THE TREATMENT AND PREVENTION OF MALARIA
ABSTRACT
Malaria is an overwhelming global health problem that can lead to complications and death if not appropriately treated. Many antimalarial drugs can cause severe, and sometimes, fatal adverse effects; thus, the benefit-to-risk ratio must be addressed before drug therapy is initiated. This article reviews the etiology, epidemiology, prophylaxis, and treatment of malaria.
Malaria in humans is a protozoan (parasite) red blood cell infection that may be caused by one of four species of the genus Plasmodium: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae. Nearly all severe infections and deaths from malaria are caused by P. falciparum. The severity of P. falciparum malaria is due to the organism’s ability to invade young and old red blood cells. The other species of Plasmodium do not have this ability.
INTRODUCTION
Although malaria was eradicated from the United States in the early 1950s, the incidence of imported malaria is increasing as more people travel worldwide. Malaria affects 300 million to 500 million people yearly, resulting in 1.5 million to 1.7 million deaths annually.1,2 In the U.S., most malaria cases occur in immigrants or military personnel returning from areas where malaria is endemic.3
Malaria tends to be found in tropical and subtropical countries where there are areas of stagnant water and higher temperatures, both of which foster the survival of the Anopheles mosquito. Malaria occurs in more than 100 countries in Africa, Central and South America, Southeast Asia, the Middle East, Hispaniola (divided between Haiti and the Dominican Republic), and the Indian subcontinent. From March to November, U.S. troops in the Middle East and Afghanistan are susceptible to malaria. Since 2001, about 80 military personnel per year have developed malaria.4 Malaria is not found in southern Europe, Taiwan, Singapore, or the Caribbean islands, except Hispaniola.
Etiology
Malaria is transmitted primarily by the bite of an infected female Anopheles mosquito; however, in the U.S., cases also occur through exposure of infected blood products (e.g., blood transfusion) or transplanted organs, as well as through congenital transmission.
Mainly at dusk and dawn, the female mosquito ingests blood from an infected human. The mosquito harbors parasites in its stomach and injects them into whomever it bites, after the parasites undergo a cycle of development. In humans, the parasite begins an asexual development phase that continues until antimalarial medication is initiated. In this stage, the parasite grows and divides in the liver, eventually reentering the bloodstream and infecting red blood cells. The infected red blood cells then rupture, and the parasites invade other red blood cells.5 P. falciparum divides approximately every 48 hours.5
Clinical and Laboratory Features of Malaria
Nonimmune persons (not previously exposed) show an atypical clinical picture that initially presents with flu-like symptoms, often leading to a delay in diagnosis.6 As the disease progresses, classic symptoms appear, including chills, headache, abdominal pain, malaise (due to anemia), dry cough, sweating, and fever, which can follow a regular pattern of spikes every 48 or 72 hours. 7,8
Physical signs include splenomegaly, orthostatic hypotension, jaundice, and hepatomegaly.9 Other clinical complications are renal failure, hypoglycemia, lactic acidosis, and pulmonary edema.
Laboratory findings include thrombocytopenia (60% of cases; most common laboratory abnormality), hyperbilirubinemia, and hemolytic anemia. The leukocyte count is usually normal or low; however, neutrophilia with a marked increase in band forms is present. The severity of infection depends on the number of laboratory abnormalities.
Generally, an attack of malaria does not confer immunity; however, patients who have experienced several attacks of malaria will have progressively less severe symptoms. Death from malaria is due primarily to anemia and general lowering of immune resistance. Individuals with the sickle trait (sickle cell anemia) are immune to malaria.
