Continuing Education Activity

When treating patients suspected of having malaria, it is essential that treatment does not commence until the diagnosis of malaria has been established. The obvious exception is in waiting for confirmation to treat suspected malaria if the patient shows signs of severe malaria, and clinical suspicion for malaria is high. This activity reviews the indications, contraindications, adverse events, and other key elements of antimalarial therapy in the clinical setting related to the essential points needed by members of an interprofessional team managing the care of patients with a malarial infection require treatment.

Objectives:

• Identify the mechanism of action of various members of the antimalarial class.
• Outline the contraindications and toxicity of antimalarial drugs.
• Review the appropriate follow-up and monitoring of antimalarial agents.
• Explain the importance of antimalarial therapy and how it affects therapeutic strategy to improve care coordination and communication among the interprofessional team when using these agents to achieve therapeutic outcomes.

Indications

When treating patients suspected of having malaria, it is important that treatment does not start until there is a definitive diagnosis of malaria. To guide malaria treatment appropriately, it is important to identify three factors: (1) the infecting Plasmodium species, (2) the clinical status of the patient, and (3) the drug susceptibility of the infecting parasites (the geographic area from where the infection was acquired from and any previous antimalarial medications). The obvious exception is in waiting for confirmation to treat suspected malaria if the patient shows signs of severe malaria, and clinical suspicion for malaria is high.[1][2][3]

By identifying the infecting Plasmodium species, the healthcare practitioner can identify which infections will progress to severe manifestations and which will not. Also, some infections can remain dormant in the liver as hypnozoites and can lead to a relapse. The clinical status of a patient can fall into two main categories: uncomplicated malaria or severe malaria. The main difference in treatment is that uncomplicated malaria is treated with oral antimalarials, while severe malaria gets treated with parenteral antimalarials. Last, healthcare practitioners can select an appropriate treatment course by determining the drug susceptibility of the infecting Plasmodium species. Practitioners can do this by looking at where the patient was when they acquired the infection and if they have received any previous treatment with antimalarials.

Mechanism of Action

Chloroquine phosphate is the preferred agent if the infection is considered uncomplicated and is caused by chloroquine-sensitive P. falciparum and works by inhibiting parasite growth by concentrating within the parasite acid vesicles, thereby raising internal pH. Hydroxychloroquine is also an acceptable first-line treatment of chloroquine-sensitive P. falciparum and has a similar mechanism of action as chloroquine phosphate.[4][5]

Primaquine phosphate is utilized as an add-on agent to either chloroquine phosphate or hydroxychloroquine when infections are caused by P. vivax or P. ovale with chloroquine sensitivity. This medication works by eliminating the hypnozoites that remain dormant in the patient’s liver, which reduces the risk of patient relapse.[6]

Atovaquone-proguanil is utilized in infections caused by P. falciparum with chloroquine resistance. This combination product acts as an antimalarial as atovaquone selectively inhibits parasite mitochondrial electron transport, and proguanil inhibits dihydrofolate reductase disrupting deoxythymidylate synthesis.

Artemether-lumefantrine is an alternative first-line option for the treatment of malaria caused by chloroquine-resistant P. falciparum. The proposed mechanism of action for both agents is to inhibit nucleic acid and protein synthesis.[7]

Quinine sulfate plus doxycycline, tetracycline, or clindamycin is a second-line option for treating malaria caused by chloroquine-resistant P. falciparum. Quinine intercalates into DNA, disrupting the parasites' replication and transcription to exert its antimalarial effects.

For the treatment of uncomplicated chloroquine-resistant P. vivax, there are three options considered to have equal efficacy.

• Quinine sulfate plus doxycycline or tetracycline plus primaquine phosphate

• Atovaquone-proguanil plus primaquine phosphate

• Mefloquine plus primaquine phosphate

• Mefloquine’s antimalarial effects are similar to quinine sulfate’s effects listed above.

Quinidine gluconate is the drug of choice for suspected severe malaria because it is the only parenterally available antimalarial drug. Severe malaria is characterized by the presence of parasites in the blood and any of the following conditions: altered mental status, seizures, respiratory distress, circulatory collapse, renal failure, anemia, thrombocytopenia, liver failure, and acidosis. The most common causative agent of severe malaria is P. falciparum. Quinidine gluconate acts primarily as an intraerythrocytic schizonticide, with little effect upon sporozoites or upon pre-erythrocytic parasites. Quinidine is gametocidal to P. vivax and P. malariae, but not to P. falciparum. Clindamycin, doxycycline, or tetracycline should be added to quinidine therapy when treating severe malaria in either IV or oral form, depending on the patient's clinical condition.[8]

Administration

Chloroquine phosphate dosing for chloroquine-sensitive P. falciparum is 1000 mg by mouth immediately, followed by 500 mg by mouth at hours 6, 24, and 48 hours. An alternative in chloroquine-sensitive infections is to use Hydroxychloroquine 800 mg by mouth immediately, followed by 400 mg orally at hours 6, 24, 48 hours. Other malaria infections that would follow the same protocol would be P. malariae or P. knowlesi.

