Pharmacology_Katzung

Pharmacology_Katzung. 3For drugs other than primaquine, begin 1–2 weeks before departure (except 2 days before for doxycycline and Malarone) and continue for 4 weeks after leaving the endemic area (except 1 week for Malarone). All dosages refer to salts. 4Screen for glucose-6-phosphate dehydrogenase (G6PD) deficiency before using primaquine. TABLE 52–3 Treatment of malaria. Uncomplicated infections with chloroquine-resistant Severe or complicated infections with P falciparum Coartem (artemether, 20 mg, plus lumefantrine, 120 mg), four tablets twice daily for 3 days Artesunate,2 2.4 mg/kg IV, every 12 hours for 1 day, then daily for 2 additional days; follow with 7-day oral course of doxycycline or clindamycin or full treatment course of Coartem, Malarone, or mefloquine Quinidine gluconate,4,5 10 mg/kg IV over 1–2 hours, then 0.02 mg/kg IV/min


Pharmacology_Katzung

Pharmacology_Katzung. Quinidine gluconate,4,5 10 mg/kg IV over 1–2 hours, then 0.02 mg/kg IV/min Quinidine gluconate4,5 15 mg/kg IV over 4 hours, then 7.5 mg/kg IV over 4 hours every 8 hours Malarone, four tablets (total of 1 g atovaquone, 400 mg proguanil) daily for 3 days Mefloquine, 15 mg/kg once or 750 mg, then 500 mg in 6–8 hours Quinine sulfate, 650 mg 3 times daily for 3 days, plus doxycycline, 100 mg twice daily for 7 days, or clindamycin, 600 mg twice daily for 7 days Artemether,3 3.2 mg/kg IM, then 1.6 mg/kg/d IM; follow with oral therapy as for artesunate Quinine dihydrochloride,3–5 20 mg/kg IV, then 10 mg/kg every 8 hours 1All dosages are oral and refer to salts unless otherwise indicated. See text for additional information on all agents, including toxicities and cautions. See CDC guidelines (phone: 770-488-7788; www.cdc.gov) for additional information and pediatric dosing. 2Available in the United States only on an investigational basis through the CDC (phone: 770-488-7788).


Pharmacology_Katzung

Pharmacology_Katzung. 2Available in the United States only on an investigational basis through the CDC (phone: 770-488-7788). 3Not available in the USA. 4Cardiac monitoring should be in place during intravenous administration of quinidine or quinine. Change to an oral regimen as soon as the patient can tolerate it. 5Avoid loading doses in persons who have received quinine, quinidine, or mefloquine in the prior 24 hours. G6PD, glucose-6-phosphate dehydrogenase.


Pharmacology_Katzung

Pharmacology_Katzung. chemoprophylaxis. Intramuscular injections or intravenous infu- sions of chloroquine hydrochloride can result in severe hypotension and respiratory and cardiac arrest, and should be avoided. Amodiaquine is closely related to chloroquine, and it probably shares mechanisms of action and resistance. Amodiaquine was widely used to treat malaria because of its low cost, limited toxicity, and, in some areas, effectiveness against chloroquine-resistant strains Chloroquine is contraindicated in patients with psoriasis or of P falciparum, but toxicities, including agranulocytosis, aplastic porphyria. It should generally not be used in those with retinal anemia, and hepatotoxicity, have limited its use. However, recent or visual field abnormalities or myopathy, and should be used reevaluation has shown that serious toxicity from amodiaquine is with caution in patients with liver, neurologic, or hematologic uncommon. The most important current use of amodiaquine is disorders. The antidiarrheal


Pharmacology_Katzung

Pharmacology_Katzung. shown that serious toxicity from amodiaquine is with caution in patients with liver, neurologic, or hematologic uncommon. The most important current use of amodiaquine is disorders. The antidiarrheal agent kaolin and calciumand in combination therapy. The World Health Organization (WHO) magnesium-containing antacids interfere with the absorption of lists artesunate plus amodiaquine as a recommended therapy for chloroquine and should not be co-administered. Chloroquine is falciparum malaria (Table 52–4). This combination is now available considered safe in pregnancy and for young children. as a single tablet (ASAQ, Arsucam, Coarsucam) and is the first-line


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 52–4 WHO recommendations for the treatment of falciparum malaria. Data from World Health Organization: Guidelines for the Treatment of Malaria, 3rd ed. World Health Organization. Geneva, 2015. therapy for the treatment of uncomplicated falciparum malaria in many countries in Africa. Long-term chemoprophylaxis with amodiaquine is best avoided because of its apparent increased toxicity with long-term use, but short-term seasonal malaria chemoprevention with amodiaquine plus sulfadoxine-pyrimethamine (monthly treatment doses for 3–4 months during the transmission season) is now recommended by the WHO for the Sahel sub-region of Africa.


Pharmacology_Katzung

Pharmacology_Katzung. Piperaquine is a bisquinoline that was used widely to treat chloroquine-resistant falciparum malaria in China in the 1970s–1980s, but its use waned after resistance became widespread. More recently, piperaquine combined with dihydroartemisinin (Artekin, Duocotecxin) showed excellent efficacy and safety for the treatment of falciparum malaria, although very recently decreased efficacy has been seen in southeast Asia, linked to decreased activity of both components of the combination. Piperaquine has a longer half-life (~28 days) than amodiaquine (~14 days), mefloquine (~14 days), or lumefantrine (~4 days), leading to a longer period of post-treatment prophylaxis with dihydroartemisinin-piperaquine than with the other leading artemisinin-based combinations; this feature should be particularly advantageous in high-transmission areas. Dihydroartemisinin-piperaquine is now the first-line therapy for the treatment of uncomplicated falciparum malaria in some countries in Asia. As


Pharmacology_Katzung

Pharmacology_Katzung. particularly advantageous in high-transmission areas. Dihydroartemisinin-piperaquine is now the first-line therapy for the treatment of uncomplicated falciparum malaria in some countries in Asia. As dihydroartemisinin-piperaquine offers extended protection against malaria, there is interest in chemoprevention with monthly dosing of the drug, which has shown excellent efficacy in children and pregnant women in Africa.


Pharmacology_Katzung

Pharmacology_Katzung. Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide (Figure 52–2), the active component of an herbal medicine that has been used as an antipyretic in China for more than 2000 years. Artemisinin is insoluble and can only be used orally. Analogs have been synthesized to increase solubility and improve antimalarial efficacy. The most important of these analogs are artesunate (water-soluble; oral, intravenous, intramuscular, and rectal administration), artemether (lipid-soluble; oral, intramuscular, and rectal administration), and dihydroartemisinin (water-soluble; oral administration).


Pharmacology_Katzung

Pharmacology_Katzung. Artemisinin and its analogs are complex 3and 4-ring structures (Figure 52-2). They are rapidly absorbed, with peak plasma levels occurring promptly. Half-lives after oral administration are 30–60 minutes for artesunate and dihydroartemisinin, and 2–3 hours for artemether. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisinin. Drug levels appear to decrease after a number of days of therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The artemisinins are now widely available, but monotherapy for the treatment of uncomplicated malaria is strongly discouraged. Rather, co-formulated artemisinin-based combination therapies are recommended to improve efficacy and prevent the selection of artemisinin-resistant parasites. The oral combination regimen Coartem (artemether-lumefantrine) was approved by the U.S. Food and Drug Administration (FDA) in 2009, and it may be considered the new first-line therapy in the USA for uncomplicated falciparum malaria, although it may not be widely available. Intravenous artesunate is available from the CDC; use is initiated by contacting the CDC, which will release it for appropriate indications (falciparum malaria with signs of severe disease or inability to take oral medications) from stocks stored around the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Artemisinin and its analogs are very rapidly acting blood schizonticides against all human malaria parasites. Artemisinins have no effect on hepatic stages. They are active against young, but not mature gametocytes. The antimalarial activity of artemisinins appears to result from the production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge. Artemisinin resistance is not yet a widespread problem, but delayed clearance of P falciparum infections and decreased treatment efficacy in parts of Southeast Asia demonstrate a worrisome focus of resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Artemisinin-based combination therapy is now the standard of care for treatment of uncomplicated falciparum malaria in nearly all endemic areas. The leading regimens are highly efficacious, safe, and well tolerated. These regimens were developed because the short plasma half-lives of the artemisinins led to unacceptably high recrudescence rates after short-course therapy, which were reversed by inclusion of longer-acting drugs. Combination therapy also helps to protect against the selection of artemisinin resistance. However, with completion of dosing after 3 days, the artemisinin components are rapidly eliminated, and so selection of resistance to partner drugs is of concern.


Pharmacology_Katzung

Pharmacology_Katzung. The WHO recommends five artemisinin-based combinations for the treatment of uncomplicated falciparum malaria (Table 52–4). One of these, artesunate-sulfadoxine-pyrimethamine is not recommended in many areas owing to unacceptable levels of resistance to sulfadoxine-pyrimethamine, but it is the first-line therapy in some countries. The other recommended regimens are available as combination formulations, although manufacturing standards may vary. Artesunate-mefloquine is highly effective in Southeast Asia, where resistance to many antimalarials is common; it is the first-line therapy in some countries in Southeast Asia and South America. This regimen is less practical for other areas, particularly Africa, because of its relatively high cost and poor tolerability. Either artesunate-amodiaquine or artemetherlumefantrine is the standard treatment for uncomplicated falciparum malaria in most countries in Africa and some additional endemic countries on other continents.


Pharmacology_Katzung

Pharmacology_Katzung. artesunate-amodiaquine or artemetherlumefantrine is the standard treatment for uncomplicated falciparum malaria in most countries in Africa and some additional endemic countries on other continents. Dihydroartemisininpiperaquine is a newer regimen that has shown excellent efficacy; it is a first-line therapy for falciparum malaria in parts of Southeast Asia. Artesunate-pyronaridine (Pyramax) was recently approved, and it appears to offer efficacy similar to that of other combinations, but data are limited, especially for young children. Of concern, increased failure rates for artesunate-mefloquine and dihydroartemisinin-piperaquine have been reported recently in parts of Southeast Asia, in the setting of decreased activity of both components of the regimens.