Treatment
Treatment for malaria should not be started until a laboratory diagnosis has been confirmed. 10,11 Malaria should be considered in the differential diagnosis of patients with unexplained fever who are returning home from a malaria-endemic area.5 A blood film can distinguish falciparum malaria from non -falciparum malaria. Once diagnosed, malaria should be treated as a medical emergency because P. falciparum infections may rapidly progress and become fatal. The other Plasmo dium species rarely cause severe manifestations. The choice of medication depends on:
• The species of infecting Plasmodium;
• The clinical condition of the patient–patients with uncomplicated malaria (e.g., not presenting with anemia, renal failure, pulmonary edema, shock, acidosis, jaundice, or convulsion) can be treated with oral antimalarial drugs, whereas patients with complications should be treated aggressively with parenteral antimalarial drugs12; and
• The geographic area where the infection was acquired–some areas harbor parasites that are resistant to certain drugs.13
The following drugs are used for the treatment of malaria in the U.S. (Table 1):
Quinine and Quinidine: Quinine has been used for more than three centuries. Intravenous quinine is the most widely used drug in the treatment of severe falciparum malaria resistant to other antimalarials.5 In the U.S., quinidine gluconate, the dextrorotatory optical diastereoisomer of quinine, is the only available intravenous antimalarial drug and may be used in place of quinine; however, it has many severe adverse effects, including cardiotoxicity (e.g., supraventricular and ventricular ectopic beats, ventricular tachycardia, sinus bradycardia), necessitating electrocardiographic monitoring (QRS complex and QTc interval).10 Thus, most physicians prefer to use quinine.
Quinine has a fast onset of action with a short elimination half-life and has been shown to have an additive effect when combined with antibiotics such as clindamycin, tetracycline, or doxycycline.14
Quinine and quinidine are alkaloids derived from cinchona bark and are capable of killing the parasite before it enters the red blood cells or while it is dormant in the host. Adverse effects of these drugs are mainly due to hypersensitivity to the cinchona alkaloids and are referred to as cinchonism. These effects encompass many signs/symptoms, including a bitter taste, tinnitus, sweating, hearing loss, nausea, vomiting, and abdominal pain.
Quinine and quinidine are administered with an initial loading dose via an infusion pump, followed by maintenance doses that are necessary because a single dose of quinine is disposed of in about 24 hours. Both drugs have a narrow therapeutic index; thus, dose monitoring is necessary. In patients with renal failure, the loading dose is the same, but the maintenance dose should be decreased by 30% to 50%.
Chloroquine: Chloroquine phosphate, a synthetic form of quinine, was introduced after World War II and is still the drug of choice for P. falciparum infections that are not chloroquine resistant. Since there are few reported chloroquine-resistant strains of P. malariae, P. vivax, and P. ovale, chloroquine is the drug of choice in these infections. Adverse effects include blurred vision, disturbances of accommodation, visual field defects, and night blindness, as well as abdominal upset and headache (all are reversible once discontinued). The base/salt conversions for chloroquine are confusing and a source of medication error. A chloroquine dose of 600 mg base is equivalent to 1,000 mg salt. Chloroquine accumulates in the acidic food vacuoles of the parasite, preventing hemoglobin degradation from occurring in that organelle. 15
Chloroquine-Resistant P. falciparum: Unfortunately, P. falciparum is highly resistant to chloroquine in most areas of the world, particularly in Africa.14 Chloroquine is slowly being replaced by sulfonamide-pyrimethamine in many parts of Africa; however, resistance also is developing rapidly to this drug.14 Resistance involves a reduced accumulation of the drug in the organelle and increased rate of efflux from the parasite.16 If resistance is present, treatment choices consist of either qui-
nine sulfate plus doxycycline, tetracycline, or clindamycin; or atovaquone-proguanil; or mefloquine. Mefloquine is used only when the other options are contraindicated, because it may cause severe neuropsychiatric reactions. The preferred quinine sulfate combination uses either doxycycline or tetracycline because studies show these drugs are associated with better clinical results than is clindamycin. Quinine treatment should be continued for seven days for infections acquired in Southeast Asia and for three days for infections from Africa or South America.
The treatment options listed above are the same for pediatric patients, except that the drug dose is determined by the weight of the child. Since tetracyclines, including doxycycline, are contraindicated in children younger than 8 years, it is recommended that quinine be given alone for seven days or with clindamycin and atovaquone-proguanil to treat chloroquine-resistant P. falciparum strains.
Hydroxychloroquine Sulfate: An antimalarial drug also used to treat inflammation in rheumatoid arthritis, systemic/discoid lupus erythematosus, and other connective disorders, hydroxychloroquine sulfate is chemically related to chloroquine but has different therapeutic and toxic doses. It is as active as chloroquine against P. falciparum but is associated with less ocular toxicity; however, the CDC has found it to be less effective than chloroquine. Adverse effects include retinal or visual field changes, fatigue, vertigo, nausea and vomiting, abdominal cramps, and hemolysis in patients with glucose-5-phosphate dehydrogenase deficiency.
