Efficacy of drug prophylaxis - Europe PMC

Journal of the Royal Society of Medicine Supplement No. 17 Volume 82 1989

Session 3: Preventative Measures - Balancing Risks

Efficacy of drug prophylaxis P A Phillips-Howard BSc PhD Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT Keywords: Plasmodium falciparum; chemoprophylaxis; adverse drug reactions; efficacy; compliance; malaria

Summary With the spread of chloroquine resistant Plasmodium falciparum the control of malaria has become increasingly complex1. In recent years, particular concern has arisen over how best to prevent malaria in non-immune international travellers2. Prior to the recognition of the potential toxicity of some antimalarial drugs, malaria preventive guidelines switched from chloroquine to the newer compound antimalarial drugs and to amodiaquine; this adjustment was made when sentinel cases alerted clinicians that breakthrough infections occurred in travellers to East Africa taking chloroquine prophylaxis3 5. Changes were also supported by data

derived from field studies illustrating the effectiveness of these drugs for therapy in indigenous populations6-9. However, international studies have now documented serious adverse reactions to pyrimethamine/dapsonel°, pyrimethamine/sulphadoxine'1, and amodiaquine'2, and caution is required with their use13. Rates in British users concur with international estimates14. Specialists preparing malaria preventive guidelines have, therefore, preferred to recommend the use of relatively safe antimalarial drugs, like chloroquine and proguanil, provided they offer non-immune travellers adequate protection against P. falciparum infections2. Substantial difficulty has arisen, however, in the

Table 1. The action and recommended dosage of chemoprophylactic drugs The action of single chemoprophylactic drugs Causal Suppressive

Combined drugs

DHFRI

4 amino-quinolines

proguanil pyrimethamine chlorproguanil

chloroquine (Nivaquine, Avloclor,

DHFRI/Sulphas pyrimethamine plus sulphadoxine (Fansidar) pyrimethamine plus dapsone (Maloprim, Deltaprim) pyrimethamine plus sulphalene (Metakelfin) DHFRI/Sulphal quinoline methanol pyrimethamine plus sulphadoxine plus mefloquine (Fansimef)

Causal/suppressive

Resochin)

amodiaquine (Camoquin) sulphas sulphadoxine1

dapsonel sulphalenel quinoline methanols

mefloquine Recommended doses of each drug currently recommended: = Drug Dose Tablets Proguanil: 200 mg Two pyrimethamine: 25mg = One chloroquine: 300 mg* Two amodiaquine: 400 mg Two pyrimethamine/ 25 mg/ One sulphadoxine: 500 mg pyrimethamine/ 12.5 mg/ = One dapsone: 100 mg pyrimethamine/ 25 mg/ One sulphalene: 500 mg mefloquine: 250 mg = One

Weekly

doxycycline:

Daily

100 mg

Timing Daily Weekly Weekly Weekly Weekly

Current recommendations see footnote2 not advised: low efficacy see footnote2 not advised: risk of toxicity not advised. risk of toxicity

Weekly

limited: risk of toxicity incomplete protection3 not available in Britain

Weekly

'Sole use of sulpha drugs not recommended 2Malarious areas with resistance, combine chloroquine with proguanil 3Blood drug levels inadequate 5 days after tablet administered *Chloroquine base

drug: safety/efficacy requires monitoring new drug safety/efficacy requires monitoring new