Pharmacology_Katzung

Pharmacology_Katzung. Artemisinins also have outstanding efficacy in the treatment of complicated falciparum malaria. Large randomized trials and meta-analyses have shown that intramuscular artemether has an efficacy equivalent to that of quinine and that intravenous artesunate is superior to intravenous quinine in terms of parasite clearance time and—most important—patient survival. Intravenous artesunate also has a superior side-effect profile when compared with intravenous quinine or quinidine. Thus, intravenous artesunate has replaced quinine as the standard of care for the treatment of severe falciparum malaria. Artesunate and artemether have also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available.


Pharmacology_Katzung

Pharmacology_Katzung. Artemisinins are generally very well tolerated. The most commonly reported adverse effects are nausea, vomiting, diarrhea, and dizziness, and these may often be due to underlying malaria rather than the medications. Rare serious toxicities include neutropenia, anemia, hemolysis, elevated liver enzymes, and allergic reactions. In addition, delayed hemolysis after artemisinins for severe malaria appears to be quite common (estimated in 13% of cases), typically beginning 2–3 weeks after therapy, with 73% of identified cases requiring transfusion. Irreversible neurotoxicity has been seen in animals, but only after doses much higher than those used to treat malaria. Artemisinins have been embryotoxic in animal studies, but rates of congenital abnormalities, stillbirths, and abortions were not elevated in women who received artemisinins during pregnancy, compared with those of controls. Based on this information and the significant risk of malaria during pregnancy, the WHO recommends


Pharmacology_Katzung

Pharmacology_Katzung. not elevated in women who received artemisinins during pregnancy, compared with those of controls. Based on this information and the significant risk of malaria during pregnancy, the WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy (quinine plus clindamycin is recommended during the first trimester), and intravenous artesunate for the treatment of severe malaria during all stages of pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Quinine and quinidine remain important therapies for falciparum malaria—especially severe disease—although toxicity may complicate therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. The alkaloid quinine was purified in 1820 and has been used in the treatment and prevention of malaria since that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1–3 hours, and is widely distributed in body tissues. The use of a loading dose in severe malaria allows the achievement of peak levels within a few hours. Individuals with malaria develop higher plasma levels of quinine than healthy controls, but toxicity is not increased, apparently because of increased protein binding. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased


Pharmacology_Katzung

Pharmacology_Katzung. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine.


Pharmacology_Katzung

Pharmacology_Katzung. Quinine is a rapid-acting, highly effective blood schizonticide against the four species of human malaria parasites. The drug is gametocidal against P vivax and P ovale but not P falciparum. It is not active against liver stage parasites. The mechanism of action of quinine is unknown. Resistance to quinine is common in some areas of Southeast Asia, especially border areas of Thailand, where the drug may fail if used alone to treat falciparum malaria. However, quinine still provides at least a partial therapeutic effect in most patients. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Parenteral treatment of severe falciparum malaria—For many years quinine dihydrochloride or quinidine gluconate were the treatments of choice for severe falciparum malaria, although intravenous artesunate is now preferred. Quinine can be administered slowly intravenously or, in a dilute solution, intramuscularly, but parenteral preparations are not available in the USA. Quinidine is available (although not always readily accessible) in the USA for the parenteral treatment of severe falciparum malaria. Quinidine can be administered in divided doses or by continuous intravenous infusion; treatment should begin with a loading dose to achieve effective plasma concentrations promptly. Because of its cardiac toxicity (see Chapter 14) and the relative unpredictability of its pharmacokinetics, intravenous quinidine should be administered slowly with cardiac monitoring. Therapy should be changed to an effective oral agent as soon as the patient has improved sufficiently. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Oral treatment of falciparum malaria—Quinine sulfate is appropriate therapy for uncomplicated falciparum malaria except when the infection was transmitted in an area without documented chloroquine resistance. Quinine is commonly used with a second drug (most often doxycycline or, in children, clindamycin) to shorten the duration of use (usually to 3 days) and limit toxicity. Quinine is not generally used to treat nonfalciparum malaria. 3. Malarial chemoprophylaxis—Quinine is not generally used in chemoprophylaxis owing to its toxicity, although a daily dose of 325 mg is effective. 4. Babesiosis—Quinine is first-line therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infections.


Pharmacology_Katzung

Pharmacology_Katzung. Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a constellation of symptoms termed cinchonism. Mild symptoms of cinchonism do not warrant the discontinuation of therapy. More severe findings, often after prolonged therapy, include more marked visual and auditory abnormalities, vomiting, diarrhea, and abdominal pain. Hypersensitivity reactions include skin rashes, urticaria, angioedema, and bronchospasm. Hematologic abnormalities include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia. Therapeutic doses may cause hypoglycemia through stimulation of insulin release; this is a particular problem in severe infections and in pregnant patients, who may have increased sensitivity to insulin. Quinine can stimulate uterine contractions, especially in the third trimester. However, this effect is mild, and quinine and quinidine remain appropriate for treatment of


Pharmacology_Katzung

Pharmacology_Katzung. sensitivity to insulin. Quinine can stimulate uterine contractions, especially in the third trimester. However, this effect is mild, and quinine and quinidine remain appropriate for treatment of severe falciparum malaria during pregnancy. Intravenous infusions of the drugs may cause thrombophlebitis.


Pharmacology_Katzung

Pharmacology_Katzung. Severe hypotension can follow too-rapid intravenous infusions of quinine or quinidine. Electrocardiographic abnormalities (QT interval prolongation) are fairly common with intravenous quinidine, but dangerous arrhythmias are uncommon when the drug is administered appropriately in a monitored setting. Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria. It appears to be due to a hypersensitivity reaction to the drug, although its pathogenesis is uncertain.


Pharmacology_Katzung

Pharmacology_Katzung. Quinine (or quinidine) should be discontinued if signs of severe cinchonism, hemolysis, or hypersensitivity occur. It should be avoided if possible in patients with underlying visual or auditory problems. It must be used with great caution in those with underlying cardiac abnormalities. Quinine should not be given concurrently with mefloquine and should be used with caution in a patient with malaria who has recently received mefloquine. Absorption may be blocked by aluminum-containing antacids. Quinine can raise plasma levels of warfarin and digoxin. Dosage must be reduced in renal insufficiency. Mefloquine is effective therapy for many chloroquine-resistant strains of P falciparum and against other species. Although toxicity is a concern, mefloquine is one of the recommended chemoprophylactic drugs for use in most malaria-endemic regions with chloroquine-resistant strains.


Pharmacology_Katzung

Pharmacology_Katzung. Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-dose treatment regimen. The terminal elimination half-life is about 20 days, allowing weekly dosing for chemoprophylaxis. With weekly dosing, steady-state drug levels are reached over a number of weeks. Mefloquine and its metabolites are slowly excreted, mainly in the feces.


Pharmacology_Katzung

Pharmacology_Katzung. Mefloquine has strong blood schizonticidal activity against P falciparum and P vivax, but it is not active against hepatic stages or gametocytes. The mechanism of action is unknown. Sporadic resistance to mefloquine has been reported from many areas, but resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance does not appear to be associated with resistance to chloroquine. 1. Chemoprophylaxis—Mefloquine is effective in prophylaxis against most strains of P falciparum and probably all other human malarial species. Mefloquine is therefore among the drugs recommended by the CDC for chemoprophylaxis in all malarious areas except those with no chloroquine resistance (where chloroquine is preferred) and some rural areas of Southeast Asia with a high prevalence of mefloquine resistance. As with chloroquine, eradication of P vivax and P ovale requires a course of primaquine.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Treatment—Mefloquine is effective in treating uncomplicated falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria, since quinine, quinidine, and artemisinins are more rapidly active, and since drug resistance is less likely with those agents. The combination of artesunate plus mefloquine showed excellent antimalarial efficacy in regions of Southeast Asia with some resistance to mefloquine, and this regimen is now one of the combination therapies recommended by the WHO for the treatment of uncomplicated falciparum malaria (Table 52–4). Artesunate-mefloquine is the first-line therapy for uncomplicated falciparum malaria in a number of countries in Asia and South America.


Pharmacology_Katzung

Pharmacology_Katzung. Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Neuropsychiatric toxicities have received a good deal of publicity, but despite frequent anecdotal reports of seizures and psychosis, a number of controlled studies have found the frequency of serious adverse effects from mefloquine to be similar to that with other common antimalarial chemoprophylactic regimens. However, concern about reported long-term effects of short-term use of mefloquine led in 2013 to the FDA adding a black box warning regarding potential neurologic and psychiatric toxicities. Leukocytosis, thrombocytopenia, and aminotransferase elevations have also been reported.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects are more common with the higher dosages of mefloquine required for treatment. These effects may be lessened by administering the drug in two doses separated by 6–8 hours. The incidence of neuropsychiatric symptoms appears to be about ten times greater than with chemoprophylactic dosing, with widely varying frequencies of up to about 50% reported. Serious neuropsychiatric toxicities (depression, confusion, acute psychosis, or seizures) have been reported in less than 1 in 1000 treatments, but some authorities believe that these toxicities are actually more common. Mefloquine can also alter cardiac conduction, and arrhythmias and bradycardia have been reported.


Pharmacology_Katzung

Pharmacology_Katzung. Mefloquine is contraindicated in a patient with a history of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, or sensitivity to related drugs. It should not be co-administered with quinine, quinidine, or halofantrine, and caution is required if quinine or quinidine is used to treat malaria after mefloquine chemoprophylaxis. The CDC no longer advises against mefloquine use in patients receiving β-adrenoceptor antagonists. Mefloquine is also now considered safe in young children, and it is the only chemoprophylactic other than chloroquine approved for children weighing less than 5 kg and for pregnant women. Available data suggest that mefloquine is safe throughout pregnancy, although experience in the first trimester is limited. An older recommendation to avoid mefloquine use in those requiring fine motor skills (eg, airline pilots) is controversial. Mefloquine chemoprophylaxis should be discontinued if significant neuropsychiatric symptoms develop.


