Treatment with Quinidine Gluconate of Persons with Severe Plasmodium falciparum Infection: Discontinuation of Parenteral Quinine

Information regarding treatment of Plasmodium falciparum malaria is available from the Malaria Branch, Division of Parasitic Diseases, Center for Infectious Diseases, CDC; telephone (404) 488-4046.

INTRODUCTION

CDC has recently reviewed data on the reported incidence in the United States of Plasmodium falciparum malaria and has evaluated available information on the effective management of severe life-threatening infections. As a result of this review, CDC has concluded that the therapeutic drug of choice in the United States for persons with complicated P. falciparum infection is parenteral quinidine gluconate, and that stocking of parenteral quinine dihydrochloride for emergency distribution is no longer required to provide optimal management of P. falciparum infections.

P. FALCIPARUM INFECTION IN THE UNITED STATES

Background Statement

P. falciparum malaria continues to be an important cause of morbidity but an uncommon, and usually preventable, cause of mortality among U.S. residents who travel abroad, visitors, and immigrants to the United States. From 1966 to 1987, CDC was notified of 1,760 persons who acquired P. falciparum infection abroad but who were diagnosed and treated in the United States; 66 of these persons died, for a case-fatality rate of 3.8% (1).

Complicated P. falciparum infection represents a medical emergency and requires aggressive and skilled medical care. An essential component of the management of severe P. falciparum infection is the prompt administration of a rapidly acting drug that kills the asexual erythrocytic stages of the parasite (a schizonticidal drug).

Therapeutic Agents

Parenteral quinine dihydrochloride has long been regarded as the most effective drug for P. falciparum infection. Because parenteral quinine is not commercially available in the United States, the CDC Drug Service has procured and provided this drug as a service to licensed U.S. physicians. Although quinine dihydrochloride has been stocked in strategic locations around the country, transportation of emergency supplies of quinine from these locations to the patient's bedside has frequently required 24-36 hours.

Quinidine, the dextrorotatory diastereoisomer of quinine, is widely available in the United States as parenteral quinidine gluconate. It is primarily used as a treatment of persons with cardiac arrhythmias; however it has also long been recognized as a potent antimalarial (2-4). On an equimolar basis, quinidine is a more active antimalarial than quinine for P. falciparum (5,6). Therefore, the dosage of quinidine required for the effective treatment of persons with P. falciparum malaria is lower than the dosage of quinine needed (7).

RECOMMENDATIONS

Management Of Patients

Data on the clinical efficacy and toxicity of parenteral quinidine gluconate in the United States over a 2-year period (8), as well as the experience of an expert panel convened by the World Health Organization (9), have recently been published. In general, an individual with malaria should be treated parenterally if a) vomiting is prominent and oral fluids and medication are not retained, b) there are signs or symptoms of neurologic dysfunction, or c) the peripheral asexual parasitemia is at a level of greater than 5% of erythrocytes infected. Quinidine administered by slow intravenous infusion is generally well-tolerated, even by critically ill patients, individuals with underlying cardiac disease, and children (6,10,11). Nevertheless, patients requiring parenteral quinidine ideally should be treated in intensive-care facilities where central hemodynamic and electrocardiographic monitoring is available. Close attention to the patient's hydration and blood glucose are required. Electrocardiographic changes, such as prolongation of the QT-interval and widening of the QRS complex, may be an accurate indicator of both plasma concentration and incipient cardiotoxicity (12-14). Most critical-care facilities in the United States are capable of monitoring quinidine blood concentrations.