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definition of 'adequate protection'. Field studies in indigenous communities with partial immunity can provide concise biological measures of parasite resistance to drugs15. Unfortunately, these data cannot be used directly to determine the expected efficacy of chemoprophylactic drugs in non-immune populations2. The transmission of malaria and the degree and intensity of resistance vary even within small geographical areas. Comprehensive patterns of resistance cannot be mapped out on a countrywide or regional basis for logistic reasons, and are restricted focally to discrete study locations. Furthermore, it is not clear how closely we can correlate the therapeutic potency of antimalarial drugs for semi-immune populations with the prophylactic potency of drugs used by non-immune subjects. An exhaustive review of the efficacy of antimalarial drugs, using both therapeutic and prophylactic data, is clearly unfeasible. A summary of most therapeutic studies has been documented elsewhere'5. This paper focuses instead on the efficacy of chemoprophylaxis in the reduction of morbidity. It draws together efficacy data generated from studies conducted in both partially immune and non-immune populations. Modifications to current malaria preventive guidelines are discussed. Antimalarial drugs available as chemoprophylactic agents The pharmacokinetic and therapeutic properties of antimalarial drugs and their mechanism of action have been comprehensively reviewed'6. Drugs used for chemoprophylaxis are described (Table 1). The modes of action are: Causal prophylaxis protects against malaria attacks by the prevention of the development of sporozoites or pre-erythrocytic asexual stages in the liver. These drugs are commonly refered to as 'antifols': they act by blocking the enzyme dihydrofolate reductase. Because of their similar mode of action, proguanil, pyrimethamine and chlorproguanil (the long acting analogue of proguanil), do not offer additional protection when taken together. Suppressive prophylaxis protects against malaria attacks by inhibiting asexual schizogony in the erythrocytes. Drugs with a suppressive action include: the 4 amino-quinolones, chloroquine and amodiaquine; the sulpha drugs, namely sulphadoxine, dapsone and sulphalene; some antibiotics, primarily tetracycline (doxycycline); and the quinoline methanols, like mefloquine. Other drugs have suppressive properties but are restricted to treatment because of their short half lives; these include quinine and the newer drugs halofantrine and artemisinin. Supressive treatment and cure. This denotes the continuous application of suppressive drugs after leaving a malarious area, to eliminate asexual parasites from the blood and prevent a clinical attack of malaria. It is thus recommended to continue taking suppressive drugs for four weeks after the last exposure to P. falciparum. Terminal prophylaxis prevents relapses with P. vivax and P. ovale by eliminating hypnozoites (latent forms of the exoerythrocytic parasite in the liver). The drug of choice is the 8 amino-quinoline,

primaquine. Drugs may be taken singly, concurrently, or in combined forms (Table 1). Drugs have been combined in order to block the metabolic pathway of parasites

sequentially'7. The formulation of pyrimethamine/ dapsone and pyrimethamine/sulphadoxine increases the potency of components synergistically and has helped to delay the spread of resistance, although the variation in the half lives of the two components ofpyrimethamine/dapsone have reduced its protection as a weekly prophylactic drug and resistance has

developed'5. Monitoring of prophylactic efficacy Definition ofprophylactic efficacy The efficacy of a chemoprophylactic regimen has commonly been expressed as an infection rate. Rates are sometimes temporally defined according to person weeks or person months of exposure, or simply as an annual rate. The relative value of one drug to another has been achieved solely through a comparison of rates, and when available, with rates in 'control' groups taking no chemoprophylaxis. In this paper, data have been transformed into efficacy values to facilitate comparisons between studies using the conventional method of estimating efficacy. This defines efficacy as the percent (%) reduction in risk attributed to the use of a chemoprophylactic drug compared with that in similarly exposed subjects taking no chemoprophylaxis'8. Where no control data were available, percentage attack rates are given.

Population groups studied to estimate efficacy values Different methods have been employed to collect data on the efficacy of drugs. The studies reviewed are principally controlled trials in partially immune or in non-immune populations, and uncontrolled observational studies in non-immune populations. Controlled trials A few controlled trials have been conducted in partially immune populations during the last decade, some of which have assessed the efficacy of drugs in West Africa prior to the development of chloroquine resistance. This review will be limited to studies performed more recently in areas where chloroquine resistance has been reported. The studies conducted are of a high calibre, but the systematic study of the prophylactic efficacy of all new drugs has only been performed in Thailand. Studies are predominantly conducted in semi-immune populations because it is seldom possible, ethically, to allocate non-immune visitors into prophylactic and control groups. However, the influence of immunity on drug efficacy has been minimized by using schoolchildren, the least immune group, as subjects. Study methods vary but, in general, infection rates in prophylactic groups, measured as person-time infection rates, are compared with placebo groups receiving