Pharmacology_Katzung

Pharmacology_Katzung. Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale and can also be used for chemoprophylaxis against all malarial species. Primaquine phosphate is a synthetic 8-aminoquinoline (Figure 52–2). The drug is well absorbed orally, reaching peak plasma levels in 1–2 hours. The plasma half-life is 3–8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine. Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale. The drug is also gametocidal against the four human malaria species and it has weak activity against erythrocytic stage parasites. The mechanism of antimalarial action is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. Some strains of P vivax in New Guinea, Southeast Asia, Central and South America, and other areas are relatively resistant to primaquine. Liver forms of these strains may not be eradicated by a single standard treatment and may require repeated therapy. 1. Therapy (radical cure) of acute vivax and ovale malaria—Standard therapy for these infections includes chloroquine to eradicate erythrocytic forms and primaquine to eradicate liver hypnozoites and prevent a subsequent relapse. Chloroquine is given acutely, and therapy with primaquine is withheld until the G6PD status of the patient is known. If the G6PD level is normal, a 14-day course of primaquine is given. Prompt evaluation of the G6PD level is helpful, since primaquine appears to be most effective when instituted before completion of dosing with chloroquine. 2. Terminal prophylaxis of vivax and ovale malaria—


Pharmacology_Katzung

Pharmacology_Katzung. 2. Terminal prophylaxis of vivax and ovale malaria— Standard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria, because the hypnozoite forms of these parasites are not eradicated by available blood schizonticides. To diminish the likelihood of relapse, some authorities advocate the use of primaquine after the completion of travel to an endemic area. 3. Chemoprophylaxis of malaria—Daily treatment with 30 mg (0.5 mg/kg) of primaquine base provided good protection against falciparum and vivax malaria, and the drug is now listed as an alternative chemoprophylactic regimen by the CDC. 4. Gametocidal action—Primaquine renders P falciparum gametocytes noninfective to mosquitoes. Including primaquine with treatment for falciparum malaria is used in some areas to decrease transmission, and routine inclusion of single low doses of primaquine (which may be safe without testing for G6PD deficiency) is under study. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Pneumocystis jiroveci infection—The combination of clindamycin and primaquine is an alternative regimen in the treatment of pneumocystosis, particularly mild to moderate disease. This regimen offers improved tolerance compared with high-dose trimethoprim-sulfamethoxazole or pentamidine, although its efficacy against severe pneumocystis pneumonia is not well studied. Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects are leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of primaquine may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects.


Pharmacology_Katzung

Pharmacology_Katzung. Primaquine should be avoided in patients with a history of granulocytopenia or methemoglobinemia, in those receiving potentially myelosuppressive drugs (eg, quinidine), and in those with disorders that commonly include myelosuppression.


Pharmacology_Katzung

Pharmacology_Katzung. Patients should be tested for G6PD deficiency before primaquine is prescribed. When a patient is deficient in G6PD, treatment strategies may include withholding therapy and treating subsequent relapses, if they occur, with chloroquine; treating patients with standard dosing, paying close attention to their hematologic status; or treating with weekly primaquine (45 mg base) for 8 weeks. G6PD-deficient individuals of Mediterranean and Asian ancestry are most likely to have severe deficiency, whereas those of African ancestry usually have a milder biochemical defect. This difference can be taken into consideration in choosing a treatment strategy. In any event, primaquine should be discontinued if there is evidence of hemolysis or anemia. Primaquine should be avoided in pregnancy because the fetus is relatively G6PD-deficient and thus at risk of hemolysis.


Pharmacology_Katzung

Pharmacology_Katzung. Atovaquone, a hydroxynaphthoquinone (Figure 52–2), is a component of Malarone, which is recommended for the treatment and prevention of malaria. Atovaquone has also been approved by the FDA for the treatment of mild to moderate P jiroveci pneumonia. The drug is only administered orally. Its bioavailability is low and erratic, but absorption is increased by fatty food. The drug is heavily protein-bound, has a half-life of 2–3 days, and is mostly eliminated unchanged in the feces. Atovaquone acts against plasmodia by disrupting mitochondrial electron transport. It is active against tissue and erythrocytic schizonts, allowing chemoprophylaxis to be discontinued only 1 week after the end of exposure (compared with 4 weeks for mefloquine or doxycycline, which lack activity against tissue schizonts).


Pharmacology_Katzung

Pharmacology_Katzung. Initial use of atovaquone to treat malaria led to disappointing results, with frequent failures due to the selection of resistant parasites during therapy. In contrast, Malarone, a fixed combination of atovaquone (250 mg) and proguanil (100 mg), is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, and it is now approved for both indications in the USA. For chemoprophylaxis, Malarone must be taken daily (Table 52–2). It has an advantage over mefloquine and doxycycline in requiring shorter periods of treatment before and after the period at risk for malaria transmission, but it is more expensive than the other agents. It should be taken with food.


Pharmacology_Katzung

Pharmacology_Katzung. Atovaquone is an alternative therapy for P jiroveci infection, although its efficacy is lower than that of trimethoprim-sulfamethoxazole. Standard dosing is 750 mg taken with food twice daily for 21 days. Atovaquone has also been effective in small numbers of immunocompromised patients with toxoplasmosis unresponsive to other agents. Malarone is generally well tolerated. Adverse effects include abdominal pain, nausea, vomiting, diarrhea, headache, insomnia, and rash, and these are more common with the higher dosage required for treatment. Reversible elevations in liver enzymes have been reported. The safety of atovaquone in pregnancy is unknown, and its use is not advised in pregnant women. It is considered safe for use in children with body weight above 5 kg. Plasma concentrations of atovaquone are decreased about 50% by co-administration of tetracycline or rifampin.


Pharmacology_Katzung

Pharmacology_Katzung. Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim (see Chapter 46). Proguanil is a biguanide derivative (Figure 52–2). Both drugs are slowly but adequately absorbed from the gastrointestinal tract. Pyrimethamine reaches peak plasma levels 2–6 hours after an oral dose, is bound to plasma proteins, and has an elimination half-life of about 3.5 days. Proguanil reaches peak plasma levels about 5 hours after an oral dose and has an elimination half-life of about 16 hours. Therefore, proguanil must be administered daily for chemoprophylaxis, whereas pyrimethamine can be given once a week. Pyrimethamine is extensively metabolized before excretion. Proguanil is a prodrug; its triazine metabolite, cycloguanil, is active. Fansidar, a fixed combination of the sulfonamide sulfadoxine (500 mg per tablet) and pyrimethamine (25 mg per tablet), is well absorbed. Its components display peak plasma levels within 2–8 hours and are excreted mainly by the kidneys. The average half-life of


Pharmacology_Katzung

Pharmacology_Katzung. (500 mg per tablet) and pyrimethamine (25 mg per tablet), is well absorbed. Its components display peak plasma levels within 2–8 hours and are excreted mainly by the kidneys. The average half-life of sulfadoxine is about 170 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all four human malaria species. Proguanil also has activity against hepatic forms. Neither drug is adequately gametocidal or effective against hypnozoites of P vivax or P ovale. Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or gametocytes. Pyrimethamine and proguanil inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. As described in Chapter 46, inhibitors of these two enzymes provide synergistic activity when used together (see Figure 46–2).


Pharmacology_Katzung

Pharmacology_Katzung. Resistance of P falciparum to folate antagonists and sulfonamides is common in many areas. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. Resistance seriously limits the efficacy of sulfadoxine-pyrimethamine for the treatment of malaria in most areas, but in Africa most parasites exhibit an intermediate level of resistance, such that antifolates may continue to offer some preventive efficacy. 1. Chemoprophylaxis—Chemoprophylaxis with single folate antagonists is no longer recommended because of frequent resistance and toxicity. However, the antifolate combination trimethoprim-sulfamethoxazole is commonly used as a daily prophylactic therapy for HIV-infected patients in developing countries, and this regimen offers partial preventive efficacy against malaria in Africa. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Intermittent preventive therapy—A new strategy for malaria control is intermittent preventive therapy, in which high-risk patients receive intermittent treatment for malaria, regardless of their infection status. This practice is most accepted in pregnancy, with the use of two or more doses of sulfadoxinepyrimethamine after the first trimester now standard policy in Africa, although efficacy is limited. In children intermittent preventive therapy has not been widely accepted, but the WHO now recommends seasonal malaria chemoprevention with amodiaquine plus sulfadoxine-pyrimethamine in the Sahel subregion of Africa, where malaria is highly seasonal and resistance to antifolates is relatively uncommon. In most other areas drug resistance seriously limits the preventive efficacy of antifolates. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Treatment of chloroquine-resistant falciparum malaria—Fansidar is no longer a recommended therapy for malaria, and in particular it should not be used for severe malaria, since it is slower-acting than other available agents. Fansidar is also not reliably effective in vivax malaria, and its usefulness against P ovale and P malariae has not been adequately studied. Artesunate plus sulfadoxine-pyrimethamine is listed by the WHO to treat falciparum malaria (Table 52–4), but other artemisininbased combinations are generally preferred. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Toxoplasmosis—Pyrimethamine, in combination with sulfadiazine, is first-line therapy in the treatment of toxoplasmosis, including acute infection, congenital infection, and disease in immunocompromised patients. For immunocompromised patients, high-dose therapy is required followed by chronic suppressive therapy. Folinic acid is included to limit myelosuppression. The replacement of sulfadiazine with clindamycin provides an effective alternative regimen. Recent problems with pricing and availability of pyrimethamine in the USA made the use of this drug more difficult. 5.


Pharmacology_Katzung

Pharmacology_Katzung. Pneumocystosis—P jiroveci is the cause of human pneumocystosis and is now recognized to be a fungus, but this organism is discussed in this chapter because it responds to antiprotozoal drugs, not antifungals. First-line therapy of pneumocystosis is trimethoprim plus sulfamethoxazole (see also Chapter 46). Standard treatment includes high-dose intravenous or oral therapy (15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole per day in three or four divided doses) for 21 days. High-dose therapy entails significant toxicity, especially in patients with AIDS. Important toxicities include nausea, vomiting, fever, rash, leukopenia, hyponatremia, elevated hepatic enzymes, azotemia, anemia, and thrombocytopenia. Less common effects include severe skin reactions, mental status changes, pancreatitis, and hypocalcemia. Trimethoprim-sulfamethoxazole is also the standard chemoprophylactic drug for the prevention of P jiroveci infection in immunocompromised individuals. Dosing is one double-strength


Pharmacology_Katzung

Pharmacology_Katzung. and hypocalcemia. Trimethoprim-sulfamethoxazole is also the standard chemoprophylactic drug for the prevention of P jiroveci infection in immunocompromised individuals. Dosing is one double-strength tablet daily or three times per week. The chemoprophylactic dosing schedule is much better tolerated than high-dose therapy, but rash, fever, leukopenia, or hepatitis may necessitate changing to another drug.