Primaquine phosphate 26.3 mg is added to the above therapy at a dose of two tablets by mouth once a day for 14 days for chloroquine-sensitive P. vivax or P. ovale infections. Primaquine should be given with meals to decrease GI adverse effects (abdominal cramps, nausea, vomiting). If the patient vomits within 30 minutes of taking a dose, then they should repeat the dose.

Atovaquone-proguanil 250 mg/100 mg dosing is administered as four tablets once a day for three days. The other first-line treatment for malaria caused by chloroquine-resistant P. falciparum is artemether-lumefantrine 20 mg/120 mg dosed as four tablets immediately and at 8 hours, followed by four tablets twice daily on days 2 and 3. It should be taken with a meal or a milky drink to increase absorption, as the rate of absorption of atovaquone is dependent on the amount administered with dietary fat.[9]

When treating chloroquine-resistant P. vivax or P. falciparum, sulfate is given as 650 mg by mouth three times a day for 3 or 7 days with the 7-day regimen used for infections acquired in Southeast Asia. The addition of doxycycline, tetracycline, and clindamycin is given as a 7-day course as well.

Mefloquine is administered as 750 mg by initial mouth dose followed by 500 mg by mouth, given 6 to 12 hours after the initial dose. Mefloquine requires administration with food and at least 8 ounces of water. An additional full dose is necessary if vomiting occurs within 30 minutes after the dose; if it occurs within 30 to 60 minutes after the dose, an additional half-dose should be given. This agent can be useful as a third-line option for the treatment of malaria caused by chloroquine-resistant P. falciparum or a first-line option for the treatment of uncomplicated chloroquine-resistant P. vivax.[10]

Quinine gluconate, used as the only IV option for severe malaria treatment, is given as a loading dose of 10mg/kg IV over one to two hours, followed by a continuous infusion of 0.02 mg/kg/minute for at least 24 hours. Patients may alternatively receive a 24 mg/kg loading dose infused over four hours, followed by 12 mg/kg over four hours dosed every eight hours. IV quinidine should continue until the parasite density is less than 1% and the patient can tolerate oral medications. After discontinuation of IV quinine, the patient should switch to oral quinine for the remainder of treatment. Renal adjustments are not necessary when calculating loading doses of IV quinidine gluconate. If a patient has a creatinine clearance less than or equal to 1 mL/minute, the maintenance dose should be reduced by 25%. The addition of doxycycline, tetracycline, or clindamycin to intravenous (IV) quinidine is also given as a 7-day course.[11]

Adverse Effects

Many patients will experience gastrointestinal upset (GI), headache, blurred vision, and insomnia when taking chloroquine. It rarely has been shown to cause QT interval prolongation. Its use requires caution in patients with a previous history of GI disorders, conduction abnormalities, or patients taking QT-prolonging drugs. Side effects of hydroxychloroquine are similar to chloroquine, although hydroxychloroquine is most commonly an alternative for patients who cannot tolerate the GI side effects of chloroquine.[12] Both of these drugs have been reported to cause psoriatic exacerbations.[13][14][15]

Primaquine is known to cause hemolytic anemia in patients with G6PD deficiency. A G6PD level should be taken before administering primaquine to determine if the patient can receive this medication. The common side effect of primaquine is mainly limited to GI disturbances, such as abdominal pain, nausea, and vomiting.[16]

Common side effects of atovaquone-proguanil are abdominal pain, nausea, vomiting, headache, and increased serum transaminases (AST/ALT). Vomiting is of particular note because absorption may decrease in patients with diarrhea or vomiting. Healthcare providers should consider using an antiemetic in patients with vomiting or diarrhea that may impact the absorption of their medication. Atovaquone-proguanil may also enhance the anticoagulant effect of warfarin. Patients taking both drugs should be monitored closely for increased bleeding episodes.

Artemether-lumefantrine's most common side effects include headache, fever, dizziness, fatigue, nausea and vomiting, and anorexia. Of note, for this medication, muscular effects are common and usually manifest as weakness and/or myalgia. The most serious side effect associated with this agent is QT prolongation, especially in concomitant use with other medications that can prolong the QT interval.

Doxycycline and tetracycline are usually well-tolerated, but some GI upset can be seen and, less commonly, ultraviolet photosensitivity. Patients should apply sunscreen liberally to avoid photosensitivity. Patients also may have a side effect of Candida vaginitis, so offering women antifungal self-treatment for management is recommended. Clindamycin most commonly causes GI disturbances, most notably diarrhea, and is the most common antibiotic associated with C. difficile infections post-treatment.

