Problems in the therapy of mixed malarial infections: a case of infection with Plasmodium falciparum and P. malariae treated with mefloquine and halofantrine.

Mixed malarial infections of Plasmodium falciparum and P. malariae are not uncommon but they may often be overlooked l?ecause there is a tendency for P. falcipa"fm .to predommate and the parasitaemia with P. malanae IS usually very low. Therapy of cases of mixed infections with P. falciparum !lnd P. malaria~, P. vivax or P. ovale should clearly ~e almed at P. falctparum as the potentially lethai infectIO~S a~ent (COOK, 1988), .followed by a course of primaqume m the case of P. vlvax or P. ovale. For non-immune subjects, mefloquine and halofantrine are the currently .recommende~ ~rst line drugs for uncomplic~ted fa1clparum malana Inlported from African countnes where chloroquine resistance is common (WHO 1992). ' However, very limited information is available concerning the efficacy of these 2 drugs in the treatment of quartan malaria. DIXON and co-workers (1983) have successfully used mefloquine to treat a case of P. malariae and they reported rather slow resolution of fever and parasitaemia. Similarly, WEINKE et al. (1993) reported the successful treatment of 2 cases of P. malariae infection. (one mixed with P. falciparum) with halofantrine, but In both reports the follow-up period was only 28 d. B:ere we report a patient with a mixed infection of P. fal~lparum and P. malariae treated initially with mefloqUIne and subsequently with halofantrine; the possible failure ofboth drugs is discussed. In July 1991 a 46 years old German woman presented at ~ peripheral hospital in qermany with fever (39·2°C), chills, .headache and anoreXla of 3 d duration, 12 d after returrung from 2 weeks' holiday in Kenya. She denied ~aving taken any malaria chemoprophylaxis or anti-malanal treatment. The diagnosis of fa1ciparum malaria was made by exarnination of blood films which had been sent to our institute for confirrnation. The initial parasitaemia was 3% (136 OOO/IlL). Other than a thrombocytopenia of 128 OOO/IlL. there was no abnormality or sign of complicated malana. Consequently she was treated with mefloquine in a total dose of 1500 mg (750 mg followed by 500 mg 6 h later and 250 ~g after a further 12 h), equivalent to 20 mg/kg body wel~ht. She did not vomit after taking the drug. Fever had dlsappeared by day 4 and parasitaemia by day 6. The patient was discharged on day 7, clinically fully recovered. In October 1991 (78 d later) the patient presented again ~t the same hospital with fever (40°C), shivering and chilis. She had not been abroad since her last hospital admission. Suspecting a P. falciparum recrudescence treatment with halofantrine was started immediately: However, all blood slides sent to us clearly revealed a P. malariae monoinfection. She was given 3 doses of halofan trine, 500 mg, orally at intervals of 6 h. Again there was no vomiting and recovery was uneventful. Clearance of fever and parasitaemia occurred at days 3 and 4 respectively. Treatment was repeated one week after the initial course, using the same dose of halofantrine. In January 1992 (106 d after her first admission) the patient presented a third time at the same hospital with fever and headache. Again P. malariae was detected in thick and thin blood films sent to us, although she had not travelIed to a malaria endemic area since her last admis~ion. Apart from mild splenomegaly no other abnormahty could be found and again she was treated with 2 full courses of halofantrine with an interval of one week. Her ~ever and para~itae~ia cleared by days 2 and 8 respectIvely. After this thlrd treatment the patient was finally referred to us for further counselling and was advised to consult us directly in case of further symptoms. !o date (March 1993,410 d after her last therapy) she is In good health, no further episode of fever attributable to malarial infection has occurred, and repeated blood films have always been negative for Plasmodium. In this patient we observed a recrudescence of P. malariae infection more than 2 months after mefloquine tre~tment. There ca~ be no doubt that the drug was sufficlently absorbed, smce concomitant infection with P falciparum was cleared promptly. Therefore one migh~ conclude that mefloquine failed to eradicate a very low parasitaemia of P. malariae, which had been overlooked at the init~al examiJ?-ation. Alternatively it is possible that P. ma!a~~e parasltes were not present in peripheral blood InltIally, due to a longer incubation period and when p~rasitaemia developed later, the plasma l:vel of mefloqume was no longer sufficient to clear the infection completely. In ~he case of ha!ofantrine, on the other hand, poor absorptIon resultIng m low plasma concentrations may have caused the first. t~erapy failure even though a second course was adffilrustered after one week, which in fa1ciparum malaria is thought to have almost 100% efficacy in non-immune subjects (NOTHDURFT et al., 1993). This explanation appears to be more likely than true halofantrine resistance. Such a view is also supported by the fact that the s~cond treatment with halofantrine has obviously resulted In complete cure. Nevertheless, it cannot be ruled out completely that the plasma level of halofantrine needed for effective treatment of P. malariae is higher than that for P. falciparum. Interestingly, both clinical episodes of P. malariae monoinfection in our patient occurred more than 2 months after the initial mefloquine and halofantrine treatment (78 and 106 d, respectively) and would not have been detected in the usual28 d observation period. We conclude that double infections with P. falciparum and P. malanae may pose some therapeutic difficulties when treated with mefloquine or halofantrine. Since ~here has been litt!e experience to date with these 2 drugs In quartan malana, recrudescence of P. malariae after such mixed infections should be treated with chloroquine, w~ich remains the treatment of choice. It is par~lcularly Important to make a thorough species diagnosis In such cases before treatment is given.