Pharmacology_Katzung

Pharmacology_Katzung. Most patients tolerate pyrimethamine and proguanil well. Gastrointestinal symptoms, skin rashes, and itching are rare. Mouth ulcers and alopecia have been described with proguanil. Fansidar uncommonly causes severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Severe reactions appear to be much less common with single-dose or intermittent therapy, compared to regular chemoprophylaxis, and use of the drug has been justified by the risks associated with falciparum malaria.


Pharmacology_Katzung

Pharmacology_Katzung. Rare adverse effects with Fansidar are those associated with other sulfonamides, including hematologic, gastrointestinal, central nervous system, dermatologic, and renal toxicity. Folate antagonists should be used cautiously in the presence of renal or hepatic dysfunction. Although pyrimethamine is teratogenic in animals, Fansidar has been safely used in pregnancy. Proguanil is considered safe in pregnancy. In pregnant women receiving Fansidar preventive therapy, high-dose folate supplementation (eg, 5 mg daily) should be replaced by the standard recommended dosage (0.4–0.6 mg daily) to avoid potential loss of protective efficacy.


Pharmacology_Katzung

Pharmacology_Katzung. A number of antibiotics are modestly active antimalarials. Bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast. None of the antibiotics should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials.


Pharmacology_Katzung

Pharmacology_Katzung. Tetracycline and doxycycline (see Chapter 44) are active against erythrocytic schizonts of all human malaria parasites. They are not active against liver stages. Doxycycline is used in the treatment of falciparum malaria in conjunction with quinine, allowing a shorter and better-tolerated course of that drug. Doxycycline is also used to complete treatment courses after initial treatment of severe malaria with intravenous quinine, quinidine, or artesunate. In all of these cases a 1-week treatment course of doxycycline is carried out. Doxycycline has also become a standard chemoprophylactic drug, especially for use in areas of Southeast Asia with high rates of resistance to other antimalarials, including mefloquine. Doxycycline adverse effects include gastrointestinal symptoms, esophagitis, candidal vaginitis, and photosensitivity. Clindamycin (see Chapter 44) is slowly active against erythrocytic schizonts and can be used after treatment courses of quinine, quinidine, or artesunate in


Pharmacology_Katzung

Pharmacology_Katzung. candidal vaginitis, and photosensitivity. Clindamycin (see Chapter 44) is slowly active against erythrocytic schizonts and can be used after treatment courses of quinine, quinidine, or artesunate in those for whom doxycycline is not recommended, such as children and pregnant women. Antimalarial activity of azithromycin and fluoroquinolones has also been demonstrated, but efficacy for the therapy or chemoprophylaxis of malaria has been suboptimal.


Pharmacology_Katzung

Pharmacology_Katzung. Antibiotics are also active against other protozoans. Tetracycline and erythromycin are alternative therapies for the treatment of intestinal amebiasis. Clindamycin, in combination with other agents, is effective therapy for toxoplasmosis, pneumocystosis, and babesiosis. Spiramycin is a macrolide antibiotic that is used to treat primary toxoplasmosis acquired during pregnancy. Treatment lowers the risk of the development of congenital toxoplasmosis. HALOFANTRINE, LUMEFANTRINE, & PYRONARIDINE Halofantrine hydrochloride, a phenanthrene-methanol, is effective against erythrocytic (but not other) stages of all four human malaria species. Oral absorption is variable and enhanced by food. Because of toxicity concerns, it should not be taken with meals. The half-life is about 4 days and excretion is mainly in the feces. Halofantrine is not available in the USA (although it has been approved by the FDA), but it is available in malaria-endemic countries.


Pharmacology_Katzung

Pharmacology_Katzung. Halofantrine (three 500 mg doses at 6-hour intervals, repeated in 1 week for nonimmune individuals) is rapidly effective against P falciparum, but its use is limited by cardiac toxicity. It is generally well tolerated. The most common adverse effects are abdominal pain, diarrhea, vomiting, cough, rash, headache, pruritus, and elevated liver enzymes. Of greater concern, the drug alters cardiac conduction, with dose-related prolongation of QT and PR intervals. Rare instances of dangerous arrhythmias and deaths have been reported. The drug is contraindicated in patients who have cardiac conduction defects or who have recently taken mefloquine. Halofantrine is embryotoxic in animals and therefore contraindicated in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Lumefantrine, an aryl alcohol, is available only as a fixed-dose combination with artemether (Coartem, Riamet), which is now the first-line therapy for uncomplicated falciparum malaria in many countries. In addition, Coartem is approved in many nonendemic countries, including the USA. The half-life of lumefantrine, when used in combination, is 3–4 days. Drug levels may be altered by interactions with other drugs, including those that affect CYP3A4 metabolism. Oral absorption is variable and improved when the drug is taken with food. Since lumefantrine is not associated with the toxicity concerns of halofantrine, Coartem should be administered with fatty food to maximize antimalarial efficacy. Coartem is highly effective in the treatment of falciparum malaria when administered twice daily for 3 days. Coartem can cause minor prolongation of the QT interval, but this appears to be clinically insignificant, and the drug does not carry the risk of dangerous arrhythmias seen with


Pharmacology_Katzung

Pharmacology_Katzung. daily for 3 days. Coartem can cause minor prolongation of the QT interval, but this appears to be clinically insignificant, and the drug does not carry the risk of dangerous arrhythmias seen with halofantrine and quinidine. Coartem is very well tolerated. The most commonly reported adverse events have been gastrointestinal disturbances, headache, dizziness, rash, and pruritus, and in many cases these toxicities may have been due to underlying malaria or concomitant medications rather than to Coartem.


Pharmacology_Katzung

Pharmacology_Katzung. Pyronaridine, a Mannich base acridine, has been studied as an antimalarial for many years and used as monotherapy in China. It is now available in combination with artesunate as Pyramax. Pyronaridine is well absorbed orally without important food effects. It has a half life of about 8 days, with primarily renal elimination. Artesunate-pyronaridine has generally demonstrated excellent efficacy against falciparum and vivax malaria, although a recent report showed lower efficacy in Cambodia. It has generally been well tolerated. Adverse events have included eosinophilia and transaminitis. A general recommendation for use of artesunatepyronaridine to treat malaria awaits further evaluation of efficacy in children and of potential hepatic toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Amebiasis is infection with Entamoeba histolytica. This organism can cause asymptomatic intestinal infection, mild to moderate colitis, severe intestinal infection (dysentery), ameboma, liver abscess, and other extraintestinal infections. The choice of drugs for amebiasis depends on the clinical presentation (Table 52–5). Treatment of Specific Forms of Amebiasis 1. Asymptomatic intestinal infection—Asymptomatic carriers generally are not treated in endemic areas, but in nonendemic areas they are treated with a luminal amebicide. A tissue amebicidal drug is unnecessary. Standard luminal amebicides are diloxanide furoate, iodoquinol, and paromomycin. Each drug eradicates carriage in about 80–90% of patients. Therapy with a luminal amebicide is also required in the treatment of all other forms of amebiasis. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Amebic Colitis—Metronidazole plus a luminal amebicide is the treatment of choice for amebic colitis and dysentery. Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease. Dehydroemetine or emetine can also be used, but are best avoided because of toxicity. 3. Extraintestinal Infections—The treatment of choice for extraintestinal infections is metronidazole plus a luminal amebicide. A 10-day course of metronidazole cures over 95% of uncomplicated liver abscesses. For unusual cases in which initial therapy with metronidazole has failed, aspiration of the abscess and the addition of chloroquine to a repeat course of metronidazole should be considered. Dehydroemetine and emetine are toxic alternative drugs. TABLE 52–5 Treatment of amebiasis. Not all preparations are available in the USA.1 Clinical Setting Drugs of Choice and Adult Dosage Alternative Drugs and Adult Dosage


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 52–5 Treatment of amebiasis. Not all preparations are available in the USA.1 Clinical Setting Drugs of Choice and Adult Dosage Alternative Drugs and Adult Dosage Mild to moderate intestinal infection Hepatic abscess, ameboma, and other extraintestinal disease Luminal agent: Diloxanide furoate,2 500 mg 3 times daily for 10 days Iodoquinol, 650 mg 3 times daily for 21 days Paromomycin, 10 mg/kg 3 times daily for 7 days Metronidazole, 750 mg 3 times daily (or 500 mg IV every 6 hours) for 10 days Tinidazole, 2 g daily for 3 days Metronidazole, 750 mg 3 times daily (or 500 mg IV every 6 hours) for 10 days Tinidazole, 2 g daily for 3 days Metronidazole, 750 mg 3 times daily (or 500 mg IV every 6 hours) for 10 days Tinidazole, 2 g daily for 5 days Tetracycline, 250 mg 3 times daily for 10 days Erythromycin, 500 mg 4 times daily for 10 days Tetracycline, 250 mg 3 times daily for 10 days Dehydroemetine2 or emetine,2 1 mg/kg SC or IM for 3–5 days


Pharmacology_Katzung

Pharmacology_Katzung. Erythromycin, 500 mg 4 times daily for 10 days Tetracycline, 250 mg 3 times daily for 10 days Dehydroemetine2 or emetine,2 1 mg/kg SC or IM for 3–5 days Dehydroemetine2 or emetine,2 1 mg/kg SC or IM for 8–10 days, followed by (liver abscess only) chloroquine, 500 mg twice daily for 2 days, then 500 mg daily for 21 days 1Route is oral unless otherwise indicated. See text for additional details and cautions. 2Not available in the USA. Metronidazole, a nitroimidazole (Figure 52–3), is the drug of choice in the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections. Tinidazole, a related nitroimidazole, appears to have similar activity and a better toxicity profile. It offers simpler dosing regimens and can be substituted for the indications listed below. Pharmacokinetics & Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Pharmacokinetics & Mechanism of Action Oral metronidazole and tinidazole are readily absorbed and permeate all tissues by simple diffusion. Intracellular concentrations rapidly approach extracellular levels. Peak plasma concentrations are reached in 1–3 hours. Protein binding of both drugs is low (10–20%); the half-life of unchanged drug is 7.5 hours for metronidazole and 12–14 hours for tinidazole. Metronidazole and its metabolites are excreted mainly in the urine. Plasma clearance of metronidazole is decreased in patients with impaired liver function. The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antiprotozoal and antibacterial activity. The mechanism of tinidazole is assumed to be the same. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Amebiasis—Metronidazole or tinidazole is the drug of choice in the treatment of all tissue infections with E histolytica. Neither drug is reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection. 2. Giardiasis—Metronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower than that for amebiasis, and the drug is thus better tolerated. Efficacy after a single treatment is about 90%. Tinidazole is at least equally effective, and can be used as a single dose. 3. Trichomoniasis—Metronidazole is the treatment of choice. A single dose of 2 g is effective. Metronidazole-resistant organisms can lead to treatment failures. Tinidazole may be effective against some of these resistant organisms.


