Malaria medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete cure.

Medical Therapy

The treatment approach in patients with suspected or confirmed malaria varies according to several factors namely travel history, species of Plasmodium, severity of presentation, and availability of certain therapeutic agents.

Initial Assessment & Severe Malaria

The first step in the management of patients with malaria is to conduct a clinical assessment of status and disease severity, as well as determination of the degree of parasitemia. Signs of severe malarial disease include any of the following: prostration, impaired consciousness/coma, respiratory distress, convulsions, shock, pulmonary edema, acute respiratory distress syndrome, abnormal bleeding, jaundice, severe anemia, acute kidney injury, disseminated intravascular coagulopathy, acidosis, hemoglobinuria, and parasitemia >5%. Patients with severe disease require rapid resuscitation and medical therapy. The most vital step in the management is immediate initiation of appropriate parenteral treatment. Unlike patients who appear stable clinically, patients with severe malaria do not require speciation prior to initiation of medical therapy. The therapeutic regimen in such patients consists of intravenous quinidine gluconate plus either tetracycline, doxycycline, or clindamycin. Other supportive measures include admission to the intensive care unit, continuous monitoring of cardiac function, glycemia, parasitemia, hemoglobin and electrolytes. Exchange transfusions may also be considered in patients with a degree of parasitemia >10%.

Uncomplicated Malaria

In patients with clinically and bacteriologically uncomplicated malaria, speciation is required to tailor medical therapy. For most non-falciparum species, chloroquine remains the first line therapeutic agent. It is important to add primaquine to the treatment regimen in patients with documented P. vivax and P. ovale infections to eradicate liver hypnozoites (dormant liver spores that are responsible for recurrence). Patients infected with P. malaria do not require primaquine as the species is not capable of forming hypnozoites. Patients diagnosed with P. falciparum malaria require hospitalization given the risk of progression to severe malaria. These patients have to be monitored on daily basis with a blood film and a full physical exam. The choice of drug in these patients depends on two main factors: the area of acquisition of the parasite, and the center at which the patient is being treated.

Despite being the mainstay of therapy since its introduction, empiric treatment with chloroquine in patients with P. falciparum is no longer recommended due to a sharp increase in resistance. A detailed travel history is important to determine where the infection was acquired. Most malaria endemic countries have reported chloroquine resistant strains, with the exception of Central America west of Panama Canal, Mexico, Hispaniola, certain parts of China, and the Middle East (see figure below). If acquired in any of the latter sites then treatment with chloroquine is adequate. Acquisition from all other endemic countries requires other therapeutic regimens such as oral quinine with either tetracycline, doxycycline, or clindamycin as a first line therapy in the United States, otherwise atovaquone-proguanil or mefloquine if the primary regimen is unavailable.

Worldwide, the treatment of both complicated and uncomplicated P. falciparum malaria requires a combination therapy that includes artemisinin derivatives. According to the 2010 WHO guidelines on the treatment of malaria, the following regimens are first line for the treatment of uncomplicated P. falciparum: artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, and artesunate plus sulfadoxine-pyrimethamin. For patients with severe P. falciparum malaria, artesunate IV or IM is first line followed by IV quinidine. The artemisinin derivatives clear parasites very rapidly have been shown to reduce mortality in severe malaria compared with parenteral quinine. Artemisins are not widely available in the United States and their use is not common practice. Only oral artemether plus lumefantrine is available, while IV atresunate can be obtained through the CDC part of an investigational drug protocol.

