An Imported Case of Severe Falciparum Malaria with Prolonged Hemolytic Anemia Clinically Mimicking a Coinfection with Babesiosis

While imported falciparum malaria has been increasingly reported in recent years in Korea, clinicians have difficulties in making a clinical diagnosis as well as in having accessibility to effective anti-malarial agents. Here we describe an unusual case of imported falciparum malaria with severe hemolytic anemia lasting over 2 weeks, clinically mimicking a coinfection with babesiosis. A 48-year old Korean man was diagnosed with severe falciparum malaria in France after traveling to the Republic of Benin, West Africa. He received a 1-day course of intravenous artesunate and a 7-day course of Malarone (atovaquone/proguanil) with supportive hemodialysis. Coming back to Korea 5 days after discharge, he was readmitted due to recurrent fever, and further treated with Malarone for 3 days. Both the peripheral blood smears and PCR test were positive for Plasmodium falciparum. However, he had prolonged severe hemolytic anemia (Hb 5.6 g/dl). Therefore, 10 days after the hospitalization, Babesia was considered to be potentially coinfected. A 7-day course of Malarone and azithromycin was empirically started. He became afebrile within 3 days of this babesiosis treatment, and hemolytic anemia profiles began to improve at the completion of the treatment. He has remained stable since his discharge. Unexpectedly, the PCR assays failed to detect DNA of Babesia spp. from blood. In addition, during the retrospective review of the case, the artesunate-induced delayed hemolytic anemia was considered as an alternative cause of the unexplained hemolytic anemia.

Compliance with Atovaquone-Proguanil against Malaria of Korean Travelers Abroad / 감염과화학요법

BACKGROUND: Recently, many Korean people travel abroad where malaria is prevalent. However, in Korea, relatively little is known about compliance of chemoprophylaxis against malaria. This study was performed to determine the factors influencing compliance of chemoprophylaxis against malaria in Korean travelers. MATERIALS AND METHODS: Face to face interview, telephone interview and e-mail correspondence were performed to 241 people who were prescribed with atovaquone-proguanil at the international travelers' clinic of National Medical Center between February 2007 and October 2007. RESULTS: Total of 55 people out of 235 reported one or more events of adverse reactions after chemoprophylaxis (total 76 events). However, in 38 adverse events the link between chemoprophylaxis and adverse events were very weak. Compliance of malaria chemoprophylaxis with atovaquone-proguanil was 53.9% in the study group. The predictive factors for non-compliance were package tour, travel of business affair and young age group. Conclusions: Compliance of malaria chemoprophylaxis in Korea travelers was low compared with Dutch and French studies. More efforts to increase compliance are needed, especially in travelers on package tour, business travel and people under age 40.

Compliance with Atovaquone-Proguanil against Malaria of Korean Travelers Abroad / 감염과화학요법

BACKGROUND: Recently, many Korean people travel abroad where malaria is prevalent. However, in Korea, relatively little is known about compliance of chemoprophylaxis against malaria. This study was performed to determine the factors influencing compliance of chemoprophylaxis against malaria in Korean travelers. MATERIALS AND METHODS: Face to face interview, telephone interview and e-mail correspondence were performed to 241 people who were prescribed with atovaquone-proguanil at the international travelers' clinic of National Medical Center between February 2007 and October 2007. RESULTS: Total of 55 people out of 235 reported one or more events of adverse reactions after chemoprophylaxis (total 76 events). However, in 38 adverse events the link between chemoprophylaxis and adverse events were very weak. Compliance of malaria chemoprophylaxis with atovaquone-proguanil was 53.9% in the study group. The predictive factors for non-compliance were package tour, travel of business affair and young age group. Conclusions: Compliance of malaria chemoprophylaxis in Korea travelers was low compared with Dutch and French studies. More efforts to increase compliance are needed, especially in travelers on package tour, business travel and people under age 40.