Pharmacology_Katzung

Pharmacology_Katzung. Nausea, headache, dry mouth, and a metallic taste in the mouth occur commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, encephalopathy, and neutropenia. Taking the drug with meals lessens gastrointestinal irritation. FIGURE 52–3 Structural formulas of other antiprotozoal drugs. Pancreatitis and severe central nervous system toxicity (ataxia, encephalopathy, seizures) are rare. Metronidazole has a disulfiramlike effect, so that nausea and vomiting can occur if alcohol is ingested during therapy. The drug should be used with caution in patients with central nervous system disease. Intravenous infusions have rarely caused seizures or peripheral neuropathy. The dosage should be adjusted for patients with severe liver or renal disease. Tinidazole has a similar adverse-effect profile, although it appears to be somewhat better tolerated than metronidazole.


Pharmacology_Katzung

Pharmacology_Katzung. Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. Metronidazole and its metabolites are mutagenic in bacteria and tumorigenic in mice. Data on teratogenicity are inconsistent. Metronidazole is thus best avoided in pregnant or nursing women, although congenital abnormalities have not clearly been associated with use in humans. Iodoquinol (diiodohydroxyquin), a halogenated hydroxyquinoline, is an effective luminal amebicide. Pharmacokinetic data are incomplete but 90% of the drug is retained in the intestine and excreted in the feces. The remainder enters the circulation, has a half-life of 11–14 hours, and is excreted in the urine as glucuronides. Iodoquinol is effective against organisms in the bowel lumen but not against trophozoites.


Pharmacology_Katzung

Pharmacology_Katzung. Infrequent adverse effects include diarrhea—which usually stops after several days—anorexia, nausea, vomiting, abdominal pain, headache, rash, and pruritus. Some halogenated hydroxyquinolines can produce severe neurotoxicity with prolonged use. Iodoquinol is not known to produce these effects at its recommended dosage, and this dosage (Table 52-5) should never be exceeded. Iodoquinol should be taken with meals to limit gastrointestinal toxicity. It should be used with caution in patients with optic neuropathy, renal or thyroid disease, or nonamebic hepatic disease. The drug should be discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever). It is contraindicated in patients with intolerance to iodine.


Pharmacology_Katzung

Pharmacology_Katzung. Diloxanide furoate is a dichloroacetamide derivative. It is an effective luminal amebicide but is not active against trophozoites. In the gut, diloxanide furoate is split into diloxanide and furoic acid; about 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is promptly excreted in the urine. The unabsorbed diloxanide is the active antiamebic substance. Diloxanide furoate is not available commercially in the USA but can be obtained from some compounding pharmacies. It does not produce serious adverse effects. Flatulence is common, but nausea and abdominal cramps are infrequent and rashes are rare. The drug is not recommended in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Paromomycin sulfate is an aminoglycoside antibiotic (see also Chapter 45) that is not significantly absorbed from the gastrointestinal tract. It is used as a luminal amebicide and has no effect against extraintestinal organisms. The small amount absorbed is slowly excreted unchanged, mainly by glomerular filtration. However, the drug may accumulate with renal insufficiency and contribute to renal toxicity. Paromomycin appears to have similar efficacy and less toxicity than other luminal agents; in one study it was superior to diloxanide furoate in clearing asymptomatic infections. As it is readily available, paromomycin can be considered the antiamebic luminal agent of choice in the USA. Adverse effects include occasional abdominal distress and diarrhea. Parenteral paromomycin is now used to treat visceral leishmaniasis and is discussed separately in the text that follows.


Pharmacology_Katzung

Pharmacology_Katzung. Emetine, an alkaloid derived from ipecac, and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytica, but because of major toxicity concerns their use is limited to unusual circumstances in which severe amebiasis requires effective therapy and metronidazole cannot be used. Dehydroemetine is preferred because of its somewhat better toxicity profile. The drugs should be used for the minimum period needed to relieve severe symptoms (usually 3–5 days) and administered subcutaneously (preferred) or intramuscularly in a supervised setting. Adverse effects, which are generally mild with use for 3–5 days but increase over time, include pain, tenderness, and sterile abscesses at the injection site; diarrhea, nausea, and vomiting; muscle weakness and discomfort; and minor electrocardiographic changes. Serious toxicities include cardiac arrhythmias, heart failure, and hypotension.


Pharmacology_Katzung

Pharmacology_Katzung. The primary drugs used to treat African trypanosomiasis are listed in Table 52–6, and those for other protozoal infections are listed in Table 52–7. Important antiprotozoal drugs that are not covered elsewhere are discussed below. Pentamidine has activity against trypanosomatid protozoans and against P jiroveci, but toxicity is significant.


Pharmacology_Katzung

Pharmacology_Katzung. Pentamidine has activity against trypanosomatid protozoans and against P jiroveci, but toxicity is significant. Pentamidine is an aromatic diamidine (Figure 52–3) formulated as an isethionate salt. The drug is only administered parenterally. It leaves the circulation rapidly, with an initial half-life of about 6 hours, but is bound avidly by tissues. Pentamidine thus accumulates and is eliminated very slowly, with a terminal elimination half-life of about 12 days. Only trace amounts of pentamidine appear in the central nervous system, so it is not effective against CNS African trypanosomiasis. Pentamidine can also be inhaled as a nebulized powder for the prevention of pneumocystosis. Absorption into the systemic circulation after inhalation appears to be minimal. The mechanism of action of pentamidine is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Pneumocystosis—Pentamidine is a well-established alternative therapy for pulmonary and extrapulmonary disease caused by P jiroveci. The drug has somewhat lower efficacy and greater toxicity than trimethoprim-sulfamethoxazole. The standard dosage is 3 mg/kg/d intravenously for 21 days. Significant adverse reactions are common, and with multiple regimens now available to treat P jiroveci infection, pentamidine is best reserved for patients with severe disease who cannot tolerate or fail other drugs. Pentamidine is also an alternative agent for primary or secondary prophylaxis against pneumocystosis in immunocompromised individuals, including patients with advanced AIDS. For this indication, pentamidine is administered as an inhaled aerosol (300 mg inhaled monthly). The drug is well tolerated in this form. Its efficacy is good but less than that of daily trimethoprim-sulfamethoxazole. TABLE 52–6 Treatment of African trypanosomiasis.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 52–6 Treatment of African trypanosomiasis. 1Available in the USA from the Drug Service, CDC, Atlanta, Georgia (phone: 404-639-3670; www.cdc.gov/laboratory/drugservice/). TABLE 52–7 Treatment of other protozoal infections. Not all preparations are available in the USA.1 Visceral (L donovani, L chagasi, L infantum) or mucosal (L braziliensis) Cutaneous (L major, L tropica, L mexicana, L braziliensis) Sodium stibogluconate, 20 mg/kg/d IV or IM for 28 days Amphotericin (liposomal preparations preferred (3 mg/kg/d IV on days 1–5, 14, and 21)); various other dosing regimens, including single dose Miltefosine, 2.5 mg/kg/d for 28 days Paromomycin,15 mg/kg for 21 days Sodium stibogluconate, 20 mg/kg/d IV or IM for 20 days Meglumine antimoniate Pentamidine, 2–4 mg/kg IM daily or every other day for up to 15 doses Combinations of listed drugs Pregnancy Spiramycin, 3 g daily until delivery


Pharmacology_Katzung

Pharmacology_Katzung. Pentamidine, 2–4 mg/kg IM daily or every other day for up to 15 doses Combinations of listed drugs Pregnancy Spiramycin, 3 g daily until delivery TABLE 52–7 Treatment of other protozoal infections. Not all preparations are available in the USA.1 (Continued) Tinidazole, 2 g once 1Additional information may be obtained from the Parasitic Disease Drug Service, Parasitic Diseases Branch, CDC, Atlanta, Georgia (phone: 404-639-3670; www.cdc.gov/ laboratory/drugservice/). 2Established, relatively simple dosing regimens are provided. Route is oral unless otherwise indicated. See text for additional information, toxicities, cautions, and discussions of dosing for the more rarely used drugs, many of which are highly toxic. 3Specific recommendations for leishmaniasis vary geographically. Combination regimens are increasingly used.


