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Antiparasitic Effects.

The highly lipophilic compound Atovaquone closely resembles the structure ubiquinone.

Atovaquone is potently active (in animals and in vitro) against

In combination with azithromycin it is also used against Babesia (medication after JJ Burrascano, East Hampton, N.Y. and KB Liegner, Armonk, N.Y., USA).

IC50 ranges between 0.1 to 3.0 mg/L against rat Pneumocystis carinii (mechanism of action against this organism unknown).

Its inhibitory effect being analog to ubiquinone, in sensitive parasites atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis. For illustration, cytochrome bc1 complex (complex III) seems to serve as a highly discriminating molecular target for atovaquone in Plasmodia (Fry and Beesley, 1991; Fry and Pudney, 1992).

Physicians' Desk Reference:
Mechanism of action: atovaquone is a hydroxy-1,4-naphtoquinone, an analog of ubiquinone, with antipneumocystic activity.

Therapeutic Uses.

Toxicity and Side Effects.

The drug appears to cause few acute adverse effects. Nevertheless, more clinical evaluation is needed, particularly to detect possible rare, unusual, or long-term toxic effects.

Precautions and Contraindications.

The safety of atovaquone needs to be further evaluated in Carcinogenicity, mutagenicity, and teratogenicity have not been found thus far in routine tests. Note that therapeutic doses can cause maternal toxicity and interfere with normal fetal development in rabbits.

Atovaquone may have the ability to compete with certain drugs for binding to plasma proteins. Correspondingly, therapy with rifampicin, a potent inducer of drug metabolism, seems to reduce plasma atovaquone levels.

Caution is advised in using the drug in patients with severe liver disease, since it is not known whether atovaquone induces or inhibits the hepatic metabolism or biliary uptake / elimination of other drugs.

Absorption, Fate, and Excretion.

Atovaquone has a low aqueous solubility, and that is probably the reason for the poor bioavailability of atovaquone after oral administration. Physicians' Desk Reference: Mepron Suspension of Glaxo-Wellcome

Costs in Germany


Dohn, M.N., Weinberg, W.G., Torres, R.A., Follansbee, S.E., Caldwell, P.T., Scott, J.D., Gathe, J.C., Jr., Haghighat, D.P., Sampson, J.H., Spotkov, J., Deresinski, S.C., Meyer, R.D., Lancaster, D.J., and the atovaquone Study Group. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann. Intern. Med., 1994, 121:174-180.

Fry, M., and Beesley, J.E. Mitochondria of mammalian Plasmodium spp. Parasitology, 1991, 102:17-26.

Fry, M., and Pudney, M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4¢-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem. Pharmacol., 1992, 43:1545-1553.

Haile and Flaherty, 1993: No reference given In Goodman & Gilman's

Hughes, W.T., Gray, V.L., Gutteridge, W.E., Latter, V.S., and Pudney, M. Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob. Agents Chemother., 1990, 34:225-228.

Hughes, W., Leoung, G., Kramer, F., Bozzette, S.A., Safrin, S., Frame, P., Clumeck, N., Masur, H., Lancaster, D., Chan, C., Lavelle, J., Rosenstock, J., Falloon, J., Feinberg, J., LaFon, S., Rogers, M., and Sattler, F. Comparison of atovaquone (566C80) with trimethoprim-sulfmethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N. Engl. J. Med., 1993, 328:1521-1527.

Wong, S.-Y., and Remington, J.S. Biology of Toxoplasma gondii. AIDS, 1993, 7:299-316.


Babesia Species

after: Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA, Medical Microbiology, 3rd. ed., Mosby-Year Book, Inc., St. Louis, 1998.

Babesia are sporozoan parasites living inside host cells. Morphologically they resemble plasmodia. Babesiosis is an infection of a variety of animals such as cattle, deer, and rodents. Humans are accidental hosts. Infection is transmitted by the ticks of the Ixodes type. In the United States, Babesia microti is the usual cause of babesiosis.

Physiology and Structure: Humans are infected by a tick bite, when the infected tick has been attached for several hours. So prompt removal of ticks can be protective. After the infectious pyriform bodies are introduced into the bloodstream, they invade erythrocytes. After multiplication by binary fission the parasite lyses the erythrocyte, releasing the merozoites stage of the parasite cycle. These can reinfect other cells and maintain the infection. Infected cells can also be ingested by feeding ticks, and then additional replication can take place. Tick populations can also be infected by transovarian transmission. The infected cells in humans resemble the ring forms of Plasmodium flaciparum, but malarial pigment or other growth stages characteristically seen with infections by Plasmodia are not seen when carefully examining blood smears.

Epidemiology: The number of different species of Babesia exceeds 70 in Africa, Asia, Europe and North America with Babesia microti causing the disease along the northeastern shore of the U.S, with Ixodes dammini being the tick responsible for transmitting babesiosis in that area. The natural reservoir hosts are small rodents, such as field mice and voles. In endemic areas serological studies have demonstrated a high incidence of past exposure to Babesia. It is assumed that most infections are asymptomatic or mild. Babesia divergens, which has been reported more frequently from Europe, causes severe and often fatal infections in people who had their spleen removed by surgery. Most infections follow tick bites. Nevertheless, tansfusion-related infections have been demonstrated.

