefloquine alone. But the drop out rate was not significantly different between treatment groups. (9) Atovaquone should be taken with food, to improve absorption. (10) The atovaquone + proguanil combination is expensive and is not refunded in France. In contrast, curative treatment with quinine is cheap, and is fully refunded. (11) Mefloquine and quinine remain the treatments of choice for uncomplicated malaria where there is chloroquine resistance. The atovaquone + proguanil combination is useful if mefloquine and quinine are contraindicated; unlike halofantrine, this combination does not carry the risk of serious drug interactions. In the prophylactic setting, the lack of experience with atovaquone means it should only be used as a second line option, after mefloquine, for short-term prophylaxis in areas with a high prevalence of chloroquine resistance.     

Mefloquine for Malaria Chemoprophylaxis 1992–1998: A Review

Mefloquine is an orally administered blood schizontocide for the chemoprophylaxis of malaria in nonimmune travelers. New pharmacokinetic data has shown that food increases the bioavailability of mefloquine. Steady-state pharmacokinetics of weekly prophylaxis in long term travelers have shown that toxic accumulation does not occur and that weekly dosing is associated with protective levels of the drug. The pharmacokinetics of mefloquine are highly stereospecific and all pharmacokinetic parameters, except tmax are significantly different for the (+) and (-) enantiomers. Mefloquine and its metabolite are not appreciably removed by hemodialysis. Steady-state levels of mefloquine can be attained in a reduced time frame of 4 days compared to 7-9 weeks using a loading dose strategy of 250 mg mefloquine daily for 3 days followed thereafter by weekly mefloquine dosage. This strategy, is however, associated with a higher incidence of an adverse event (AE). Cumulative evidence suggests a high protective efficacy of mefloquine (>91%) in nonimmune travelers to areas of chloroquine resistant Plasmodium falciparum (CRPF) except for clearly defined regions of multi-drug resistance. Reports from sub-Saharan Africa indicate a low but increasing level of resistance to this drug. Mefloquine resistance is associated with halofantrine and quinine resistance but not with chloroquine resistance. Penfluridol has been shown to reverse P. falciparum mefloquine resistance in vitro. There is some controversy regarding the tolerabilty of mefloquine for malaria chemoprophylaxis. A review of the studies conducted during 1992-1998 shows that in the reporting of any AE the incidence lies in the range (12-90%) and where there is a comparator, is equivalent to the incidence reported for almost all alternative regimens. When some measure of subjective severity is applied to the rating of AE, it appears that 11-17% of travelers are, to some extent, incapacitated by AE. Major studies and worldwide monitoring have shown that serious events are rare. A recent meta-analysis showed that rates of withdrawal and overall incidence of AE with mefloquine were not significantly higher than those observed with comparator regimens except that mefloquine was more likely to cause insomnia and fatigue. Withdrawals in mefloquine arms were higher than in placebo arms. No performance deficit or functional impairment was observed in five clinical toxicity studies of mefloquine prophylaxis, including a study of driving performance. There is limited data regarding use of mefloquine in pregnancy. Early animal studies have documented teratogenic and embryotoxic effects associated with the use of high dose mefloquine. Two studies have shown a relatively high incidence of spontaneous abortions in mefloquine users. Cumulative evidence, however, is reassuring and has led the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to sanction the use of mefloquine in pregnant women during the second and third trimesters. In conclusion, mefloquine prophylaxis is recommended for travelers to high risk areas of chloroquine resistant Plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug associated adverse events.     

Use of Malaria Prevention Measures by North American and European Travelers to East Africa

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.     

Malaria chemoprophylaxis advice: survey of South African community pharmacists' knowledge and practices

