Transcript Antimalaria Treatment

Antimalaria Treatment
Al-anoud Al-jifri
Internal Medicine/ID consultant
8/11/2009
Antimalarial drugs
• Antimalarial drugs are used for the treatment
and prevention of malaria infection.
• Most antimalarial drugs target the erythrocytic
stage of malaria infection, which is the phase of
infection that causes symptomatic illness.
• The extent of pre-erythrocytic (hepatic stage)
activity for most antimalarial drugs is not well
characterized.
*Life cycle of Plasmodium
Antimalarial drugs
• Treatment of the acute blood stage infection is
necessary for malaria caused by all malaria
species.
• For infection due to Plasmodium ovale or P.
vivax, terminal prophylaxis is required with a
drug active against hypnozoites (which can
remain dormant in the liver for months -- and
occasionally years -- after the initial infection).
QUINOLINE DERIVATIVES
• Include chloroquine, amodiaquine, quinine,
quinidine, mefloquine, primaquine, lumefantrine
and halofantrine.
• These drugs have activity against the erythrocytic
stage of infection; primaquine also kills intrahepatic
forms and gametocytes.
• The drugs act by accumulating in the parasite food
vacuole and forming a complex with heme that
prevents crystallization in the plasmodium food
vacuole.
• Heme polymerase activity is inhibited, resulting in
accumulation of cytotoxic free heme.
4-aminoquinolines
Chloroquine: has activity against the blood stages
of Plasmodium ovale, P. malariae, and
susceptible strains of P. vivax and P. falciparum.
Widespread resistance in most malaria-endemic
countries has led to decline in its use for the
treatment of P. falciparum, although it remains
effective for treatment of P. ovale, P. malariae,
and, in most regions, P. vivax.
Chloroquine
MECHANISM OF ACTION :
• Binds to and inhibits DNA and RNA polymerase;
interferes with metabolism and hemoglobin
utilization by parasites; inhibits prostaglandin
effects;
• chloroquine concentrates within parasite acid
vesicles and raises internal pH resulting in
inhibition of parasite growth;
• may involve aggregates of ferriprotoporphyrin IX
acting as chloroquine receptors causing membrane
damage; may also interfere with nucleoprotein
synthesis.
Chloroquine
PHARMACODYNAMICS / KINETICS
• Duration: Small amounts may be present in urine months following
discontinuation of therapy
• Absorption: Oral: Rapid (~89%)
• Distribution: Widely in body tissues (eg, eyes, heart, kidneys, liver, lungs)
where retention prolonged; crosses placenta; enters breast milk
• Metabolism: Partially hepatic
• Half-life elimination: 3-5 days
• Time to peak, serum: 1-2 hours
• Excretion: Urine (~70% as unchanged drug); acidification of urine
increases elimination.
CONTRAINDICATIONS :
Hypersensitivity to chloroquine or any component of the formulation; retinal
or visual field changes
Chloroquine
• Chloroquine penetrates into most tissues and
therefore has a large volume of distribution.
▫ As a result, serum drug levels may be maintained
for up to two months.
• Chloroquine is only administered orally;
intravenous infusion is associated with
significant toxicity.
Chloroquine
• Among chloroquine-resistant parasites, there is
decreased accumulation of drug within the food
vacuole.
• Mutations in the gene encoding the chloroquine
resistance transporter protein (PfCRT), located
in the food vacuole, are associated with
chloroquine resistance both in vitro and in vivo.
Chloroquine
DOSING: ADULTS
• Malaria, suppression or prophylaxis: Oral: 500 mg/week
(300 mg base) on the same day each week; begin 1-2
weeks prior to exposure; continue for 4-6 weeks after
leaving endemic area; if suppressive therapy is not begun
prior to exposure, double the initial loading dose to 1 g
(600 mg base) and administer in 2 divided doses 6 hours
apart, followed by the usual dosage regimen.
• Malaria, acute attack: Oral: 1 g (600 mg base) on day 1,
followed by 500 mg (300 mg base) 6 hours later,
followed by 500 mg (300 mg base) on days 2 and 3.
