SYMPOSIUM ON ANTIMICROBIAL AGENTS-Part VII
Antiparasitic Agents JON E. ROSENBLATT, M.D., Division ofInfectious Diseases and Internal Medicine and Section of Clinical Microbiology
In recent years, introduction of new and more effective agents has improved the overall therapy for parasitic infections. This field, however, is still plagued by numerous problems, including the development of resistance to antimicrobial agents (especially with malaria), unavailability of agents in the United States or lack of approval by the Food and Drug Administration, and major toxicities or lack of experience in pregnant women and children, which limits use in these groups of patients. Widespread resistance of Plasmodium falciparum to chloroquine and other agents has complicated the treatment and prophylaxis of this type of malaria. A combination of quinine and Fansidar is usually effective oral therapy for falciparum malaria; quinidine may be administered if intravenous therapy is needed. Metloquine, which is currently recommended for prophylaxis against chloroquine-resistant P. falciparum, is also effective for single-dose oral treatment, although this regimen has not yet been approved by the Food and Drug Administration. Metronidazole has been widely used for treatment of gastroenteritis due to Entamoeba histolytica and Giardia lamblia (not approved by the Food and DrugAdministration for the latter) and is considered safe and effective. A new macrolide, azithromycin, has been reported to be effective for cryptosporidiosis in experimental animals; currently, no effective therapy is available for human infections. Combinations of sulfonamides with other antifolates, trimethoprim or pyrimethamine, are recommended therapy for Pneumocystis carinii pneumonia or toxoplasmosis, respectively. Therapies for the various types of leishmaniasis and trypanosomiasis are complex, often toxic, and often of limited efficacy. The benzimidazoles are effective for roundworm infections, although thiabendazole has severe toxic effects. The recent introduction of ivermectin has revolutionized the treatment and control of onchocerciasis. Another relatively new agent, praziquantel, is a true broad-spectrum anthelmintic agent that is effective against most trematodes, many adult cestodes, and larval cestodes as well (especially cysticerci of Taenia solium).
OVERVIEW In the first three sections of this article, the material is organized in terms of treatment of specific parasitic infections. Information about individual drugs and their adverse effects is summarized in Table 1. Throughout, the recommended dosages are for adults unless otherwise specified. Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 67:276-287,1992
The references and bibliography listed at the end of this article should be consulted for further information.
ANTIMALARIAL AND ANTI-BABESIA AGENTS Treatment of Chloroquine-Sensitive Plasmodium-The "chloroquine-sensitive" Plasmodium organisms generally include P. vivax, P. malariae, P. ovale, and a few strains of P. falciparum (found mainly in western Africa, the Middle East, Central America, and the Caribbean). Malaria caused by these organisms can be treated with orally administered chloroquine phosphate in an initial dose of 600 mg base 276
Mayo Clio Proc, March 1992, Vol 67
(equivalent to 1.0 g of the compound), followed by 300 mg base in 6 hours and then 300 mg base at 24 hours and 48 hours after the initial dose. If parenteral treatment is needed, chloroquine hydrochloride can be administered intramuscularly, 200 mg base every 6 hours. Alternatively, quinidine gluconate can be administered intravenously in the regimen described in the next section for malaria due to chloroquineresistant P. falciparum. Each of the aforementioned agents will eradicate Plasmodium organisms that have infected erythrocytes. Recently, P. vivax resistant to chloroquine has been reported from Papua New Guinea and the Solomon Islands.' Presumably, these strains would be susceptible to agents used against chloroquine-resistant P. falciparum (see subsequent material). In addition, experimental infections in monkeys with one of these strains have been cured with amodiaquine,' but this drug is not available in the United States. For many years, this 4-aminoquinoline has been an alternative to chloroquine for treating malaria; it is known to be active against some, but not all, strains of chloroquineresistant P. [alciparum. In malaria caused by P. vivax and P. ovale, primaquine phosphate (15 mg base once a day for 14 days) should be administered as soon as the chloroquine regimen is completed. This treatment will eradicate the exoerythrocytic phase of the parasite that is sequestered in the liver. For P. malariae and P. falciparum, primaquine treatment is unnecessary because their life cycles include no extended exoerythrocytic stage. Therefore, malaria slides must be examined in laboratories capable of accurately identifying the correct species of Plasmodium in order to avoid unnecessary delays in providing appropriate treatment. Primaquine should not be given to pregnant patients or those with glucose-c-phosphate dehydrogenase deficiency. Treatment of Chloroquine-Resistant Malaria.