Pentavalent antimony is still the drug of choice in the treatment of visceral leishmaniasis. Pantavalent antimony can cause a wide range of adverse effects, the most serious of which are cardiotoxicity and hepatotoxicity. Acute pancreatitis is a rarely reported adverse effect. An infant who developed pancreatitis during meglumine antimoniate treatment for visceral leishmaniasis and who was successfully treated with a combination of allopurinol and ketoconazole is reported. Pentavalent antimonials have been the drugs of choice for treatment of visceral leishmaniasis (VL) since the 1940s. 1, 2 They should be administered for at least 28 days because of the risk of relapse and resistance even though drugs have toxic effects on many organ systems. Alternative treatment regimens that are less toxic, such as allopurinol and ketoconazole, have been tried in recent years. Acute pancreatitis is a well-known toxic adverse effect of therapy with antimonial compounds for adult patients with VL, especially in the presence of immunosuppression caused by HIV infection or renal transplantation. 3–9 Screening the pediatric literature in English, we have noticed that this complication in childhood has not been previously reported. We report an infant who developed pancreatitis during meglumine antimoniate treatment for VL and was subsequently cured with allopurinol and ketoconazole therapy. Case report. A 2-year-old male infant was admitted to the outpatient clinics with a history of intermittent high grade fever and sweating for 1 month and abdominal distension for 1 week. The infant’s temperature was 39.5°C, pulse 140/min and blood pressure 100/60 mm Hg. The liver and the spleen were palpated 6 and 10 cm, respectively, below the costal margin. The rest of the physical examination was unremarkable. The laboratory examinations revealed a total white blood cell count of 2700/mm 3 with normal differential, hemoglobin 7.7 g/dl, platelets 56 000/mm 3, erythrocyte sedimentation rate 40 mm/h and C-reactive protein 140 mg/l. Direct Coombs test was negative, and the reticulocyte count was 1.5%. The coagulation studies disclosed the following values: prothrombin time 15.9 s (range, 10 to 14 s); activated partial thromboplastin time 43.5 s (range, 26 to 40 s); fibrinogen 80 mg/dl (range, 200 to 400 mg/dl); and D-dimer 2506 mg/l (range, 125 to 375 mg/l). Serum albumin and globulin were 2.8 and 5.9 g/l, respectively. Serum amylase and lipase values were 82 units/l (range, 0 to 220 units/l) and 12 units/l (range, 3 to 32 units/l), respectively. Renal function tests and hepatic enzymes were normal. Abdominal ultrasonography showed only hepatosplenomegaly with a spleen span of 155 mm. The patient was hospitalized with a probable diagnosis of visceral leishmaniasis which was confirmed by demonstration of the amastigotes of Leishmania in stained smears of the bone marrow. The specimen from the bone marrow was not cultured so the species could not be identified. Therapy with meglumine antimoniate (Glucantime, Rhône Poulenc, France) 5 mg/kg/day was started, and the dosage was doubled every other day to reach 20 mg/kg/day. The patient was also given infusions of fresh frozen plasma because the coagulation studies on admission had revealed the picture of subacute disseminated intravascular coagulation. Electrocardiogram, complete blood count, serum electrolytes, hepatic enzymes, amylase and lipase were monitored weekly. Two days after reaching the full dose of treatment (on the sixth day of admission), the patient’s temperature returned to normal, his general condition improved and his liver and spleen began to shrink, but the serum amylase increased to 254 units/l. Because the patient was asymptomatic, the treatment was not interrupted. However, on Day 10 of full dose treatment, he complained of abdominal pain and vomiting and the abdomen was tender with a rebound phenomenon. A presumptive diagnosis of acute pancreatitis was confirmed by serum amylase and lipase values up to 1557 and 320 units/l, respectively, and by ultrasound findings of dilatation and edema of pancreatic ducts. Meglumine antimoniate treatment was stopped, and the pancreatitis was managed conservatively. Two days after discontinuation of therapy, the patient’s fever increased and the spleen and liver also began to enlarge. Therapy with allopurinol (20 mg/kg/day) plus ketoconazole (5 mg/kg/day) was initiated in consideration of relapse of leishmaniasis. While receiving this treatment regimen, the patient became afebrile, the spleen and liver sizes began to decrease, pancytopenia improved and albumin:globulin ratio and serum amylase and lipase returned to normal. The picture of acute pancreatitis recovered uneventfully. The treatment regimen with allopurinol plus ketoconazole was continued for 21 days. After discharge the patient was followed monthly. Three months later there were no signs of relapse, he had neither fever nor hepatosplenomegaly and his complete blood count and routine blood chemistry values were normal. Discussion. We believe that this is the first published case of acute pancreatitis developing during the treatment with meglumine antimoniate for VL of infancy. Pancreatitis as an adverse effect of antimonial therapy was first reported by Donovan et al. 3 in 1990, and other case reports were subsequently published. 