Pharmacology_Katzung

Pharmacology_Katzung. 3Specific recommendations for leishmaniasis vary geographically. Combination regimens are increasingly used. 4P jiroveci (carinii in animals) has traditionally been considered a protozoan because of its morphology and drug sensitivity, but molecular analyses have shown it to be most closely related to fungi. 2. African trypanosomiasis (sleeping sickness)—Pentamidine has been used since 1940 and is the drug of choice to treat the early hemolymphatic stage of disease caused by Trypanosoma brucei gambiense (West African sleeping sickness). The drug is inferior to suramin for the treatment of early East African sleeping sickness. Pentamidine should not be used to treat late trypanosomiasis with central nervous system involvement. A number of dosing regimens have been described, generally providing 2–4 mg/kg daily or on alternate days for a total of 10–15 doses. Pentamidine has also been used for chemoprophylaxis against African trypanosomiasis, with dosing of 4 mg/kg every 3–6 months.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Leishmaniasis—Pentamidine is an alternative to sodium stibogluconate and newer agents for the treatment of visceral leishmaniasis. The drug has been successful in some cases that have failed therapy with antimonials. The dosage is 2–4 mg/kg intramuscularly daily or every other day for up to 15 doses, and a second course may be necessary. Pentamidine has also shown success against cutaneous leishmaniasis, but it is not routinely used for this purpose. Pentamidine is a highly toxic drug, with adverse effects noted in about 50% of patients receiving 4 mg/kg/d. Rapid intravenous administration can lead to severe hypotension, tachycardia, dizziness, and dyspnea, so the drug should be administered slowly (over 2 hours), and patients should be recumbent and monitored closely during treatment. With intramuscular administration, pain at the injection site is common, and sterile abscesses may develop.


Pharmacology_Katzung

Pharmacology_Katzung. Pancreatic toxicity is common. Hypoglycemia due to inappropriate insulin release often appears 5–7 days after onset of treatment, can persist for days to several weeks, and may be followed by hyperglycemia. Reversible renal insufficiency is also common. Other adverse effects include rash, metallic taste, fever, gastrointestinal symptoms, abnormal liver function tests, acute pancreatitis, hypocalcemia, thrombocytopenia, hallucinations, and cardiac arrhythmias. Inhaled pentamidine is generally well tolerated but may cause cough, dyspnea, and bronchospasm.


Pharmacology_Katzung

Pharmacology_Katzung. Pentavalent antimonials, including sodium stibogluconate (pentostam; Figure 52–3) and meglumine antimoniate, are first-line agents for cutaneous and visceral leishmaniasis except in parts of India, where the efficacy of these drugs has diminished greatly. The drugs are rapidly absorbed and distributed after intravenous (preferred) or intramuscular administration and eliminated in two phases, with a short initial (about 2-hour) half-life and a much longer terminal (>24-hour) half-life. Treatment is given at a dosage of 20 mg/kg once daily intravenously or intramuscularly for 20 days in cutaneous leishmaniasis and 28 days in visceral and mucocutaneous disease.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of action of the antimonials is unknown. Their efficacy against different species may vary, possibly based on local drug resistance patterns. Cure rates are generally quite good, but resistance to sodium stibogluconate is increasing in some endemic areas, notably in India where other agents (eg, amphotericin or miltefosine) are generally recommended. Few adverse effects occur initially, but the toxicity of stibogluconate increases over the course of therapy. Most common are gastrointestinal symptoms, fever, headache, myalgias, arthralgias, and rash. Intramuscular injections can be very painful and lead to sterile abscesses. Electrocardiographic changes may occur, most commonly T-wave changes and QT prolongation. These changes are generally reversible, but continued therapy may lead to dangerous arrhythmias. Thus, the electrocardiogram should be monitored during therapy. Hemolytic anemia and serious liver, renal, and cardiac effects are rare.


Pharmacology_Katzung

Pharmacology_Katzung. Nitazoxanide is a nitrothiazolyl-salicylamide prodrug. It is approved in the USA for use against Giardia lamblia and Cryptosporidium parvum. It is rapidly absorbed and converted to tizoxanide and tizoxanide conjugates, which are subsequently excreted in both urine and feces. The active metabolite, tizoxanide, inhibits the pyruvate-ferredoxin oxidoreductase pathway. Nitazoxanide appears to have activity against metronidazole-resistant protozoal strains and is well tolerated. Unlike metronidazole, nitazoxanide and its metabolites appear to be free of mutagenic effects. Other organisms that may be susceptible to nitazoxanide include E histolytica, Helicobacter pylori, Ascaris lumbricoides, several tapeworms, and Fasciola hepatica. The recommended adult dosage is 500 mg twice daily for 3 days.


Pharmacology_Katzung

Pharmacology_Katzung. Current therapies for all forms of trypanosomiasis are seriously deficient in efficacy, safety, or both. Availability of these therapies is also a concern, since they are supplied mainly through donation or nonprofit production by pharmaceutical companies. For visceral leishmaniasis, liposomal amphotericin, miltefosine, and paromomycin are effective, and combinations of these agents have shown promising results.


Pharmacology_Katzung

Pharmacology_Katzung. Suramin is a sulfated naphthylamine that was introduced in the 1920s. It is the first-line therapy for early hemolymphatic East African trypanosomiasis (T brucei rhodesiense infection), but because it does not enter the central nervous system, it is not effective against advanced disease. Suramin is less effective than pentamidine for early West African trypanosomiasis. The drug’s mechanism of action is unknown. It is administered intravenously and displays complex pharmacokinetics with very tight protein binding. Suramin has a short initial half-life but a terminal elimination half-life of about 50 days. The drug is slowly cleared by renal excretion.


Pharmacology_Katzung

Pharmacology_Katzung. Suramin is administered after a 200-mg intravenous test dose. Regimens that have been used include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks. Combination therapy with pentamidine may improve efficacy. Suramin can also be used for chemoprophylaxis against African trypanosomiasis. Adverse effects are common. Immediate reactions can include fatigue, nausea, vomiting, and, more rarely, seizures, shock, and death. Later reactions include fever, rash, headache, paresthesias, neuropathies, renal abnormalities including proteinuria, chronic diarrhea, hemolytic anemia, and agranulocytosis.


Pharmacology_Katzung

Pharmacology_Katzung. Melarsoprol is a trivalent arsenical that has been available since 1949 and is first-line therapy for advanced central nervous system East African trypanosomiasis, and second-line therapy (after eflornithine) for advanced West African trypanosomiasis. After intravenous administration it is excreted rapidly, but clinically relevant concentrations accumulate in the central nervous system within 4 days. Melarsoprol is administered in propylene glycol by slow intravenous infusion at a dosage of 3.6 mg/kg/d for 3–4 days, with repeated courses at weekly intervals, if needed. A new regimen of 2.2 mg/kg daily for 10 days had efficacy and toxicity similar to what was observed with three courses over 26 days. Melarsoprol is extremely toxic. The use of such a toxic drug is justified only by the severity of advanced trypanosomiasis and the lack of available alternatives. Immediate adverse effects include fever, vomiting, abdominal pain, and arthralgias. The most important toxicity is a reactive


Pharmacology_Katzung

Pharmacology_Katzung. of advanced trypanosomiasis and the lack of available alternatives. Immediate adverse effects include fever, vomiting, abdominal pain, and arthralgias. The most important toxicity is a reactive encephalopathy that generally appears within the first week of therapy (in 5–10% of patients) and is probably due to disruption of trypanosomes in the central nervous system. Coadministration of corticosteroids may decrease the likelihood of encephalopathy. Common consequences of the encephalopathy include cerebral edema, seizures, coma, and death. Other serious toxicities include renal and cardiac disease and hypersensitivity reactions. Failure rates with melarsoprol appear to have increased recently in parts of Africa, suggesting drug resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Eflornithine (difluoromethylornithine), an inhibitor of ornithine decarboxylase, is the only new drug registered to treat African trypanosomiasis in the last half-century. It is now the first-line drug for advanced West African trypanosomiasis, but is not effective for East African disease. Eflornithine is administered intravenously, and good central nervous system drug levels are achieved. The elimination half-life is about 3 hours. The usual regimen is 100 mg/kg intravenously every 6 hours for 7–14 days (14 days was superior for a newly diagnosed infection). Eflornithine appears to be as effective as melarsoprol against advanced T brucei gambiense infection, but its efficacy against T brucei rhodesiense is limited by drug resistance. Combining eflornithine with a 10-day course of nifurtimox afforded efficacy against West African trypanosomiasis similar to a 14-day regimen of eflornithine alone, with simpler and shorter treatment (injections every 12 hours for 7 days). Toxicity from


Pharmacology_Katzung

Pharmacology_Katzung. afforded efficacy against West African trypanosomiasis similar to a 14-day regimen of eflornithine alone, with simpler and shorter treatment (injections every 12 hours for 7 days). Toxicity from eflornithine is significant, but considerably less than that from melarsoprol. Adverse effects include diarrhea, vomiting, anemia, thrombocytopenia, leukopenia, and seizures. These effects are generally reversible. Increased experience with eflornithine and increased availability of the compound in endemic areas may lead to its replacement of suramin, pentamidine, and melarsoprol in the treatment of T brucei gambiense infection.


Pharmacology_Katzung

Pharmacology_Katzung. Benznidazole is an orally administered nitroimidazole for the treatment of American trypanosomiasis (Chagas disease) that probably has improved efficacy and safety compared to nifurtimox. These drugs can eliminate parasites and prevent progression when used to treat acute infection, but activity against chronic Chagas disease is suboptimal. In a recent randomized trial, treatment of Chagas cardiomyopathy with benznidazole did not offer clinical benefit. Standard dosage is 5 mg/kg/d in two or three divided doses for 60 days, given with meals. Important toxicities, which are generally reversible, include rash (in 20–30% of those treated), peripheral neuropathy, gastrointestinal symptoms, and myelosuppression.


Pharmacology_Katzung

Pharmacology_Katzung. Nifurtimox, a nitrofuran, is a standard drug for Chagas disease. Nifurtimox is also used in the treatment of African trypanosomiasis in combination with eflornithine. Nifurtimox is well absorbed after oral administration and eliminated with a plasma half-life of about 3 hours. The drug is administered at a dosage of 8–10 mg/kg/d in three divided doses with meals for 60–90 days. Toxicity related to nifurtimox is common. Adverse effects include nausea, vomiting, abdominal pain, fever, rash, headache, restlessness, insomnia, neuropathies, and seizures. These effects are generally reversible but often lead to cessation of therapy before completion of a standard course.