vitamins. East Africa Renewed interest in proguanil has stimulated prophylactic studies in Kenya19. The efficacy of chlorproguanil taken by children at a weekly dose of 20 mg was assessed on the coast of Kenya in 1985. A breakthrough rate was calculated of four episodes per 100 person weeks compared with 6.9 in controls; giving an efficacy value for chlorproguanil of 42%.. Chlorproguanil taken alone was thus considered to be inadequate for prophylaxis. The low efflcacy was, in part, associated with


underdosing and with the metabolism of chlorproguanil which (as with proguanil) varies substantially between individuals. Other results, however, suggest that 'antifols' are effective in certain areas of East Africa20; an efficacy value of 77% was calculated for proguanil 200 mg in a controlled trial conducted in the Rift Valley of Kenya during 1987. A prospective trial in non-immune visitors to Tanzania compared the efficacy of chloroquine plus proguanil with pyrimethamine/sulphadoxine (PS) plus chloroquine between 1984 and 198521. The efficacy of the two combinations was not significantly different and rates were very high; a 1% breakthrough rate occurred in the PS plus chloroquine group and between 0.3% and 2.7% in those taking chloroquine plus proguanil.

Central/Southern Africa Two studies have measured the efficacy of chloroquine and 'antifols' (proguanil and chlorproguanil) in areas of Central and Southern Africa. Proguanil prophylaxis was assessed in Namibian refugee children in Angola22. Proguanil reduced febrile episodes, presumptive treatment and hospitalization, but after four months P. falciparum was found in 19% of the proguanil group compared with 28% of the placebo group; suggesting the efficacy of proguanil was very low at 27%. A double blind study conducted in children in Burundi between 1985 and 1986, assessed the efficacy of chlorproguanil 20 mg and chloroquine 200 mg base alone and in combination23. Breakthrough rates were very high on each prophylactic regimen; the efficacy of chloroquine plus chlorproguanil was 4%, in chlorproguanil alone 8%, and in chloroquine alone 35%. The addition of chlorproguanil thus appeared to increase infection rates in chloroquine users. West Africa The efficacy of chlorproguanil was compared with that of pyrimethamine/dapsone (PD) used by children in The Gambia between 1983 and 198524. The PD group experienced significantly fewer episodes of fever with parasitaemia (0.2%) compared with the placebo group (1.3%) but there was no significant difference for the chlorproguanil group (0.8%). Efficacy values were 85% for PD, and 38% for chlorproguanil. In a tolerability study conducted in 211 non-immune subjects in Nigeria, none experienced infections taking the combination of pyrimethamine/sulphadoxine with mefloquine (MSP) but neither did any of the 'control' group who had taken chloroquine alone25.

South East Asia Prophylactic studies of newer drugs have been conducted in a multidrug resistant area of Thailand. The efficacy of doxycycline 50 mg was compared with 100 mg26. Its efficacy was estimated to be 79% at the lower daily dose and 89% at the higher (recommended) dose, but differences in rates were not significant. The efficacy of the daily sulpha drug sulphisoxazole (75 mg/kg) taken alone and in combination with proguanil were measured in a separate study27. Infection rates were 1.4% in the control group, 0.7% for proguanil, 1.1% for sulphisoxazole but less than 0.001% when the two drugs were taken together. Efficacy values were 44% for proguanil and 24% for sulphisoxazole, but when both were taken concomitantly their efficacy was 95%, suggesting a strong synergistic effect between the two drugs. In another study in a similarly exposed

population, the efficacy of proguanil 200 mg alone was estimated to be 50%28. One study, conducted in a multidrug resistant area in Burma in 1985, investigated the value of pyrimethamine/sulphadoxine (PS) combined with mefloquine (MSP) and compared it with double doses of PS29. After five months of prophylaxis, infection rates were 44% in those taking PS in divided doses, 70% in PS users taking two tablets once weekly, but only 1% in those using MSP.