Chloroquine
• Side effects of chloroquine include headaches,
dizziness, abdominal discomfort, vomiting, and
diarrhea.
• Chloroquine may also produce pruritus in some
patients; this has been noted to occur most
frequently in African populations.
▫ The pruritus is transient, lasting 48 to 72 hours,
and is not responsive to antihistamines.
Chloroquine
• Severe adverse reactions are extremely rare.
• Some are associated only with prolonged use,
such as neuromyopathy with long-term
prophylaxis and retinopathy with high-dose
administration for treatment of rheumatologic
diseases (total doses of 1 g/kg or prophylaxis for
greater than one year).
• Rare cases of idiosyncratic reactions, such as
erythema multiforme and bone marrow toxicity,
have been reported.
Amodiaquine
• It is similar in structure to chloroquine, and there is
cross resistance between the two drugs, although
amodiaquine retains some activity against
chloroquine resistant parasites in vivo and in vitro.
• Amodiaquine has been taken off the market in the
United States due to the risk of toxicity associated
with prolonged administration for prophylaxis.
• The most serious adverse effects of amodiaquine are
agranulocytosis and hepatotoxicity, which have been
reported in European travelers using amodiaquine
to prevent malaria.
Amodiaquine
• Amodiaquine is commonly used in malaria
endemic countries as one of the few drugs
available to treat chloroquine-resistant
infections and is available in coformulation with
Artesunate .
• Amodiaquine is well tolerated when
administered as a single course of treatment
over three days.
Amodiaquine
• Risk for adverse effects related to Amodiaquine
may be increased in patients with HIV infection.
• Risk of neutropenia was higher among HIVpositive children than HIV-negative children,
particularly among patients receiving
antiretroviral therapy.
4-methanolquinolines
Quinine and quinidine :
• Quinine is a derivative from the bark of the
South American Cinchona tree and exists in oral
and parenteral forms.
▫ In malaria-endemic regions it is the most
commonly used parenteral antimalarial drug.
• Quinidine is a stereoisomer of quinine available
in parenteral formulation and is very effective
for treatment of severe malaria.
Quinine
MECHANISM OF ACTION :
Depresses oxygen uptake and carbohydrate metabolism; intercalates into DNA,
disrupting the parasite's replication and transcription.
PHARMACODYNAMICS / KINETICS
• Absorption: mainly from upper small intestine
• Distribution: varies with severity of infection
Intraerythrocytic levels are ~30% to 50% of the plasma concentration; distributes poorly
to the CSF (~2% to 7% of plasma concentration)
• Protein binding: 69% to 92% in healthy subjects; 78% to 95% with malaria
• Metabolism: Primarily hepatic via CYP450 enzymes, including CYP3A4 and 2C19; forms
metabolites; major metabolite, 3-hydroxyquinine, is less active than parent
• Bioavailability: 76% to 88% in healthy subjects; increased with malaria
• Half-life elimination:
Children: ~3 hours in healthy subjects; ~12 hours with malaria
Healthy adults: 10-13 hours
• Time to peak, serum:
Children: 2 hours in healthy subjects; 4 hours with malaria
Adults: 1-3 hours in healthy subjects; 1.2-11 hours with malaria
• Excretion: Urine (<20% as unchanged drug)
Quinine
DOSING: ADULTS
Treatment of chloroquine-resistant malaria: 648
mg every 8 hours for 7 days with tetracycline,
doxycycline, or clindamycin.
CONTRAINDICATIONS :
Hypersensitivity to quinine or any component of the
formulation; hypersensitivity to mefloquine or
quinidine (cross sensitivity reported); prolonged QT
interval; myasthenia gravis; optic neuritis; G6PD
deficiency; history of black water fever; thrombotic
thrombocytopenia purpura, hemolytic uremic
syndrome, thrombocytopenia
Quinidine
MECHANISM OF ACTION:
• Class Ia antiarrhythmic agent; depresses phase
O of the action potential; decreases myocardial
excitability and conduction velocity, and
myocardial contractility by decreasing sodium
influx during depolarization and potassium
efflux in repolarization; also reduces calcium
transport across cell membrane.
