Malaria Overview

• Etiology

• Diagnosis

• Clinical Presentations (Subjective)

• Clinical Presentations (Objective)

• Clinical Considerations

• Factors resulting in Fatal Outcomes

• Parasitic Life Cycle

  • Developmental Stages (human)

  • Interspecies Life Cycle Differences

• Antimalarial Drug Classification

  • 4-aminoquinolines

  • 8-aminoquinoline

  • dihydrofolate reductase inhibitors

  • sulfones and sulfonamides

  • antibiotics

  • combinations

• Site of Drug action & Parasitic Life Cycle

• Drugs that prevent infection

• Drugs that prevent attacks & cure

• Malaria Prophylaxis

• Treatment: All Species

• Treatment: chloroquine-resistant P. falciparum

Specific Antimalarial Drugs

• Chloroquine (Aralen)

  • Overview/pharmacokinetics

  • Dosing considerations

  • Antimalarial activity

  • Selective toxicity/Adverse effects

  • Contraindications

  • Chloroquine (Aralen) resistance

  • Clinical Uses:

• Mefloquine (Lariam)

  • Overview

  • Antimalarial properties

  • Clinical Uses

  •  Adverse reactions

  • Contraindications

• Primaquine

  • Antimalarial properties

  • Clinical Uses

• Pyrimethamine-proguanil (Chloroguanide)

  • Antimalarial characteristics

  • Clinical Uses

  • Toxoplasmosis treatment

  • Adverse Effects

  • Contraindications/Cautions

Sulfonamides & Sulfones

• Overview: sulfonamides & sulfones

• Pyrimethamine-sulfadoxine (Fansidar)

Quinine (Quinamm) & Quinidine

• Overview: Quinine (Quinamm)

• Antimalarial activity

• Pharmacological Effects

• Clinical uses

•  Adverse effects

• Quinidine gluconate (Quinaglute, Quinalan)

Amebiasis

• Overview

  • Diagnostic criteria

  • Clinical manifestations: subjective

  • Extraintestinal amebiasis

  • Objective clinical manifestations

  • Differential Diagnosis

  • Life-cycle/Laboratory/Microscopy

• Drugs Used to Treat Amebiasis

  • Chloroquine (Aralen)

  • Emetine (generic) & Dehydroemetine (Mebadin)

  • Diloxanide furoate (Furamide)

  • Iodoquinol (Yodoxin, Moebequin)

  • Metronidazole (Flagyl) in amebiasis & other protozoal infections

  • Paromomycin (Humatin)

Leishmania

• Overview

• Causal Agents

• Life Cycle

• Clinical Characteristics

• Microscopy

• Pharmacological management

• Malaria-Overview

  •  Most important parasitic infection

    •  New cases/year = 120 million; deaths = > 1 million

    •  Over the past 10 years, incidence of P falciparum imported cases (USA) has risen > 10X

      • increase secondary:

        1. to failure of mosquito eradication programs

        2. and to increasing resistance of P. falciparum to antimalarial drugs

    •  Most U.S. cases found in travelers [occasionally: transfusion recipients & intravenous drug users]

  •  "Causal Agents:Blood parasites of the genus Plasmodium.   There are approximately 156 named species of Plasmodium which infect various species of vertebrates.""-CDC )

  • Four Plasmodium species causative for human malaria

    •  Plasmodium vivax

    •  Plasmodium malariae

    •  Plasmodium ovale

    •  Plasmodium falciparum

      •  produces most serious complications; including death

  • Factors which determined antimalarial agent efficacy:

    •  species

    •  life-cycle stage-dependencies

  • Etiology:

    •  Transmission: bite of the female anopheline mosquito, only arthropod vector

      • transmission does not occur < 60 ^oF or when temperature > 100 ^oF

      • incubation period: 8-10 days at least (ambient temperature dependent)

    •  Widely distributed in Asia, Africa, Latin America and the Caribbean Basin.