Uncontrolled observational studies There is a paucity of information on the efficacy of prophylactic drugs used by non-immune temporary visitors to, and transient residents of, malarious areas. Studies conducted to measure direct values have been scientifically less sophisticated and restricted to select groups because travellers disperse widely to areas of varying endemicity and are difflcult to access. Drug use patterns are derived from self reported use which, for logistic reasons, have not been verified. Importantly, the exposure to infection is heterogeneous. Not all malaria infections are confirmed microscopically. Studies have focused on select cohorts, national monitoring of drug use patterns in travellers and malaria cases, and ongoing malaria surveillance studies at national and local level. Cohorts Three studies have been conducted using cohorts of non-immune visitors in Africa. Data from Tanzania, pooled between 1977 and 1983, indicated that the uncontrolled efficacy of proguanil 200 mg alone or in combination with chloroquine was 95%30. Chloroquine alone had an efficacy of 16%, but when combined with pyrimethamine/dapsone (PD) was 62%. However, PD taken alone appeared to be less effective than taking no prophylaxis, and similar values were recorded for proguanil 100 mg. A retrospective cohort study of expatriates in Malawi in 1987 indicated that both chloroquine and proguanil were effective31. However, infection rates per annum were exceptionally high in all groups and 61.5% of subjects taking no prophylaxis reported infections during the year's study. Chloroquine plus proguanil offered 86% protection, and proguanil and chloroquine taken alone had efficacies of 67% and 64%, respectively. A recent prospective study in short term visitors to Kenya indicated that 600 mg chloroquine weekly had a high efficacy but that the standard chloroquine dosage (300 mg) offered no protection32. Pyrimethamine/ sulphadoxone was highly effective; with an efficacy of 80% alone and 83% when taken with chloroquine. Mefloquine was 100% effective.

Discrete cohorts Military personnel on exercise have been monitored to evaluate the effectiveness of prophylaxis. In 1985, of the 120 troops visiting Papua New Guinea, 19 (16%) had microscopically confirmed P. falciparum infections33. All were reported to have complied fully with the prophylactic regimen of chloroquine 300 mg base weekly and proguanil 200 mg daily. In 1985 and 1986, none of the 408 soldiers visiting Southern Malaysia became infected whilst taking proguanil 200 mg daily and strict antimosquito measures3. This was, however, a low risk area and no control group was available to assess the efficacy of these measures. At the end of 1988, 19% of a troop of soldiers visiting the coast of Kenya,

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26

u7e

Chloroquine

Proguanil

CQ-Proguanil

Maloprim

Reported prophylaxis

Figure 1. Prophylactic efficacy values. British travellers visiting East and West Africa, 1987

Chloroquine

Proguanil

CO-Proguanil

Maloprim

Reported prophylaxis Compliance status sell reported

Figure 2. Compliance with drug prophylaxis. The influence of compliance on efficacy values in West Africa, 1987 100%

Efficacy values Fully oompliant

Loes compliant

80%

60% 40%-

20%-

Chloroquine

Proguanil

CC-Proguanil

of 54% and 73% in East and West Africa, respectively (Figure 1). Chloroquine alone, and proguanil alone, were estimated to have a protective efficacy of 54% and 36% in East Africa, and 60% and 68% in West Africa, respectively. Pyrimethamine/dapsone was effective in West Africa, with an efficacy of 61% but was poorly effective in East Africa since the efficacy value was only 9%. Compliance with prophylaxis strongly influenced the degree of protection offered by each drug regimen. In West Africa full compliance with chloroquine plus proguanil achieved 78% protection, compared with an efficacy of 45% in the less compliant (Figure 2). Similar values were evident in proguanil users but the efficacy of chloroquine was 50% higher in fully compliant compared with less compliant users. In those to East Africa, full compliance improved values for chloroquine and for chloroquine plus proguanil, but not for proguanil used alone (Figure 3). Rates of infection in all non compliant drug users in East Africa equated with rates in travellers taking no prophylaxis. A less intensive study of this nature was performed in American and Swiss travellers returning from Kenya between 1983 and 19845. The efficacy of pyrimethamine/sulphadoxone plus chloroquine was estimated to be 91% and for chloroquine alone was 42%. No account was taken of compliance.