Quinidine
PHARMACODYNAMICS / KINETICS
• Distribution: decreased with congestive heart failure, malaria;
increased with cirrhosis; crosses placenta; enters breast milk
• Protein binding:
Newborns: 60% to 70%; decreased protein binding with cyanotic
congenital heart disease, cirrhosis, or acute myocardial infarction
Adults: 80% to 90%
• Metabolism: Extensively hepatic (50% to 90%) to inactive
compounds
• Bioavailability: Sulfate: 80%; Gluconate: 70%
• Half-life elimination, plasma: Children: 2.5-6.7 hours; Adults: 6-8
hours; prolonged with elderly, cirrhosis, and congestive heart failure
• Excretion: Urine (15% to 25% as unchanged drug)
Quinidine
CONTRAINDICATIONS :
• Hypersensitivity to quinidine or any component of
the formulation; thrombocytopenia;
thrombocytopenic purpura; myasthenia gravis;
heart block greater than first degree; idioventricular
conduction delays (except in patients with a
functioning artificial pacemaker); those adversely
affected by anticholinergic activity; concurrent use
of quinolone antibiotics which prolong QT interval,
cisapride, amprenavir, or ritonavir.
Quinidine
DOSING: ADULTS
Dosage expressed in terms of the salt: 267 mg of quinidine
gluconate = 275 mg of quinidine polygalacturonate = 200 mg
of quinidine sulfate.
ADMINISTRATION:
• Administer around-the-clock to promote less variation in
peak and trough serum levels
• Oral: Do not crush, chew, or break sustained release dosage
forms.
• Parenteral: When injecting I.M., aspirate carefully to avoid
injection into a vessel; maximum I.V. infusion rate: 10
mg/minute.
USE:
Quinidine gluconate (I.V. formulation) and quinidine sulfate:
Treatment of malaria (Plasmodium falciparum).
Quinine and Quinidine
• The adverse effects of quinine and quinidine include
a complex of symptoms referred to as cinchonism:
tinnitus, nausea, headaches, dizziness and disturbed
vision.
• These effects typically resolve with cessation of the
medication. These symptoms do not warrant change
in drug dose.
• However, toxicity often interferes with compliance
in completing the course of therapy.
• Less commonly, hypersensitivity reaction with
bronchospasm and cutaneous manifestations, such
as flushing and urticaria, may occur.
Quinine and Quinidine
• Quinine has a short half-life. When given orally it must be
administered three times per day; when administered together with
one week of tetracycline antibiotics or clindamycin, the duration of
therapy is three to seven days.
• The drug should be given for seven days if the infection is acquired
in an area where decreased quinine susceptibility has been reported,
such as Southeast Asia .
• For severe disease, quinine can be administered intravenously or
intramuscularly.
• Intravenous administration of quinidine and quinine should be as
an infusion because rapid boluses are associated with hypotension.
• To hasten parasite clearance time, an initial loading dose of
parenteral quinine or quinidine is appropriate if the patient has not
received treatment with these agents recently.
• After initial improvement on parenteral therapy, patients can be
switched to oral medication.
Quinine and Quinidine
• Quinine and quinidine have a narrow therapeutic
window; overdosage may lead to cardiotoxicity,
including arrhythmias and hypotension, blindness
or deafness.
• Quinidine is the more cardiotoxic of these agents:
cardiac monitoring including serial blood pressure
measurements should always be in place when
quinidine is administered, to monitor for
prolongation of the QT interval and ventricular
tachycardia.
• Blood sugar levels should be monitored with
intravenous infusion, as both quinine and quinidine
stimulate insulin production.
Mefloquine
MECHANISM OF ACTION:
• it is a quinoline-methanol compound
structurally similar to quinine.
• mefloquine's effectiveness in the treatment and
prophylaxis of malaria is due to the destruction
of the asexual blood forms of the malarial
pathogens that affect humans, Plasmodium
falciparum, P. vivax, P. malariae, P. ovale.
Mefloquine
PHARMACODYNAMICS / KINETICS
•
•
•
•
•
•
•
•
Absorption: Well absorbed.
