Continuing from last week, of the four treatment regimes recommended for uncomplicated (chloroquine-resistant) falciparum malaria, Artemether-lumefantrine (Coartem™), an artemesinin-combination therapy, will frequently be the treatment of choice.
The most common adverse reactions reported in adults are headache, anorexia, dizziness, physical weakness, arthralgia and myalgia, although these are difficult to separate from the symptoms of malaria. The most common adverse reactions reported in children are fever, cough, vomiting, loss of appetite, and headache.
For treatment of complicated malaria, parenteral Quinine is recommended. Adverse reactions may include: hypoglycemia, auditory and visual disturbances, and cardiac dysrhythmias. Quinine cannot be combined with coartemether, chloroquine, or halofantrine, and mefloquine should only be administered 12 hours after the last dose of quinine (risk of seizures, cardiac toxicity).
For chemoprophylaxis of falciparum malaria, there are several alternatives depending on the region of travel, and patient-specific considerations including preference of dosing frequency. It is important to choose a chemoprophylactic regime that will be well tolerated in order to optimize adherence. Choices include Atovaquone/Proguanil (Malarone™), Doxycycline, and Mefloquine (Lariam™). Chloroquine can only be used for chemoprophylaxis in the regions of the world where malaria is still chloroquine-sensitive (Central America west of Panama Canal, Haiti, the Dominican Republic, and most of the Middle East).
Malarone is generally well-tolerated, but adverse reactions can include: cough, diarrhea, dizziness, headache, anorexia, oral sores, nausea, stomach pain, vomiting, and weakness. Adverse reactions associated with Doxycycline include: gastrointestinal disturbances, esophageal ulcerations, and photosensitivity. Doxycycline is contraindicated in pregnant and breastfeeding women and in children under 8 years of age, and should not be given with dairy products.
Adverse reactions associated with Mefloquine include: gastrointestinal disturbances, dizziness, and headache. Rarely, Mefloquine can cause cardiac dysrhythmias, hypo or hypertension, and skin rash. Occasionally at treatment dose levels (less often at prophylaxis levels), Mefloquine can cause severe neuropsychiatric reactions. Patients should be screened for history of mental illness and substance abuse prior to starting Mefloquine. Mefloquine is contraindicated in patients on sodium valproate, phenytoin, carbamazepine (risk of seizures), coarthemeter, chloroquine, or halofantrine (risk of seizures, cardiac toxicity). See also above under quinine.
Sources:
Centers for Disease Control and Prevention. Reasons for Considering or Avoiding Certain Drugs for the Prevention of Malaria. Available from: http://www.cdc.gov/malaria/control_prevention/drug_avoidance.htm.
Medecins Sans Frontieres. (2006). Essential Drugs: Practical Guidelines. 3rd Ed.
Monday, November 16, 2009
Friday, November 6, 2009
Treatment of Falciparum Malaria
The most important first step in the treatment of malaria is species identification through microscopy. The morphology of various malarial parasites show distinct characteristics, but given the low incidence of imported malaria in the United States, species identification can often be difficult for laboratory technicians. In addition, microscopy (especially using thin smears) can miss low levels of parasitemia. Rapid diagnostic tests have shown to be effective in endemic areas, but only for detection falciparum malaria, and have not yet been approved for use in the United States. Rapid tests for vivax, ovale, and malariae species are still under development. Parasite nucleic acid detection using PCR is available in reference laboratories, but the CDC only recommends using PCR to confirm a diagnosis by microscopy. If the species cannot be identified, or if there is strong clinical suspicion which cannot be confirmed through laboratory testing, treatment for falciparum malaria should be initiated immediately.
Just a quick note on P. vivax and P. ovale strains: These species of malaria have prolonged liver phases, during which the parasite lies dormant in forms referred to as “hypnozoites.” In order to eliminate these parasites in the liver, and to prevent future relapses, patients require treatment with chloroquine or quinine, plus a 14 day course of primaquine (“the radical cure” for malarial infection). One more note of caution: prior to administering primaquine, patients must be evaluated for G6PD deficiency, since it can cause hemolytic anemia. Consequently, primaquine is contraindicated in pregnancy because the G6PD status of the fetus cannot be determined. Primaquine should be added to treatment regimes for patients with falciparum malaria who are co-infected with vivax or ovale species.
It is also essential to determine the patient’s travel history, and to correlate this with regional patterns of resistance. Chloroquine resistance is widespread, and as such, chloroquine should only be used in the treatment of uncomplicated falciparum malaria for travelers returning from areas with chloroquine-sensitive strains (Central America west of Panama Canal, Haiti, the Dominican Republic, and most of the Middle East). Additionally, it’s important to ask patients about chemoprophylaxis. In case of resistance, providers should choose drug regimes that do not include medications that were used for prophylaxis (even intermittently).
It is recommended that patients with uncomplicated AND severe falciparum malaria be hospitalized. Given the rapid progression of disease, and the high mortality rates among cases of severe falciparum malaria, antimalarial treatment should be initiated urgently.
