Crisis for Severe Malaria Treatment in United States

Janis C. Kelly

August 19, 2019

Tropical medicine experts are warning that the United States faces a malaria public health emergency since Eli Lilly has stopped producing quinidine gluconate, the only intravenous drug approved by the US Food and Drug Administration (FDA) for treatment of severe malaria. Meanwhile, the number of US residents coming from or visiting malaria-endemic regions is rising and the last stocks of quinidine expired on April 1, 2019.

Currently in the United States there are approximately 2000 cases of malaria each year, of which about 17% are severe cases with a mortality rate approaching 50%. Severe malaria typically includes neurologic symptoms, severe anemia (hemoglobin level < 70 g/L), hyperparasitemia (≥ 5%), acute renal injury, acute respiratory distress syndrome, or jaundice.

In a commentary published today in Annals of Internal Medicine, Rebecca A. Krey, MD, from the Division of General Pediatrics, Boston Children's Hospital, Massachusetts, and Mark A. Travassos, MD, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, warn that intravenous treatment of severe Plasmodium falciparum malaria should begin within 2 hours of symptom presentation. The treatment available on a compassionate basis from the Centers of Disease Control & Prevention (CDC) — injectable artesunate — has an average delivery time of 8 hours for transport from one of 10 CDC depots to the nearest airport, after which it still must be transported to the hospital.

Krey and Travassos write, "At present, the prospects for timely, effective treatment of severe malaria in the United States are grim. Careful preparation and action on the part of clinicians, hospitals, federal agencies, and professional societies are needed to prevent a catastrophe."

Peter Hotez, MD, dean of the National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, told Medscape Medical News, "This important paper sounds an alert about a major problem: Hospital formularies no longer have intravenous quinidine gluconate. If a patient comes in with severe Plasmodium falciparum malaria, that is a medical emergency because we often don't have more than a couple of hours before the number of malaria parasites in the blood increase to a potentially fatal level. Falciparum malaria is one of the leading killers of people in the world, especially children, and we don't have much of a window for getting appropriate treatment into the patient."

Hotez added that hospitals in Houston, which has one of the largest Nigerian expatriate communities in the world and many residents from Ghana and Tanzania, are seeing a steady stream of malaria cases. He added, "We have one of the artesunate depots described in this paper, but that is just not adequate. We need intravenous artesunate drugs on formulary and immediately available in hospital. That's priority number one."

The authors also suggest hospitals develop a malaria preparedness plan similar to plans developed for the 2014 Ebola outbreak. They also urge the US Department of Health & Human Services to coordinate a unified national preparedness plan for severe malaria.

The authors recommend questioning patients about recent travels outside the country. Those who are febrile and have recently traveled to malaria-endemic regions should immediately have a rapid diagnostic test for malaria, and a thick and thin blood smear should be sent for an immediate reading. If the rapid diagnostic is positive and a red flag for severe malaria is present (see below) the clinician should call the CDC Malaria Hotline at (770) 488-7788 — or at (770) 488-7100 after hours — to start the process of obtaining intravenous artesunate without waiting for the results of the blood smear.

Red flags indicating severe malaria are impaired consciousness; seizures; deep breathing and respiratory distress; acute pulmonary edema/acute respiratory distress syndrome; acute renal insufficiency; clinical jaundice; hypoglycemia; weakness such that the patient cannot sit, stand, or walk without assistance; shock (low systolic blood pressure or delayed capillary refill); abnormal bleeding or disseminated intravascular coagulation; acidosis; inability to tolerate oral medication; hemoglobin level < 70 g/L; hemoglobinuria; hyperlactatemia; or hyperparasitemia (≥ 5%).

The CDC recommends starting treatment with oral medication such as atovaquone-proguanil, artemether-lumefantrine, or mefloquine while awaiting the arrival of injectable artesunate, but the authors and Hotez note that this will not reduce parasitemia as rapidly as intravenous treatment and is not feasible in many cases.

Hotez said, "The problem with oral antimalarial for patients with severe malaria is that many times patients are very sick or unconscious and cannot take oral medications. I could put a nasogastric tube down and do it that way, but that's really suboptimal. An infectious disease-trained clinician would want to move more quickly. I understand CDC's reluctance to send out artesunate because it is our last antimalarial drug, and apart from the question of limited supplies, the worry is that unnecessary use could promote resistance. But the current situation is not tenable."

Krey and Travassos also urge hospitals to have transportation arrangements in place to pick up intravenous artesunate from the airport depot and to be prepared to immediately transfer patients with suspected malaria to another hospital if testing is not readily available, if the hospital laboratory is not able to read blood smears for malaria parasites, or if infectious disease expertise is unavailable.

Quinidine, a class 1a cardiac antiarrhythmic, fell out of commercial favor following the development of newer antiarrhythmic medications, and in 2017 Eli Lilly discontinued production. All three experts would like to see some pressure from professional groups and regulatory bodies on Eli Lilly to resume production of quinidine gluconate until production can be taken up by a generic pharmaceutical maker and/or a US manufacturer can be found for injectable artesunate. Artesunate is the standard of care for severe malaria in endemic regions but is not approved by the FDA. Krey and Travassos report that there are currently no pending applications for artesunate manufacture in the United States and that the CDC uses supplies from the US Army Medical Research and Materiel Command.

Hotez commented, "This is a wake-up call. We need to have a US strategy for production and seeking approval for artesunate, including ways to incentivize that, perhaps beyond priority review vouchers. In the meantime, there's an urgency to getting Eli Lilly or another pharmaceutical company to start making intravenous antimalarial drugs and getting them on hospital formularies."

The authors and Hotez have disclosed no relevant financial relationships.

Ann Intern Med. Published online August 19, 2019. Abstract

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