Maloprim

Reported prophylaxis Compiiance status sell reperted

Figure 3. Compliance with drug prophylaxis. The influence of compliance on efficacy values in East Africa, 1987

again using chloroquine plus proguanil, became infected with P. falciparum. It was unclear, however, what proportion had observed strict compliance with the regimen (Malaria Reference Laboratory, unpublished). Chloroquine 300 mg plus proguanil were used by expeditioners in South West Cameroon in 1988; unverified infections in 11 of the 15 inferred an attack rate of 73%. Of 140 expeditioners visiting the same area the following year, 23 (16%) became infected. Differences in attack rates have been ascribed to the use of permethrin treated bednets and full compliance with prophylaxis in the latter group. National monitoring of travellers and malaria cases The prophylactic drug use of travellers returning to Britain during 1987 and of British cases with P. falciparum infections in 1987 was used to establish universal efficacy values'8. In all users the combination of chloroquine plus proguanil had an efficacy

Ongoing surveillance National malaria surveillance reports between 1986 and 1988 indicated that the incidence of infection in British cases taking chloroquine plus proguanil has risen sharply (Malaria Reference Laboratory, unpublished). Cases on this regimen returning from East Africa rose, proportionately, from 20% to 51% of all cases, from 3% to 15% of all cases from West Africa, and from 0% to 26% of all cases from Central and Southern Africa. Local surveillance of infections in Peace Corps Volunteers taking chloroquine identified sudden outbreaks of P. falciparum infections in Benin and Togo in 1987; attack rates of 1% were reported over a 6-month period36. These data, and further reports of breakthroughs in Ghana, alert us to the fact that chloroquine resistance has spread widely into West Africa.

Factors influencing the efficacy of antimalarial drugs Many factors are known to influence the disposition and bioavailability of drugs and their subsequent effectiveness in protecting individuals against P. falciparum infections. Some of the prominent factors recently reported are: Loading doses: The blood concentration of chloroquine, after the first weekly 300 mg dose, is subtherapeutic37. Short term visitors may thus only obtain effective drug levels (and a steady drug state) after they have returned from their trip abroad. A loading dose of 600mg of chloroquine has been recommended for initial prophylaxis but has not received general recognition. Antagonism: Pyrimethamine/sulphadoxine, amodiaquine, mefloquine, quinine and artemisinin, when assessed in combination with chloroquine in vitro, appear to be markedly antagonistic, with both chloroquine sensitive and chloroquine reistant strains of P. falciparum38. This suggests that some drugs taken together or sequentially may have decreased effectiveness both for prophylaxis and for therapy.


Individual metabolism: Individual and racial differences in the absorption and metabolism of 'antifols' have been recognized quite recently19'39. Further studies are required, since this indicates that the protective effect of certain drugs may vary widely between individuals, and some persons may be receiving little protection despite full adherence with the prescribed regimen. Absorption related to food intake: A controlled experiment illustrated that peak chloroquine levels in subjects given a high fat/protein meal, at the time of dosing, were significantly greater than in subjects who had fasted or who had taken a low fat/protein meal40. No advice is currently given to prophylactic users on the type of food to be taken prior to routine prophylaxis. Compliance: A two to fourfold decrease in the effectiveness of drug prophylaxis was estimated in British travellers who had not complied fully with their prophylactic regimen. Further information is required to determine what proportion of doses may be missed before the efficacy of a drug regimen diminishes.

Application of results for malaria prophylactic recommendations Information currently available on the efficacy of drugs is by no means comprehensive. The results of some studies conflict with others. However, certain trends are evident and may be used as a basis to guide prophylactic recommendations. A full summary of recommendations for travellers from the United Kingdom is presented elsewhere41.

Chloroquine or proguanil Efficacy data suggest that the sole use of these drugs is now limited to countries where resistance is rarely reported; for example some countries in the Middle East and Latin America. Recent studies indicate that neither chloroquine 300 mg weekly nor proguanil 200 mg daily, taken alone, offer adequate protection against P. falciparum in East Africa. The efficacy of proguanil alone is particularly low, and similar values for chlorproguanil suggest this is also so in other areas of Central Africa. Chloroquine appeared to have a low efficacy in East Africa, even in the early 1980s, although some data suggest full compliance or double dosing increases its effect. The Peace Corps studies indicate the sudden reduction in the effectiveness of chloroquine in West Africa.

