Treatment of Malaria: Guidelines For Clinicians (United States)
Part 3: Alternatives for Pregnant Women and Treatment of Severe Malaria
Alternatives For Pregnant Women
Malaria infection in pregnant women is associated with high risks of both maternal and perinatal morbidity and mortality. While the mechanism is poorly understood, pregnant women have a reduced immune response and therefore less effectively clear malaria infections. In addition, malaria parasites sequester and replicate in the placenta. Pregnant women are three times more likely to develop severe disease than non-pregnant women acquiring infections from the same area. Malaria infection during pregnancy can lead to miscarriage, premature delivery, low birth weight, congenital infection, and/or perinatal death.
For pregnant women diagnosed with uncomplicated malaria caused by P. malariae, P. vivax, P. ovale, or chloroquine-sensitive P. falciparum infection, prompt treatment with chloroquine (treatment schedule as with non-pregnant adult patients) is recommended. Alternatively, hydroxychloroquine, may be given instead. For women in their second or third trimesters, artemether-lumefantrine is an additional option. For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, women in the second and third trimesters can be treated with artemether-lumfantrine, and for all trimesters, mefloquine or a combination of quinine sulfate and clindamycin is recommended. Quinine treatment should continue for 7 days for infections acquired in Southeast Asia and for 3 days for infections acquired elsewhere; clindamycin treatment should continue for 7 days regardless of where the infection was acquired. For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. vivax infection, prompt treatment with artemether-lumfantrine (second and third trimesters) or mefloquine (all trimesters) is recommended.
Doxycycline and tetracycline are generally not indicated for use in pregnant women. However, in rare instances, doxycycline or tetracycline can be used in combination with quinine if other treatment options are not available or are not being tolerated, and the benefit of adding doxycycline or tetracycline is judged to outweigh the risks.
According to its U.S. labels, atovaquone/proguanil is not indicated for use in pregnant women because there are no adequate, well-controlled studies in pregnant women. However, for pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, atovaquone-proguanil may be used if other treatment options are not available or are not being tolerated, and if the potential benefit is judged to outweigh the potential risks.
For P. vivax or P. ovale infections, primaquine phosphate for radical treatment of hypnozoites should not be given during pregnancy. Pregnant patients with P. vivax or P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy. The chemoprophylactic dose of chloroquine phosphate is 300mg base (=500 mg salt) orally once per week. After delivery, pregnant patients with P. vivax or P. ovale infections who do not have G6PD deficiency should be treated with primaquine. Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy as described below.
Treatment of Severe Malaria
Patients who are considered to have manifestations of more severe disease should be treated aggressively with parenteral antimalarial therapy regardless of the species of malaria seen on the blood smear. Oral antimalarial drugs are not recommended for the initial treatment of severe malaria. If severe malaria is strongly suspected but a laboratory diagnosis cannot be made at that time, blood should be collected for diagnostic testing as soon as it is available and parenteral antimalarial drugs may be started.
Since 1991, quinidine gluconate has been the only parenterally administered antimalarial drug available in the United States. It is recommended to give a loading dose of 6.25 mg base/kg (=10 mg salt/kg) of quinidine gluconate infused intravenously over 1-2 hours followed by a continuous infusion of 0.0125 mg base/kg/min (=0.02 mg salt/kg/min). An alternative regimen is an intravenous loading dose of 15mg base/kg (=24 mg salt/kg) of quinidine gluconate infused intravenously over 4 hours, followed by 7.5mg base/kg (=12mg/kg salt) infused over 4 hours every 8 hours, starting 8 hours after the loading dose (see package insert). At least 24 hours of quinidine gluconate infusion (or 3 intermittent doses) are recommended; once the parasite density is < 1% and the patient can take oral medication, the patient can complete the treatment course with an oral regimen such as oral quinine at the same dosage for uncomplicated malaria (for a combined treatment course of quinidine/quinine for 7 days for malaria acquired in Southeast Asia and 3 days for malaria acquired elsewhere). Other oral regimens such as atovaquone-proguanil or artemether-lumefantrine may be used instead of an oral quinine based regimen.
Initial (including loading) doses of parenteral quinidine do not need to be reduced in persons with renal failure. If renal failure persists or the patient does not improve clinically, the maintenance dosage should be reduced by one third to one half on the third treatment day.