In general, patients with uncomplicated falciparum malaria can be treated with oral medication. For those patients who have returned from areas with chloroquine-sensitive strains, the dose, according to the CDC guidelines, is as follows:
Chloroquine phosphate (Aralen™ and generics): 600 mg PO immediately, followed by 300 mg PO at 6, 24, and 48 hours.
The CDC recommends four possible treatment plans for uncomplicated falciparum malaria acquired in regions with chloroquine-resistance (or when patients acquired malaria in a region where the sensitivity pattern is not known). Of the four treatment plans, two utilize medications which are commonly used for chemoprophylaxis (Atovaquone-proguanil or Malarone™, and Mefloquine or Lariam™). Therefore , these treatment protocols will not be appropriate for some patients. Additionally, Mefloquine when administered at treatment doses is associated with a high risk of severe neuropsychiatric reactions. A third protocol utilizes Quinine Sulfate, plus Doxycycline, Tetracycline, or Clindamycin (for children or women who are pregnant or breastfeeding). However, this treatment plan is associated with significant adverse effects, including Quinine-induced hypoglycemia, and gastrointestinal distress related to Doxycycline.
A treatment regime which includes artemesinin-combination therapy is recommended by WHO, and is one of the four regimes recommended by the CDC. In April 2009, the FDA approved Artemether and Lumefantrine (Coartem) as an oral therapy for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least 5 kgs. The following treatment protocol is from the CDC:
Artemether-lumefantrine (Coartem™), 1 tablet = 20mg artemether and 120 mg lumefantrine
A 3-day treatment schedule with a total of 6 oral doses is recommended for both adult and pediatric patients based on weight. The patient should receive the initial dose, followed by the second dose 8 hours later, then 1 dose po bid for the following 2 days.
5 - <15 kg: 1 tablet per dose
15 - <25 kg: 2 tablets per dose
25 - <35 kg: 3 tablets per dose
≥35 kg: 4 tablets per dose
The most common adverse reactions reported in adults are headache, anorexia, dizziness, physical weakness, arthralgia and myalgia, although these are difficult to separate from the symptoms of malaria. The most common adverse reactions reported in children are fever, cough, vomiting, loss of appetite, and headache.
While some patients may tolerate Coartem better than other treatment regimes, Coartem may not be available in all areas of the United States. If there are no contraindications, patients should receive medications that are appropriate for their malarial species and sensitivity patterns, and which can be administered without delay.
For severe malaria, or in cases when oral medications cannot be used, parenteral quinine plus Doxycycline, Tetracycline, or Clindamycin should be used. Parenteral quinine is cardiotoxic and should only be administered in an ICU setting with continuous cardiac monitoring and frequent blood pressure monitoring. Regular blood glucose monitoring is also required. As another option, parenteral Artesunate is currently being considered as an investigational new drug (IND).
Supportive therapy for cases of severe malaria may include antipyretic meds, monitoring of fluid I&Os, hemodialysis in the case of renal impairment, supplemental oxygen or (in extreme cases) mechanical ventilation, transfusion, vitamin K for DIC, and diazepam for seizures. Exchange transfusion is recommended in cases of falciparum when parasitemia is greater than 10 percent, or in patients with coma, renal failure, or ARDS, regardless of the level of parasitemia.
The CDC website is a great resource, and they have a helpful treatment table to guide prescribing practice:
http://www.cdc.gov/malaria/pdf/treatmenttable.pdf
Sunday, November 1, 2009
Signs and Symptoms of Falciparum Malaria
Malaria is generally transmitted by the bite of an infected female Anopheles mosquito (although rarely, cases of transfusion-related and congenital malaria can occur). The infecting sporozoite travels to the liver, and in 8 hours is undetectable in the blood. Within the hepatocytes, the sporozoites divide and form a cyst-like structure called a schizont that contains thousands of merozoites. When the schizont matures, it ruptures, releasing the merozoites into the bloodstream where it invades red blood cells.
This period between the bite of the mosquito and the invasion of RBCs by malaria parasites is called the prepatent period. Again, for the sake of simplicity, I will concentrate on P. falciparum malaria on this blog. It's important to establish the species of malaria prior to beginning treatment, and to keep in mind that patients can be infected with multiple species of malaria parasites. (Will come back to this later! Please stay tuned!)
In falciparum malaria, this process lasts from 8 to 25 days (on average, usually around 10). 90% of returning travelers with falciparum malaria present with symptoms within 30 days of departure from the malaria-endemic area.
Symptoms of malaria are often vague, and can resemble flu-like symptoms with fever, headache, and malaise. Semi-immune patients (and non-immune patients on chemoprophylaxis) generally have lower levels of parasitemia, shorter fever duration, as well as shorter parasite clearance time. Fever is the main presenting symptom, although the severe headache may also prompt patients to seek care.