Recommended Indications and Doses of Common Anti-malarial Agents

Anti-malarial Agent	Indication	Dosing
Chloroquine phosphate	P. falciparum from chloroquine-sensitive areas P. vivax from chloroquine-sensitive areas All P ovale All P. malariae	1g oral load, followed by 500 mg orally at 6, 24, and 48 h
Hydroxychloroquine	Same as chloroquine (second line agent)	800 mg oral load, followed by 400 mg orally at 6, 24, and 48 h
Atovaquone-Proguanil	P. falciparum from chloroquine-resistant areas	250 mg atovaquone/100 mg proguanil (1 tab) orally 4 times daily for 3 days
Primaquine phosphate	Cure of P. vivax and P. ovale (to eliminate hypnozoites)	30 mg orally once daily for 14 days
Clindamycin*	P. falciparum or P. vivax from chloroquine-resistant areas	20 mg/kg/day orally for 3 days or 10 mg/kg IV load, followed by 5 mg/kg IV every 8 hours
Doxycycline*	P. falciparum or P. vivax from chloroquine-resistant areas	100 mg orally twice daily for 7 days or 100 mg IV every 12 hours for 7 days (can switch from IV to PO)
Tertacycline*	P. falciparum or P. vivax from chloroquine-resistant areas	250 mg orally 4 times daily for 7 days or 250 mg IV 4 times daily for 7 days (can switch from IV to PO)
Mefloquine	P. falciparum or P. vivax from chloroquine-resistant areas except Thailand-Burmese and Thailand-Cambodian border regions	750 mg oral load, followed by 500 mg orally 6-12 hours after initial dose
Quinine sulfate	P. falciparum or P. vivax from chloroquine-resistant areas	650 mg orally 3 times daily for 3 days or 7 days if acquired from Southeast Asia
Quinidine gluconate	Severe malaria (all species Unable to tolerate oral agents Parasitemia>10%	10 mg/kg IV load over 1-2 hours, then 0.02 mg/kg/min continuous infusion for at least 24 hours
Artemether-lumefantrine	All P. falciparum (outside US)	1.5 mg/kg - 9 mg/kg orally twice daily for 3 days
Dihydroartemisinin–piperaquine	All P. falciparum (outside US)	2·5 mg/kg – 20 mg/kg orally once daily for 3 days
Artesunate	All P. falciparum (outside US) First line IV agent for severe malaria(outside US)	In severe malaria: 2.4 mg/kg IV or IM load, followed by 2.4 mg/kg at 12 h and 24 h; continue injection once daily if necessary In uncomplicated malaria: Monotherapy not recommended, 4mg/kg orally once daily for 3 days combined with a single oral dose of sulfadoxine–pyrimethamine 25/1.25 mg/kg or mefloquine 8 mg/kg orally daily for 3 days

Antimalarial Drugs

Further information: [[:Antimalarial drugs]]

There are several families of drugs used to treat malaria. Chloroquine is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of Plasmodium falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world. In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine.

There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs may be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used. One drug currently being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the beta blocker propranolol. Propranolol has been shown to block both Plasmodium's ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role in combination therapies.

Currently available anti-malarial drugs include:

• Artemether-lumefantrine (Therapy only, commercial names Coartem® and Riamet®)
• Artesunate-amodiaquine (Therapy only)
• Artesunate-mefloquine (Therapy only)
• Artesunate-Sulfadoxine/pyrimethamine (Therapy only)
• Atovaquone-proguanil, trade name Malarone (Therapy and prophylaxis)
• Quinine (Therapy only)
• Chloroquine (Therapy and prophylaxis; usefulness now reduced due to resistance)
• Cotrifazid (Therapy and prophylaxis)
• Doxycycline (Therapy and prophylaxis)
• Mefloquine, trade name Lariam (Therapy and prophylaxis)
• Primaquine (Therapy in P. vivax and P. ovale only; not for prophylaxis)
• Proguanil (Prophylaxis only)
• Sulfadoxine-pyrimethamine (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)
• Hydroxychloroquine, trade name Plaquenil (Therapy and prophylaxis)

The development of drugs was facilitated when Plasmodium falciparum was successfully cultured. This allowed in vitro testing of new drug candidates.

Extracts of the plant Artemisia annua, containing the compound artemisinin or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand. One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted. Since 2001 the World Health Organization has recommended using artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent WHO treatment guidelines for malaria recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that SERCA, a calcium pump in the endoplasmic reticulum may be associated with artemisinin resistance. Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA. However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.

Counterfeit Drugs

Sophisticated counterfeits have been found in Thailand, Vietnam, Cambodia and China, and are an important cause of avoidable death in these countries. There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.