MALARIA...6.3-Plasmodium falciparum [Centers for Disease Control and Prevention ... P. falciparum...

-----------------------------------------------------------------------------------------------------------------------------------------------------------------------Louisiana Office of Public Health – Infectious Disease Epidemiology Section of 24

MALARIA

Revised 02/05/2019

Contents 1-Epidemiology ............................................................................................................................................. 2 2-Life Cycle .................................................................................................................................................. 2 3-Vector Phase .............................................................................................................................................. 3 4-Epidemiologic Classification of Cases ...................................................................................................... 4 5-Clinical Description ................................................................................................................................... 4 6-Laboratory Tests ........................................................................................................................................ 5

6.1-Blood Smears ...................................................................................................................................... 5 6.2-Timing: ............................................................................................................................................... 5 6.3-Plasmodium falciparum [Centers for Disease Control and Prevention (CDC)] ................................. 5 6.4-Plasmodium vivax ............................................................................................................................... 6 6.5-Plasmodium ovale ............................................................................................................................... 7 6.6-Plasmodium malariae ......................................................................................................................... 7

7-Treatment ................................................................................................................................................... 8 7.1.Treatment: General Approach ............................................................................................................. 8 7.2- P. falciparum Infections .................................................................................................................... 8 7.3-P. falciparum or Species Not Identified ............................................................................................. 9 7.4-P. malariae ......................................................................................................................................... 9 7.5-P. vivax and P. ovale .......................................................................................................................... 9 7.6-Antimalarials: Adverse Reactions and Contraindications ................................................................ 10

7.6.1-Chloroquine Phosphate and Hydroxychloroquine Sulfate ......................................................... 11 7.6.2-Atovaquone/proguanil ............................................................................................................... 11 7.6.3-Artemisin ................................................................................................................................... 11 7.6.4-Mefloquine ................................................................................................................................. 11 7.6.5-Primaquine ................................................................................................................................. 12 7.6.6-Quinine and Quinidine ............................................................................................................... 12 7.6.7-Doxycycline ............................................................................................................................... 14 7.6.8- Halofantrine (Marketed as Halfan) ........................................................................................... 14 7.6.9-Clindamycin ............................................................................................................................... 14 7.6.10-Artesunate ................................................................................................................................ 15 7.6.11-Tafenoquine ............................................................................................................................. 15 7.6.13-Treatment of Chloroquine-Susceptible Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium falciparum ................................................................................................ 15 7.6.14-Treatment of Chloroquine-Resistant Plasmodium falciparum ................................................ 16 7.6.15-Treatment of Chloroquine-Resistant Plasmodium vivax ......................................................... 16

8-Surveillance ............................................................................................................................................. 16 8.1-Case Definition ................................................................................................................................. 16 8.2-Investigation ..................................................................................................................................... 17 8.3-Hospital Precaution and Isolation: .................................................................................................... 17

9-Malaria Prevention for Travelers ............................................................................................................. 17 9.1-Inform the Traveler About the Degree of Risk of Malaria Infection: ............................................... 17 9.2-Recommend Precautions Against Mosquito Bites. ........................................................................... 18 9.3-Prophylactic Treatment:.................................................................................................................... 18


9.4-Stand-by Treatment .......................................................................................................................... 19 9.5-Immediate Treatment ........................................................................................................................ 19

9.5.1-Advise the Traveler to Seek Immediate Treatment in Case of Fever. ....................................... 19 9.5.2-Malaria Deaths ........................................................................................................................... 19 9.5.3-Presumptive Self-Treatment of Malaria .................................................................................... 19

9.6-Antimalarial Drug Dosages, Schedules and Warnings for Prophylaxis Overseas ............................ 20 9.6.1-Drugs Used in the Prophylaxis of Malaria................................................................................. 20

9.7-Prophylaxis Recommendations According to Resistance Status ...................................................... 21 9.7.1-Travel to Areas with Chloroquine-resistant P. falciparum ........................................................ 21 9.7.2-Travel to Areas with Mefloquine-resistant P. falciparum ......................................................... 22 9.7.3-Travel to Areas with Chloroquine-sensitive P. falciparum ....................................................... 22

9.8-Chemoprophylaxis for Infants, Children and Adolescents ............................................................... 22 9.9-Chemoprophylaxis during Pregnancy and Lactation ........................................................................ 23 9.10-Lactation ......................................................................................................................................... 23 9.11-Educate Patients on the Signs and Symptoms of Malaria .............................................................. 23 9.12-Self-Treatment ................................................................................................................................ 23

Malaria is caused by an intracellular protozoa of the genus Plasmodium. The four species that cause hu-man malaria are

P. malariae P. vivax P. falciparum P. ovale

1-Epidemiology

Malaria is transmitted by the bite of an infected female Anopheles mosquito or through direct inoculation of infected red blood cells, i.e., congenital malaria, transfusion malaria and malaria from contaminated needles. 2-Life Cycle The life cycle of malaria is complex and certain aspects differ according to the Plasmodium species in-volved.

The infective stages of plasmodia called sporozoites, are injected during feeding from the salivary glands of the infected mosquito into the blood stream through subcutaneous capillaries. Human Pre-erythrocytic Phase (before becoming red blood cells): Sporozoites enter the liver cells, where they multiply asexually. There, the nucleus undergoes repeated division, forming thousands of uninucleate merozoites. There is no inflammatory reaction in the surrounding liver tissue. After six to 16 days from the time of infection, the hepatic cell containing the tissue schizonts ruptures and the merozoites enter the circulation. Human Exo-erythrocytic Phase (outside the red blood cell): P. falciparum and P. malariae schizonts all rupture at about the same time; none persist in the liv-er. The only “exo” erythrocytic phase for these two species occur before the invasion of red blood cells. There is NO continuous cycle in the liver. P. vivax and P. ovale have a continuous exo-erythrocytic cycle: Some parasites remain dormant in the liver (hypnozoites) for weeks, months, or even years before developing and resulting in relapses of erythrocytic infection.

All four species of malaria can cause chronic infections with fever occurring more than once.


Human Erythrocytic Phase (in the red blood cell): Merozoites released from tissue schizonts invade erythrocytes. Red Blood Cell (RBC) Asexual Stages: The youngest stages in the RBC are small, rounded trophozoites, known as ring forms. During devel-opment, they use the hemoglobin, leaving as the product of digestion an iron-containing pigment, hematin or hemozoin, which can be seen in the cytoplasm of the parasite as dark granules. They grow in the red blood cell and when nuclear division occurs the parasite is called a schizont. This asexual multiplication is the erythrocytic schizogony. The infected erythrocytes rupture, liberating merozo-ites, which must invade new RBCs. The erythrocytic cycle of schizogony is repeated many times. The periodicity of schizogony differs according to species. RBC Sexual Stages: From three to 15 days after the onset of symptoms, subpopulations of merozoites differentiate into sexual forms, gametocytes, i.e., female macrogametocytes and male microgametocytes. The duration of gametocytogony is assumed to be four days in P. vivax infections and ten or more days in P. falci-parum infections.

3-Vector Phase

When feeding on an infected human, the female Anopheles ingests gametocytes, which develop in the gut of the mosquito. The nucleus of the male gametocyte divides and forms long, thread-like flagel-lum that break free and produce microgametes. These fertilize the female macrogamete to produce a zygote.

The zygote gets wedged in the outer surface of the stomach and rounds up into an oocyst. An infected Anopheles may have ten to several hundred oocysts. The oocyst enlarges and the nucleus divides then forms finger-like processes, which become fusiform sporozoites. The oocyst ruptures, liberating thou-sands of motile sporozoites that migrate to the salivary glands. The female mosquito is now infective.

Sporogony varies from eight to 35 days, depending on external temperature and on the malaria spe-cies.