BACKGROUND: Over 3 million South African residents travel to malarious areas annually. Given pharmacists' ready accessibility and travel clinics' incapacity to service total potential demand, South African community pharmacists' malaria chemoprophylaxis knowledge and practice were assessed. METHODS: Covert survey. Pharmacies were approached at random and asked for malaria chemoprophylaxis recommendations. A standard questionnaire indicating a 3-day stay in either Maputo (N= 43; malarious) or Harare (N= 25; non-malarious) was used. RESULTS: Maputo group: 41/43 (95%) pharmacists correctly identified need for chemoprophylaxis; 3/41 (7%) recommended an ineffective drug. Eight of 41 (20%) enquired about diving, and 6/41 (15%) enquired about epilepsy or mental illness; despite positive responses mefloquine, was nevertheless recommended. Harare group: 12/25 (48%) incorrectly advised chemoprophylaxis was necessary; 4/12 (33%) sought contraindications; all prophylaxis recommended was considered effective. Overall, 54/68 (79%) pharmacists correctly determined whether chemoprophylaxis was required or not; 6/53 (11%) of all recommended chemoprophylaxis included "alternative" antimalarials; 1/68 (1%) consulted external advice before making recommendations; 11/53 (21%) referred travelers to a physician; 1/68 (1%) referred to a travel clinic. Pharmacies were significantly more likely (Fisher exact, p < 0.0001) to recommend unnecessary prophylaxis (12/25; 48%) than to advise against necessary prophylaxis (2/43; 5%). CONCLUSIONS: Pharmacists are willing to give malaria chemoprophylaxis advice but appear to overprescribe; although unnecessary adverse events may result, this may be the preferred error in a falciparum-dominated region. Pharmacists' knowledge of contraindications, willingness to consult external resources, and knowledge of antimalarials' effectiveness could be improved. Pharmacists appear unwilling to refer to travel clinics. An effective intervention to improve the safety and accuracy of pharmacists' advice might be the provision of a simple aid listing effective antimalarials and their contraindications, illustrated with a malaria risk map. Improving the safety and accuracy of pharmacists' advice would increase significantly travelers' access to reliable travel health information.     

Antimalarial chemoprophylaxis in infants and children

The evolving patterns of drug resistance in malaria parasites and changes in recommendations for malaria prevention present a challenge to physicians who advise travellers on chemoprophylaxis. Because compliance with personal protection measures is usually low, children should receive appropriate chemoprophylaxis, including breast-fed infants who are not protected through maternal chemoprophylaxis. For travel to areas where chloroquine resistance has not yet been reported (i.e. parts of Central America, the Caribbean and parts of the Middle East), chloroquine alone is sufficient for antimalarial prophylaxis. Mefloquine is the drug of choice for chemoprophylaxis in areas with chloroquine-resistant Plasmodium falciparum, and can be given to infants and young children. The combination of chloroquine and proguanil is well tolerated in children but is much less effective against drug-resistant malaria. Further research is needed to determine the best dosage regimen for antimalarial drugs used for chemoprophylaxis in children.     

Factors influencing the pattern of imported malaria

BACKGROUND: Data on imported malaria in industrialized areas are known to be incomplete because of underreporting and lack of homogeneity. These facts and the complexity of factors influencing the transmission of malaria render their interpretation difficult. The relevance of various factors is usually not fully considered, although their impact on recommendations for chemoprophylaxis may be important. METHODS: All malaria cases imported from Kenya from 1988 to 1996 that were reported to the Federal Office of Public Health of Switzerland were analyzed. The reciprocal impact on data interpretation with regard to Plasmodium species, chemoprophylaxis, onset of first symptoms after return, male or female sex, seasonal fluctuation, duration of stay, nationality groups, and fatal outcome was analyzed. RESULTS: Multivariate analysis showed a significant impact of Plasmodium species, regular chemoprophylaxis, and long duration of stay on the latency of malaria attacks. African origin and repeated stays were confounders with regard to adherence to chemoprophylaxis. The local situation of malaria transmission and the development of tourist figures were found to influence the evolution of malaria rates. These factors must be analyzed simultaneously to prevent errors in data interpretation. A higher proportion of tertian malaria cases (caused by Plasmodium vivax or Plasmodium ovale) than in previous reports was recorded owing to the impact of chemoprophylaxis and longer outbreak latencies. Seventy-five percent of tertian malaria cases were diagnosed within 6 months after return. CONCLUSIONS: Factors influencing the pattern of imported malaria must be assessed in relation to each other, especially if data from different countries and various chemoprophylaxis regimens are compared. Furthermore, regular malaria chemoprophylaxis with mefloquine given until 4 weeks after return from an endemic area is not adequate to prevent tertian malaria. Regular chemoprophylaxis was found to cause longer latencies for all malaria species.     

Treatment of malaria--1990

Malaria has become an increasingly common health problem in the 1970s and 1980s, both in areas where infection is endemic and in travellers returning to non-endemic areas. The severity of infection varies widely, depending on the plasmodial species involved, and there is an extensive chemotherapeutic armamentarium currently available to combat malarial infection. Drug chemistry, pharmacokinetics, mechanism of drug action and resistance, and toxicities are outlined for the cinchona alkaloids (quinine and quinidine), chloroquine, amodiaquine, pyrimethamine, the sulphonamides, pyrimethamine/sulfadoxine, mefloquine, pyrimethamine/sulfadoxine/mefloquine, the sesquiterpene lactones, primaquine, and other drugs. A knowledge of the distribution of drug resistance is vital for the provision of effective antimalarial therapy, and current information in this area is outlined. Chloroquine remains the mainstay of treatment for the erythrocytic stages of Plasmodium vivax, P. ovale, P. malariae, and chloroquine-sensitive P. falciparum malaria. The dormant hepatic stages of P. vivax and P. ovale also require further treatment with primaquine. Quinine, alone or in combination with other drugs, is the primary agent used to treat chloroquine-resistant falciparum malaria. Falciparum infection can rapidly become fatal, therefore its complications of multiple organ failure, heavy parasitaemias, cerebral malaria, and hypoglycaemia must be recognised and managed promptly. Because these protozoal parasitic infections are now encountered throughout the world and can become life-threatening, a wide variety of practitioners must become more familiar with their correct treatment.     