Chloroquine plus proguanil The efficacy of chloroquine 300 mg weekly, in combination with proguanil 200 mg daily, appears to have fallen substantially; particularly for multidrug resistant areas of Oceania, South East Asia and South America. Its continued use for visitors to East Africa, especially coastal areas, and parts of Central and Western Africa (for example the Cameroons) is also questionable. The efficacy of this combination has been higher in West Africa, but it is not clear whether its effectiveness will rapidly decline.

Other drug regimens The compound antimalarial pyrimethamine/sulphadoxine (PS) has a higher efficacy than chloroquine or proguanil. Use of PS has, however, been restricted because of its association with serious cutaneous

reactions. Despite sentinel case reports of breakthroughs, corroberated by adequate blood drug levels, Swiss studies still suggest that PS retains high efficacy in East Africa. It also remains the principal drug carried by travellers for emergency self therapy in the event of an attack of malaria. The effectiveness of pyrimethamine/dapsone (PD) is less clear. Although British studies suggest that it has a particularly low efficacy in East Africa, it has received renewed interest when combined with chloroquine or with proguanil. The latter combination makes little sense, pharmacokinetically, since synergy occurs between the 'antifol' and dapsone, not between the 'antifols'. PD has been widely encouraged in Central African countries and the results suggest that it does have a higher efficacy there. Indeed, PD also seems to have good efficacy in West Africa. Recent results show that, currently, mefloquine offers a high degree of protection in drug resistant areas; it has thus been advocated for use in East Africa, some countries of Central and Western Africa, Oceania, and the Amazonas region of South America. However, mefloquine has a long half life and users are recommended to switch from weekly to fortnightly dosing after 4 weeks of use to prevent the potentially toxic accumulation of drug. British specialists consequently currently only advise mefloquine for travellers abroad for 3 weeks or less41. Additionally, it is recognized that parasite resistance to mefloquine may evolve rapidly in chloroquine resistant areas and therapeutic failures have already been documented42'43. Doxycycline offers another alternative for highly resistant areas but attention must be given to the side effects with this drug in pregnant women and young children.

Conclusions Estimates of the protective efficacy of antimalarial drugs are essential in order to ensure that the most effective, but safe, chemoprophylactic regimen can be prescribed to healthy individuals travelling abroad. However, studies of drug efficacy are extremely sparse and little information is available to provide a sound basis for decision making. General practitioners and physicians must, however, prescribe for their patients and should be aware of the following general points. First, no chemoprophylactic regimen is 100% effective, and measures to protect against mosquito bites must always be recommended in conjunction with drug prophylaxis. Second, the effectiveness of chemoprophylactic drugs must always be balanced against their potential toxicity. Efficacy data do indicate that the degree of protection afforded by the safer chemoprophylactic drugs, like chloroquine and proguanil, has fallen in recent years, particularly in East Africa and some countries of Central and Western Africa. The compound antimalarial drugs appear to have retained greater efficacy but their use has been restricted because of the unacceptibly high incidence of adverse reactions. It is unclear whether the continued increase in risk of potentially life threatening infections with P. falciparum may, in future years, necessitate the use of compound antimalarials or the use of other newer drugs known to have toxic side effects. Currently, the available data are not adequate to suggest that this is justified. Mefloquine and doxycycline appear to provide a high degree of protection in multiple drug resistant areas but their safety has to be fully established before