Atovaquone-Proguanil: FDA-approved in 2000, atovaquone-proguanil (Malarone) is a combination drug that is used for the prevention and treatment of uncomplicated chloroquine-resistant P. falciparum malaria. It is given orally at the same time each day with food or milk to prevent nausea and vomiting. If the patient vomits within 30 minutes of taking a dose, the dose should be repeated.
Mefloquine: Mefloquine, a quinoline-methanol compound, is slowly eliminated from the body (half-life of two to three weeks), with much of the drug remaining after it is discontinued.17 Thus, adverse effects may occur for weeks to months after stopping the drug. Mefloquine is used for the oral treatment of uncomplicated multidrug-resistant P. falciparum malaria.
Primaquine Phosphate: Primaquine phosphate in conjunction with chloroquine is used to eradicate any parasitic forms that may remain dormant in the liver, thus preventing relapses in P. vivax and P. ovale infections. Since primaquine phosphate can cause hemolytic anemia in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency, patients must be screened for G6PD deficiency before starting treatment.18,19 Because of gastrointestinal intolerance, many physicians will wait until malaria develops before starting primaquine therapy. When other antimalarial drugs cannot be taken, prim aquine may be used prophylactically.
Artemisinin Derivatives: Artemisinin (qinghaosu), derived from the artemisia annua plant, is a Chinese herbal remedy and covers a group of products, including artesunate and arte m ether. While artem isinin derivatives are widely used in Southeast Asia for quinine-resistant P. falciparum infection, they are not approved in Western countries. They are effective for the treatment of quinine-resistant P. falciparum infection.
Malaria Prophylaxis
Since there is no vaccine for malaria, people must prevent or reduce the number of mosquito bites. Options include not going outdoors at dusk and dawn, when mosquitoes feed, unless the arms and legs are covered, and unless using an insect repellent that has an N,N-diethyl-meta-toluamide (DEET) content of about 30% (e.g., Muskol, RID), and using insectide-impregnated bed nets.8 Caution should be used when applying DEET in children because serious adverse effects can occur when it is used excessively. These repellents can be applied to a child’s clothing rather than the skin. Use of insecticides such as DDT and malathion has reduced the number of malaria cases in some countries.
A risk-benefit assessment is necessary for deciding whether a healthy person should take medication for an infection they have an unknown chance of acquiring.20 Individuals traveling to malarious areas should take prophylactic medication to prevent malaria. The CDC conducts malaria surveillance to guide prevention recommendations for travelers and identify episodes of local transmission. While medication choice varies, health care professionals typically consider the age of the patient, the species of malaria in an area, and drug susceptibility when prescribing prophylactically. Information on prophylactic medications is found at www.cdc.gov/travel/malariadrugs2.htm and in Table 2 . Adverse effects of these antimalarial drugs are rare at prophylactic doses. 21 Chloroquine is no longer the chemoprophylactic medication of choice due to the presence of drug-resistant P. falciparum strains in most of the world.8
Doxycycline is recommended for individuals unable to tolerate mefloquine and for those traveling to areas where there is mefloquine resistance. Doxycycline is initiated one to two days before travel and is continued for four weeks after return home. The adult dose is 100 mg once a day. Doxycycline is contraindicated in pregnant women and children younger than 8 years.
Mefloquine is used widely because it has a long half-life and once-weekly dosing. It should be initiated at one 250-mg tablet per week for two weeks prior to travel, and then dosed as one tablet per week during travel and one tablet for four weeks upon return home. 8
Atovaquone-proguanil (one tablet contains 250 mg atovaquone/100 mg proguanil) must be taken daily. It is started two days before travel and continued during travel and seven days after return home.22
Summary
All cases of malaria must be reported to the CDC. The control of epidemic malaria is a priority for the international health community, which has set specific targets for the early detection and effective control of epidemics.23
The incidence of malaria in American soldiers in the Middle East is increasing, along with the importation of malaria brought to the U.S. from travelers, immigrants, and soldiers returning home.
As many drugs have severe adverse effects, a definitive diagnosis of malaria must be made before treatment is initiated. Once diagnosed, P. falciparum malaria in a an individual who does not have immunity should be treated as an emergency. Additionally, use of chemoprophylaxis is a balance between the risks of adverse side effects and of acquiring the disease, all of which may lead to death. Resistance to antimalarials is developing rapidly in many parts of the world, so the search for the next first-line malaria drug is ongoing.
