Rationale:

• Quinidine gluconate is the only recommended treatment for severe malaria in the U.S., but intravenous quinine formulations are not available in the U.S.
• Hospital pharmacies may not carry quinidine on formulary and may not know how to obtain it readily.
• Even if obtained, many physicians will be unfamiliar with quinidine, because this drug has been largely replaced with newer antiarrythmic agents.
• Quinidine has a narrow therapeutic window and must be used with extreme care, because potentially fatal adverse reactions can occur even at treatment doses.

Evidence:

• In order to avoid the need to stock quinine throughout hospitals in the U.S., the CDC recommended the use of quinidine instead for the treatment of severe malaria (120). Although quinine is much less cardiotoxic than quinidine, requiring no continuous ECG monitoring during its administration, quinine is not commercially available in the U.S., nor can it now be obtained from the CDC on an emergency basis.
• The CDC published information on the availability and use of parenteral quinidine gluconate for severe or complicated malaria, including arrangement for rapid shipment of the drug and a CDC malaria hotline (770-488-7788) (121).
• One study showed that quinidine was available for immediate use in only 64% of secondary and 55% of tertiary care hospitals in Ontario, Canada (122).
• In patients receiving drugs that prolong the QT interval, particularly when coadministered with drugs that suppress hepatic metabolism, the use of quinidine can be problematic. Patients with malaria and acute renal failure may not clear quinidine effectively, as suggested by a study in which the elimination half-life of quinine was prolonged in malaria (123).
• Several case reports illustrating the use of quinidine in the treatment of severe malaria have been published (124). These reports highlight common clinical scenarios, such as adjustment of infusion rates associated with elevated quinidine blood levels, prolonged QTc intervals, and arrhythmias, as well as hypoglycemia, hypotension, and vomiting.
• One study conducted in normal volunteers and patients with malaria showed that quinidine administration resulted in increased insulin levels and decreased serum glucose levels (93).
• A review of clinical trials showed that quinine plus clindamycin may be an excellent option for the treatment of nonsevere malaria (125).
• Bacteremia complicating severe malaria is not uncommon in infants and children (78; 126) and should be considered when any patient's clinical status deteriorates abruptly.

Comments:

• Points-of-care are directed to physicians practicing in the U.S. and may differ from therapeutic practices elsewhere, including the use of such drugs as quinine and artemisinin derivatives.
• In addition to quinine, artemisinin derivatives (e.g., artemether, artesunate) are used worldwide to treat severe malaria (127). Artemisinins result in rapid clearance of parasites and clinical improvement (usually within 24 to 36 hours) and are well-tolerated and safe in adults, children, and pregnant women. Several million people have taken artemisinins to date with no significant adverse or treatment-limiting effects being reported (128). Although neurotoxicity can occur with supraphysiological doses in animals, it has never been reported in humans (129). A review of 23 trials available in the Cochrane library found artemisinins were at least as effective as quinine for the treatment of severe malaria (130).
• The FDA is currently investigating the use of intrarectal artesunate in the initial treatment of acute malaria in patients who cannot take medications by mouth and for whom parenteral therapy is not available. This drug is not yet approved and remains unavailable in the U.S. Recent studies indicate that intrarectal suppositories of artemisinins are as effective and safe as quinine infusions in the treatment of uncomplicated, moderately severe, and cerebral malaria in children and adults (131; 132; 133).