Atovaquone resistance

Kessl, J. J., Meshnick, S. R., and Trumpower, B. L. (2007). Modeling the molecular basis of atovaquone resistance in parasites and pathogenic fungi. Trends Parasitol. 23,494—501. 

For uncomplicated falciparum malaria there are several options (with the major drawback in brackets) halofantrine (arrhytmia), mefloquine (neurotoxicity), quinine (vomiting, tinnitus), artemether (recrudescence), atovaquone-proguanil (possible fast development of resistance). 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Travelers to areas endemic for chloroquine-resistant disease Mefloquine, doxycycline, or atovaquone/proguanil Excellent... 

Malarone Areas with chloroquine-resistant P falciparum 1 tablet (250 mg atovaquone/100 mg proguanil) daily... 

Uncomplicated infections with chloroquine-resistant P falciparum Quinine sulfate, 650 mg 3 times daily for 3-7 days Malarone, 4 tablets (total of 1 g atovaquone, 400 mg proguanil) daily for 3 days... 

Chloroquine-resistant Quinine Artemisinin derivatives Atovaquone-proguanil Mefloquine Pyrimethamine-sulfadoxine Antibacterials (e.g., clindamycin, doxycycline, sulfamethoxazole, or tetracycline] ... 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

Pneumocystosis, caused by Pneumoq/stis carinii (now classified as a fungus), is an important cause of potentially fatal pneumonia in the immimo-suppressed. It is treated with co-trimoxazole in high dose (120 mg/kg daily in 2-4 divided doses for 14 days by mouth or i.v. infusion). Intolerant or resistant cases may benefit from pentamidine or, if mild to moderate, from atovaquone, or trimetrexate (given with calcium folinate). Co-trimoxazole by mouth or intermittent inhaled pentamidine are used for prophylaxis in patients with AIDS. 

Atovaquone acts synergistically with proguanil, and the combination of these two drugs (Malarone ) is highly efficacious in the treatment of uncomplicated malaria (8), including that against multidrug resistant forms, and in prophylaxis (9). It has not yet been widely marketed, so data on rare adverse effects are currently sparse. 

In P. falciparum (chloroquine-resistant) infections, a dose of 750 mg mefloquine followed by 500 mg 12 hours later is recommended. The pediatric dose of mefloquine is 15 mg/kg (<45 kg) followed by 10 mg/kg 8 to 12 hours later.Intravenous quinidine gluconate followed by oral quinine should be administered for severe illness, as already indicated.A second drug needs to be administered in chloroquine-resistant P. falciparum, and this second drug should follow the oral quinidine regimen either a single dose of three tablets of pyrimethamine-sulfadoxine (Fansidar) on the last day of intravenous quinidine or clindamycin 900 mg three times daily for 3 to 5 days. An alternative oral treatment for chloroquine-resistant P falciparum infection in adults, especially in those with a history of seizures or psychiatric disorders, is the combination of atovaquone 250 mg and proguanil 100 mg (Malarone) (4 tablets daily... 

Srivastava, I. K., Morrisey, J. M., Darrouzet, E., Daldal, F., and Vaidya, A. B. (1999). Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria... 

Resistance to atovaquone in P. falciparum develops readily. Mutations in resistant organisms have been mapped to the mitochondrially encoded cytochrome b gene. Resistance can be prevented by combining proguanil with atovaquone, but it remains to be seen how long this will be effective. 

In contrast to cycloguanil, resistance to the intrinsic antimalarial activity of proguanil itself, either alone or in combination with atovaquone, has yet to be documented. 

Chemoprophylaxis for travelers to geographic regions where chloroquine-resistant P falciparum is endemic is best provided by (A) Atovaquone Mefloquine Primaquine... 

Resistance to atovaquone used as a monotherapy may have been associated with the pharmacokinetics of the drug. Atovaquone is quite lipophilic and has slow uptake, resulting in the pathogen experiencing low concentrations of the drug over an extended period of time, both of which encourage the development of resistance. A single-point mutation appears to be sufficient for resistance (44). To date, resistance to the combination has not been reported. 

An isolated report describes a 22-month-old girl treated with phenytoin, sodium valproate and topiramate for epilepsy and then with quinine sulfate (initially intravenously, then orally) followed by a single dose of sul-fadoxine/pyrimethamine for malaria. Her malaria film became negative after 4 days of the 7-day quinine course. About 1 month later she was found to have recrudescent falciparum malaria, which was treated with quinine sulfate and then atovaquone/proguanil. Although it is possible that quinine resistance may have occurred, the authors also considered that enzyme induction by phenytoin may have led to suboptimal quinine levels. Although quinine does not appear to affect phenytoin levels, the isolated case report suggests that levels of quinine may be reduced in the presence of phenytoin and it would seem prudent to monitor carefully concurrent use. 

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