Malaria Patients Out of ICU in 4 Days With IV Artesunate

Janis C. Kelly

August 25, 2015

Intravenous (IV) artesunate is safe and effective in patients with severe malaria, according to a retrospective case series analysis published online August 25 in the Annals of Internal Medicine.

Approximately 1500 cases of malaria occur in the United States each year in individuals who have recently traveled to or lived in malaria-endemic areas. Treating these patients became more challenging when hospital pharmacies stopped routinely stocking quinidine, the only treatment approved by the US Food and Drug Administration for severe malaria.

Artesunate replaced quinidine in World Health Organization recommendations and in the developing world, but the commonly used product was not made according to current good manufacturing practice (CGMP) guidelines and is not approved by the US Food and Drug Administration. Researchers at the Walter Reed Army Institute of Research, Silver Spring, Maryland, developed a new CGMP IV artesunate formulation that was successful in phase 1 and phase 2 studies and is available from the Centers for Disease Control and Prevention (CDC) for compassionate use under an investigational new drug protocol.

Patrick S. Twomey, MD, from US Army Medical Materiel Development Activity, Fort Detrick, Maryland, and colleagues analyzed data from the first 102 patients with severe or complicated malaria who received the drug under the investigational new drug protocol.

Symptoms improved or resolved within 3 days, and the median time to negative parasitemia was 42.7 hours. "Median time to starting a follow-on oral therapy was 4 days, and this was independent of baseline renal, hepatic, or neurologic status," the authors write.

"Median time to discharge from the ICU was also 4 days, even for patients who had severe liver disease or cerebral malaria at baseline. This finding, in particular, highlights the clinical benefit of artesunate among patients with dire clinical presentations."

Mortality was 7 deaths (6.9%), all of which were attributed to the severity of malaria.

Eligibility criteria for treatment under the IND included

  • microscopic confirmation of malaria or a strong clinical suspicion of severe malaria if microscopic diagnosis was unavailable;

  • inability to tolerate oral medications, parasitemia of 5% or higher, or severe malaria (impaired consciousness, seizures, circulatory collapse or shock, pulmonary edema or acute respiratory distress syndrome, acidosis, acute renal failure, abnormal bleeding or disseminated intravascular coagulation, jaundice, or hemoglobin levels lower than 70 g/L); and

  • problems with quinidine availability, inefficacy, intolerance, or contraindications.

"The main reason patients received artesunate was that it was available faster than quinidine," the authors explain.

After a request from a treating physician, the CDC shipped artesunate to the treating hospital, where the powdered drug was reconstituted with a prepackaged phosphate buffer and administered in four weight-based doses (2.4 mg/kg) immediately and at 12, 24, and 48 hours after the first dose. Follow-on oral antimalarial therapy was at the choice of the treating physician and was meant to begin a minimum of 4 hours after the last artesunate dose. The researchers retrospectively analyzed data for a maximum of 7 days from the beginning of artesunate treatment.

At baseline, 35% of patients had cerebral malaria (which has a mortality rate of 15% - 30% with treatment and 100% without treatment), and 17% had severe liver damage. Sixty-three percent were black or African American, 25% were white, and mean age was 38.1 years (range, 1 - 72 years). Three patients were pregnant, all of whom were in their third trimester. Of these, one gave birth before her artesunate treatment began, and the other two were treated and delivered healthy infants vaginally within 1 month.

Median time to negative parasitemia in the 87 patients evaluable for clinical benefit was 42.7 hours; this was not affected by baseline renal impairment, hepatic impairment, or cerebral malaria. Similarly, the safety analysis of 102 patients showed that 73 (72%) were discharged from the ICU within 7 days after beginning treatment (median, 4 days), and this was not affected by the presence of severe liver disease or cerebral malaria. Patients with prior quinidine exposure had remained in the ICU for slightly longer (6 vs 4 days; P = .004), as did those with renal failure (median, 7 vs 4 days; P = .018).

The most common adverse effects were anemia and increased hepatic enzyme levels, which the authors described as "consistent with symptoms expected in patients with severe malaria."

"The aim of the CDC-060 IND protocol was to make CGMP artesunate available to U.S. patients with severe and complicated malaria for whom quinidine was problematic or unavailable," the authors conclude. "Data abstracted from CDC-060, as presented here, indicate that artesunate was safe and clinically beneficial for most U.S. patients who were treated with the drug during the targeted period, which supports the use of artesunate as a quinidine alternative."

Physicians caring for patients who may be candidates for artesunate should contact the CDC malaria hotline (telephone: 770-488-7788, or 770-488-7100 after hours).

The study was supported by the Office of the Surgeon General, Department of the US Army. One coauthor is a full-time US Army product manager responsible for the development of IV artesunate. Another coauthor reports an army contract with the US Army Medical Research and Materiel Command. The other authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online August 25, 2015. Abstract

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