As with treatment of uncomplicated P. falciparum, quinidine/quinine therapy should be combined with doxycycline, tetracycline, or clindamycin. If the patient is unable to tolerate oral therapy, doxycycline (100mg every 12 hours) or clindamycin (5 mg base/kg every 8 hours) may be given intravenously until the patient can be switched to oral therapy. Rapid intravenous administration of doxycycline or clindamycin should be avoided. If the patient can tolerate oral therapy, doxycycline (100 mg every 12 hours), tetracycline (250mg every 6 hours), or clindamycin (20 mg base/kg/day divided three times per day) for 7 days are options.
Parenteral quinidine gluconate is cardiotoxic and so a baseline EKG should be obtained before initiating therapy. Quinidine should be administered in an intensive care setting with continuous cardiac and frequent blood pressure monitoring. At the dosages required for the treatment of falciparum malaria, quinidine gluconate may cause ventricular arrhythmia, hypotension, hypoglycemia, and prolongation of the QTc interval. The quinidine gluconate infusion should be slowed or stopped for an increase in the QRS complex by > 50%, a QTc interval > 0.6 seconds, a QTc interval that is prolonged by more than 25% of the baseline value, or hypotension unresponsive to fluid challenge. Because most deaths from severe malaria occur within the first 24-48 hours, the goal of a loading dose is to quickly reach therapeutic concentrations at a time when they are needed most. Recent use of other drugs that may prolong the QTc interval (e.g., quinine or mefloquine) should be considered when determining whether a patient should receive a loading dose of quinidine gluconate. Because there is less evidence on which to base decisions with quinidine gluconate, recommendations for administration of a loading dose are based on experience with loading doses of quinine. A loading dose of quinidine gluconate should be given unless the patient has received more than 40 mg/kg quinine in the previous 2 days or has received mefloquine in the previous 12 hours. Consulting a cardiologist and a physician with experience in treating malaria is advised when treating malaria patients in the United States with quinidine gluconate. Glucose must be monitored closely as quinidine- (or quinine-) induced hyperinsulinemic hypoglycemia can occur.
With the advent of newer anti-arrhythmic agents, quinidine gluconate has been dropped from many hospital formularies and fewer clinicians have experience with the drug. To ensure the availability of quinidine in U.S. health care facilities, hospital drug services need to maintain or add quinidine gluconate injection to formularies. If quinidine gluconate injection is not available on the hospital formulary, the hospital should be able to immediately locate a nearby health care facility that stocks it. If a local source cannot be found, quinidine gluconate should be requested from the local or regional distributor or the Eli Lilly Company directly by telephone (1-800-821-0538).
If quinidine is unavailable, or in patients with adverse effects or contraindications to quinidine, or in patients with a parasitemia >10% of baseline at 48 hours after initiation of IV quinidine, parenteral artesunate is available as an investigational new drug through CDC. If both quinidine and artesunate can be obtained in similar time frames the treating physician may choose either option. To obtain artesunate for the treatment of severe malaria or for assistance in diagnosing or managing patients with malaria, health care professionals can contact CDC’s malaria hotline (770-488-7788, or toll-free 855-856-4713 Monday-Friday 9am to 5pm EST; 770-488-7100 after hours, weekends and holidays and ask to have the malaria clinician on-call paged.)
While exchange transfusion has not been proven beneficial in an adequately powered randomized controlled trial, it has been an option in the treatment of severe malaria since 1974. Exchange transfusion was thought to have beneficial effects by removing infected red cells, improving the rheological properties of blood, and reducing toxic factors such as parasite-derived toxins, harmful metabolites, and cytokines. The risks of exchange transfusion include fluid overload, febrile and allergic reactions, metabolic disturbances (e.g., hypocalcemia), red blood cell alloantibody sensitization, transmissible infection, and line sepsis. Previously, CDC recommended that exchange transfusion be strongly considered for certain severely ill persons, persons with a parasite density of more than 10% or if complications such as cerebral malaria, acute respiratory distress syndrome, or renal complications exist. Exchange transfusion is thought to have beneficial effects by removing infected red cells, improving the rheological properties of blood, and reducing toxic factors such as parasite-derived toxins, harmful metabolites, and cytokines. The risks of exchange transfusion include fluid overload, febrile and allergic reactions, metabolic disturbances (e.g., hypocalcemia), red blood cell alloantibody sensitization, transmissible infection, and line sepsis. Thus, the potential benefits of exchange transfusion should be weighed against the risks. The parasite density should be monitored every 12 hours until it falls below 1%, which usually requires the exchange of 8-10 units of blood in adults. In 2013 CDC conducted an analysis of cases of severe malaria treated with exchange transfusion and was unable to demonstrate a survival benefit of the procedure. CDC no longer recommends the use of exchange transfusion as an adjunct procedure for the treatment of severe malaria.