Quinine-Resistant Severe Falciparum Malaria Effectively Treated with Atovaquone and Proguanil Hydrochloride Combination Therapy

□ CASE REPORT □

Quinine-resistant Severe Falciparum Malaria Effectively Treated with Atovaquone and Proguanil Hydrochloride Combination Therapy

Hitoji UCHIYAMA, Akio OKAMOTO, Katsuaki SATO, Tomohiro YAMADA, Sadatsugu MURAKAMI, Seiichi YONEDA, Yoshihiro KAJITA,Tatsuya TEGOSHI*andNaoki ARIZONO*

Abstract ial and ovale. Patients with falciparum malaria, also known as malignant malaria, tend to follow severe clinical sequelae A 22-year-old Japanese man noticed pyrexia and diar- and death from diagnostic and therapeutic delay. Chloro- rhea after travel to Guinea. Notable physical findings in- quine-resistant falciparum malaria is now worldwide, and re- cluded hepatosplenomegaly. Treatment with oral quinine sistance to sulfadoxine/pyrimethamine, quinine, mefloquine and minocycline was started after definitive diagnosis of and halofantrine is spreading gradually (2, 3). Thus, appro- falciparum malaria by blood smear. Initially, parasitemia priate treatment for falciparum malaria is an essential prereq- and body temperature decreased but by the third night of uisite to avoid severe sequelae and patient death. A therapy his temperature increased to 40°C with a slight commonly referenced guideline is shown from the World increase of parasite count. When quinine treatment was Health Organization (WHO) in 2000 (4, 5). We have only a changed to atovaquone/proguanil, his temperature limited experience in treating severe falciparum malaria, pre- dropped immediately and complete plasmodial elimina- sumably quinine resistant, with atovaquone/proguanil combi- tion was confirmed on microscopic examination. Sub- nation (Malarone) in Japan. Here, we report a case of severe sequent recrudescence of the disease was not observed. It falciparum malaria successfully treated with this combina- was concluded that the antimalarial treatment with tion (Malarone). atovaquone/proguanil might become invaluable in Japan. (Internal Medicine 43: 624–627, 2004) Case Report

Key words: falciparum malaria, parasitemia, hemolytic ane- A 22-year-old Japanese man visited Guinea from March mia, disseminated intravascular coagulation 10 to June 8, 2002 to study the local music. He developed syndrome, quinine, atovaquone/proguanil com- abdominal pain, nausea and aqueous diarrhea without blood bination after he returned home on June 11. After developing a high- grade fever on June 14, he came to the emergency room of our hospital and was admitted to the hospital with the im- pression of acute enteral infection. Introduction Physical examination on admission revealed a slender man (height: 169 cm, body weight: 53.5 kg) who was lethar- Malaria, which is caused by plasmodium parasites trans- gic but alert and oriented. He had a body temperature of 40.2 mitted by anopheline mosquitoes, is endemic in tropical and °C, but had normal blood pressure (116/72 mmHg) and a subtropical countries where it causes considerable ecomonic regular pulse rate of 90 beats/minute. His conjunctivae were and social burdens. As globalization proceeds, encounter not pale or icteric. Examination of his heart, lungs and abdo- with imported malaria cases is not infrequent in countries men was unremarkable except for hepatosplenomegaly (his such as Japan, United States and European nations (1). liver and spleen were both palpated two finger breadths There are four kinds of malaria: falciparum, vivax, malar- below the costal margin).

From the Department of Medicine, Nantan General Hospital, Kyoto and *the Department of Medical Zoology, Kyoto Prefectural University of Medicine, Kyoto Received for publication October 31, 2003; Accepted for publication February 26, 2004 Reprint requests should be addressed to Dr. Hitoji Uchiyama, the Department of Medicine, Nantan General Hospital, 25 Ueno, Yagi-cho, Funai-gun, Kyoto 629-0141

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Table 1. Laboratory Data on Admission

Hematology Blood chemistry Urinalysis WBC 2,640/l Na 138 mEq/l Spg 1.004 meta 1.0% K 4.4 mEq/l pH 7.5 band 31.0% Cl 100 mEq/l Protein (–) seg 31.0% T-Bil 1.3 mg/dl Sugar (–) lymph 29.0% AST 76 IU/l Blood (–) mono 5.0% ALT 64 IU/l Urobilinogen Normal baso 2.0% LDH 337 IU/l Bilirubin (–) Atyp-lymph 1.0% ALP 144 IU/l Ketone (–) RBC 420×104/l S-Amy 38 IU/l Sediment Hb 12.0 g/dl T-Chol 85 mg/dl WBC <1/HPF Hct 35.9% BUN 7.4 mg/dl RBC <1/HPF Ret 7‰ Cr 0.70 mg/dl Plt 3.6×104/l TP 5.6 g/dl Stool PT 63% Alb 3.7 g/dl Occult blood (–) PT-INR 1.46 CRP 13.0 mg/dl Parasite ova (–) APTT 53.2 sec FBS 118 mg/dl Fibrinogen 282 mg/dl FDP 31.7 mg/l