Distribution: blood, urine, CSF, tissues; enters breast milk
Protein binding: 98%
Metabolism: Extensively hepatic to 2,8-bis-trifluoromethyl-4quinoline carboxylic acid (inactive) and other metabolites.
Bioavailability: Increased by food.
Half-life elimination: ~3 weeks (range: 2-4 weeks).
Time to peak, plasma: 6-24 hours (median: ~17 hours).
Excretion: Primarily bile and feces; urine (9% as unchanged
drug, 4% as primary metabolite)
Mefloquine
CONTRAINDICATIONS :
• Hypersensitivity to mefloquine, related
compounds (eg, quinine and quinidine), or any
component of the formulation; prophylactic use
in patients with a history of seizures or severe
psychiatric disorder (including active or recent
history of depression, generalized anxiety
disorder, psychosis, or schizophrenia).
Mefloquine
ADMINISTRATION:
• Administer with food and with at least 8 oz of water.
• When used for malaria prophylaxis, dose should be
taken once weekly on the same day each week.
• If vomiting occurs within 30 minutes after the dose, an
additional full dose should be given; if it occurs within
30-60 minutes after dose, an additional half-dose should
be given.
• Tablets may be crushed and suspended in a small
amount of water, milk, or another beverage for persons
unable to swallow tablets.
USE : Treatment of acute malarial infections and
prevention of malaria.
Mefloquine
DOSING: ADULTS
• Malaria treatment (mild-to-moderate infection): Oral: 5 tablets (1250 mg)
as a single dose. If clinical improvement is not seen within 48-72 hours, an
alternative therapy should be used for retreatment.
• Malaria prophylaxis: Oral: 1 tablet (250 mg) weekly starting 1 week before
arrival in endemic area, continuing weekly during travel and for 4 weeks
after leaving endemic area
DOSING: PEDIATRIC
• Malaria treatment: Oral: 20-25 mg/kg in 2 divided doses, taken 6-8 hours
apart (maximum: 1250 mg).
• If clinical improvement is not seen within 48-72 hours, an alternative
therapy should be used for retreatment.
• Malaria prophylaxis: Oral: 5 mg/kg/once weekly (maximum dose: 250 mg)
starting 1 week before arrival in endemic area, continuing weekly during
travel and for 4 weeks after leaving endemic area.
DOSING: RENAL IMPAIRMENT — No dosage adjustment needed in patients
with renal impairment or on dialysis.
DOSING: HEPATIC IMPAIRMENT — Half-life may be prolonged and plasma
levels may be higher. Specific dosing adjustments are not available.
Mefloquine
• Adverse effects include vomiting and dizziness.
• It can also interfere with cardiac conduction and
therefore should not be used in individuals with
cardiac conduction abnormalities.
Mefloquine
• Splitting the 25 mg/kg dose into 15 mg/kg and 10 mg/kg
over a 6 to 24 hour period may be helpful to reduce mild
adverse effects.
• When used for prophylaxis it is best started two to three
weeks prior to departure to assess tolerability, though
side effects can develop long into the prophylactic course
or even if it has been well tolerated in the past.
• The combination of mefloquine plus artesunate appears
to be effective in most regions of Southeast Asia .
• Mefloquine resistance is found primarily in Thailand.
8-aminoquinolines
Primaquine:
• is the only 8-aminoquinoline in clinical use.
• It is largely used to prevent relapse of P. ovale
and P. vivax malaria by eliminating dormant
hypnozoites, and it also has activity against the
pre-erythrocytic stage and gametocytes of P.
falciparum.
Primaquine
MECHANISM OF ACTION :
• Eliminates the primary tissue exoerythrocytic forms of P.
falciparum; disrupts mitochondria and binds to DNA.
PHARMACODYNAMICS / KINETICS
▫
▫
▫
▫
▫
Absorption: Well absorbed
Metabolism: Hepatic to carboxyprimaquine (active)
Half-life elimination: 3.7-9.6 hours
Time to peak, serum: 1-2 hours
Excretion: Urine (small amounts as unchanged drug)
CONTRAINDICATIONS :
• Use in acutely-ill patients who have a tendency to develop
granulocytopenia (eg, rheumatoid arthritis, SLE).