4–7 In these reports it was emphasized that acute pancreatitis was a rare complication of antimonial therapy. However, in 1994 Gasser et al. 8 reported a series of 49 patients with leishmaniasis, 48 of whom (98%) had chemical pancreatitis (hyperamylasemia and/or hyperlipasemia). Only ∼50% of these patients were symptomatic. Laguna et al. 9 also reported hyperamylasemia in 6 of 7 patients receiving meglumine antimoniate therapy, and only one patient was symptomatic. In conclusion the authors stated that acute pancreatitis resulting from antimonial therapy was more frequent than considered previously. 8, 9 All of the cases with acute pancreatitis reported in these studies were adults, and most of them also either had an HIV infection or were renal transplant recipients. In renal transplant recipients 10 and HIV-infected patients 11 with VL, the frequency of acute pancreatitis as a complication of antimonial therapy was 20 to 30%. Acute pancreatitis developed between the 2nd and 19th days of the treatment. Gasser et al. 8 suggested that antimonial therapy should not been stopped unless the serum amylase rises >4-fold or if the rise is associated with abdominal pain and vomiting. In our case the therapy was stopped on the 10th day of full dose treatment because of abdominal pain and vomiting, at which time the serum amylase and lipase values were 8- to 10-fold elevated. Amphotericin B is a much more potent drug than pentavalent antimony in vitro and has been used successfully to treat patients who failed pentavalent antimony therapy. 2, 12 Before 1990 its use was limited because of adverse effects. Currently new clinical formulations that include liposomal amphotericin B, amphotericin B cholesterol dispersion and amphotericin B lipid complex are more widely used in the treatment of VL than they were in the past. This is the result of an increase in resistance to pentavalent antimony and pentamidine. 12 Liposomal amphotericin B is the only drug approved by the US Food and Drug Administration for the treatment of VL. It is less toxic than pentavalent antimony, but its cost and availability will probably limit its use in developing areas. 13 Pentamidine should be considered a second line agent for VL because of an increasing clinical resistance. 2 Other drugs such as interferon gamma, granulocyte-macrophage colony-stimulating factor and paramomycin as monotherapy or in combination with pentavalent antimony are currently being studied, but the clinical experience is still not adequate to justify their general use. 2 There is a need for other alternative medications that are less toxic and less expensive as well as available. Allopurinol and ketoconazole are favorable oral agents for these reasons. Allopurinol was formerly used alone or in combination with antimonial compounds for treatment of VL. 14–16 The antileishmanial effect of this drug, which is a xanthine oxidase inhibitor, is believed to be by inducing either an accumulation of oxypurines or a deficit of other metabolites. Ketoconazole, which inhibits sterol synthesis in Leishmania spp., disrupting membranes and killing parasites, has been successfully used as a monotherapy in the treatment of VL by Wali et al. 17, 18 However, Sundar et al. 19 reported that ketoconazole was ineffective for treatment of VL. In 1993 Halim et al. 4 used the combination of allopurinol and ketoconazole for a renal transplant recipient adult with VL after the occurrence of pancreatitis from stibogluconate. Torrus et al. 20 reported that the combination of fluconazole and allopurinol was successful for treatment of VL. Finally Huesa et al. 21 used the combination of ketoconazole and allopurinol for antileishmanial therapy in a renal transplant patient. The combination of allopurinol and ketoconazole has several benefits such as different mechanisms of action, low risks of adverse effects, availability by the oral route and low cost, which is especially important for underdeveloped countries.
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