  • Diagnosis

    • Suggestive:

      •  fever/flu-like symptoms in an individual returning from travel (or native to) a malarious geographical region

      •  disease not ruled out if the patient has taken prophylactic drugs during travel

    • Definitive:

      •  observing characteristic, intraerythrocytic parasites in thick/thin blood smears (Giemsa or similar stain)

        •  if thin blood smear negative, examine thick smear (may be positive in 20-25% of patients)

        •  examination of blood smear is may be required at intervals over several days

        •  Critical factor: determined whether patient has falciparum malaria because this form may be fatal due to high-rate of erythrocyte parasitization

          • In falciparum malaria actual parasite counts (e.g. percentage of erythrocytes containing parasites) should be monitored every eight hours during the first two-three days of treatment

  • Clinical Presentations (subjective)

    •  mild, "viral"-like prodrome (headache + myalgia), preceding by 24-48 hours major symptoms

    •  Major symptoms-three phases:-6-10 hour cycle

      •  cold phase-patient complains of chills

      •  hot phase-associated with high fever, headache, vomiting, nausea, delirium

      •  defervescence, perfused sweating and sleep

  • Clinical Presentations (objective)

    •  Physical Exam:

      •  During paroxysmal period: high fever (up to 106 ^oF)

      •  Orthostatic hypotension (falciparum malaria)

      •  Splenomegaly +/- hepatomegaly: frequency = 33% of cases

      •     Faint scleral icterus (scleral icterus-definition: jaundice observed in the white supporting tunic of the eyeball) -commonly seen

      •  Neurological complications-occasionally seen in falciparum malaria; symptoms include seizures, hallucinations, meningismus (meningismus-definition: excitation, followed by cortical depression with vomiting, constipation, and thermic disorders due to pain in the meningeocortical region of the brain)

    •  Laboratory:

      • mild, normochromic, normocytic anemia-usually present

      • falciparum malaria: anemia may be severe - schistocytes present on blood smear

  • Clinical Considerations:

    •  Infection by P falciparum (non-immune individual) = medical emergency

      •  Death may occur within several hours

      •  If > 20% of erythrocytes are parasitized,: mortality equals 50%

      •  Consequences of significant parasitization:

        •  Rapidly progressing hemolytic anemia, splenic erythrocyte sequestration, possible immune hemolytic anemia, significant intravascular hemoglobin release causing hemoglobinuria and renal failure (blackwater fever)

        •  Vasodilation causing significant, rapid fluid shifts resulting in orthostasis, hyponatremia, cerebral & pulmonary edema

        •  Parasitized erythrocytes (P falciparum) become "stickier", less deformable resulting in microthrombus formation (capillary sludging)

    •  Most important factors resulting in fatal outcomes:

      1. failure to take prophylaxis

      2. delay in obtaining medical attention

      3. misdiagnosis

      4. advanced age

• Parasitic Life Cycle

  • Mosquitoes become infected by ingesting human blood containing parasites (in the sexual form).

  • Sporozoites (developed in mosquito) are transmitted into humans during the mosquito's next feeding

    •  Developmental stages in the human:

      •  exoerythrocytic stage {sprorozoites multiplying (liver) forming tissues schizonts}

      •  parasites leave the liver, entering the bloodstream, as merozoites, beginning the erythrocytic stage

        1. invasion of red blood cells

        2. multiplying in red blood cells forming blood schizonts

        3. cell rupture, releasing new merozoites

        4. cycle repetition

      •  Concurrently, gametocytes {sexual stage} form, released into circulation where they may be ingested by another mosquito

• Center for Disease Control Description of Life Cycle "The malaria parasite life cycle involves two hosts.  During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host.  After initial replication in the liver (exoerythrocytic schizogony), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony).   Multiplication of the blood stage parasites is responsible for the clinical manifestations of the disease.  In the blood, some parasites differentiate into sexual erythrocytic stages (gametocytes).   The gametocytes, after ingestion by an Anopheles mosquito during a blood meal, undergo a sporogonic cycle yielding sporozoites.  Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.    Of note, in P. vivax and P. ovale, a dormant stage (hypnozoites) can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later."

  • Life Cycle Differences between Species

    •  P falciparum & P. malariae:

      •  one cycle of liver invasion and multiplication

      •  infection (hepatic) ends in < four weeks [spontaneously]

      •  infection confined to erythrocytes

        • after four weeks, treatment of erythrocytic infection would be curative

    •  P vivax & P ovale:

      •   Following liver invasion, sprorozoites induce a dormant stage (hypnozoite)-causes recurrences or relapses

      •   Treatment must eliminate parasites both from liver and erythrocytes

    • P falciparum:

      • blood stage parasites

      • gametocytes

      • ring-stage parasites

      • schizonts

      • trophozoites

• Antimalarial Drugs: Classification

  • 4-aminoquinolines

    •  chloroquine

    •  primaquine (generic)