Treatment Regimen With Quinidine Gluconate

Results of a study of patients infected with P. falciparum and treated in the United States (8), show that continuous-infusion quinidine gluconate produces effective drug concentrations. A loading dose of 10 mg of quinidine gluconate (equivalent to 6.2 mg of quinidine base)/kg of body weight is given over 1-2 hours, followed by a constant infusion of 0.02 mg of quinidine gluconate/kg/minute. Plasma quinidine levels greater than 6 mgm/mL, QT interval greater than 0.6 sec, or QRS widening beyond 25% of baseline are indications for slowing infusion rates (12,13). Persons with hypoglycemia, which may be a manifestation of P. falciparum malaria and which is exacerbated by quinine/quinidine-induced hyperinsulinemia, should be treated with intravenous dextrose (9). Parenteral therapy should continue until parasitemia is less than 1% (generally, within 48 hours) and/or until oral medication can be tolerated. When patients with cerebral malaria are treated, clinical improvement is usually observed within 72 hours. If improvement does not occur, drug resistance or inadequate drug delivery, complications of malaria, or other etiologies for the illness should be investigated. Treatment is continued (usually with oral quinine) for a total of 3-7 days, depending on the geographic origin of the infecting parasite. Therapy with an additional antimalarial is advised, e.g. tetracycline 250 mg every 6 hours for 7 days (12,13,15).

Discontinuation of Parenteral Quinine from CDC

The U.S. Food and Drug Administration and the drug manufacturer have recently amended the indications for the use of quinidine gluconate to include therapy for persons with complicated P. falciparum infection. Recent publications describing the clinical use of parenteral quinidine have apparently already influenced the therapy for persons with severe malaria in the United States; since 1985, there have been only two requests for parenteral quinine dihydrochloride, despite the fact that the incidence of P. falciparum infections has increased by 53% (16). The demonstrated efficacy and safety of parenteral quinidine gluconate and the general unavailability of parenteral quinine that has caused delays in administering an antimalarial drug to critically ill individuals underscore the need to initiate the routine use of parenteral quinidine gluconate in the United States. Therefore, parenteral quinine dihydrochloride will no longer be available from the CDC Drug Service.

References

1. Greenberg AE, Lobel HO. Mortality from Plasmodium falciparum malaria in travelers from the United States, 1959 to 1987. Ann Intern Med 1990; 113:326-7.

2. Sanders JP, Dawson WT. Efficacy of quinidine in malaria. JAMA 1932;99: 1773-7.

3. Taggart JV, Earle DP, Berliner RW, et al. Studies on the chemotherapy of the human malarias. III. The physiological disposition and antimalarial activity of the cinchona alkaloids. J Clin Invest 1948;27: 80-6.

4. Phillips RE, Warrell DA, White NJ, Looareesuwan S, Karbwang J. Intravenous quinidine for the treatment of severe falciparum malaria. N Engl J Med 1985;312:1273-8.

5. White NJ, Looareesuwan S, Warrell DA, Chongsuphajaisiddhi T, Bunnag D, Harinasuta T. Quinidine in falciparum malaria. Lancet 1981;2:1069-71.

6. Rudnitsky G, Miller KD, Pudua T, Stull TL. Continuous-infusion quinidine gluconate for treating children with severe Plasmodium falciparum malaria. J Infect Dis 1987;155:1040-3.

7. White NJ. The pharmacokinetics of quinine and quinidine in malaria. Acta Leiden 1987;55:65-76.

8. Miller KD, Greenberg AE, Campbell CC. Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion. N Engl J Med 1989;321:65-70.

9. Warrell DA, Molyneux ME, Beales PF, eds. Severe and complicated malaria, 2nd ed. Trans R Soc Trop Med Hyg 1990;84(Suppl)2:28-9,31.

10. Swerdlow CD, Yu JO, Jacobson E, et al. Safety and efficacy of intravenous quinidine. Am J Med 1983;75:36-42.

11. White NJ. Drug treatment and prevention of malaria. Eur J Clin Pharmacol 1988;34:1-14.

12. White, NJ, Plorde JJ. Malaria. In: Wilson JD, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 12th ed. New York: McGraw-Hill, Inc. 1990:782-8.

13. Krogstad DJ. Malaria. In: Wyngarden JB, Smith LH Jr, Bennett JC, Plum F, eds. Cecil's Textbook of Medicine. 19th ed. Philadelphia: WB Saunders, 1991 (in press).

14. White NJ, Looareesuwan S, Warrell DA. Quinine and quinidine: a comparison of EKG effects during the treatment of malaria. J Cardiovasc Pharmacol 1983;5:173-5.

15. Drugs for Parasitic Infections. Med Lett Drugs Ther 1990;32:23-32.

16. CDC. Malaria surveillance. Atlanta: CDC, 1984-1989.

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