• Concurrent use with other medications causing hemolytic anemia or
myeloid bone marrow suppression.
• Concurrent use with or recent use of quinacrine.
Primaquine
DOSING: ADULTS
The CDC recommends screening for G6PD deficiency prior
to initiating treatment with primaquine.
Dosage expressed as mg of base (15 mg base = 26.3 mg
primaquine phosphate).
• Relapse prevention of P. vivax malaria:
▫ CDC recommendations: Uncomplicated malaria (P. vivax
and P. ovale): Oral: 30 mg once daily for 14 days;
alternative regimen (recommended for mild G6PD
deficiency): 45 mg once weekly for 8 weeks
• Prevention of chloroquine-resistant malaria (unlabeled
use; CDC guidelines): Oral: Initiate 1-2 days prior to
travel and continue for 7 days after departure from
malaria-endemic area: 30 mg once daily
Primaquine
• It can cause hemolytic anemia in those with glucose-6phosphate dehydrogenase (G6PD) deficiency. Therefore,
patients should receive primaquine only if G6PD
deficiency has been excluded.
• Also cause gastrointestinal upset that can be minimized
if taken with food.
• Primaquine is contraindicated in pregnancy and
breastfeeding.
• Hypnozoite resistance to primaquine is difficult to
assess.
▫ Parasitemia within the first 4-6 weeks of an initial infection
may be due to failure of the blood stage treatment,
inadequate adherence, or primaquine failure.
Lumefantrine and Halofantrine
• Are similar in structure to the 4-methanolquinolines.
• These drugs are active against most chloroquine-resistant parasites
although there is cross-resistance between halofantrine and
mefloquine.
• Lumefantrine is a long-acting partner drug to artemether in a widely
used fixed-dose combination; the half-life of lumefantrine is 3 to 6
days.
• An important determinant of lumefantrine efficacy is drug level; the
oral bioavailability is highly variable and increases up to three- to
four-fold when taken with a high fat meal.
• Lumefantrine is well tolerated, with rare mild adverse reactions
such as diarrhea, nausea, abdominal pain and vomiting.
• There is no evidence of significant cardiotoxicity associated with
lumefantrine use.
• Halofantrine has been effective in chloroquine- and mefloquineresistant malaria, although cardiac toxicity (dose-dependent
prolongation of the PR and QTc intervals) limits its use, and it is not
available in the United States.
ANTIFOLATES
• Antifolates include sulfonamides,
pyrimethamine, proguanil and dapsone.
• These drugs act synergistically to target enzymes
involved in folate synthesis, a pathway required
for parasite DNA synthesis.
Mechanism of action of antifolates
Sulfadoxine and pyrimethamine
MECHANISM OF ACTION :
• Sulfadoxine interferes with bacterial folic acid synthesis and growth via
competitive inhibition of para-aminiobenzoic acid; pyrimethamine inhibits
microbial dihydrofolate reductase, resulting in inhibition of tetrahydrofolic
acid synthesis
PHARMACODYNAMICS / KINETICS
• Absorption: Well absorbed
• Distribution: Sulfadoxine: Well distributed like other sulfonamides;
•
Pyrimethamine: Widely distributed, mainly in blood cells,
kidneys, lungs, liver, and spleen
• Metabolism: Pyrimethamine: Hepatic; Sulfadoxine: None
• Half-life elimination: Pyrimethamine: 80-95 hours; Sulfadoxine: 5-8 days
• Time to peak, serum: 2-8 hours
• Excretion: Urine (as unchanged drug and several unidentified metabolites)
Sulfadoxine and pyrimethamine
USE :
• Treatment of Plasmodium falciparum malaria in patients in
whom chloroquine resistance is suspected.
• Malaria prophylaxis for travelers to areas where chloroquineresistant malaria is endemic.
