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Alternatives
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Severe Malaria | References
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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 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 1974.15 CDC recommends that exchange
transfusion be strongly considered for persons with a parasite density
of more than 10% or if complications such as cerebral malaria, non-volume
overload pulmonary edema, or renal complications exist.14 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.18 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.14 The
technical aspects of exchange transfusion have been discussed in a review
by Powell and Grima.18
References
- World malaria situation in 1994. Part I. Population
at risk. Wkly Epidemiol Rec, 1997. 72(36):
p. 269-74.
- Breman, J.G., The ears of the hippopotamus: manifestations,
determinants, and estimates of the malaria burden. Am
J Trop Med Hyg, 2001. 64(1-2 Suppl): p.
1-11.
- Shah, S., et al., Malaria surveillance--United States,
2002. MMWR Surveill Summ, 2004. 53(1):
p. 21-34.
- CDC, Congenital malaria as a result of Plasmodium malariae--North
Carolina, 2000. MMWR Morb Mortal Wkly Rep, 2002. 51(8):
p. 164-5.
- CDC, Probable transfusion-transmitted malaria--Houston,
Texas, 2003. MMWR Morb Mortal Wkly Rep, 2003. 52(44):
p. 1075-6.
- CDC, Local transmission of Plasmodium vivax malaria--Palm
Beach County, Florida, 2003. MMWR Morb Mortal Wkly Rep,
2003. 52(38): p. 908-11.
- Greenberg, A.E. and H.O. Lobel, Mortality from Plasmodium
falciparum malaria in travelers from the United States, 1959
to 1987. Ann Intern Med, 1990. 113(4):
p. 326-7.
- Moore, T.A., et al., Imported malaria in the 1990s.
A report of 59 cases from Houston, Tex. Arch Fam Med,
1994. 3(2): p. 130-6.
- Kain, K.C., et al., Imported malaria: prospective analysis
of problems in diagnosis and management. Clin Infect
Dis, 1998. 27(1): p. 142-9.
- Kain, K.C., et al., Malaria deaths in visitors to
Canada and in Canadian travellers: a case series. Cmaj,
2001. 164(5): p. 654-9.
- Svenson, J.E., et al., Imported malaria. Clinical
presentation and examination of symptomatic travelers. Arch
Intern Med, 1995. 155(8): p. 861-8.
- Kyriacou, D.N., et al., Emergency department presentation
and misdiagnosis of imported falciparum malaria. Ann
Emerg Med, 1996. 27(6): p. 696-9.
- White, N.J., The treatment of malaria. N Engl
J Med, 1996. 335(11): p. 800-6.
- Zucker, J.R. and C.C. Campbell, Malaria. Principles
of prevention and treatment. Infect Dis Clin North Am,
1993. 7(3): p. 547-67.
- Severe falciparum malaria. World Health Organization,
Communicable Diseases Cluster. Trans R Soc Trop Med
Hyg, 2000. 94 Suppl 1: p. S1-90.
- CDC, Availability and use of parenteral quinidine
gluconate for severe or complicated malaria. MMWR Morb
Mortal Wkly Rep, 2000. 49(50): p. 1138-40.
- Miller, K.D., A.E. Greenberg, and C.C. Campbell, Treatment
of severe malaria in the United States with a continuous
infusion of quinidine gluconate and exchange transfusion. N
Engl J Med, 1989. 321(2): p. 65-70.
- Powell, V.I. and K. Grima, Exchange transfusion for
malaria and Babesia infection. Transfus Med Rev, 2002. 16(3):
p. 239-50.
- Luxemburger, C., et al., The epidemiology of severe
malaria in an area of low transmission in Thailand. Trans
R Soc Trop Med Hyg, 1997. 91(3): p. 256-62.
- Nosten, F., et al., The effects of mefloquine treatment
in pregnancy. Clin Infect Dis, 1999. 28(4):
p. 808-15.
Page last modified : August 2, 2007
Content source: Division of Parasitic Diseases
National Center for Zoonotic, Vector-Borne, and Enteric Diseases (ZVED)
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