Mefloquine side effects include GI upset, lightheadedness, headache, difficulty concentrating, mood swings, and strange dreams. A US box warning is that mefloquine can cause neuropsychiatric effects even after discontinuation. Symptoms to monitor include anxiety, depression, nightmares, hallucinations, dizziness, and paranoia. Severe neuropsychiatric reactions involve seizures, suicidal ideation, and psychosis.

A baseline EKG is recommended before using quinidine gluconate or oral quinine due to its potential to cause QTc prolongation. Once quinidine is initiated, continuous telemetry monitoring is recommended. A patient’s infusion should be stopped or slowed if any of the following occurs: an increase in the QRS complex by more than 50%, increase in QTc interval by more than 0.6 seconds, QTc prolongation of more than 25% from baseline, or hypotension that is unresponsive to fluid challenge. Other serious side effects associated with quinine and quinidine include central nervous system disturbances such as dizziness, confusion, and headache, and severe skin conditions from bullous dermatitis to Steven-Johnson syndrome and toxic epidermal necrolysis.[12]

Contraindications

Chloroquine and hydroxychloroquine have few contraindications. Either a previous hypersensitivity to any 4-aminoquinoline compounds or the underlying presence of retinopathy is the only absolute exclusions to these medications. Patients also should be tested for a G6PD deficiency before starting chloroquine or hydroxychloroquine. Patients with a G6PD deficiency are at increased risk for hemolysis when given these drugs. Both chloroquine and hydroxychloroquine are safe to use throughout pregnancy.

Primaquine is contraindicated in pregnancy and breastfeeding and in patients with severe G6PD deficiency and acutely ill patients with a tendency to develop granulocytopenia (rheumatoid arthritis, SLE, etc.). Use also is strongly discouraged in conjunction with medications that can cause hemolytic anemia or myeloid bone marrow suppression.[17]

Atovaquone-proguanil is not intended for use in patients less than 5 kg or pregnant or breastfeeding women. It should not be used in patients with severe renal impairment (CrCl less than 30 mL/min) because proguanil gets excreted in the urine.

Artemether-lumefantrine is contraindicated only if a patient has a previous hypersensitivity reaction to either medication or in the concurrent use with strong CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin.  

Contraindications for doxycycline and tetracycline include pregnant women, children less than eight years of age, or previous hypersensitivity to any tetracycline antibiotics. Clindamycin’s only true contraindications are a prior history of hypersensitivity reactions to it or lincomycin and to avoid use when less toxic antibiotics are appropriate due to the increased risk of severe and possibly fatal colitis.

Contraindications for mefloquine use include known hypersensitivity to the drug, history of seizures or major psychiatric disorder, and a recent history of depression or anxiety. Mefloquine correlates with sinus bradycardia and QT interval prolongations. It should be used with caution in patients with cardiac conduction disorders or using antiarrhythmic agents. Mefloquine is safe for administration during all trimesters of pregnancy.

Contraindications for both quinine and quinidine include thrombocytopenia, thrombocytopenic purpura, myasthenia gravis, any heart block greater than first degree, QT prolongation, or in combination with medications that can also cause QT prolongation.[18]

Enhancing Healthcare Team Outcomes

Because of mass migration, malaria cases are now being diagnosed in the USA. Malaria can have a diverse presentation, and it is essential to be aware of this diagnosis when evaluating a patient with a fever or a traveler from the tropics. All interprofessional team members, including healthcare workers, including nurse practitioners, need to know the basic features of the antimalarial medications and parameters to monitor, as these drugs do have potent adverse effects. G6PD screening is recommended if the patient will start on chloroquine, hydroxychloroquine, and primaquine. If the patient has known mild to moderate G6PD deficiency or unknown status and is on any of these three medications, then it is recommended to obtain a baseline CBC as well as a CBC on day three and day 8 of therapy.  

A baseline ECG is recommended with primaquine, artemether-lumefantrine, mefloquine, quinine, and quinidine. Continuous telemetry monitoring for hypotension and cardiac conduction changes is recommended while patients are on IV quinidine. Also, periodic blood glucose monitoring to check for hypoglycemia should be performed while on IV therapy.

A negative pregnancy test for women of childbearing age should be performed before starting primaquine.

Nurses and pharmacists should assist the team in educating the patient and family regarding the safe use of these medications. Pharmacists also need to verify dosing and perform medication reconciliation, reporting any issues to the team.

An infectious disease expert should always be consulted when dealing with a patient with malaria because of drug resistance and constant changes in the drugs recommended.[19][20]

The interprofessional healthcare team approach can result in improved outcomes for malaria patients [Level 5]