DOSING: ADULTS
• Treatment of acute malaria attacks: Oral: A single dose of the
following number of Fansidar® tablets is used in sequence
with quinine or alone: 3 tablets
• Malaria prophylaxis: A single dose should be carried for selftreatment in the event of febrile illness when medical
attention is not immediately available: Oral: 3 tablets
Sulfadoxine and pyrimethamine
Adverse effects :
• Mild adverse effects include gastrointestinal upset and headache.
Mild bone marrow suppression may occur, and sulfadoxine can
precipitate hemolysis in patients with G6PD deficiency.
• Severe cutaneous toxicity due to the sulfa moiety can occur,
including erythema multiforme, Stevens-Johnson syndrome, and
toxic epidermal necrosis.
CONTRAINDICATIONS :
• Hypersensitivity to any sulfa drug, pyrimethamine, or any
component of the formulation; porphyria, megaloblastic anemia;
• Repeated prophylactic use is contraindicated in patients with renal
failure, hepatic failure, or blood dyscrasias; children <2 months of
age due to competition with bilirubin for protein binding sites;
pregnancy (at term).
Atovaquone-proguanil
MECHANISM OF ACTION:
• Inhibits electron transport in mitochondria resulting in the inhibition of key metabolic
enzymes responsible for the synthesis of nucleic acids and ATP.
• Resistance to atovaquone is mediated by mutations in the cytochrome b gene.
▫
However, the combination retains excellent clinical efficacy for treatment and prevention
throughout the world even in the presence of antifolate resistance
PHARMACODYNAMICS / KINETICS
• Absorption: Significantly increased with a high-fat meal
• Protein binding: >99%
• Metabolism: Undergoes enterohepatic recirculation
• Bioavailability: 32% to 62%
• Half-life elimination: 1.5-4 days
• Excretion: Feces (>94% as unchanged drug); urine (<1%)
ADMINISTRATION : Must be administered with meals. Shake suspension gently before use.
Once opened, the foil pouch can be emptied on a dosing spoon, in a cup, or directly into the
mouth.
USE : Acute oral treatment of mild-to-moderate Pneumocystis jirovecii pneumonia (PCP) in
patients who are intolerant to co-trimoxazole; prophylaxis of PCP in patients who are
intolerant to co-trimoxazole
Atovaquone-proguanil
Adverse effects include:
• abdominal pain, vomiting, diarrhea, headache
and pruritis.
• Among adults in Thailand, mild asymptomatic
increases in transaminases were observed
shortly after initiating therapy, although they
normalized by day 14.
CONTRAINDICATIONS : Life-threatening allergic
reaction to atovaquone or any component of the
formulation.
ANTIMICROBIALS
• Tetracycline, doxycycline, and clindamycin target
prokaryotic protein synthesis.
• In malaria parasites, these drugs appear to target the
apicoplast, an organelle derived from prokaryotic
ancestors.
• They have relatively slow antimalarial activity because
they exert their toxic effects in the subsequent cycle of
cell division.
• They are typically paired with fast-acting antimalarials
(usually quinine).
• Doxycycline has a longer half life than tetracycline so is
used more commonly.
• Resistance has not been detected to tetracycline,
doxycycline or clindamycin.
ANTIMICROBIALS
• Adverse effects are common with the tetracyclines and
interfere with adherence.
• Gastrointestinal discomfort and candidiasis are the most
frequent complaints.
• Doxycycline therapy also poses a risk of esophageal
ulceration. Photosensitivity can occur with doxycycline,
which can be concerning for fair-skinned travelers using
it as prophylaxis for travel to the tropics.
• Tetracyclines should not be given to pregnant women or
children less than 8 years old because of the risk of
deposition in growing bones and teeth.
• Clindamycin is the preferred alternative in these groups.
ARTEMISININ DERIVATIVES
• The artemisinins are derived from the leaves of
the Chinese sweet wormwood plant, Artemisia
annua.
• They have been used in China for the treatment
of malaria for over 2000 years and came to
attention outside of China in the 1970s and
1980s.
Artemisinins
• Artemisinins act by binding iron, breaking down
peroxide bridges leading to the generation of free
radicals that damage parasite proteins.
