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Part 3: Alternatives for Pregnant Women § Treatment: Severe Malaria

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Alternatives for Pregnant Women | Treatment: Severe Malaria | References

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Treatment summary in tabular form (Updated March 6, 2007)
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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. Pregnant women are three times more likely to develop severe disease than non-pregnant women acquiring infections from the same area. In addition, malaria parasites sequester and replicate in the placenta.¹⁹ 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. As a 2nd line alternative for treatment, hydroxychloroquine may be given instead. For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, prompt treatment with 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 in Africa or South America; 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 quinine for seven days is recommended regardless of where the infection was acquired. There are no adequate, well-controlled studies to support the addition of clindamycin to quinine when treating chloroquine-resistant P. vivax infections.

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. label, atovaquone/proguanil is classified as a pregnancy category C medication and is generally not indicated for use in pregnant women because there are no adequate, well-controlled studies of atovaquone and/or proguanil hydrochloride 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. There are no data on the efficacy of atovaquone/proguanil in the treatment of chloroquine-resistant P. vivax infections.

Mefloquine is also a pregnancy category C medication and is generally not indicated for treatment in pregnant women. Mefloquine has not been associated with an increased risk of congenital abnormalities; however, a possible association with mefloquine treatment during pregnancy and an increase in stillbirths has been reported.²⁰ CDC recommends mefloquine only when no other treatment options are available 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: Severe Malaria

Patients who are considered to have manifestations of more severe disease should be treated aggressively with parenteral antimalarial therapy. Oral antimalarial drugs (such as oral quinine, chloroquine, or mefloquine) are not recommended for the initial treatment of severe malaria. If severe malaria is strongly suspected but the first blood smear does not demonstrate parasites, a trial of parenteral antimalarial drugs should be given.¹⁵ If there is clinical evidence of severe malaria but the blood smear is reported as P. vivax, P. ovale or P. malariae, the patient should be treated for falciparum malaria in case of a mixed infection or misdiagnosis.¹⁵

Since 1991, quinidine gluconate has been the only parenterally administered antimalarial drug available in the United States.¹⁶ 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).¹⁷ 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 (=12 mg/kg salt) infused over 4 hours every 8 hours, starting 8 hours after the loading dose (see package insert). Quinidine levels should be maintained in the range of 3-8 mg/L.^{13, 14} At least 24 hours of quinidine gluconate infusion are recommended (or 3 intermittent doses); once the parasite density is < 1% and the patient can take oral medication, the patient can complete the treatment course with oral quinine at a dosage of 10 mg salt/kg every 8 hours (for a combined treatment course of quinidine/quinine for 7 days in Southeast Asia and 3 days in Africa and South America).¹⁴

Initial (including loading) doses of parenteral quinine or 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.¹⁵

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 hyclate (100 mg 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 (250 mg 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 should be administered in an intensive care setting with continuous cardiac and frequent blood pressure monitoring.^15,17 At the dosages required for the treatment of falciparum malaria, quinidine gluconate may cause ventricular arrhythmia, hypotension, hypoglycemia, and prolongation of the QTc interval.¹⁶ 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.^14,15 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.¹⁶ Because there is less collected experience 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.¹⁵ Consulting a cardiologist and a physician with experience in treating malaria is advised when treating malaria patients in the United States with quinidine gluconate. 16 Glucose must be monitored closely as quinidine- (or quinine-) induced hyperinsulinemic hypoglycemia can occur.¹⁷

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 gluconate in U.S. health care facilities, hospital drug services need to maintain or add quinidine gluconate to formularies. If quinidine 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. In the event that quinidine gluconate is needed acutely and is not available by the aforementioned routes, pharmacists and clinicians should contact Eli Lilly Company directly; telephone 1-800-821-0538. Assistance from the company to arrange a rapid shipment of the drug is available between the hours of 6AM and 6PM. If further assistance is needed in managing patients with malaria, health care professionals can contact CDC’s malaria hotline (770-488-7788 Monday-Friday 8am to 4:30pm EST; 770-488-7100 after hours, weekends and holidays and ask to have the malaria clinician on-call paged.)

On June 21, 2007, CDC’s Investigational New Drug Application (IND) for intravenous artesunate went into effect. This IND allows for use of an investigational antimalarial medication (intravenous artesunate) to be used for the treatment of severe malaria.

more: Artesunate for the treatment of severe malaria

References

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