Pharmacology_Katzung

Pharmacology_Katzung. This important antifungal drug (see Chapter 48) is an alternative therapy for visceral leishmaniasis, especially in parts of India with high-level resistance to sodium stibogluconate. Liposomal amphotericin has shown excellent efficacy at a dosage of 3 mg/kg/d intravenously on days 1–5, 14, and 21. Other regimens that have shown good efficacy in India include 4 doses of 5 mg/kg over 4–10 days and a single dose of 15 mg/kg. With single-dose therapy, an amphotericin lipid emulsion had similar efficacy to that of the liposomal formulation. Efficacy of amphotericin appears to be lower in Africa. Nonliposomal amphotericin (1 mg/kg intravenously every other day for 30 days) is more toxic, less expensive, also efficacious, and widely used in India. However, in an Indian trial a single infusion of liposomal amphotericin showed noninferior efficacy and decreased cost compared to a standard 30-day course of amphotericin. Amphotericin is also used for cutaneous leishmaniasis in some areas. The


Pharmacology_Katzung

Pharmacology_Katzung. of liposomal amphotericin showed noninferior efficacy and decreased cost compared to a standard 30-day course of amphotericin. Amphotericin is also used for cutaneous leishmaniasis in some areas. The use of amphotericin, and especially liposomal preparations, is limited in developing countries by difficulty of administration, cost, and toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Miltefosine is an alkylphosphocholine analog that is the first effective oral drug for visceral leishmaniasis. It has recently shown excellent efficacy in the treatment of visceral leishmaniasis in India, where it is administered orally (2.5 mg/kg/d with varied dosing schedules) for 28 days. It was also recently shown to be effective in regimens including a single dose of liposomal amphotericin followed by 7–14 days of miltefosine. A 28-day course of miltefosine (2.5 mg/kg/d) was also effective for the treatment of New World cutaneous leishmaniasis. Vomiting and diarrhea are common but generally short-lived toxicities. Transient elevations in liver enzymes and nephrotoxicity are also seen. The drug should be avoided in pregnancy (or in women who may become pregnant within 2 months of treatment) because of its teratogenic effects. Miltefosine is registered for the treatment of visceral leishmaniasis in India and some other countries, and—considering the serious limitations of other


Pharmacology_Katzung

Pharmacology_Katzung. because of its teratogenic effects. Miltefosine is registered for the treatment of visceral leishmaniasis in India and some other countries, and—considering the serious limitations of other drugs, including parenteral administration, toxicity, and resistance—it may become the treatment of choice for that disease. Miltefosine may also have a role in the treatment of cutaneous leishmaniasis; the drug was noninferior to meglumine antimoniate for this indication in South American children. Resistance to miltefosine develops readily in vitro.


Pharmacology_Katzung

Pharmacology_Katzung. Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. It is much less expensive than amphotericin or miltefosine. A trial in India showed excellent efficacy, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. However, a recent trial showed poorer efficacy in Africa, with the cure rate for paromomycin significantly inferior to that with sodium stibogluconate. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin has also shown good efficacy when topically applied, alone or with gentamicin, for the treatment of cutaneous leishmaniasis.


Pharmacology_Katzung

Pharmacology_Katzung. Drug Combinations Used in the Treatment of Visceral Leishmaniasis The use of drug combinations to improve treatment efficacy, shorten treatment courses, and reduce the selection of resistant parasites has been an active area of research. In a recent trial in India, compared to a standard 30-day (treatment on alternate days) course of amphotericin, noninferior efficacy and decreased adverse events were seen with a single dose of liposomal amphotericin plus a 7-day course of miltefosine, a single dose of liposomal amphotericin plus a 10-day course of paromomycin, or a 10-day course of miltefosine plus paromomycin. In a trial in East Africa, compared to a standard 30-day course of sodium stibogluconate, similar efficacy was seen with a 17-day course of sodium stibogluconate plus paromomycin. Artemether/lumefantrine Coartem, Riamet Atovaquone Generic, Mepron Chloroquine Generic, Aralen Clindamycin Generic, Cleocin Doxycycline Generic, Vibramycin Eflornithine Vaniqa, Ornidyl


Pharmacology_Katzung

Pharmacology_Katzung. Artemether/lumefantrine Coartem, Riamet Atovaquone Generic, Mepron Chloroquine Generic, Aralen Clindamycin Generic, Cleocin Doxycycline Generic, Vibramycin Eflornithine Vaniqa, Ornidyl Iodoquinol Diquinol, Yodoxin Mefloquine Generic, Lariam Metronidazole Generic, Flagyl Paromomycin Generic, Humatin Pentamidine Pentam 300, Pentacarinat, pentami-dine isethionate, Nebupent (aerosol) Tinidazole Generic, Tindamax *Available in the USA only from the Drug Service, CDC, Atlanta, Georgia (phone: 404-639-3670; www.cdc.gov/laboratory/drugservice/). Kappagoda S, Singh U, Blackburn BG: Antiparasitic therapy. Mayo Clin Proc 2011;86:561. Medical Letter: Drugs for parasitic infections. Med Lett Drugs Ther 2013;Supplement. Ashley EA et al: Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014;371:411.


Pharmacology_Katzung

Pharmacology_Katzung. Ashley EA et al: Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014;371:411. Baird KJ, Maguire JD, Price RN: Diagnosis and treatment of Plasmodium vivax malaria. Adv Parasitol 2012;80:203. Boggild AK et al: Atovaquone-proguanil: Report from the CDC expert meeting on malaria chemoprophylaxis (II). Am J Trop Med Hyg 2007;76:208. Bukirwa H et al: Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev 2014;(3):CD006404. Dondorp AM et al: Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial. Lancet 2010;376:1647. Efferth T, Kaina B: Toxicity of the antimalarial artemisinin and its derivatives. Crit Rev Toxicol 2010;40:405. German PI, Aweeka FT: Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet 2008;47:91.


Pharmacology_Katzung

Pharmacology_Katzung. German PI, Aweeka FT: Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet 2008;47:91. Hill DR et al: Primaquine: Report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg 2006;75:402. John GK et al: Primaquine radical cure of Plasmodium vivax: A critical review of the literature. Malar J 2012;11:280. McGready R et al: Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: A population-based study. Lancet Infect Dis 2012;12:388. Morris CA et al: Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J 2011;10:263. Nadjm B, Behrens RH: Malaria: An update for physicians. Infect Dis Clin North Am 2012;26:243. Nosten F et al: Antimalarial drugs in pregnancy: A review. Curr Drug Saf 2006;1:1.


Pharmacology_Katzung

Pharmacology_Katzung. Nadjm B, Behrens RH: Malaria: An update for physicians. Infect Dis Clin North Am 2012;26:243. Nosten F et al: Antimalarial drugs in pregnancy: A review. Curr Drug Saf 2006;1:1. Rehman K, et al: Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis 2014;29:268. Rosenthal PJ: Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008;358:1829. Rosenthal PJ: The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 2013;89:1025. Stepniewska K, White NJ: Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrob Agents Chemother 2008;52:1589. Taylor WR, White NJ: Antimalarial drug toxicity: A review. Drug Saf 2004; 27:25. Tilley L et al: Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol 2016 32:682. White NJ: Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 2007;7:549.


Pharmacology_Katzung

Pharmacology_Katzung. Tilley L et al: Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol 2016 32:682. White NJ: Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 2007;7:549. White NJ et al: Malaria. Lancet 2014;383:723. Whitty CJ, Chiodini PL, Lalloo DG: Investigation and treatment of imported malaria in non-endemic countries. BMJ 2013;346:f2900. World Health Organization: Guidelines for the treatment of malaria. Geneva. 2015. www.who.int/malaria/publications/atoz/9789241549127/en/. Fox LM, Saravolatz LD: Nitazoxanide: A new thiazolide antiparasitic agent. Clin Infect Dis 2005;40:1173. Granados CE et al: Drugs for treating giardiasis. Cochrane Database Syst Rev 2012;(12):CD007787. Leitsch D: Drug resistance in the microaerophilic parasite Giardia lamblia. Curr Trop Med Rep 2015;2:128. Marcos LA, Gotuzzo E: Intestinal protozoan infections in the immunocompromised host. Curr Opin Infect Dis 2013;26:295.


Pharmacology_Katzung

Pharmacology_Katzung. Marcos LA, Gotuzzo E: Intestinal protozoan infections in the immunocompromised host. Curr Opin Infect Dis 2013;26:295. Pierce KK et al: Update on human infections caused by intestinal protozoa. Curr Opin Gastroenterol 2009;25:12. Pritt BS, Clark DG: Amebiasis. Mayo Clin Proc 2008;83:1154. Ross AG et al: Enteropathogens and chronic illness in returning travelers. N Engl J Med 2013;368:1817. Rossignol JF: Cryptosporidium and Giardia: Treatment options and prospects for new drugs. Exp Parasitol 2010;124:45. Wright SG: Protozoan infections of the gastrointestinal tract. Infect Dis Clin North Am 2012;26:323. Aronson NE et al: A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate for the treatment of cutaneous Leishmania major infection. PLoS Negl Trop Dis 2010;4:e628. Ben Salah A et al: Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 2013;368:524. Bern C: Chagas’ disease. N Engl J Med 2015;373:456.


Pharmacology_Katzung

Pharmacology_Katzung. Ben Salah A et al: Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 2013;368:524. Bern C: Chagas’ disease. N Engl J Med 2015;373:456. Bhattacharya SK et al: Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 2007;196:591. Bisser S et al: Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis 2007;195:322. Brun R, Blum J: Human African trypanosomiasis. Infect Dis Clin North Am 2012;26:261. Brun R et al: Human African trypanosomiasis. Lancet 2010;375:148. Burza S et al: Five-year field results and long-term effectiveness of 20 mg/kg liposomal amphotericin B (Ambisome) for visceral leishmaniasis in Bihar, India. PLoS Negl Trop Dis 2014;8:e2603. Goto H, Lauletta Lindoso JA: Cutaneous and mucocutaneous leishmaniasis. Infect Dis Clin North Am 2012;26:293.


Pharmacology_Katzung

Pharmacology_Katzung. Goto H, Lauletta Lindoso JA: Cutaneous and mucocutaneous leishmaniasis. Infect Dis Clin North Am 2012;26:293. Hailu A et al: Geographical variation in the response of visceral leishmaniasis to paromomycin in East Africa: A multicentre, open-label, randomized trial. PLoS Negl Trop Dis 2010;4:e709. Jackson Y et al: Tolerance and safety of nifurtimox in patients with chronic Chagas disease. Clin Infect Dis 2010;51:e69. Kennedy PG: Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol 2013;12:186. Lescure FX et al: Chagas disease: Changes in knowledge and management. Lancet Infect Dis 2010;10:556. Lutje V, Seixas J, Kennedy A: Chemotherapy for second-stage human African trypanosomiasis. Cochrane Database Syst Rev 2013;(6):CD006201. Morillo CA et al: Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med 2015;373:1295.