• They act rapidly, killing blood stages of all Plasmodium
species and reducing the parasite biomass.
• Artemisinins have the fastest parasite clearance times of
any antimalarial.
• Artemisinins are active against gametocytes, the parasite
form that is infectious to mosquitoes, and their use has
been associated with reduced malaria transmission when
they were introduced in Thailand.
Artemisinin-based combination
therapies
• In general, artemisinins should not be used as a single
agent, to prevent emergence of drug resistance and to
avoid the need for prolonged therapy.
• Artemisinin-based combination therapy (ACTs) combine
the highly effective short-acting artemisinins with a
longer-acting partner to protect against artemisinin
resistance and to facilitate dosing convenience.
• ACTs are typically administered for 3 days and are often
available in fixed-dose tablets.
• Four ACTs are recommended by the WHO for the
treatment of uncomplicated malaria: artemetherlumefantrine, artesunate-amodiaquine, artesunatemefloquine and artesunate-sulfadoxine-pyrimethamine.
Artemisinins
• Intravenous artesunate is used for the treatment of severe
malaria.
• It is superior to quinine for treatment of severe malaria with
respect to clearing parasitemia and reducing mortality.
• Given the short half-life of artemisinins, intravenous therapy
must be followed by a longer acting agent once the patient is
able to tolerate oral medication.
• If used alone (via the parenteral, rectal or oral route),
artesunate must be administered for 5-7 days.
• Treatment for less than 5 days results in recurrent
parasitemia several weeks after therapy due to the very short
duration of action, rather than to artemisinin resistance.
Artemisinins
• Artemisinins are generally well tolerated.
• Type 1 hypersensitivity to the artemisinin
compounds has been reported.
• Adverse effects of orally-administered
artemisinins demonstrated transient
neurological abnormalities( nystagmus and
disturbances in balance); these effects resolved
without lasting sequelae.
Treatment
Uncomplicated P.falciparum malaria (oral):
• Mefloquine (Lariam)
• Proguanil/atovaquone (Malarone)
• Chloroquine (Aralen)
• Pyrimethamine/sulfadoxine (Fansidar)
• Quinine sulfate with antibiotics.
Severe Falciparum Malaria
• Quinine-based regimens.
• Artemisinin-based regimens
• Doxycycline, clindamycin.
Patients are considered to have severe malaria if they have:
• A parasitemia of >5 percent
• Altered consciousness
• Oliguria
• Jaundice
• Severe normocytic anemia
• Hypoglycemia
• Organ failure
Quinine-based regimens
Intravenous quinidine gluconate 10 mg/kg loading dose in normal saline
(maximum 600 mg) over one to two hours, then continuous infusion
of 0.02 mg/kg per minute
OR
Intravenous quinine dihydrochloride 20 mg salt/kg loading dose in five
percent dextrose over four hours followed by 10 mg/kg over two to
four hours every eight hours (maximum 1800 mg/day) this drug is
not available in the United States
Quinine-based regimens
• Patients who received mefloquine or other
quinine derivatives within the previous 12
hours should not receive a loading dose of
quinine or quinidine to avoid cardiotoxicity
• The dose of quinine or quinidine needs to
be reduced by one-third to one-half after
48 hours
Quinine-resistant P. falciparum
• Intravenous artemisinin
combined with tetracycline or mefloquine
Artemisinin-based regimens
• Artesunate 2.4 mg/kg IV as a first dose followed by 1.2
mg/kg at 12 and 24 hours followed by 1.2 mg/kg once daily
for six days, OR
• Artemether 3.2 mg/kg IM followed by 1.6 mg/kg daily for
six days OR
• Artemisinin suppositories 40 mg/kg intrarectally followed by
20 mg/kg at 24, 48 and 72 hours followed by an oral
antimalarial drug
Exchange transfusion
• Parasitemia is greater than 10-15% with
signs of severe malaria.
• Parasitemia is greater than 30% w/o end
organ involvement.
• Has not proven to enhance survival.
• No adequately powered trials.
• Erythrocytapheresis (RBC exchange) may be
better.