4-Epidemiologic Classification of Cases Autochthonous malaria is contracted locally. Malaria is indigenous when naturally present in an area or country. Imported malaria is acquired outside a given area Secondary cases are those derived from imported cases and are referred to as introduced malaria, Induced: Malaria acquired by blood transfusions, sharing of needles, intentional inoculation, or accidental laboratory infections is known as induced malaria Cases with insufficient information to classify are cryptic.

Imported Malaria: Increase in international air travel has resulted in the importation of malaria and other diseases to non-endemic areas. Regions where malaria has been eradicated are at continuing risk of im-porting cases. Patients often arrive during the incubation period and may not become ill until reaching home. Delays in diagnosis, misdiagnosis and inappropriate treatment may occur, resulting in excessive morbidity and mortality. Physicians and public health officials must remain aware of the possibility of imported malarial infections.

The incubation period varies according to species: usually 12 to 18 days for P.vivax or P.ovale; slightly shorter for P.falciparum. 5-Clinical Description

Clinical symptoms and signs of malaria are associated with the release of merozoites, malarial pigment, and debris into the circulation following rupture of infected erythrocytes. Semi-immune patients are less likely to develop severe manifestations and complications when they become infected.

Some patients have vague prodromal symptoms before parasites can be detected in the blood. These man-ifestations, i.e., malaise, myalgia, headache, anorexia and slight fever, may persist for two or three days before an acute paroxysm begins. In the initial phase of illness, the fever can be erratic or continuous. If the infection continues for three to four days, a synchronous cycle may develop with afternoon tempera-ture elevations approximately every 48 hours, the classic benign tertian periodicity. The fever can be as high as 40C (104F). The patient often feels much worse with falciparum malaria.

The typical paroxysm has an abrupt onset with a feeling of coldness and a chill. The teeth chatter and the patient covers himself. Within 30 to 60 minutes, the patient feels hot and has profuse sweating, usually a headache, malaise, and myalgia, along with a varying degree of other symptoms, e.g., nausea, vomiting, flushed face, dry and burning skin and convulsions. Temperatures of 40C to 41C (104F to 106F) are usual in primary falciparum infections, whereas with the other three species of plasmodia, fever peaks are usually lower (39C to 40C). The hot stage lasts from two to six hours. The sweating stage, in which the patient's temperature falls rapidly, lasts two to three hours. The entire paroxysm, which often begins in the early afternoon, averages nine to ten hours. Between paroxysms, the patient may feel well.

P.falciparum causes the most severe form of malarial infection. It may kill up to 25% of nonimmune adults within two weeks of a primary attack unless appropriate treatment is given.

All four species of malaria can cause chronic infections with fever occurring more than once. Recurrent parasitemia is due to proliferation of persistent erythrocytic forms and is known as recrudescence. Recru-descences occur for P. falciparum and P. malariae which have no persistent exo-erythrocytic phase. For P.vivax and P.ovale, relapses are due to persistence of parasitic forms in the liver.

Congenital malaria is rare, and its occurrence is associated with low immunity in the mother. Therefore, most cases of congenital malaria appear in areas where the prevalence of malaria is low or involve nonimmune mothers. Passive transfer of antibody across the placenta helps to protect neonates for the first six to 12 months of life. Malaria is an important cause of abortions, stillbirths and low birth weight, as well as neonatal and infant mortality.


Complications include: Splenic Rupture Cerebral Malaria is a frequent cause of mortality, especially in children and nonimmune adults. It usually develops slowly over several days but may occur early in the illness. A severe headache ap-pears. The patient becomes increasingly drowsy and confused and, if not treated rapidly, becomes de-lirious and then comatose. Hallucinations occur and the patient may appear drunk. Inpatients with cerebral malaria, very high fever, i.e., 41C to 42C (106F to 108F), can occur. The skin is often flushed and dry, as in heat stroke. Hyperpyrexia requires immediate treatment to reduce the fever. Hemolytic Anemia can be severe in patients with high parasitemias ( 5%) and in non-immune in-dividuals. Sudden intravascular hemolysis can lead to acute renal failure. Renal Failure: Mild proteinuria, azotemia and oliguria occur frequently in heavy P. falciparum in-fections. Acute renal failure often complicates severe falciparum infections with high parasitemia, and marked hemolysis in an acute tubular necrosis results from renal anoxia, a reduced renal blood flow, and deposition of hemoglobin in the renal tubules. Anuria is a poor prognostic sign, requiring peritoneal dialysis or hemodialysis. Blackwater Fever: Severe hemolysis, hemoglobinuria and renal failure make up the clinical triad of "blackwater fever."

6-Laboratory Tests 6.1-Blood Smears Definitive diagnosis of malaria depends on microscopic demonstration of parasites in the peripheral blood film.

For detection of organisms, the thick blood film is superior because it concentrates the red blood cells by a factor of 20 to 40 times. A thick film will yield three to four times as many positive findings as a thin smear and will reveal plasmodia in virtually all active clinical cases. Identification of species in the thick film is difficult because the red cells are lysed in the staining procedure and there is alteration of the mor-phologic features of the parasites. For positive identification of species, a thin blood film is often neces-sary. Thick and thin films can be made on the same slide. In doubtful cases, it may be necessary to repeat thick blood smears every four to six hours until the diagnosis is made. 6.2-Timing: Symptoms may precede detectable parasitemia by one to two days. Timing of blood smears is less im-portant than obtaining several smears daily in order to make the diagnosis. Quantitation of parasitemia is useful in following the response to therapy.

Blood smears should be stained with Giemsa stain. Leishman's stain and Wright's stain can also be used but are not as good. Rapid staining may be done with Field's stain, although this stain is less permanent.

The most important initial distinction to make is whether P. falciparum is present, because this parasite is frequently life threatening. Species identification may require expert opinion; many physicians are not sufficiently experienced in morphologic differentiation. P. falciparum is suggested by criteria such as small ring size, banana-shaped gametocytes, multiple parasites in a single erythrocyte, parasitemia greater than 2% of the red blood cells, and predominance of rings with few trophozoites and no schizonts. 6.3-Plasmodium falciparum [Centers for Disease Control and Prevention (CDC)]

https://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Pfalciparum_benchaidV2.pdf


6.4-Plasmodium vivax


6.5-Plasmodium ovale

6.6-Plasmodium malariae


The presence of granular brownish pigment in monocytes or leukocytes should alert physicians to malaria even in the absence of demonstrated parasitemia.

Parasites may also be demonstrated in a bone marrow specimen, but this is rarely required.

Antibodies, demonstrable by IFA, will appear after the first week of infection but may persist for years and is of limited use in diagnosis since it cannot differentiate between current and past infections. They are not useful for the diagnosis of acute illness. 7-Treatment

Overdosage of antimalarial drugs can be fatal. Parents should be advised to keep drugs in childproof con-tainers out of the reach of children.

7.1.Treatment: General Approach

Treatment for malaria should not be initiated until the diagnosis has been confirmed by laboratory inves-tigations. "Presumptive treatment" without the benefit of laboratory confirmation should be reserved for extreme circumstances (strong clinical suspicion, severe disease, impossibility of obtaining prompt labor-atory confirmation).

Once the diagnosis of malaria has been confirmed, appropriate antimalarial treatment must be initiated immediately. Treatment should be guided by three main factors: the infecting Plasmodium species, the clinical status of the patient and the drug susceptibility of the infecting parasites as determined by the ge-ographic area where the infection was acquired.