Pharmacology_Katzung

Pharmacology_Katzung. Morillo CA et al: Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med 2015;373:1295. Murray HW: Leishmaniasis in the United States: Treatment in 2012. Am J Trop Med Hyg 2012;86:434. Murray HW et al: Advances in leishmaniasis. Lancet 2005;366:1561. Musa A et al: Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: A randomised controlled trial. PLoS Negl Trop Dis 2012;6:e1674. Priotto G et al: Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, randomised, phase III, non-inferiority trial. Lancet 2009;374:56. Rassi A Jr, Rassi A, Marcondes de Rezende J: American trypanosomiasis (Chagas disease). Infect Dis Clin North Am 2012;26:275. Rassi A et al: Chagas disease. Lancet 2010;375:1388.


Pharmacology_Katzung

Pharmacology_Katzung. Rassi A Jr, Rassi A, Marcondes de Rezende J: American trypanosomiasis (Chagas disease). Infect Dis Clin North Am 2012;26:275. Rassi A et al: Chagas disease. Lancet 2010;375:1388. Rubiano LC et al: Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. J Infect Dis 2012;205:684. Sosa N et al: Randomized, double-blinded, phase 2 trial of WR 279,396 (paromomycin and gentamicin) for cutaneous leishmaniasis in Panama. Am J Trop Med Hyg 2013;89:557. Sundar S et al: Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: An open-label, non-inferiority, randomised controlled trial. Lancet 2011;377:477. Sundar S et al: Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis 2012;55:543.


Pharmacology_Katzung

Pharmacology_Katzung. Sundar S et al: Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis 2012;55:543. Sundar S et al: Efficacy and safety of amphotericin B emulsion versus liposomal formulation in Indian patients with visceral leishmaniasis: a randomized, open-label study. PLoS Negl Trop Dis 2014;8:e3169. Sundar S, Singh A: Recent developments and future prospects in the treatment of visceral leishmaniasis. Ther Adv Infect Dis 2016;3:98. Sundar S et al: Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010;362:504. van Griensven J, Diro E: Visceral leishmaniasis. Infect Dis Clin North Am 2012;26:309. van Griensven J et al: Combination therapy for visceral leishmaniasis. Lancet Infect Dis 2010;10:184. Vélez I et al: Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis. Am J Trop Med Hyg 2010;83:351.


Pharmacology_Katzung

Pharmacology_Katzung. Vélez I et al: Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis. Am J Trop Med Hyg 2010;83:351. This child has acute falciparum malaria, and her lethargy and abnormal laboratory tests are consistent with progres-sion to severe disease. She should be hospitalized and treated urgently with intravenous artesunate or, if this is unavailable, intravenous quinine or quinidine. She should be followed closely for progression of severe malaria, in particular neu-rologic, renal, or pulmonary complications, and if treated with quinine or quinidine should have cardiac monitoring for potential toxicities. Clinical Pharmacology of the Antihelminthic Drugs Philip J. Rosenthal, MD


Pharmacology_Katzung

Pharmacology_Katzung. Clinical Pharmacology of the Antihelminthic Drugs Philip J. Rosenthal, MD A 29-year-old Peruvian man presents with the incidental finding of a 10 × 8 × 8-cm liver cyst on an abdominal com-puted tomography (CT) scan. The patient had noted 2 days of abdominal pain and fever, and his clinical evaluation and CT scan were consistent with appendicitis. His clinical find-ings resolved after laparoscopic appendectomy. The patient immigrated to the USA 10 years ago from a rural area of Peru where his family trades in sheepskins. His father and sister have undergone resection of abdominal masses, but details of their diagnoses are unavailable. What is your differential diagnosis? What are your diagnostic and therapeutic plans?


Pharmacology_Katzung

Pharmacology_Katzung. Helminths (worms) are multicellular organisms that infect very large numbers of humans and cause a broad range of diseases. More than 1 billion people are infected with intestinal nematodes, and many millions are infected with filarial nematodes, flukes, and tapeworms in other organs. Many drugs, directed against a number of different targets, are available to treat helminthic infections. In many cases, especially in the developing world, the goal is control of infection, with elimination of most parasites, alleviating disease symptoms, and decreasing the transmission of infection. In other cases, complete elimination of parasites is the goal of therapy, although this goal can be challenging with certain helminthic infections, because of both limited efficacy of drugs and frequent reinfection after therapy in endemic areas.


Pharmacology_Katzung

Pharmacology_Katzung. Table 53–1 lists the major helminthic infections and provides a guide to the drug of choice and alternative drugs for each infection. In the text that follows, these drugs are arranged alphabetically. In general, parasites should be identified before treatment is started. Albendazole, a broad-spectrum oral antihelminthic, is the drug of choice and is approved in the USA for treatment of hydatid disease and cysticercosis. It is also used in the treatment of pinworm and hookworm infections, ascariasis, trichuriasis, and strongyloidiasis.


Pharmacology_Katzung

Pharmacology_Katzung. Albendazole is a benzimidazole carbamate. After oral administration, it is erratically absorbed (increased with a fatty meal) and then rapidly undergoes first-pass metabolism in the liver to the active metabolite albendazole sulfoxide. It reaches variable maximum plasma concentrations about 3 hours after a 400-mg oral dose, and its plasma half-life is 8–12 hours. The sulfoxide is mostly protein-bound, distributes well to tissues, and enters bile, cerebrospinal fluid, and hydatid cysts. Albendazole metabolites are excreted in the urine. Benzimidazoles are thought to act against nematodes by inhibiting microtubule synthesis. Albendazole also has larvicidal effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 53–1 Drugs for the treatment of helminthic infections.1 1Additional information may be obtained from the Parasitic Disease Drug Service, Parasitic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, 30333. Telephone: (404) 639-3670. Some of the drugs listed are not generally available in the USA. is a single dose of 400 mg orally (repeated daily for 2–3 days for heavy infections and in 2 weeks for pinworm infections). Albendazole is administered on an empty stomach when used These treatments typically achieve good cure rates and marked against intraluminal parasites but with a fatty meal when used reduction in egg counts in those not cured. For hookworm against tissue parasites.


Pharmacology_Katzung

Pharmacology_Katzung. infections and trichuriasis, albendazole at 400 mg orally once 1. Ascariasis, trichuriasis, and hookworm and pinworm daily for 3 days is now recommended, with albendazole showing infections—For adults and children older than 2 years with improved efficacy over mebendazole. For trichuriasis, combinaascariasis and pinworm infections, the treatment for ascariasis tion of either mebendazole or albendazole with ivermectin and combination of albendazole with oxantel pamoate markedly improved treatment outcomes. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Hydatid disease—Albendazole is the treatment of choice for medical therapy and is a useful adjunct to surgical removal or aspiration of cysts. It is more active against Echinococcus granulosus than against Echinococcus multilocularis. Dosing is 400 mg twice daily with meals for 1 month or longer. Daily therapy for up to 6 months has been well tolerated. One reported therapeutic strategy is to treat with albendazole and praziquantel, to assess response after 1 month or more, and, depending on the response, to then manage the patient with continued chemotherapy or combined surgical and drug therapy. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Neurocysticercosis—Indications for medical therapy for neurocysticercosis are controversial, since antihelminthic therapy is not clearly superior to therapy with corticosteroids alone and may exacerbate neurologic disease. Therapy is probably most appropriate for symptomatic parenchymal or intraventricular cysts. Corticosteroids are usually given with the antihelminthic drug to decrease inflammation caused by dying organisms. Albendazole is now generally considered the drug of choice over praziquantel because of its shorter course, lower cost, improved penetration into the subarachnoid space, and increased drug levels (as opposed to decreased levels of praziquantel) when administered with corticosteroids. Albendazole is given in a dosage of 400 mg twice daily for up to 21 days. Albendazole combined with praziquantel improves efficacy in patients with multiple brain cysts. 4.


Pharmacology_Katzung

Pharmacology_Katzung. Other infections—Albendazole is the drug of choice in the treatment of cutaneous larva migrans (400 mg daily for 3 days), visceral larva migrans (400 mg twice daily for 5 days), intestinal capillariasis (400 mg daily for 10 days), microsporidial infections (400 mg twice daily for 2 weeks or longer), and gnathostomiasis (400 mg twice daily for 3 weeks). It also has activity against taeniasis (400 mg daily for 3 days), trichinosis (400 mg twice daily for 1–2 weeks), and clonorchiasis (400 mg twice daily for 1 week). There have been reports of effectiveness in treatment of opisthorchiasis, toxocariasis, and loiasis. Albendazole is included in programs to control lymphatic filariasis. It appears to be less active than diethylcarbamazine or ivermectin for this purpose, but it is included in combination with either of those drugs in control programs. Albendazole has been recommended as empiric therapy to treat those who return from the tropics with persistent unexplained eosinophilia.


Pharmacology_Katzung

Pharmacology_Katzung. in combination with either of those drugs in control programs. Albendazole has been recommended as empiric therapy to treat those who return from the tropics with persistent unexplained eosinophilia. Albendazole has activity against giardiasis, but with decreased efficacy compared to tinidazole.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Reactions, Contraindications, & Cautions When used for 1–3 days, albendazole is nearly free of significant adverse effects. Mild and transient epigastric distress, diarrhea, headache, nausea, dizziness, lassitude, and insomnia can occur. In long-term use for hydatid disease, albendazole is well tolerated, but it can cause abdominal distress, headaches, fever, fatigue, alopecia, increases in liver enzymes, and pancytopenia. Blood counts and liver function should be monitored during long-term therapy. The drug should not be given to patients with known hypersensitivity to other benzimidazole drugs or to those with cirrhosis. The safety of albendazole in pregnancy and in children younger than 2 years has not been established. Exposure to albendazole is increased by dexamethasone, praziquantel, and cimetidine, and decreased by phenytoin, phenobarbital, carbamazepine, and ritonavir.