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they can be prescribed widely, Third, the efficacy of any drug is substantially reduced if users do not comply fully with the recommended regimen and whenever physicians prescribe they need to remind their patients that full compliance with the recommended regimen is essential. Better data on the protective efflcacy and potential toxicity of all prophylactic drugs is clearly needed. Physicians can play a major role in the provision of this important information by ensuring that malaria cases (and their use of prophylaxis) and patients with suspect reactions are reported in full to the correct authorities. References 1 Najera JA. Malaria and the work of WHO. Bull WHO 1989;67:229-43 2 World Health Organisation. Development of recommendations for the protection of short stay travellers to malaria endemic areas: memorandum from two WHO meetings. Bull WHO 1988;66:177-96 3 Fogh S, Jepsen S, Effersoe P. Chloroquine resistant plasmodium falciparum malaria in Kenya. Trans R Soc Trop Med Hyg 1979;73:228-9 4 Kean BH. Chloroquine resistant falciparum malaria from Africa. JAMA 1979;241:395 5 Campbell CC, Collins WE, Chin W, Teutsch SM, Moss DM. Chloroquine resistant plasmodium falciparum from East Africa. Lancet 1979;ii:1151-54 6 Pearlman EJ. Thiemanum W, Casteneda BF. Chemosuppressive field trials in Thailand II The supression of Plasmodium falciparum and Plasmodium vivax parasitaemias by a diformyldapsone-pyrimethamine combination. Am J Trop Med Hyg 1975;24:901-9 7 Pearlman EJ. Lampe RM, Thiemanun W, Kennedy RS. Chemosuppressive field trials in Thailand III The suppression of Plasmodium falciparum and Plasmodium vivax parasitaemias by a sulfadoxine-pyrimethamine combination. Am J Trop Med Hyg 1977;26:1108-1115 8 Spencer HC, Oloo AJ, Watkins WM, Sixsmith DG, Churchill FC, Koech DK. Amodiaquine more effective than chloroquine against Plasmodium falciparum malaria on the coast of Kenya. Lancet 1984;i:956-7 9 Watkins WM, Sixsmith DG, Spencer HC, et al. Effectiveness of amodiaquine as a treatment for chloroquine resistant Plasmodium falciparum infections in Kenya. Lancet 1984;i:357-9 10 Friman G, Nystrom-Rosander C, Bjorkman A, Jonsell G, Lekas G. A granulocytosis associated with malaria prophylaxis with Maloprim. Br Med J 1983; 286: 1244-5 11 Miller KD, Lobel HO, Satriale RF, Kinitsky JN, Stern R, Campbell CC. Severe cutaneous reactions among American travellers using pyrimethamine sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg

1986;35:451-8 12 Hatton C, Peto T, Bunch C, et al. Frequency of severe neutro penia associated with amodiaquine prophylaxis against malaria. Lancet 1986;i:411-13 13 Peto TEA, Gilks CF. Strategies for the prevention of malaria in travellers: comparison of drug regimens by means of risk benefit analysis. Lancet 1986;i:1256-60 14 Phillips-Howard PA, West L. Serious adverse reactions to pyrimethaamine/sulphadoxine, pyrimethaniine/dapsone and to amodiaquine in Britain (submitted) 15 Peters W. Chemotherapy and drug resistance in malaria

London: Academic Press, 1987 16 Desjardins RE, Doberstyn EB, Wernsdorfer WH. The treatment and prophylaxis of malaria In: Wernsdorfer WH, McGregor I, eds. Malaria,~Principles and practices of malariology. Edinburgh: Churchill Livingstone, 1988 17 Merkli B, Richle RW. Studies on the resistance to single and combined antimalarials in the Plasmodium berghei mouse model. Acta Trop 1980;37:22-231