Determination of the infecting Plasmodium species for treatment purposes is important for three main reasons:

P. falciparum infections can cause rapidly progressive severe illness or death while the non-falciparum ( P. vivax, P. ovale, or P. malariae) species rarely cause severe manifestations;

P. vivax and P. ovale infections require treatment for the hypnozoite forms that remain dormant in the liver and can cause a relapsing infection

and P. falciparum and P. vivax species have different drug resistance patterns in differing geo-graphic regions

7.2- P. falciparum Infections The urgent initiation of appropriate therapy is especially critical. The second factor affecting treatment is the clinical status of the patient. Patients diagnosed with malaria are generally categorized as having ei-ther uncomplicated or severe malaria. Patients diagnosed with uncomplicated malaria can be effectively treated with oral antimalarials. However, patients who have one or more of the following clinical criteria (impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, acute respira-tory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding,


acidosis, hemoglobinuria, jaundice, repeated generalized convulsions and/or parasitemia of > 5%) are considered to have manifestations of more severe disease and should be treated aggressively with paren-teral anti-malarial therapy.

Finally, knowledge of the geographic area where the infection was acquired provides information on the likelihood of drug resistance of the infecting parasite and enables the treating clinician to choose an ap-propriate drug or drug combination and treatment course. If the diagnosis of malaria is suspected and cannot be confirmed, or if the diagnosis of malaria is confirmed but species determination is not possible, antimalarial treatment effective against P. falciparum must be initiated immediately.

After initiation of treatment, the patient's clinical and parasitologic status should be monitored. In infec-tions with P. falciparum or suspected chloroquine-resistant P. vivax, blood smears should be made to con-firm adequate parasitologic response to treatment (decrease in parasite density followed by clearance). 7.3-P. falciparum or Species Not Identified

For P. falciparum infections acquired in areas without chloroquine-resistant strains, which include Central America west of the Panama Canal, Haiti, the Dominican Republic and most of the Middle East, patients should be treated with oral chloroquine. A chloroquine dose of 600 mg base (= 1,000 mg salt) should be given initially, followed by 300 mg base (= 500 mg salt) at 6, 24, and 48 hours after the initial dose for a total chloroquine dose of 1,500 mg base (= 2,500 mg salt). As a second line alternative for treatment, a hydroxychloroquine dose of 620 mg base (= 800 mg salt) po can be given immediately, followed by 310 mg base (= 400 mg salt) po at 6, 24, and 48 hours after the initial does for a total hydroxychloroquine dose of 1,550 mg base (= 2,000 mg salt). For P. falciparum infections acquired in areas with chloroquine-resistant strains, three treatment options are available. The first two treatment options are quinine sulfate plus doxycycline, tetracycline, or clindamycin; or atovaquone-proguanil (Malarone). Both of these options are very efficacious. For the quinine sulfate combination options, quinine sulfate plus either doxycycline or tetracycline is generally preferred to quinine sulfate plus clindamycin because there are more data on the efficacy of quinine plus doxycycline or tetracycline. Quinine treatment should continue for seven days for infections acquired in Southeast Asia and for three days for infections acquired in Africa or South America. The third option, mefloquine, is associated with a higher rate of severe neuropsychiatric reactions when used at treatment doses. This third option is recommended only when the quinine sulfate combination or atovaquone-proguanil options cannot be used.

For pediatric patients, the treatment options are the same as for adults except the drug dose is adjusted by patient weight. The pediatric dose should never exceed the recommended adult dose. For children young-er than eight years old, doxycycline and tetracycline are generally not indicated; therefore, quinine (given alone for a full seven days regardless of where the infection was acquired or given in combination with clindamycin as recommended above), and atovaquone-proguanil are recommended treatment options for chloroquine-resistant P. falciparum infections; mefloquine can be considered if these options are not available. In rare instances, doxycycline or tetracycline can be used in combination with quinine in chil-dren younger than eight years old if other treatment options are not available or are not tolerated, and the benefit of adding doxycycline or tetracycline is judged to outweigh the risk.

If infections initially attributed to “species not identified” are subsequently diagnosed as being due to P. vivax or P. ovale, additional treatment with primaquine should be administered (see P. vivax and P. ovale, below). 7.4-P. malariae

There has been no widespread evidence of chloroquine resistance in P. malariae species; therefore, chlo-roquine remains the drug of choice for all P. malariae infections. As a second line alternative for treat-ment, hydroxychloroquine may be given instead. 7.5-P. vivax and P. ovale Chloroquine (hydroxychloroquine as second line alternative for treatment) remains the treatment of choice for all P. vivax and P. ovale infections except for P. vivax infections acquired in Papua New Guin-


ea or Indonesia. Reports have confirmed a high prevalence of chloroquine-resistant P. vivax in these two specific areas. Rare case reports of chloroquine-resistant P. vivax have also been documented in Burma (Myanmar), India, and South America. Persons acquiring P. vivax infections from regions other than Pa-pua New Guinea or Indonesia should initially be treated with chloroquine. If the patient does not respond to chloroquine, treatment should be changed to one of the two regimens recommended for chloroquine-resistant P. vivax infections.

Persons acquiring P. vivax infections in Papua New Guinea or Indonesia should initially be treated with a regimen recommended for chloroquine-resistant P. vivax infections. The two treatment regimens for chlo-roquine-resistant P. vivax infections are quinine sulfate plus doxycycline or tetracycline, or mefloquine. These two treatment options are equally recommended. There are no adequate, well-controlled studies to support the use of atovaquone-proguanil to treat chloroquine-resistant P. vivax infections.

In addition to requiring blood stage treatment, infections with P. vivax and P. ovale can relapse due to hypnozoites that remain dormant in the liver. To eradicate the hypnozoites, patients should be treated with a 14-day course of primaquine phosphate. The CDC has recently changed its recommendations for treat-ing hypnozoites by increasing the recommended primaquine phosphate dose to 30 mg (base) by mouth daily for 14 days. Because primaquine can cause hemolytic anemia in persons with glucose-6-phosphate-dehydrogenase (G6PD) deficiency, persons must be screened for G6PD deficiency prior to starting pri-maquine treatment. For persons with borderline G6PD deficiency or as an alternate to the above regimen, primaquine may be given at the dose of 45 mg (base) orally one time per week for eight weeks; consulta-tion with an expert in infectious disease and/or tropical medicine is advised if this alternative regimen is considered in G6PD-deficient persons. Primaquine must not be used during pregnancy.

For pediatric patients, the treatment options are the same as for adults except the drug dose is adjusted by patient weight. The pediatric dose should never exceed the adult recommended adult dose. For children younger than eight years old, doxycycline and tetracycline are generally not indicated; therefore, quinine (given alone for seven days) or mefloquine are recommended treatment options for chloroquine-resistant P. vivax infections. In rare instances, doxycycline or tetracycline can be used in combination with quinine in children younger than eight years old if other treatment options are not available, are not being tolerat-ed and the benefit of adding doxycycline or tetracycline is judged to outweigh the risk. Primaquine should be given to pediatric patients only after they have been screened for G6PD deficiency.

The choice of malaria chemotherapy is based on the infecting species, possible drug resistance and the severity of disease. Severe malaria is defined as a parasitemia greater than 5%, signs of central nervous system or other end-organ involvement, shock, acidosis and/or hypoglycemia. Patients with severe malar-ia require intensive care and parenteral treatment until the parasite density falls below 1% and they are able to tolerate oral therapy. Exchange transfusion may be warranted when parasitemia exceeds 10%. 7.6-Antimalarials: Adverse Reactions and Contraindications

Most drugs used in treatment are active against the parasite forms in the blood (the form that causes dis-ease) and include:

Chloroquine Atovaquone-proguanil (Malarone®) Artemether-lumefantrine (Coartem®) Mefloquine (Lariam®) Quinine Quinidine Doxycycline (used in combination with quinine) Clindamycin (used in combination with quinine) Artesunate (not licensed for use in the United States, but available through the CDC malaria hot-

line) https://www.cdc.gov/malaria/diagnosis_treatment/artesunate.html .