WBC: white blood cell, meta: metamyelocyte, seg: segmented neutrophil, lymph: lymphocyte, mono: monocyte, baso: basophil, atyp-lymph: atypical lymphocyte, RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, INR: international normalized ratio, APTT: activated partial thromboplastin time, FDP: fibrin degradation products, T-Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, S-Amy: serum amylase, T-Chol: total cholesterol, BUN: blood urea nitrogen, Cr: creatinine, TP: total protein, Alb: albumin, CRP: C-reactive protein, FBS: fasting blood sugar, Spg: specific gravity.

On admission, notable laboratory data included leuko- cytopenia, anemia, and severe thrombocytopenia (Table 1). Prothrombin and activated partial thromboplastin times were prolonged on coagulation examination, and fibrin degradation products were positive. Additional chemistries showed mild liver function test abnormalities, low total cholesterol, hypoproteinemia and an elevated CRP. Urinalysis was normal and there were no parasite ova identified in the stool. A chest X-ray and thoracic computed tomography (CT) did not demonstrate cardiomegaly, lung edema, or pleural ef- fusion. Abdominal CT revealed mild hepatomegaly and moderate splenomegaly (Fig. 1). Abdominal ultrasonography confirmed moderate splenomegaly (Splenic index: 6.2×5.8 cm). Because of our suspicion of enteral infection at the time of hospitalization, fluid replacement and antibiotics (fosfomycin and levofloxacin) were started. However, his fever continued and both his anemia and thrombocytopenia wors- Figure 1. Computed tomography of the abdomen showing mild ened. hepatomegaly and moderate splenomegaly. On the third hospital day, Plasmodium falciparum trophozoites were identified on a high power field examination of a Wright Giemsa-stained thin smear of peripheral blood (Fig. tion (DIC) syndrome was recognized, this case was classified 2). No mature schizonts or gametocytes were identified in as severe falciparum malaria. Administration of nafamostat that smear. In this specimen, the erythrocyte infection rate mesilate was started as a treatment of DIC, and oral quinine was 9.4%, and parasite density was 208,000/l. hydrochloride (500 mg of salt given three times daily) and A graph of the patient’s body temperature, hemoglobin minocycline was started for falciparum malaria. Shortly after concentration, and platelet count during his hospital course is treatment began, his body temperature and parasite load im- shown in Fig. 3. Since disseminated intravascular coagula- proved dramatically. However, his body temperature and

Internal Medicine Vol. 43, No. 7 (July 2004) 625 UCHIYAMA et al

Therefore, his treatment with quinine hydrochloride was stopped after giving for three days and it was changed to atovaquone/proguanil combination (Malarone) (1,000 mg atovaquone/400 mg proguanil given once daily for three days). Subsequently, both his body temperature and infected erythrocyte percentage began to decrease. No particular side effects of atovaquone/proguanil combination therapy were recognized, and the clinical course was favorable. During his hospital course, his platelet count fell to 19,000/l, but platelet transfusion was not necessary. In addition, his hemoglobin concentration fell to 9.1 g/dl, but packed red blood cell transfusion was not necessary. We determined that the etiol- ogy of his anemia was hemolysis based upon an elevated Figure 2. Trophozoites of Plasmodium falciparum in the pe- total bilirubin concentration (2.3 mg/dl on June 19), elevated ripheral blood obtained on the third hospital day. Some eryth- LDH concentration (521 IU/l on June 19), and low hapto- rocytes were infected with multiple plasmodial parasites. No globin concentration (40 mg/dl on June 18, type 1-1, normal mature schizonts or gametocytes were identified anywhere in range; 130–327 mg/dl). This condition was improved with this specimen. conservative treatment only. On the third day of atovaquone/ proguanil combination therapy, no infected erythrocytes were identified on peripheral blood smear, and only a few in- infected erythrocyte numbers (parasite density and erythro- tracellular altered parasite bodies were identified within the cyte infection rate) began to increase again. Given his fever, erythrocytes (Fig. 4). No recrudescence of signs or symp- a diagnosis of black water fever was considered at that time, toms developed, and he was discharged from the hospital but it was excluded because he did not have the without complication on June 29. No infected erythrocytes hemoglobinuria expected with this disease, and quinine- were identified after treatment was completed. resistant malaria was more likely in that clinical setting.

Figure 3. Clinical course and alterations of malaria parasite density. FOM: fosfomycin, LVFX: levofloxacin, MINO: minocycline, BT: body temperature, Hb: hemoglobin concentration, Plt: platelet count, PD: parasite density.