-The treatment of malaria due to chloroquine-resistant P. falciparum is complex and subject to frequent change because of the rapid emergence of drug resistance. Physicians should monitor the Morbidity and Mortality Weekly Report, published by the Centers for Disease Control, for such changes or should consult their Malaria Branch (telephone 404-4884046) for advice on the treatment of such cases. Adult patients infected with P. falciparum should be assumed to harbor chloroquine-resistant strains unless it can be verified that none was present in the geographic area where they became infected. If oral therapy is feasible, quinine sulfate (650 mg three times a day for 3 days) should be administered in conjunction with three tablets (all at once) of a combination of pyrimethamine and sulfadoxine (Fansidar). Alternatives to Fansidar include either tetracycline (250 mg four times a day for 7 days) or clindamycin (900 mg three times a day for 3
ANTIPARASITIC AGENTS
277
days). The latter has been used to treat cases of falciparum malaria in Brazil. 3 Mefloquine, a relatively new antimalarial agent, is a 4-quinoline derivative with good activity against the schizonts of Plasmodium. It can be used as an alternative to the oral quinine combinations against chloroquineresistant P. falciparum in a single 1,250-mg dose, although this regimen has not yet been approved by the Food and Drug Administration. Unfortunately, mefloquine-resistant strains of falciparum malaria have recently been reported from Southeast Asia." This situation will bear close watching to determine the extent of the problem in the future. Furthermore, dizziness and vomiting are relatively common side effects, and seizures and an acute brain syndrome have been reported. The drug is not recommended for use in children, pregnant patients, or those using ~-blocker cardiac drugs. Parenteral treatment of malaria is indicated in the following situations: (1) severe vomiting is present; (2) signs and symptoms of neurologic dysfunction, pulmonary edema, or renal failure are noted; or (3) the peripheral parasitemia is at a level of more than 5% of erythrocytes infected (not including gametocytes).' Supplies of intravenously administered quinine are no longer maintained by the Centers for Disease Control; currently, quinidine gluconate is the recommended drug for parenteral therapy. A loading dose of 10 rug/kg of quinidine gluconate is administered during a 1- to 2-hour period, followed by a constant infusion of 0.02 mg/kg per minute. The patient should be in an intensive-care unit with close electrocardiographic monitoring. Intravenous therapy should be continued until the parasitemia is at a level of less than 1% and the neurologic signs have diminished or oral medications can be tolerated (see previous paragraph). Some clinicians recommend the performance of exchange transfusions if cerebral malaria is present or if the parasitemia reaches a level of 10% (or both)." This procedure, however, remains somewhat controversial in the management of severe cases of malaria. Gametocytes may persist for several days in the blood of patients with faleiparum malaria who have responded well clinically to appropriate treatment. This finding does not indicate the need for further treatment of the patient's infection. If exposure to Anopheles mosquitoes is ongoing, however, the patient may serve as a reservoir for spread of the infection to others. In such situations, some physicians opt to administer a gametocidal agent such as primaquine (single dose of 45 mg base) to lessen the hazard of transmission of the infection through insect vectors. Several additional agents with antimalarial activity are being actively investigated. Some new fluoroquinolone antimicrobial agents, including ciprofloxacin, have considerable in vitro activity against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.' They have
278
Mayo Clin Proc,March 1992, Vol 67
ANTIPARASITIC AGENTS
Table l.-8ummary of Antimicrobial Agents Used for Treating Parasitic Infections and Their Main Side EfTects* Agent
Indications
Contraindications Not Not Not Not
Azithromycin Benznidazole
Hydatid cyst, intestinal nematodes Leishmaniasis Malaria Amebic meningoencephalitis, leishmaniasis Cryptosporidiosis, toxoplasmosis American trypanosomiasis
Bithionol Chloroquine
Fasciola hepatica Malaria
Not approved by FDA
Clindamycin Dapsone
Malaria, babesiosis, toxoplasmosis Pneumocystis carinii pneumonia
Not approved by FDA Not approved by FDA
Diethylcarbamazine
Filariasis (not onchocerciasis)
Diloxanide furoate Doxycycline
Amebiasis (asymptomatic) Malaria (prophylaxis)
Pregnancy; available from CDC Pregnancy, children