Most antimalarial drugs are well-tolerated; most travelers do not need to stop taking their drug because of side effects. However, if the traveler is particularly concerned about side effects, discuss the possibility of starting their drug early (three to four weeks in advance of their trip). If the drug cannot be tolerated, another antimalarial drug should be prescribed

7.6.1-Chloroquine Phosphate and Hydroxychloroquine Sulfate Side effects that can occur include gastrointestinal disturbance, headache, dizziness, blurred vision, in-somnia and pruritus, but generally these effects do not require that the drug be discontinued. High doses of chloroquine, such as those used to treat rheumatoid arthritis, have been associated with retinopathy; this serious side effect appears to be extremely unlikely when chloroquine is used for routine weekly ma-laria prophylaxis. Chloroquine and related compounds may exacerbate psoriasis. 7.6.2-Atovaquone/proguanil The most common adverse effects reported in persons using atovaquone/proguanil for prophylaxis are abdominal pain, nausea, vomiting and headache. Atovaquone/proguanil should not be used in infants less than 5 kg, pregnant women, women breast-feeding infants less than 5 kg, or patients with severe renal impairment (creatinine clearance < 30mL/min). 7.6.3-Artemisin Although quinine may often produce side effects, it is effective in vivo against all strains of P. falciparum studied thus far. Because quinidine is two–to-threefold more active than quinine, because its serum and plasma levels can be measured in most American hospitals and because parenteral quinine is no longer available in the U.S., quinidine is preferable to quinine for parenteral use in the United States.

Artemisinin derivatives such as artemether are effective in children with P. falciparum infection; they may clear parasitemia and coma more rapidly than does quinine. A controlled study in Thailand has sug-gested that intravenous artesunate followed by mefloquine is more effective than either artesunate or mef-loquine alone and may prevent the late recrudescences typically observed with artesunate alone. Addition-al controlled studies suggest that artemisinin suppositories may clear P. falciparum parasitemia as rapidly as intravenous artesunate, and that artemether is as effective as quinine for severe and cerebral malaria. Because artemisinin treatment is frequently associated with late recrudescences, additional drugs such as mefloquine, tetracycline, or pyrimethamine sulfadoxine are often given after the initial treatment with artemisinin to prevent recrudescence three to four weeks later. Anecdotal reports of embryo toxicity in rats and mice and pathologic evidence of neurotoxicity in dogs suggest that artemisinin derivatives should not be given to pregnant women and should be used with caution until these issues have been resolved. Note that comparative studies of artemether and quinine have not found an increase in neurotoxicity with artemether.] As with quinine, there is no evidence of high-level resistance to artemisinin or its derivatives 7.6.4-Mefloquine Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have resistance to multiple medications, and is one of several antimalarial medications recommended by the CDC for this purpose. It is also recommended by the Infectious Disease Society of America for malaria prophylaxis as a first or second-line agent, depending on resistance patterns in the malaria found in the geographic region visited. It is typically taken for one to two weeks before entering an area with malaria. Doxycycline and atovaquone/proguanil provide protection within one to two days and may be better tol-erated. If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of halofan-trine and quinine for treatment may be ineffective.

Mefloquine has been associated with rare serious adverse reactions (e.g. psychoses or seizures), at prophylactic doses; these reactions are more frequent with the higher doses used for treatment. Other side effects that occur with prophylactic doses include gastrointestinal disturbance, headache, insomnia, ab-normal dreams, visual disturbances, depression, anxiety disorder and dizziness. Other more severe neuro-psychiatric disorders occasionally reported during post-marketing surveillance include sensory and motor neuropathies (including parasthesia, tremor and ataxia), agitation or restlessness, mood changes, panic attacks, forgetfulness, confusion, hallucinations, aggression, paranoia and encephalopathy. On occasions, psychiatric symptoms have been reported to continue long after mefloquine has been stopped. During


prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness, or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be dis-continued and an alternative drug substituted.

Mefloquine is contraindicated for use by travelers with a known hypersensitivity to mefloquine or related compounds (e.g. quinine and quinidine) and in persons with active depression, a recent history of depres-sion, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders. Meflo-quine is contraindicated in persons with a history of seizures (not including the type of seizure caused by high fever in childhood). It should be used with caution in persons with psychiatric disturbances or a pre-vious history of depression. A review of available data suggests that mefloquine may be used in persons concurrently on beta blockers, if they have no underlying arrhythmia. However, mefloquine is not rec-ommended for persons with cardiac conduction abnormalities. Any traveler receiving a prescription for mefloquine must also receive a copy of the Food and Drug Administration (FDA) Medication Guide https://www.fda.gov/downloads/Drugs/Drugsafety/ucm088616.pdf. 7.6.5-Primaquine The most common adverse event in G6PD-normal persons is gastrointestinal upset if primaquine is taken on an empty stomach—this problem is minimized or eliminated if primaquine is taken with food.

Primaquine can cause hemolysis in G6PD-deficient persons, which can be fatal. Before primaquine is used, G6PD deficiency MUST be ruled out by appropriate laboratory testing. 7.6.6-Quinine and Quinidine -Since 1991, quinidine gluconate has been the only parenterally administered antimalarial drug available in the United States. It will no longer be available in the U.S. for the treatment of severe malaria. Quinine is still available in many countries. It comes as: - tablet 200 mg, 300 mg base (as sulfate) - injection 150 mg, 300 mg base (as dihydrochloride) per ml in 2-ml ampoule 9quinine anhydrous base 100 mg is equivalent to 122 mg of quinine hydrochloride dihydrate or quinine dihydrochloride or 121 mg of quinine sulfate dehydrate).

Quinine, an alkaloid derived from the bark of the cinchona tree, is a blood schizontocidal agent that is more toxic than chloroquine. Its use has become reestablished because of the widespread emergence of chloroquine-resistant - and, more recently, multiple-drug-resistant - strains of malarial parasites.

Quinine is rapidly absorbed when taken orally and peak plasma concentrations are attained after one to three hours. It is highly protein-bound but it readily crosses the placental barrier and small amounts pene-trate into the cerebrospinal fluid. It is metabolized in the liver, has a plasma half-life of 10 hours and is subsequently excreted in the urine, mainly as hydroxylated metabolites.

Quinine is used in the treatment of falciparum malaria in areas of multiple-drug-resistant P. falciparum. It is administered parenterally to patients with severe or complicated malaria who cannot take drugs by mouth because of coma, convulsions or vomiting. It is administered orally to less seriously ill patients with infections likely to be resistant to chloroquine or mefloquine, sometimes in combination with py-rimethamine/sulfadoxine or a tetracycline.

Quinine should be given orally for the treatment of uncomplicated multi-drug-resistant falciparum malaria and to complete the treatment of patients with severe or complicated malaria, who are initially treated parenterally. If part or all of a dose is vomited within one hour, the same amount must be readministered immediately. Adults: 500 mg (equivalent to quinine sulfate dihydrate 600 mg) every eight hours for three, seven or 10 days. Children: 8.2 mg (equivalent to quinine sulfate dihydrate 10 mg)/kg every eight hours for three, seven or 10 days.

The duration of treatment depends on the local susceptibility of P. falciparum to quinine and on whether treatment is combined with pyrimethamine/sulfadoxine or tetracycline.


-Whenever possible, blood glucose should be monitored throughout treatment. Both the disease itself and the administration of quinine may promote insulin secretion and induce hypoglycaemia. This may require correction by infusion of a 20% or 50% glucose solution. In patients who are seriously ill, treat-ment should always be accompanied by continuous infusion of carbohydrates.

Hemolysis can occasionally be severe enough to warrant discontinuation of quinine treatment if an alter-native is available.

-Quinine should not be withheld during pregnancy, despite its alleged abortifacient properties at high dosage, since it safeguards the life of the mother.

Attention should be given to the considerable risk of hypoglycemia in pregnant women with severe ma-laria.

-Serious reactions are infrequent provided the plasma concentration is not allowed to rise above 15 mg/l.