El citocromo P-450 y la respuesta terapéutica a los antimaláricos / Cytochrome P-450 and the response to antimalarial drugs

OBJETIVOS: Evaluar la relación entre los factores genéticos y fenotípicos del sistema enzimático del citocromo P-450 y la respuesta terapéutica antimalárica a la cloroquina, la amodiaquina, la mefloquina y el proguanil, así como determinar la influencia de algunos factores biológicos y sociales del hospedero en el comportamiento de este complejo enzimático. MÉTODOS: Revisión sistemática de las bases de literatura biomédica PubMed, Excerpta Medica, LILACS y SciELO mediante descriptores en español e inglés. Se usaron los siguientes descriptores: "CYP-450" y "citocromo P-450" y sus combinaciones con "proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "farmacocinética de proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "resistencia a proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "metabolismo", "farmacogenética", "enfermedad", "inflamación", "infección", "enfermedad hepática", "malaria", "nutrición" y "desnutrición". Estos mismos términos se usaron en inglés. La búsqueda se limitó a los artículos publicados en español, inglés y portugués hasta el 30 de junio de 2005 y a cuatro medicamentos antimaláricos: amodiaquina, cloroquina, mefloquina y proguanil. RESULTADOS: Algunos factores genéticos del citocromo P-450 humano (principalmente su polimorfismo), así como otros de tipo biológico y social (la propia presencia de enfermedad, inflamación o infección, la administración de medicamentos antimaláricos y su combinación, y el estado nutricional del paciente), influyen en la actividad de ese complejo enzimático. Solo en la última década se ha abordado el estudio de las bases genéticas de los citocromos y se han podido dilucidar los mecanismos de algunas interacciones entre fármacos y del metabolismo de estos, lo que ha permitido caracterizar el proceso de biotransformación de la amodiaquina y de la cloroquina. Se espera que nuevas investigaciones permitan responder a las interrogantes que aún subsisten, entre ellas cuál es la ruta metabólica de otros medicamentos antimaláricos, la distribución en la población de los alelos de las enzimas que participan en su metabolismo, y la contribución de tales mutaciones al fracaso terapéutico, y predecir la respuesta a los tratamientos antimaláricos. CONCLUSIONES. La respuesta terapéutica a los medicamentos antimaláricos es un proceso multifactorial y poco comprendido, por lo que no es posible asignar a un fenotipo o a un genotipo una determinada responsabilidad en la respuesta terapéutica antimalárica. Se debe contemplar la influencia de factores biológicos y sociales, tales como la alimentación, el estado nutricional y cualquier proceso inflamatorio e infeccioso concomitante, que puedan ser frecuentes en las zonas con malaria endémica.

OBJECTIVES. To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. METHODS. We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina"), "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. RESULTS. Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism), as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status) influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. CONCLUSIONS. The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.

The susceptibility of Plasmodium falciparum to pyrimethamine and cycloguanil in a malarial area of Quang Binh

PCR-RFLP and DNA sequencing techniques were used for Pyrimethamine (PYR) and Cycloguanil (CYC) resistant mutations. The study results showed that 46 of 58 Plasmodium falciparum isolates were genotype resistant to pyrimethamine (79.31%). Thirty-one isolates were taken in vitro microscopic examination and revealed that 26 of 31 isolates were PYR resistance (83.87%) and 6 of 31 isolates of CYC resistance (19.35%). The resistant levels of these isolates were related to the mutations in DHFR genes

Proguanil plus sulfamethoxazole in the treatment of uncomplicated Plasmodium falciparum malaria.

In a malaria endemic area of Brazil where P. falciparum is highly resistant to chloroquine and Fansidar, we conducted an in vivo study to evaluate the therapeutic response of proguanil plus sulfametoxazole against Plasmodium falciparum malaria. Twenty-five adult subjects with uncomplicated P. falciparum malaria received supervised drug administration and were followed for 28 days in an inpatient hospital or in a malaria free-transmission area. The therapeutic regimen was proguanil 100 mg BID plus sulfamethoxazole 1,000 mg BID for 7 days. Of those who took all medications (n=21), 17 (81%) were cured. Recrudescent parasitemia during follow-up occurred in four (19%) patients on days 14, 19, 20 and 21 after beginning of treatment. The remaining four (16%) subjects did not complete their therapeutic regimen because the incidence of side effects. Considering the shortage of falciparum malaria therapeutic options and the urgent need for new regimens to deal with the spread of drug resistant P. falciparum, one might consider the study results as a lead to study analogous compounds, hopefully with fewer adverse reactions.