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combination with other antimalarial drugs, but the increasing prevalence of resistant organisms continues to be a problem. Patient compliance with atovaquone/proguanil combination is higher and adverse effects are fewer in comparison with mefloquine in normal persons (6). In addition, atovaquone/ proguanil combination has efficacy equal to halofantrine, which has a cardiotoxic side effect (7). At present, atovaquone/proguanil combination seems to be one of the promis- ing antimalarial drugs that are well tolerated and have a lowest incidence of resistance (8). Although notable side effects have not been reported in the clinical use of atovaquone/proguanil combination to date, we still need some Figure 4. Peripheral blood smears on the third day of caution: recently, a case of Stevens-Johnson syndrome was re- atovaquone/proguanil combination therapy. Degenerated para- ported which developed in a patient who received atova- site bodies were identified within a few erythrocytes. Intact quone/proguanil combination for antimalarial prophylaxis (9). plasmodial parasites were not found. Body temperature elevation and an increase of parasitemia after three days of therapy with quinine and minocycline was seen in the present case, and the efficacy of this therapy Discussion was considered inadequate. Black water fever was suspected as the cause of fever elevation at first, but this possibility As globalization proceeds and travels to and from tropical was later rejected because there were no abnormalities in uri- and subtropical malaria endemic areas becomes more fre- nalysis in spite of the existing hemolytic anemia. However, quent, the incidence of malaria imported from these regions subsequent atovaquone/proguanil combination resulted in a has increased in Japan as well as in many European and rapid decrease in the patient’s body temperature and North American countries. Serious conditions such as cere- parasitemia with complete elimination of plasmodial para- bral malaria or black water fever associated with falciparum sites within three days. malaria frequently follow the course to patient’s death. In conclusion, we described a case of the falciparum ma- Emergence of drug-resistant falciparum malaria and its laria successfully treated with atovaquone/proguanil combi- spreading worldwide further put difficulties in the treatment nation (Malarone). The patient also had hemolytic anemia of some malaria cases. Therefore, to avoid the severe com- and DIC as complications of malaria, but these conditions plications in patients with falciparum malaria, it is critically were improved by conservative treatment. important to make diagnosis promptly and institute effective therapy as soon as possible. Complications of severe References falciparum malaria, as listed by the WHO, include cerebral malaria, acute renal failure, lung edema, hypoglycemia, se- 1) Ohtomo H, Takeuchi T. Studies on current trend of imported malaria in vere anemia, DIC or shock state. A patient is diagnosed as Japan. Jpn J Trop Med Hyg 26: 151–156, 1998. having severe falciparum malaria if they have even one of 2) White NJ. The treatment of malaria. N Engl J Med 335: 800–806, 1996. these conditions and they need to be treated in a completely 3) White NJ. Antimalarial drug resistance and combination therapy. equipped medical institution’s intensive care unit. Because Philos Trans R Soc Lond B Biol Sci 354: 739–749, 1999. DIC was recognized in our case, the patient met WHO crite- 4) World Health Organization. Severe Falciparum Malaria. Trans Royal ria for having severe falciparum malaria, although there was Soc. Trop Med Hyg 94 (Suppl 1): 1–74, 2000. no bleeding tendency and his morbidity from DIC was not 5) World Health Organization. Management of severe and complicated malaria. WHO: 1–56, 1991. severe. The pathogenesis of DIC in malarial infection is not 6) Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil clear, and true DIC is rare according to the WHO guidelines. versus mefloquine for malaria prophylaxis in nonimmune travelers: Because heparin is generally contraindicated in malarial Results from a randomized, double-blind study. Clin Infect Dis 33: DIC, the efficacy of nafamostat mesilate without the use of 1015–1021, 2001. fresh frozen plasma and platelet transfusions in the treatment 7) Bouchaud O, Monlun E, Muanza K, et al. Atovaquone plus proguanil versus halofantrine for the treatment of imported acute uncomplicated of DIC is an interesting issue. plasmodium falciparum malaria in non-immune adults: a randomized There are several drugs now available for the treatment of comparative trial. Am J Trop Med Hyg 63: 274–279, 2000. falciparum malaria. Chloroquine resistance has been identi- 8) Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malar- fied worldwide and sulfadoxine/pyrimethamine resistance has oneTM (atovaquone and proguanil hydrochloride): a review of its clinical also been reported in some areas. Mefloquine is now fre- development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg 60: 533–541, 1999. quently used for uncomplicated falciparum malaria, but resis- 9) Emberger M, Lechner AM, Zelger B. Stevens-Johnson syndrome asso- tance and neuropsychiatric adverse effects are occasionally ciated with Malarone antimalarial prophylaxis. Clin Infect Dis 37: e5– reported. Quinine shows good results particularly when in 7, 2003.

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