Signs of mild to moderate cinchonism (tinnitus, headache, blurred vision, altered auditory acuity, nausea and diarrhea) often supervene after the third day of treatment. These rarely, if ever, constitute grounds for withdrawal. However, if, as a result of non-compliance, quinine has to be withdrawn prematurely, tetra-cycline must be administered for a further seven days.

Idiosyncratic reactions can also occur, but they are uncommon. They include pruritic, urticarial or erythematous rashes, subcutaneous or submucous hemorrhage, and edema of the eyelids, mucous membranes and lungs. Hemoglobinuria and asthma are rare.

Hypoglycemia should be treated promptly with supplementary glucose. Renal damage, culminating in acute renal failure and anuria, is a frequent terminal event in malar-

ia. Rarely, anuria is a consequence of blackwater fever, a syndrome comprising massive hemoly-sis, hemoglobinemia and hemoglobinuria. Although this has been ascribed in the past to inade-quate quinine therapy, the supporting evidence is insecure. Blackwater fever certainly occurs in patients who have not received treatment with quinine.

Dose-related adverse effects are largely limited to the cardiovascular, gastrointestinal and central nervous systems. They usually arise from excessive infusion, but quinine accumulation can result from oral administration.

-Overdosage: The most frequently encountered signs of overdosage are: • Tinnitus, decreased auditory acuity and vertigo. Permanent deafness has resulted from exposure to toxic

doses. • Amblyopia, constricted visual fields, diplopia and night blindness. Recovery is slow but usually com-

plete. • Quinidine-like effects resulting in hypotension, conduction disturbances, anginal symptoms and ventric-

ular tachycardia. • Hypoglycemia. • A local irritant effect on the gastrointestinal tract resulting in nausea, vomiting, abdominal pain and diar-rhea.

A single oral dose greater than 3g is capable of causing serious and potentially fatal intoxication in adults, preceded by depression of the central nervous system and seizures. Much smaller doses can be lethal in children.

Dysrhythmias, hypotension and cardiac arrest can result from the cardiotoxic action and ocular toxicity can lead to blindness.

Emesis should be induced and gastric lavage undertaken as rapidly as possible. Activated charcoal should then be administered.

Supportive measures, to be employed as necessary, include ventilation, and symptomatic treatment of dysrhythmias, cardiac failure and convulsions. No specific measures of proven efficacy exist to reduce the toxicity or to promote the excretion of quinine.


7.6.7-Doxycycline Doxycycline can cause sun sensitivity, usually manifested as an exaggerated sunburn reaction. Travelers on doxycycline should be advised to protect themselves by avoiding prolonged sun exposure and by using sunscreen that absorbs long-wave UVA radiation.

Doxycycline use may be associated with an increased frequency of Candida vaginitis. Travelers should be advised to take an over-the-counter yeast medication or a prescription drug or cream.

Gastrointestinal side effects (nausea or vomiting) may be minimized by taking the drug with a meal and a full glass of water. Travelers should be advised not to take doxycycline before going to bed to avoid esophagitis.

Doxycycline should not be taken by persons allergic to tetracyclines, pregnant women and by children younger than eight years of age.

Vaccination with the oral typhoid vaccine Ty21a should be delayed for more than 24 hours after taking a dose of doxycycline. 7.6.8- Halofantrine (Marketed as Halfan) Halofantrine is widely used overseas to treat malaria. The CDC does not recommend the use of Halfan because of serious cardiac complications, including death. Travelers should be advised to avoid Halfan unless they have been diagnosed with life-threatening malaria and no other options are immediately avail-able. 7.6.9-Clindamycin Clinical trials from the 1970s and 1980s have shown the efficacy, safety, and practicability of the treat-ment of Plasmodium falciparum malaria with clindamycin. Two reviews from the early 1990s have sum-marized these studies in detail. Since then, interest in clindamycin as an antimalarial has renewed and a number of recent clinical trials have evaluated clindamycin, both alone and as a partner in a combination, as a treatment for malaria.

Clindamycin (7-chloro-lincomycin) is a semisynthetic derivative of lincomycin and was introduced in the 1960s as an antibiotic.

It is available as clindamycin hydrochloride for oral administration in capsules, as clindamycin phosphate for intramuscular or intravenous injection, and as clindamycin palmitate for oral suspensions.

When given orally, clindamycin is well absorbed and peak concentrations are found after about 45 minutes. It is metabolized into three major, biologically active derivatives and is mainly excreted into the bile, with about 20% excreted by the kidneys. The normal elimination half-life of about two to four hours is not altered in patients with severe renal disease, but impaired liver function leads to a prolongation of elimination.

The activity of clindamycin against anaerobic bacteria makes it an important agent in clinical practice. Furthermore, it is active against organisms such as Plasmodium, Toxoplasma, Babesia,and Pneumocyst-is spp. Clindamycin is the drug of choice for prophylaxis of Toxoplasma chorioretinitis in newborn in-fants and is part of recommended regimens against both Babesia microti and Babesia divergens. In com-bination with pyrimethamine or primaquine, it is an alternative regimen for the treatment of toxoplasmo-sis and pneumocystosis, respectively.

In vitro, clindamycin and its three major metabolites show strong inhibitory effects on P. falciparum , possibly by targeting the apicoplast. The drug accumulates slowly in the parasite. This is reflected in dose-response curves that show a plateau effect at concentrations above 0.01 μg/ml and demonstrates that a relevant inhibition can be achieved only through an exposure over more than three days. This could ex-plain the slow onset of clinical action seen in vivo.


7.6.10-Artesunate Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinidine for severe malaria. Often it is used as part of combination therapy. It is not used for the prevention of malaria. Artesunate can be given by IV, IM, or taken by mouth.

Artesunate is generally well tolerated. Side effects may include a slow heartbeat, allergic reaction, dizzi-ness, and low white blood cell levels. During pregnancy it appears to be a safer option, even though ani-mal studies have found harm to the baby. Use is likely alright during breastfeeding. It is in the artemis-inin class of medication.

Artesunate is on the World Health Organization's (WHO) List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is $2.09 to $2.57 USD per dose. It is not commercially available in the United States; however, it can be gotten from the CDC. Artesunate was originally made from the sweet wormwood plant.

Artesunate is the first-line, WHO-recommended treatment for severe malaria but is neither FDA-approved nor commercially available in the United States, the CDC said in a statement. It is unknown when IV artesunate will be FDA approved, as the approval process requires a drug company to submit a new drug application to FDA. Since 2007, the CDC has made IV artesunate available under an investiga-tional new drug (IND) protocol in cases where quinidine is not available, not tolerated, or not working. The CDC said that it anticipates the supply of IV artesunate available under this IND protocol, will be sufficient to treat the number of severe malaria cases that occur in the United States. 7.6.11-Tafenoquine Tafenoquine under the commercial name of Krintafel is an 8-aminoquinoline drug investigated as a po-tential treatment for malaria, as well as for malaria prevention.

The proposed indication for tafenoquine is for treatment of the hypnozoite stages of Plasmodium vi-vax and Plasmodium ovale that are responsible for relapse of these malaria species even when the blood stages are successfully cleared. This is only now achieved by administration of daily primaquine for 14 days. The main advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment may be sufficient to clear hypnozoites. The shorter regimen has been described as an advantage.

Like primaquine, tafenoquine causes hemolysis in people with G6PD deficiency. Indeed, the long half-life of tafenoquine suggests that particular care should be taken to ensure that individuals with severe G6PD deficiency do not receive the drug.

The dose of tafenoquine has not been firmly established, but for the treatment of Plasmodium vivax ma-laria, a dose of 800 mg over three days has been used.

In 2018, the U.S. FDA approved single dose tafenoquine for the radical cure (prevention of relapse) of Plasmodium vivax malaria.