    •  quinine (Quinamm)

    •  quinacrine (Atabrine HCl)

    •  mefloquine (Lariam)

  • Dihydrofolate reductase inhibitors

    •  chloroguanide

    •  pyrimethamine (Daraprim)

    •  trimethoprim (generic)

  • 8-aminoquinoline

    •  primaquine

  • Sulfones and Sulfonamides

    •  sulfadiazine

    •  dapsone

  • Antibiotics

    •  tetracycline (Achromycin), doxycycline (Vibramycin, Doryx)

    •  halofantrine (Halfan)

  • Drug Combinations

    •  pyrimethamine-sulfadoxine (Fansidar)

    •  pyrimethamine-dapsone (Maloprim)

• Site of Drug Action: Parasite Life-Cycle-- classification

  •  Tissue schizonticides -- drugs eliminating tissue schizonts or latent hypnozoites (hepatic)

  •  Blood schizonticides or suppressive agents (acting on blood schizonts) -- e.g.: chloroquine, amodiaquine, proguanil (Paludrine), pyrimethamine (Daraprim), mefloquine (Lariam), quinine (Quinamm)

  •  Gametocides: -- prevent infection by mosquitoes by destroying blood gametocytes

    • P. falciparum -- primaquine

    • P vivax, P. malariae, P ovale -- chloroquine

  •  Sporonticidal drugs --cause gametocides to become noninfective in the mosquito {example drugs: pyrimethamine (Daraprim), proguanil (Paludrine)}

• Drugs that prevent infection:

  • Pyrimethamine (Daraprim) & proguanil (Paludrine)-- dihydrofolate reductase inhibitors

    •  Mechanism: prevent maturation of P falciparum hepatic schizonts

• Drugs that prevent attacks and cure

  • Blood schizonticides --destruction of circulating plasmodia

    •  when used long enough (four weeks) cures P falciparum and P. malariae malaria

  • Primaquine: eliminates persistent liver hypnozoites of P vivax and P ovale; when given in combination with a blood schizonticide is curative

• Malaria Chemoprophylaxis-prevents attacks of all malaria forms and eliminates P falciparum & P. malariae infections

  • For regions with chloroquine-sensitive P. falciparum malaria {Central America west of the Panama Canal; Caribbean; North Africa; parts of the middle East}-Chloroquine

  • For regions with chloroquine-resistant P falciparum malaria:

    •  Preferred: mefloquine (Lariam)

    •  Alternative #1: doxycycline (Vibramycin, Doryx)

    •  Alternative #2: chloroquine + proguanil (Paludrine)

  • Eradication of P vivax & P ovale malaria infections:

    •  Primaquine

• Treatment of malaria:

  • All species (except chloroquine-resistant P falciparum)

    •  Oral treatment (P falciparum or P. malariae): chloroquine phosphate

    •  Oral treatment of P vivax or P ovale infection:chloroquine + primaquine phosphate

    •  Parenteral treatment (severe attacks): quinine (Quinamm) or quinidine gluconate (Quinaglute, Quinalan) followed by oral chloroquine when possible {followed with primaquine if infection is caused by P vivax or P ovale}

  • Treatment of infection in chloroquine-resistant P falciparum

    • Oral: quinine sulfate:

      •  plus doxycycline (Vibramycin, Doryx) or clindamycin (Cleocin) OR

      •  quinine sulfate plus pyrimethamine (Daraprim) and sulfadiazine OR

      •  quinine sulfate plus tetracycline (Achromycin) OR

      •  quinine sulfate plus pyrimethamine (Daraprim) + sulfadoxine (once only)

    • Oral alternative: mefloquine (Lariam)

    • Oral alternative: halofantrine (Halfan)

    • Parenteral (severe attacks)

      •  quinine dihydrochloride or quinidine gluconate + intravenous doxycycline (Vibramycin, Doryx) or clindamycin (Cleocin) {note begin oral treatment with quinine sulfate plus the second drug as soon as possible}

Primary Reference: Goldsmith, R. S., Antiprotozoal Drugs in Basic and Clinical Pharmacology (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 838-861.

Primary Reference: McLellan, S.L.F and Kozarsky, P.E., Malaria and Babesiosis in Medicine for the Practicing Physician (Hurst, J. W., ed) Appleton-Lange, 1996, pp. 465-469