Antiparasitic Agents JON E. ROSENBLATT, M.D., Division ofInfectious Diseases and Internal Medicine and Section of Clinical Microbiology
In recent years, introduction of new and more effective agents has improved the overall therapy for parasitic infections. This field, however, is still plagued by numerous problems, including the development of resistance to antimicrobial agents (especially with malaria), unavailability of agents in the United States or lack of approval by the Food and Drug Administration, and major toxicities or lack of experience in pregnant women and children, which limits use in these groups of patients. Widespread resistance of Plasmodium falciparum to chloroquine and other agents has complicated the treatment and prophylaxis of this type of malaria. A combination of quinine and Fansidar is usually effective oral therapy for falciparum malaria; quinidine may be administered if intravenous therapy is needed. Metloquine, which is currently recommended for prophylaxis against chloroquine-resistant P. falciparum, is also effective for single-dose oral treatment, although this regimen has not yet been approved by the Food and Drug Administration. Metronidazole has been widely used for treatment of gastroenteritis due to Entamoeba histolytica and Giardia lamblia (not approved by the Food and DrugAdministration for the latter) and is considered safe and effective. A new macrolide, azithromycin, has been reported to be effective for cryptosporidiosis in experimental animals; currently, no effective therapy is available for human infections. Combinations of sulfonamides with other antifolates, trimethoprim or pyrimethamine, are recommended therapy for Pneumocystis carinii pneumonia or toxoplasmosis, respectively. Therapies for the various types of leishmaniasis and trypanosomiasis are complex, often toxic, and often of limited efficacy. The benzimidazoles are effective for roundworm infections, although thiabendazole has severe toxic effects. The recent introduction of ivermectin has revolutionized the treatment and control of onchocerciasis. Another relatively new agent, praziquantel, is a true broad-spectrum anthelmintic agent that is effective against most trematodes, many adult cestodes, and larval cestodes as well (especially cysticerci of Taenia solium).
OVERVIEW In the first three sections of this article, the material is organized in terms of treatment of specific parasitic infections. Information about individual drugs and their adverse effects is summarized in Table 1. Throughout, the recommended dosages are for adults unless otherwise specified. Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 67:276-287,1992
The references and bibliography listed at the end of this article should be consulted for further information.
ANTIMALARIAL AND ANTI-BABESIA AGENTS Treatment of Chloroquine-Sensitive Plasmodium-The "chloroquine-sensitive" Plasmodium organisms generally include P. vivax, P. malariae, P. ovale, and a few strains of P. falciparum (found mainly in western Africa, the Middle East, Central America, and the Caribbean). Malaria caused by these organisms can be treated with orally administered chloroquine phosphate in an initial dose of 600 mg base 276
Mayo Clio Proc, March 1992, Vol 67
(equivalent to 1.0 g of the compound), followed by 300 mg base in 6 hours and then 300 mg base at 24 hours and 48 hours after the initial dose. If parenteral treatment is needed, chloroquine hydrochloride can be administered intramuscularly, 200 mg base every 6 hours. Alternatively, quinidine gluconate can be administered intravenously in the regimen described in the next section for malaria due to chloroquineresistant P. falciparum. Each of the aforementioned agents will eradicate Plasmodium organisms that have infected erythrocytes. Recently, P. vivax resistant to chloroquine has been reported from Papua New Guinea and the Solomon Islands.' Presumably, these strains would be susceptible to agents used against chloroquine-resistant P. falciparum (see subsequent material). In addition, experimental infections in monkeys with one of these strains have been cured with amodiaquine,' but this drug is not available in the United States. For many years, this 4-aminoquinoline has been an alternative to chloroquine for treating malaria; it is known to be active against some, but not all, strains of chloroquineresistant P. [alciparum. In malaria caused by P. vivax and P. ovale, primaquine phosphate (15 mg base once a day for 14 days) should be administered as soon as the chloroquine regimen is completed. This treatment will eradicate the exoerythrocytic phase of the parasite that is sequestered in the liver. For P. malariae and P. falciparum, primaquine treatment is unnecessary because their life cycles include no extended exoerythrocytic stage. Therefore, malaria slides must be examined in laboratories capable of accurately identifying the correct species of Plasmodium in order to avoid unnecessary delays in providing appropriate treatment. Primaquine should not be given to pregnant patients or those with glucose-c-phosphate dehydrogenase deficiency. Treatment of Chloroquine-Resistant Malaria.