7.6.12-Changing Medications during Chemoprophylaxis as a Result of Side Effects Antimalarial drugs have different modes of action that affect the parasite at different stages of the life cy-cle. If medications need to be changed because of side effects, there are some special considerations. Travelers who start with medications such as mefloquine or doxycycline, but must switch to ato-vaquone/proguanil during or after travel, should continue their atovaquone/proguanil for four weeks after switching or one week after returning, whichever is longer, but not beyond four weeks after return. Assistance with the management of travelers who need to discontinue their antimalarial drug and switch to another is available at the CDC Malaria Hotline (770-488-7788). 7.6.13-Treatment of Chloroquine-Susceptible Plasmodium vivax, Plasmodium ovale, Plasmodium malar-iae and Plasmodium falciparum Chloroquine-susceptible infections may be treated orally using a total dose of 25 mg chloroquine base/kg given over three days. Patients unable to take oral medications may be treated initially with parenteral chloroquine and then switched to oral chloroquine when they are able to take oral medications. Even for persons with central nervous system involvement, there are no advantages of quinine (or other antimalari-


al agents) over chloroquine for infections due to chloroquine-susceptible parasites. Halofantrine is contra-indicated in pregnant or lactating women. Because of its arrhythmogenic potential, intravenous chloro-quine must be given as a carefully controlled infusion to avoid a large bolus in the heart. Pruritus is an important side effect of chloroquine (and halofantrine), and is particularly common in sub-Saharan Afri-ca, although its pathogenesis is unclear. 7.6.14-Treatment of Chloroquine-Resistant Plasmodium falciparum Persons able to take oral medications may be treated with quinine, mefloquine, halofantrine, or py-rimethamine sulfadoxine, assuming that they did not receive the same drug for chemoprophylaxis. Be-cause most parasites resistant to mefloquine are also resistant to halofantrine, halofantrine should not be used to treat persons who acquire P. falciparum infection while receiving mefloquine chemoprophylaxis. Halofantrine can result in prolongation of the QT interval and ventricular arrhythmias in susceptible per-sons receiving higher than recommended doses as well as in those with recent or concurrent mefloquine therapy, QT prolongation, or thiamine deficiency. Because fatalities have occurred with halofantrine, al-ternative drugs are preferred when possible. Halofantrine is contraindicated in pregnant or lactating wom-en. Because resistance to pyrimethamine sulfadoxine is common in areas with chloroquine resistance, persons given pyrimethamine sulfadoxine should be watched carefully to ensure that the drug is effective. 7.6.15-Treatment of Chloroquine-Resistant Plasmodium vivax Thus far, all persons with chloroquine-resistant P. vivax infection have responded to treatment with oral mefloquine or halofantrine. 8-Surveillance

Malaria is a condition reportable within one business day of the diagnosis. 8.1-Case Definition

Clinical Description Signs and symptoms are variable; however, most patients experience fever. In addition to fever, common symptoms include headache, back pain, chills, sweats, myalgia, nausea, vomiting, rarely diarrhea and cough. Untreated Plasmodium falciparum infection can lead to coma, renal failure, pulmonary edema and death. The diagnosis of malaria should be considered for any person who has these symptoms and who has traveled to an area in which malaria is endemic. Asymptomatic parasitemia can occur among persons who have been long-term residents of areas in which malaria is endemic.

Laboratory Criteria for Diagnosis: Demonstration of malaria parasites in blood films or detection of species-specific parasite DNA using nucleic acid testing.

Case Classification: Confirmed - an episode of microscopically confirmed malaria parasitemia or detection of Plasmodium species by nucleic acid test in any person (symptomatic or asymptomatic) diagnosed in the United States, regardless of whether the person experienced previous episodes of malaria while outside the country.

Comment: A subsequent attack experienced by the same person but caused by a different Plasmodium species is counted as an additional case. A subsequent attack experienced by the same person and caused by the same species in the U.S. may indicate a relapsing infection or treatment failure caused by drug resistance.

Cases are also classified according to the following WHO categories:

Indigenous: malaria acquired by mosquito transmission in an area where malaria is a regular occurrence Introduced: malaria acquired by mosquito transmission from an imported case in an area where malaria is not a regular occurrence Imported: malaria acquired outside a specific area (e.g., the United States and its territories)


Induced: malaria acquired through artificial means (e.g., blood transfusion, common syringes, or malari-otherapy) Relapsing: renewed manifestation (i.e., of clinical symptoms and/or parasitemia) of malarial infection that is separated from previous manifestations of the same infection by an interval greater than any interval resulting from the normal periodicity of the paroxysms Cryptic: an isolated case of malaria that cannot be epidemiologically linked to additional cases 8.2-Investigation

The purpose of investigation is to confirm suspected cases and identify species, to document recent travel history and to identify other travelers who may have been exposed and classify the case according to epi-demiologic origin.

Upon receipt of a report of a malaria case, contact the physician and/or hospital to confirm the diagnosis. Verify the species of malaria.

Investigate the source of exposure, i.e. recent travel history, blood transfusion, foreign residence, etc. and document the history of malaria chemoprophylaxis.

Identify any other individuals at risk, (i.e., fellow travelers or blood bank, etc.)

If a history of needle sharing is obtained from the patient, investigate and refer all persons who shared the equipment for treatment.

If the malaria is a transfusion-induced case, all donors must be located and their blood examined for ma-larial parasites and for antimalarial antibodies. Those individuals that are parasite-positive donors should be referred for treatment. 8.3-Hospital Precaution and Isolation: Standard precautions 9-Malaria Prevention for Travelers

P. falciparum malaria is a life threatening disease for all persons infected but especially for those who have been recently infected and have no immunity to it. Every year, some 10,000 U.S. travelers are in-fected during their travel and become sick when returning home. About 100 people die although preven-tion was possible. Globally, about two billion people are at risk of malaria, 270 million are infected and one million die from malaria each year. 9.1-Inform the Traveler About the Degree of Risk of Malaria Infection: To advise travelers on malaria risk and prophylaxis it is necessary to know the distribution of malaria worldwide (see map on page 18). There are four zones of malaria risk. Prophylaxis has to be adapted to the area:

Malaria-free areas: Western and Eastern Europe, U.S., Canada, former U.S.S.R., northern Asia (Ko-rea, Japan), Australia, North Pacific Islands, most South Pacific Islands (from New Caledonia to Easter Islands). Low-risk malaria, P. vivax and P. malariae, no chloroquine resistant P. falciparum (CRPF) or no P. falciparum: Southwest Saudi Arabia, Egypt and most of the Middle East, Iran, China, Peru and Bo-livia. Malaria transmission is seasonal and low. There is no risk in urban and in high altitude areas. Low-risk malaria but some CRPF: Southern part of the Arabian peninsula, Afghanistan, Pakistan, most of India and Philippines. High-risk malaria and CRPF: Inter-tropical Africa, Amazon basin, the Indochinese peninsula, Indo-nesia, New Guinea, Solomon Islands and Vanuatu.


Malaria Endemic Areas

1 No malaria risk 2 Low risk, no chloroquine resistant Plasmodium falciparum 3 Low risk, some chloroquine resistant Plasmodium falciparum 4 High risk, chloroquine resistant Plasmodium falciparum

9.2-Recommend Precautions Against Mosquito Bites. This advice is as important as the prophylactic treatment.

Avoid going out at night or wear long sleeve shirts and long trousers and avoid dark colors which attract mosquitoes. Apply insect repellent (with NN diethyl-m-toluamide -DEET- or dimethyl phtalate). Follow the in-structions on the bottle. Do not exceed the dose, particularly in children. Spend nights in well-maintained buildings with screened doors and windows. If the building is not insect-proof, sleep under a mosquito net. Make sure that the net is not torn and that no mosquitoes are trapped inside. Tuck the net under the mattress. Insecticide sprays, electric insecticide dispenser with pyrethroid tablets and pyrethroid mosquito coil are useful but do not replace a good mosquito net.

9.3-Prophylactic Treatment: The decision is based on the risk of malaria in the country AND the area traveled.