Clinical Symptoms: The incubation period ranges from 1 to 4 weeks. Thereafter, symptomatic patients feel a general malaise, fever and weakness. During the progressing infection, with increased destruction of erythrocytes, hemolytic anemia develops, possibly resulting in renal failure. Hepatomegaly and splenomegaly can develop in advanced disease. Low-grade parasitemia may persist for weeks. Susceptibility and severe disease increase after splenectomy (or functional asplenia), immunosuppression and at advanced age.

Lab Diagnosis: Exam of blood smears is the appropriate method. Personnel must be experienced in distinguishing between Babesia and Plasmodia. Negative smears may result when parasitemia is low-grade. These infections can be diagnosed by culture tests using hamsters as medium.

Piroplasmosis (Babesiosis)

From: Burrascano JJ, The New Lyme Disease: Diagnostic Hints And Treatment Guidelines For Tick Borne Illnesses, 1998Piroplasms (Babesia) are not bacteria, they are protozoans (i.e. lacking a cell wall and having a membrane bound nucleus). Therefore, they will not be eradicated by any of the currently used Lyme treatment regimens. Therein lies the significance of coinfections. If a Lyme patient has been extensively treated yet is still ill, suspect a piroplasm.

Diagnosis: The evaluation of a Lyme patient must begin with testing for currently known tick borne pathogens.

Borrelia and Babesia antigen detection tests (antigen capture and PCR) are especially helpful Unfortunately, over a dozen protozoans other than Babesia microti can be found in ticks, yet commercial tests for only B. microti are available at this time, so as in Borrelia, clinical assessment is the primary diagnostic tool.

Babesia are parasites, and I suggest that if a coinfection is found involving this organism, treat this first, so that subsequent therapy for Borrelia and Ehrlichia will be more effective.

Clinical Symptoms: Classic teachings state that acute infections are usually only seen in those with some form of immune compromise.

Visualizing Babesial forms on peripheral smears can make the diagnosis in this situation.

In those with intact immune systems, a mild flu-like illness appears 1 to 2 weeks after exposure and clears without treatment over 6 to 8 weeks. In either case, it is imperative to test for Borrelia and Ehrlichia.

When coinfection exists,

Signs of coinfection include out of proportion to the other Borrelial symptoms. Testing is not at all definitive, yet should include Newer direct assays are currently being researched, as this is an active area of investigation. Always consider coinfection in your current Lyme patients who are not responding fully to appropriate therapy.


See also:

Infections in Medicine16(5):319-320, 326, 1999

Bug Vectors: Ticks and Human Babesiosis

Jerome Goddard, PhD

University of Mississippi School of Medicine, Jackson, Miss.


Babesiosis, frequently confused with malaria, occurs most often in the northeastern United States. Recently, new species of Babesia have been isolated from symptomatic patients in Missouri and the Pacific Coast of the United States. Treatment for babesiosis remains quinine sulfate plus clindamycin. [Infect Med 16(5):319-320, 326, 1999. © 1999 SCP Communications, Inc.]

Antimicrob Agents Chemother 1999 Jun;43(6):1334-9

A mechanism for the synergistic antimalarial action of atovaquone and proguanil.

Srivastava IK, Vaidya AB

Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania 19129, USA.


A combination of atovaquone and proguanil has been found to be quite effective in treating malaria, with little evidence of the emergence of resistance when atovaquone was used as a single agent. We have examined possible mechanisms for the synergy between these two drugs. While proguanil by itself had no effect on electron transport or mitochondrial membrane potential (DeltaPsim), it significantly enhanced the ability of atovaquone to collapse DeltaPsim when used in combination. This enhancement was observed at pharmacologically achievable doses. Proguanil acted as a biguanide rather than as its metabolite cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone effect; another DHFR inhibitor, pyrimethamine, also had no enhancing effect. Proguanil-mediated enhancement was specific for atovaquone, since the effects of other mitochondrial electron transport inhibitors, such as myxothiazole and antimycin, were not altered by inclusion of proguanil. Surprisingly, proguanil did not enhance the ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites. These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses DeltaPsim in malaria parasites. This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance. The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner.

PMID: 10348748, UI: 99277989

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WESTPORT, Jun 22 (Reuters Health) - The synergism between the antimalarial agents atovaquone and proguanil appears to be the result of an interaction that targets parasite mitochondria while leaving host mitochondria unaffected.

"We have found what appears to be a novel mechanism by which this synergistic effect occurs," Dr. Akhil B. Vaidya told Reuters Health, "...that is, by collapsing the charge characteristic of the parasite mitochondria."

Dr. Vaidya and colleague Dr. Indresh K. Srivastava, both of the MCP Hahnemann School of Medicine in Philadelphia, Pennsylvania, discovered that proguanil enhances the ability of atovaquone to collapse mitochondrial membrane potential "...without affecting electron transport inhibition."

Other drugs that inhibit mitochondrial electron transport did not have the same effect on atovaquone, the scientists report in the June issue of Antimicrobial Agents and Chemotherapy.

The findings appear to account for the surprising efficacy of the drug combination, Dr. Vaidya told Reuters Health. Together, proguanil and atovaquone are 100% effective against malaria, the researcher said, while on its own, atovaquone has a 30% failure rate.

Although the new data provide some insight into the synergistic interaction between proguanil and atovaquone, "...we still don't understand exactly how this happens at the molecular level," Dr. Vaidya noted in the interview.


version: July 8, 2010