Malaria protection measures used by in-flight travelers to South African game parks

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.     

Artemisinins in malaria treatment in the UK

Malaria is a potentially life-threatening disease caused by protozoal parasites of the genus Plasmodium. It is mainly a problem in developing countries, and cases in the UK involve travellers coming from endemic areas. Resistance is increasing to several antimalarial drugs (e.g. chloroquine, mefloquine, antifolates). Another group of drugs, known as artemisinins, have come into widespread use more recently. An oral artemisinin-combination therapy (ACT) is now one of the standard licensed treatments for uncomplicated malaria in the UK. However, the parenteral artemisinin for severe malaria, artesunate, is not licensed in developed countries. Here we consider the role of artemisinins as treatment for malaria in the UK.     

Malaria antibodies and mefloquine levels among United Nations troops in Angola

BACKGROUND: The United Nations deployed about 8,000 soldiers in a peacekeeping mission in Angola. Malaria is the most common disease there and consequently it was the major risk to the UN troops. Most of them are from malaria free areas. As a result of improper prophylactic measures there were many cases of malaria, including some deaths in 1995. In February-March 1996, an Israeli team was sent to Angola to evaluate the malaria situation among UN soldiers. This paper deals specifically with some aspects of chemoprophylaxis and diagnosis. The efforts were concentrated in one particular area where malaria incidence had been reported as the highest. METHODS: Blood samples were collected from nonimmune soldiers who were using mefloquine as a prophylactic drug and were exposed to malaria. The mefloquine and the antimalarial antibody plasma levels were monitored. RESULTS: While the local laboratory indicated that about 80% had a malaria episode, the serological results revealed that only 5 soldiers of the 56 (9%) examined had antimalarial antibodies, of which 3 were Angolans. Despite a controlled prophylactic regimen there was considerable variability in mefloquine plasma levels: 46% of the samples were below the required prophylactic level and 26% above it. All patients who were proven positive with malaria by both microscopic and serologic observation had a low level of mefloquine. CONCLUSIONS: In field conditions, a kit which identifies plasmodial antigens, is preferable, to a microscopic diagnostic method. Controlled mefloquine prophylaxis may not prevent malaria, especially when blood levels are low. The reason for the low mefloquine blood levels is not clear and needs further evaluation.     

Tolerability and Effectiveness of Malaria Chemoprophylaxis with Mefloquine or Chloroquine with or without Co-medication

Background :To determine the relevance of drug interactions with co-medication for effectiveness and tolerability of antimalarial chemoprophylaxis.
Method: A database (MALPRO2) on travelers on their flight home from Africa to Europe between July 1988 and December 1991 was reanalyzed. It contains data on prophylaxis with mefloquine (n = 48,264), with chloroquine (6,752), with chloroquine plus proguanil (19,727), and with no prophylaxis (3,871). The comparison of rates of malaria incidence and adverse events (AEs) between users and nonusers of co-medication was expressed by relative risk (RR).
Results: Fifty-three percent of travelers (63% of females, 43% of males) used co-medication in all prophylaxis groups, with an average of 1.35 additional drugs per person and about two AEs reported per person. With the exception of antidiarrheals plus mefloquine, malaria incidence with co-medication was lower (RR = 0.8) than without co-medication. In all regimens, the proportion of travelers reporting AEs was about 1.5-fold with co-medication (p<.01);that reporting severe AEs was twice as high as compared to with no co-medication. Mefloquine AE rates for various classes of co-medication were similar to that of chloroquine, with highest AE and severity rates with neuropsychiatric drugs (excluding antiepileptics, RR = 1.9 and 2.9), and lowest rates with cardiovasculars (RR = 1.1 and 1.0). Various co-medications were used with different frequencies in males and females, and the latter reported more AEs.
Conclusion: These data suggest that co-medications commonly used by travelers have no significant clinical impact on safety and effectiveness of prophylaxis with mefloquine or chloroquine. Increased frequency and severity of AEs when using co-medication rather is explained by underlying illness.