Travelers who spend a short stop over in a major city with sightseeing in the city are at very low risk and often prophylaxis is not recommended. Travelers who take trips to rural areas, particularly if they spend some nights in rural areas, should take some prophylaxis.

Prophylactic treatment should start a week before departure (loading dose and to check for any immediate serious side effects). Patients should understand that prophylactic treatment DOES NOT prevent infec-tion, it only suppresses disease. It must be taken for the whole time the traveler is in the malarious area and continued for no less than four weeks (some recommend up to eight weeks) after return to a malaria-free area. They must seek prompt medical attention if they become ill.


Prophylaxis recommendation according to malaria risk (see map on page 18)

Malaria risk Areas traveled Prophylaxis 2 Low,

no CRPF Urban, daytime rural

Rural overnight None

Chloroquine 3

Low, some CRPF

Urban, daytime rural Rural overnight

None Chloroquine or

Chloroquine/Proguanil (*) 4

High, CRPF Stop-over in large urban

All other

None Mefloquine or Chloroquine/Proguanil or Doxycycline Avotaquone/Proguanil

(*) If proguanil is not available, use mefloquine instead of chloroquine/proguanil 9.4-Stand-by Treatment Used for travelers taking long trips (safaris, hiking trips) to rural areas during which prompt medical help will not be available. The treatment should be completed and prophylaxis resumed seven days after the first dose of stand-by treatment. The traveler must understand that stand-by treatment is only a temporary measure and that medical advice should be sought after self-treatment. Make sure that the traveler under-stands not to use the same dose in children. 9.5-Immediate Treatment

9.5.1-Advise the Traveler to Seek Immediate Treatment in Case of Fever. The traveler must understand that malaria can kill if treatment is delayed. (This is probably the most im-portant message that the traveler should leave with). Any symptoms, even mild symptoms appearing one week or more after entry into a malaria endemic area and up to two months after return could be due to malaria: Headache, muscular ache (particularly backache), sensation of fatigue or weakness, fever, nau-sea, vomiting or loose stools and cough could be the early signs of malaria. Prompt medical advice should be sought. Beware of physicians who rule out malaria without taking a blood smear (finger stick and ap-plication of a drop of blood on the slide). Be aware that at the early stages of malaria, a blood smear may be negative and that if symptoms persist, a repeat blood smear is necessary. The patient should always state that he/she has traveled through a malarious area when seeking medical attention. 9.5.2-Malaria Deaths Most malarial deaths among travelers have occurred because the traveler delayed seeking medical atten-tion, or did not mention the history of travel in a malarious area, or the physician ignored that important clue, or the physician was falsely reassured by an early negative blood smear or the physician was misled by a false negative blood smear (early low density parasitemia are often missed if the lab does not per-form a thick smear examination). When the diagnosis of malaria becomes obvious, it may be too late for antimalarials to prevent the fatal outcome. 9.5.3-Presumptive Self-Treatment of Malaria

Drug Adult Dose Pediatric Dose Comments

Atovaquone/proguanil (Malarone). Self-treatment drug to be used if professional medical care is not available within 24 hours. Medical care should be sought immediately after treatment.

4 tablets (each dose contains 1,000 mg atovaquone and 400mg proguanil) orally as a single daily dose for 3 consec-utive days.

Daily dose to be taken for 3 consecutive days: 5-8 kg: 2 pediatric tablets 9-10 kg: 3 pediatric tablets 11-20 kg: 1 adult tablet 21-30 kg: 2 adult tablets 31-40 kg: 3 adult tablets ≥41 kg: 4 adult tablets

Contraindicated in persons with severe renal impairment (creatinine clearance <30mL/min). Not recom-mended for self-treatment in persons on atovaquone/ proguanil prophylaxis. Not currently recommended for children <5kg, pregnant wom-en, and women breastfeeding infants <5kg.


Travelers should be advised to take their presumptive self-treatment promptly if they have a fever, chills, or other influenza-like illness and if professional medical is not available within 24 hours. Travelers should be advised to seek medical care immediately after self-treatment. 9.6-Antimalarial Drug Dosages, Schedules and Warnings for Prophylaxis Overseas Advise patients that anti-malarial drugs are most effective if taken exactly on schedule without skipping doses and that their drug should be continued post-travel for the most complete protection. Antimalarial drugs should be purchased before travel; drugs purchased overseas may not be manufactured according to United States standards and may not be effective. They may also be dangerous, contain the wrong drug or an incorrect amount of active drug, or be contaminated. 9.6.1-Drugs Used in the Prophylaxis of Malaria

Drug Usage Adult Dose Pediatric Dose Comments

Atovaquone/proguanil (Malarone™)

Prophylaxis in areas with chlo-roquine-resistant or mefloquine-resistant Plasmo-dium falciparum

Adult tablets contain 250 mg atovaquone and 100 mg proguanil hy-drochloride. 1 adult tablet orally, daily

Pediatric tablets contain 62.5 mg atovaquone and 25 mg proguanil hydrochloride. 5-8 kg: 1/2 pedi-atric tablet daily ≥8-10 kg: 3/4 pediatric tablet daily ≥10-20 kg: 1 pediatric tablet daily ≥20-30 kg: 2 pediatric tablets daily ≥30-40 kg: 3 pediatric tablets daily ≥40 kg: 1 adult tablet daily

Begin 1-2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area, and for 7 days after leaving such areas. Contraindicated in persons with severe renal impairment (creati-nine clearance < 30mL/min). Atovaquone/proguanil should be taken with food or a milky drink. Not recommended for children < 5 kg, pregnant wom-en and women breastfeeding infants weighing <5 kg.

Chloroquine phosphate (Aralen™ and generic)

Prophylaxis only in areas with chloroquine-sensitive P. falci-parum

300 mg base (500 mg salt) orally, once/week

5 mg/kg base (8.3 mg/kg salt) orally, once/week, up to maximum adult dose of 300mg base

Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. May exacerbate psoriasis

Doxycycline (Many brand names and ge-neric)

Prophylaxis in areas with chlo-roquine-resistant or mefloquine-resistant P. falci-parum

100 mg orally, daily

8 years of age or more: 2 mg/kg up to adult dose of 100mg/day

Begin 1-2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in children < 8 years of age and pregnant wom-en.

Hydroxychloroquine sulfate (Plaquenil™)

An alternative to chloroquine for primary prophy-laxis* only in areas with chlo-roquine-sensitive P. falciparum


5 mg/kg base (6.5 mg/kg salt) orally, once/week, up to maximum adult dose of 310 mg base.

Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. May exacerbate psoriasis


Drug Usage Adult Dose Pediatric Dose Comments

Mefloquine (Lariam™ and generic)

Prophylaxis in areas with chlo-roquine-resistant P. falciparum


≤9 kg: 4.6 mg/kg base (5 mg/kg salt) orally, once/week 10-19 kg: ¼ tab-let once/week 20-30 kg: ½ tab-let, once/week 31-45 kg: ¾ tab-let once/week ≥46 kg: 1 tablet, once/week

Begin 1-2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Contraindicated in persons al-lergic to mefloquine or related compounds (e.g. quinine and quinidine), and in persons with active depression, a recent histo-ry of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psy-chiatric disorders, or seizures. Use with caution in persons with psychiatric disturbances or a previous history of depression. Not recommended for persons with cardiac conduction abnor-malities.

Primaquine An option for prophylaxis in special circum-stances. Call Ma-laria Hotline (770-488-7788) for additional information.

30 mg base (52.6 mg salt) orally, daily

0.5 mg/kg base (0.8 mg/kg salt) up to adult dose, orally, daily

Begin 1-2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in persons with G6PD1 deficiency. Also contra-indicated during pregnancy and lactation unless the infant being breast-fed has a documented normal G6PD level. Use in con-sultation with malaria experts.