Malaria en Chile: 1913-2001 / Malaria in Chile from 1913 to 2001

Background: Malaria was restricted to the I Region of Chile, being Anopheles pseudopunctipennis the only vector species. In 1936 the parasitosis affected more than 50 percent of the population and 62.4 percent of military recruits, proceeding from Southern regions became infected. From 1937 to 1947, an antimalaria campaign was carried out, stressing actions on the battle against the vector and the treatment of malaria infected individuals. Since April 1945 no autochthonous cases of malaria have been detected. Aim: To update the situation of malaria in Chile. Methods: 1) Imported malaria: Analysis of occasional publications on the subject (1945-1988) and the annual reports of the Ministry of Health Department of Epidemiology (1990-2001). Annual reports on the Anopheles specimens collected -mostly larvae- in the provinces of Arica and Iquique and examined in the Parasitology Unit of the School of Medicine, University of Chile, during the period 1980-2001. Results: 1) Imported malaria. A total of 24 cases were published in the period 1945-1988. In the 1980-2001 period, the Ministry of Health recorded 66 cases with 5 (8.8 percent) deaths. 2) Anophelines: Only in 1984, 1985, 1998 and 2001 A. pseudopunctipennis foci were detected. Entomological surveillance was stressed and insecticides were applied on these focuses. Conclusions: Autochthonous malaria does not exist in Chile since 1945. The detection of malaria cases in countries where the parasitosis was eradicated, can be the result of tourism or migrations. In Chile, the Environmental Programs of Arica and Iquique perform periodical surveys in localities where mosquitoes exist. When A. pseudopunctipennis is found, the entomological vigilance is stressed and insecticide applications are reiterated until the situation is controlled

Atovaquone and proguanil hydrochloride compared with choroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone TM) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive, 1,000 mg atovaquone and 400 mg mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloriquine (cure rate 100 percent [14/14] versus 8 percent [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100 percent [5/5] and 100 percent [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarium symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100 percent for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

Pharmacokinetics of proguanil in malaria patients treated with proguanil plus atovaquone.

Clinical studies have shown atovaquone (ATQ), a new blood schizontocidal drug, in combination with proguanil (PROG) to be very effective in the treatment of acute multidrug-resistant falciparum malaria. The multiple dose pharmacokinetics of PROG were determined in Thai patients with acute falciparum malaria given PROG alone (200 mg PROG twice a day for 3 days, n = 4) and concurrently PROG and ATQ (200 mg PROG and 500 mg ATQ twice a day for 3 days, n = 12). There were no statistical differences (p > 0.05) in the area under the plasma drug concentration-time curve (AUC), apparent oral clearance (CL/F) and elimination half-life (t1/2) of PROG between patients given PROG alone and PROG/ ATQ. The median (range) kinetic values of PROG in patients given PROG alone and PROG/ATQ were respectively: CL/F = 1.25 l/h/kg (0.99-1.45) and 0.95 (0.73-1.32) l/h/kg, and t1/2 = 14.2 hours (9.3-16.8) and 13.6 hours (9.1-17.6). The CL/F and t1/2 of PROG in the Thai patients treated with the 2 treatment regimens were also comparable to values reported in healthy Thai volunteers given a standard prophylactic dose (200 mg PROG). The results of this preliminary study suggest that ATQ is unlikely to affect the pharmacokinetics of PROG to a clinically important extent at an ATQ dosage of 500 mg twice a day for 3 days in malaria infected patients.

Proguanil/sulfamethoxazole malaria chemoprophy-laxis on the Thai-Cambodian border.

383 Thai soldiers on the Thai-Cambodian border were entered into a randomized malaria chemoprophylactic trial. Proguanil (200 mg/day) combined with sulfamethoxazole (1000 or 1500 mg/day) were compared to a standard combination of weekly pyrimethamine/dapsone (Maloprim). Men receiving proguanil/sulfamethoxazole had a significantly lower malaria attack rate than those taking pyrimethamine/dapsone. This was true of both the first five-week phase in which 1000 mg of sulfamethoxazole was used (0.11 vs 0.26; p less than 0.001) and in the second ten weeks in which 1500 mg of sulfamethoxazole was used (0.13 vs 0.30; p less than 0.001). Combined relative efficacy indicated that proguanil/sulfamethoxazole was better than pyrimethamine/dapsone by 64% for Plasmodium vivax and by 38% for P. falciparum. Unenforced compliance as measured by returned pills was greater than 86% in both groups. No serious drug side-effects were observed. Proguanil/sulfamethoxazole may represent a useful chemoprophylactic option in areas of multiple drug-resistant malaria.