18 Phillips-Howard PA. The epidemiology of malaria in Britain. PhD thesis, University of London, 1988 19 Watkins WM, Brandling Bennet AD, Oloo AJ, et al. Inadequacy of chlor-proguanil 20 mg per week as chemoprophylaxis for falciparum malaria in Kenya. Lancet 1987;i:125-7 20 Nevill CG, Watkins WM, Carter JY, Munafu CG. Comparison of mosquito nets, proguanil hydrochloride, and placebo to prevent malaria. Br Med J 1988; 297:401-3 21 Fogh S, Scapira A, Bygbjerg IC, et al. Malaria chemoprophylaxis in travellers to East Africa a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine. Br Med J 1988;296:820-2 22 Saarinen M, Thoren E, Iyambo N, et al. Mass proguanil prophylaxis. Lancet 1987;i:985-6 23 Coosemans MH, Barutwanayo M, Onori E, et al. Double blind study to assess the efficacy of chlorproguanil given alone or in combination with chloroquine for malaria prophylaxis in an area with Plasmodium falciparum resistance to chloroquine, pyrimethamine and cycloguanil. Trans R Soc Trop Med Hyg 1987; 81:151-6 24 Greenwood BM, Greenwood AM, Smith AW, et al. A comparative study of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine and dapsone) as chemoprophylactics against malaria in Gambian children. Tran R Soc Trop Med Hyg 1989;83:182-8 25 Kollaritsch H, Stemberger H, Mailer H, et al. Tolerability of long term malaria prophylaxis with the combination mefloquine+sulphadoxine+pyrimethamine (Fansimef) results of a double blind field trial versus chloroquine in Nigeria. Trans R Soc Trop Med Hyg 1988;82:524-9 26 Pang LW, Limsomwong N, Singharaj P, Canfield CJ. Malaria prophylaxis with proguanil and sulfisoxazole in children living in a malaria endemic area. Bull WHO 1989;67:51-8 27 Pang LW, Limsomwong N, Singharaj P. Prophylactic treatment of vivax and falciparum malaria with low dose Doxycycline. J Infect Dis 1988;158: 1124-7 28 Limsomwong N, Pang LW, Singharaj P. Malaria prophylaxis with proguanil in children living in a malaria endemic area. Am J Trop Med Hyg 1988; 38:231-6 29 Win K, Thwe Y, Lwin TT, Win K. Combination of mefloquine with sulfadoxine-pyrimethamine compared with two sulphadoxine-pyrimethamine combinations in malaria chemoprophylaxis. Lancet 1985;ii:694-5 30 McLarty DG, Webber R, Jaatinen M, et al. Chemoprophylaxis of malaria in non-immune residents in Dar es Salaam Tanzania. Lancet 1984;ii:656-9 31 Harries AD, Foreshaw CJ, Friend HM. Malaria prophylaxis amongst British residents of Lilongwe and Kasungu. Trans R Soc Trop Med Hyg 1988;82:690-2 32 Steffen R. Malaria chemoprophylaxis in European travellers to Africa; a follow up study. Milit Med Pharm 1988;274-6 33 Henderson A, Simon JW, Melia W. Failure of malaria chemoprophylaxis with a proguanil-chloroquine combination in Papua New Guinea. Trans R Soc Trop Med Hyg 1986;80:838-40 34 Henderson A, Rixom JA. Personal protective measures plus proguanil for malaria prophylaxis in Southern Malaysia. Trans R Soc Trop Med Hyg 1986;81:981-2 35 Lobel HO, Roberts JM, Somaini B, Steffen R. Effilcacy of malaria prophylaxis in American and Swi8ss Travellers to Kenya. J Infect Dis 1987;155:1205-9 36 Moran dS, Bernard KW, Greenberg AE, et al. Failure of chloroquine treatment to prevent malaria in Americans in West Africa. JAMA 1987;2U8:2376-7 37 Brohult d, Rombo L, Sirleaf V, Bengtsson B. Weekly malaria prophylaxis 300 or 600 mg chloroquine base. Lancet 1979;ii:522

Journal of the Royal Society of Medicine Supplement No. 17 Volume 82 1989 38 Stahel E, Druilhe P, Gentilini M. Antagonism of chloroquine with other antimalarials. Trans R Soc Trop Med Hyg 1988;82:221 39 Cook IF, Cochrane JP, Edstein MD. Race linked differences in serum concentrations of dapsone, monoacetyldapsone and pyrimethamine during malaria prophylaxis. Trans R Soc Trop Med Hyg 1986;80: 897-901 40 Lagrave M, Stahel E, Betschart B. The influence of various types of breakfast on chloroquine levels. Trans R Soc Trop Med Hyg 1985;79:559 41 Malaria Reference Laboratory. Prophylaxis against malaria for travellers from the United Kingdom. Br Med J (in press)

42 Bygbjerg IC, Schapira A, Flachs H, Gomme G, Jepsen S. Mefloquine resistance of falciparum malaria from Tanzania enhanced by treatment. Lancet 1983;i: 774-5 43 Karwacki JJ, Webster HK, Limsomwong N, Shanks GD. Two cases of mefloquine resistant malaria in Thailand. Trans R Soc Trop Med Hyg 1989;83: 152

(Correspondence to Dr P A Phillips-Howard, Research and Technical Intelligence, Malaria Action Programme, World Health Organization, 1211 Geneva 27, Switzerland)

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