Classic Paroxysm of Malaria:
Cold Stage (1-2 hours) – the patient shivers or has frank rigor; the temperature rises sharply
Hot Stage (2-6 hours) – the patient is flushed, tachycardic, and has sustained high temperature
Sweating Stage (2-4 hours) – the patient is diaphoretic, and the temperature falls rapidly
Rigors are associated with the lysis of RBCs and the release of TNF-alpha. The cycling of fever and chills is dependent on the synchronization of parasitic invasion and RBC lysis. This process can take a week to develop and in falciparum malaria, the development of disease is often too rapid to allow the classic paroxysms to develop.
Percentage of patients reporting:
Fever 92%
Headache 53%
Myalgesia/Arthralgia 34%
Fatigue 27%
Emesis 18%
Diarrhea 17%
Clinical Signs:
The Malarial Triad: Fever, Anemia, Hepato-splenomegaly. Additionally, some patients may exhibit jaundice. In complicated malaria, anemia may be severe, and patients may have acidosis and hypoglycemia. The term “Blackwater Fever” used to be used to refer to patients with discolored urine resulting from haemoglobinuria and renal failure. Disseminated Intravascular Coagulation (DIC) is an occasional complication in adults.
Cerebral Malaria is the most important complication of malaria, and even with hospitalization in modern intensive care units, the mortality rate is approximately 20 percent. The case definition is “an unrousable coma in the presence of peripheral parasitemia where other causes of encephalopathy have been excluded.” Patients make exhibit seizures (note: malaria seizures can occur at any temperatures), focal neurological signs, retinal hemorrhages, and brainstem signs such as doll’s eyes. Neurological sequelae are found in 5% of survivors (10% of children) and may include cortical blindness, hypotonia, hemiparesis, and mental retardation.
The natural history of untreated malaria differs with each species. After the first instance of infection with P. falciparum, the patient will either die in the acute attack, or survive with the development of some immunity and residual anemia. Unlike other species of malaria, falciparum does not have a dormant liver stage (hypnozoites), although small numbers of mereozoites can persist in the blood stream and cause recurrent attacks (recrudescence) for up to 12 months.
Source: "Lecture Notes: Tropical Medicine" by Geoff Gil and Nick Beeching. (2009 ed.)
This period between the bite of the mosquito and the invasion of RBCs by malaria parasites is called the prepatent period. Again, for the sake of simplicity, I will concentrate on P. falciparum malaria on this blog. It's important to establish the species of malaria prior to beginning treatment, and to keep in mind that patients can be infected with multiple species of malaria parasites. (Will come back to this later! Please stay tuned!)
In falciparum malaria, this process lasts from 8 to 25 days (on average, usually around 10). 90% of returning travelers with falciparum malaria present with symptoms within 30 days of departure from the malaria-endemic area.
Symptoms of malaria are often vague, and can resemble flu-like symptoms with fever, headache, and malaise. Semi-immune patients (and non-immune patients on chemoprophylaxis) generally have lower levels of parasitemia, shorter fever duration, as well as shorter parasite clearance time. Fever is the main presenting symptom, although the severe headache may also prompt patients to seek care.
Classic Paroxysm of Malaria:
Cold Stage (1-2 hours) – the patient shivers or has frank rigor; the temperature rises sharply
Hot Stage (2-6 hours) – the patient is flushed, tachycardic, and has sustained high temperature
Sweating Stage (2-4 hours) – the patient is diaphoretic, and the temperature falls rapidly
Rigors are associated with the lysis of RBCs and the release of TNF-alpha. The cycling of fever and chills is dependent on the synchronization of parasitic invasion and RBC lysis. This process can take a week to develop and in falciparum malaria, the development of disease is often too rapid to allow the classic paroxysms to develop.
Percentage of patients reporting:
Fever 92%
Headache 53%
Myalgesia/Arthralgia 34%
Fatigue 27%
Emesis 18%
Diarrhea 17%
Clinical Signs:
The Malarial Triad: Fever, Anemia, Hepato-splenomegaly. Additionally, some patients may exhibit jaundice. In complicated malaria, anemia may be severe, and patients may have acidosis and hypoglycemia. The term “Blackwater Fever” used to be used to refer to patients with discolored urine resulting from haemoglobinuria and renal failure. Disseminated Intravascular Coagulation (DIC) is an occasional complication in adults.
Cerebral Malaria is the most important complication of malaria, and even with hospitalization in modern intensive care units, the mortality rate is approximately 20 percent. The case definition is “an unrousable coma in the presence of peripheral parasitemia where other causes of encephalopathy have been excluded.” Patients make exhibit seizures (note: malaria seizures can occur at any temperatures), focal neurological signs, retinal hemorrhages, and brainstem signs such as doll’s eyes. Neurological sequelae are found in 5% of survivors (10% of children) and may include cortical blindness, hypotonia, hemiparesis, and mental retardation.
The natural history of untreated malaria differs with each species. After the first instance of infection with P. falciparum, the patient will either die in the acute attack, or survive with the development of some immunity and residual anemia. Unlike other species of malaria, falciparum does not have a dormant liver stage (hypnozoites), although small numbers of mereozoites can persist in the blood stream and cause recurrent attacks (recrudescence) for up to 12 months.
Source: "Lecture Notes: Tropical Medicine" by Geoff Gil and Nick Beeching. (2009 ed.)
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