Counterfeit antimalarial drugs are a massive international problem and are particularly prominent in Southeast Asia and Africa.24 These drugs are manufactured to look like brand-name drugs, but they may not contain active ingredients or ingredients consistent with the package description. Expired drugs are often repackaged with new expiration dates. In 1999, counterfeit drugs caused at least 30 deaths in Cambodia.
Substandard drugs are found because of lack of or poor quality control practices and regulations in some countries. Some drug manufacturers simply want to avoid costly quality control.
Identifying counterfeit tablets has become increasingly difficult, due to sophisticated manufacturing and packaging strategies. To avoid counterfeit and substandard drugs, travelers should purchase drugs before traveling. If drugs must be purchased overseas, the consumer should inspect the packaging and make sure the drugs are in their original containers.
REFERENCES
1. Muentener P, Schlagenhauf P, Steffen R. Imported malaria (1985-95): trends and perspectives. Bull World Health Organ. 1999;77:560-566.
2. Sachs J, Malaney P. The economic and social burden of malaria. Nature. 2002;415:680-685.
3. Kain KC, Keystone JS. Malaria in travelers: epidemiology, disease, and prevention. Infect Dis Clin North Am . 1998;12:267-284.
4. Mraz S. Malaria’s a dangerous, unrelenting foe for troops deployed around the world. Stars Stripes. June 27, 2005. Available at: www.military.com.
5. Trampuz A, Jereb M, Muzlovic I, Prabhu RM. Clinical review: severe malaria. Crit Care. 2003;7:315-323.
6. Murphy GS, Oldfield EC 3rd. Falciparum malaria. Infect Dis Clin North Am. 1996;10:747-775.
7. Genton B, D’Acremont V. Clinical features of malaria in returning travelers and migrants. In: Schlagenhauf P, ed. Traveler’s Malaria. Hamilton, Ont.: BC Decker; 2001:371-392.
8. Lo Re V 3rd, Gluckman SJ. Prevention of malaria in travelers. Am Fam Physician. 2003;68:509-514.
9. Gockel HR, Heidemann J, Lorenz D, Gockel I. Spontaneous splenic rupture, in tertian malaria. Infection. 2006;34:43-45.
10. White NJ. The treatment of malaria. N Engl J Med. 1996;335:800-806.
11. Kain KC. Chemotherapy of drug-resistant malaria. Can J Infect Dis. 1996;7:25-33.
12. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg . 2000;94(suppl 1):S1-S90.
13. CDC. Part 2: Treatment: general approach and treatment: uncomplicated malaria. Atlanta, Ga.: National Center for Infectious Diseases, Division of Parasitic Diseases; 2004.
14. Lee B, Kremsner PG. Clindamycin as an antimalarial drug: review of clinical trials. Antimicrob Agents Chemother. 2002;46:2315-2320.
15. Slater AF. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmacol Ther. 1993;57:203-235.
16. Krogstad DJ, Gluzman IY, Kyle DE, et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science. 1987;238:1283-1285.
17. Simpson JA, Watkins ER, Price RN, et al. Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob Agents Chemother. 2000;44:3414-3424.
18. Spudick JM, Garcia LS, Graham DM, Haake DA. Diagnostic and therapeutic pitfalls associated with primaquine-tolerant Plasmodium vivax. J Clin Microbiol. 2005;43:978-981.
19. Carr ME Jr, Fandre MN, Oduwa FO. Glucose-6-phosphate dehydrogenase deficiency in two returning Operation Iraqi Freedom soldiers who developed hemolytic anemia while receiving primaquine prophylaxis for malaria. Mil Med. 2005;170:273-276.
20. Petersen E. Malaria chemoprophylaxis: when should we use it and what are the options? Expert Rev Anti Infect Ther. 2004;2:119-132.
21. Croft A. Malaria: prevention in travellers. BMJ. 2000;321:154-160.
22. Food and Drug Administration. FDA approves Malarone for the prevention and treatment of malaria. FDA Talk Paper. July 14, 2000.
23. Thomson MC, Doblas-Reyes FJ, Mason SJ, et al. Malaria early warnings based on seasonal climate forecasts from multi-model ensembles. Nature. 2006;439:576-579.
24. Dondorp AM, Newton PM, Mayxay M, et al. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int Health. 2004;9:1241.