Primaquine Used for pre-sumptive anti-relapse therapy (terminal prophy-laxis) to decrease the risk of relaps-es of P. vivax and P. ovale.

30 mg base (52.6 mg salt) orally, once/day for 14 days after departure from the malarious area.

0.5 mg/kg base (0.8) mg/kg salt) up to adult dose orally, once/day for 14 days after departure from the malarious area.

Indicated for persons who have had prolonged exposure to P. vivax and P. ovale or both. Con-traindicated in persons with G6PD* deficiency. Also contra-indicated during pregnancy and lactation unless the infant being breast-fed has a documented normal G6PD level.

* Glucose-6-phosphate dehydrogenase. All persons who take primaquine should have a documented normal G6PD level prior to starting the medication. 9.7-Prophylaxis Recommendations According to Resistance Status 9.7.1-Travel to Areas with Chloroquine-resistant P. falciparum

Atovaquone/proguanil (Malarone™) Atovaquone/ proguanil is a fixed combination of two drugs; in the United States, it is marketed as Malarone. Atovaquone/proguanil prophylaxis should begin one to two days before travel to malarious areas and should be taken daily, at the same time each day, while in the malarious area and daily for seven days after leaving such areas.

Doxycycline (brand names and generics)


Doxycycline prophylaxis should begin one to two days before travel to malarious areas. It should be con-tinued once a day, at the same time each day, during travel in malarious areas and daily for four weeks after the traveler leaves such areas. Note: There are insufficient data on the antimalarial prophylactic efficacy of related compounds such as minocycline (commonly prescribed for the treatment of acne). Optimally, for patients already on mino-cycline, it should be discontinued prior to travel and doxycycline started. Minocycline can be restarted after the four weeks of post-exposure doxycycline is completed.

Mefloquine (Lariam™ and generic) Mefloquine prophylaxis should begin one to two weeks before travel to malarious areas. It should be con-tinued once a week, on the same day each week, during travel to malarious areas and for four weeks after the traveler leaves such areas.

Primaquine In special circumstances and after consultation with malaria experts available through the Malaria Hotline (770-488-7788), primaquine may be used for prophylaxis for travel to areas with or without chloroquine-resistant P. falciparum. This use should generally be reserved for travelers unable to take any of the other chemoprophylaxis regimens recommended for the region of travel. Note: Travelers must be tested for G6PD deficiency (glucose-6-phosphate-dehydrogenase) and have a documented G6PD level in the normal range before primaquine use.

Primaquine prophylaxis should begin one to two days before travel to the malaria-risk area. It should be continued once a day, at the same time each day, while in the malaria-risk area and daily for seven days after leaving the malaria-risk area.

In those who are G6PD deficient, primaquine can cause hemolysis, which can be fatal. Be sure to docu-ment a normal G6PD level before prescribing primaquine. 9.7.2-Travel to Areas with Mefloquine-resistant P. falciparum

Mefloquine-resistant P. falciparum is present in eastern Burma (states of Shah, Kayin and Kayah), the western provinces of Cambodia that border Thailand and all malaria-risk areas in Thailand. Either ato-vaquone/proguanil or doxycycline can be used by travelers to these areas. 9.7.3-Travel to Areas with Chloroquine-sensitive P. falciparum

Chloroquine (Aralen™, Plaquenil™ and generic) In areas where chloroquine-resistant P. falciparum has not been reported, either chloroquine phosphate (Aralen and generic) or hydroxychloroquine sulfate (Plaquenil) may be used. Less evidence exists on hy-droxychloroquine sulfate’s effectiveness as an antimalarial drug.

Chloroquine prophylaxis should begin one to two weeks before travel to malarious areas. It should be continued once a week, on the same day of the week, during travel to malarious areas and for four weeks after a traveler leaves such areas.

Travelers unable to take chloroquine should take atovaquone/proguanil, doxycycline, mefloquine, or pri-maquine; these drugs are also effective against chloroquine-sensitive P. falciparum. 9.8-Chemoprophylaxis for Infants, Children and Adolescents

Children of any age can contract malaria; all children traveling to a malaria-risk area should take an anti-malarial drug. In the U.S., antimalarial drugs are available only in tablet form and may taste quite bitter. Pediatric dosages should be carefully calculated based on the child’s current weight; children’s dosages should never exceed adult dosage.

Full-service (compounding) pharmacists can pulverize tablets, weigh out the precise dose and place the dose in a gelatin capsule. Advise parents to open the gelatin capsule and mix the drug with something sweet such as applesauce, chocolate syrup, or jelly and to give the drug on a full stomach to minimize


stomach upset and vomiting. Parents should allow sufficient time before travel to allow preparation of these dosages.

Overdosage of antimalarial drugs can be fatal. Medication should be stored in childproof containers out of the reach of infants and children. 9.9-Chemoprophylaxis during Pregnancy and Lactation

Malarial infection in pregnant women can be more severe than in non-pregnant women. In addition, ma-laria can increase the risk for adverse pregnancy outcomes, including prematurity, abortion and stillbirth. Because malaria is such a serious illness in pregnancy and because no chemoprophylactic regimen is completely effective, women who are pregnant or likely to become pregnant should be advised to avoid travel to a malaria-risk area.

If travel cannot be avoided, then use of an effective antimalarial drug is essential.

Travel During Pregnancy to Areas with Chloroquine-sensitive P. falciparum Chloroquine phosphate or hydroxychloroquine sulfate are recommended for pregnant women traveling to areas with chloroquine-sensitive P. falciparum. Chloroquine has not been found to have any harmful ef-fects on the fetus when used in the recommended doses for weekly prophylaxis.

Travel During Pregnancy to Areas with Chloroquine-resistant P. falciparum Mefloquine is currently the only medication recommended for prophylaxis during pregnancy. Studies in-dicate that prophylactic use during second and third trimesters is not associated with adverse fetal or pregnancy outcomes. More limited data suggest it is also safe during the first trimester.

Because of insufficient data regarding the use during pregnancy, atovaquone/proguanil is not currently recommended for the prevention of malaria in pregnant women. Doxycycline is contraindicated during pregnancy because of the known risks of tetracycline on fetal development, including discoloration and dysplasia of the teeth and inhibition of bone growth. Primaquine should not be used during pregnancy because the drug may pass to a G6PD-deficient fetus and cause hemolytic anemia in utero. 9.10-Lactation

Very small amounts of chloroquine and mefloquine are excreted in breast milk; the amount of drug is not sufficient to harm the infant nor is the quantity sufficient to protect the child from malaria. Breastfeeding infants should receive the recommended dosages of antimalarials found in the table on page 19.

Very limited data are available on the use of doxycycline in lactating women; most experts consider the theoretical possibility of adverse events to be remote.

Primaquine should only be given to lactating women if both the woman and her infant have been tested for G6PD deficiency and have documented normal G6PD levels.

Because safety data is not yet available, atovaquone/proguanil is not currently recommended for women breastfeeding infants less than 5kg. 9.11-Educate Patients on the Signs and Symptoms of Malaria

Advise your patients that they can still contract malaria despite prophylaxis and anti-mosquito measures. Inform travelers that fever or flu-like illness, either while traveling or after returning home (for up to one year or more), may be malaria and that they should seek immediate medical evaluation, including thick and thin smears. 9.12-Self-Treatment

Malaria can be effectively treated early in the course of the disease; however, delay of appropriate treat-ment can have serious or even fatal consequences. Travelers who choose not to take an antimalarial drug or who are on a less than effective regimen (chloroquine in a chloroquine-resistant risk area) or who may


be in very remote areas can be given a self-treatment course of atovaquone/proguanil. Travelers on ato-vaquone/proguanil as their antimalarial drug regimen should not use atovaquone/proguanil as their self-treatment drug and should use an alternative self-treatment regimen.

MALARIA...6.3-Plasmodium falciparum [Centers for Disease Control and Prevention ... P. falciparum...

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