-The treatment of malaria due to chloroquine-resistant P. falciparum is complex and subject to frequent change because of the rapid emergence of drug resistance. Physicians should monitor the Morbidity and Mortality Weekly Report, published by the Centers for Disease Control, for such changes or should consult their Malaria Branch (telephone 404-4884046) for advice on the treatment of such cases. Adult patients infected with P. falciparum should be assumed to harbor chloroquine-resistant strains unless it can be verified that none was present in the geographic area where they became infected. If oral therapy is feasible, quinine sulfate (650 mg three times a day for 3 days) should be administered in conjunction with three tablets (all at once) of a combination of pyrimethamine and sulfadoxine (Fansidar). Alternatives to Fansidar include either tetracycline (250 mg four times a day for 7 days) or clindamycin (900 mg three times a day for 3
ANTIPARASITIC AGENTS
277
days). The latter has been used to treat cases of falciparum malaria in Brazil. 3 Mefloquine, a relatively new antimalarial agent, is a 4-quinoline derivative with good activity against the schizonts of Plasmodium. It can be used as an alternative to the oral quinine combinations against chloroquineresistant P. falciparum in a single 1,250-mg dose, although this regimen has not yet been approved by the Food and Drug Administration. Unfortunately, mefloquine-resistant strains of falciparum malaria have recently been reported from Southeast Asia." This situation will bear close watching to determine the extent of the problem in the future. Furthermore, dizziness and vomiting are relatively common side effects, and seizures and an acute brain syndrome have been reported. The drug is not recommended for use in children, pregnant patients, or those using ~-blocker cardiac drugs. Parenteral treatment of malaria is indicated in the following situations: (1) severe vomiting is present; (2) signs and symptoms of neurologic dysfunction, pulmonary edema, or renal failure are noted; or (3) the peripheral parasitemia is at a level of more than 5% of erythrocytes infected (not including gametocytes).' Supplies of intravenously administered quinine are no longer maintained by the Centers for Disease Control; currently, quinidine gluconate is the recommended drug for parenteral therapy. A loading dose of 10 rug/kg of quinidine gluconate is administered during a 1- to 2-hour period, followed by a constant infusion of 0.02 mg/kg per minute. The patient should be in an intensive-care unit with close electrocardiographic monitoring. Intravenous therapy should be continued until the parasitemia is at a level of less than 1% and the neurologic signs have diminished or oral medications can be tolerated (see previous paragraph). Some clinicians recommend the performance of exchange transfusions if cerebral malaria is present or if the parasitemia reaches a level of 10% (or both)." This procedure, however, remains somewhat controversial in the management of severe cases of malaria. Gametocytes may persist for several days in the blood of patients with faleiparum malaria who have responded well clinically to appropriate treatment. This finding does not indicate the need for further treatment of the patient's infection. If exposure to Anopheles mosquitoes is ongoing, however, the patient may serve as a reservoir for spread of the infection to others. In such situations, some physicians opt to administer a gametocidal agent such as primaquine (single dose of 45 mg base) to lessen the hazard of transmission of the infection through insect vectors. Several additional agents with antimalarial activity are being actively investigated. Some new fluoroquinolone antimicrobial agents, including ciprofloxacin, have considerable in vitro activity against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.' They have
278
Mayo Clin Proc,March 1992, Vol 67
ANTIPARASITIC AGENTS
Table l.-8ummary of Antimicrobial Agents Used for Treating Parasitic Infections and Their Main Side EfTects* Agent
Indications
Contraindications Not Not Not Not
Azithromycin Benznidazole
Hydatid cyst, intestinal nematodes Leishmaniasis Malaria Amebic meningoencephalitis, leishmaniasis Cryptosporidiosis, toxoplasmosis American trypanosomiasis
Bithionol Chloroquine
Fasciola hepatica Malaria
Not approved by FDA
Clindamycin Dapsone
Malaria, babesiosis, toxoplasmosis Pneumocystis carinii pneumonia
Not approved by FDA Not approved by FDA
Diethylcarbamazine
Filariasis (not onchocerciasis)
Diloxanide furoate Doxycycline
Amebiasis (asymptomatic) Malaria (prophylaxis)
Pregnancy; available from CDC Pregnancy, children
