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The highly lipophilic compound Atovaquone closely resembles the structure
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.
The mechanism of action against Pneumocystis carinii has not been fully
In Plasmodium species the site of action appears to be the cytochrome bc1
complex (Complex III). Several metabolic enzymes are linked to the mitochondrial
electron transport via ubiquinone. Inhibition of electron transport by
atovaquone will result in indirect inhibition of theses enzymes. The ultimate
metabolic effects of such blockade may include inhibition of nucleic acid
and ATP synthesis.
Atovaquone is useful for patients who while being able to take oral medication
do not tolerate trimethoprim-sulfamethoxazole or i.v. pentamidine isethionate
for treatment of mild to moderate Pneumocystis Carinii
Pneumonia (PCP). Note that atovaquone has not been approved for treatment
(or prophylaxis) of severe PCP
Whereas atovaquone has a higher therapeutic failure rate it stimulates
less toxic effects than either trimethoprim-sulfamethoxazole or intravenous
pentamidine (preliminary studies Hughes et al., 1993;
et al., 1994).
Successful PCP treatment as a function of steady-state
plasma atovaquone concentration (Physicians' Desk Reference).
Success = improvement of clinical and respiratory measures persisting at
least 4 weeks after cessation of therapy:
steady-state plasma atovaquone
concentration ...... treatment outcome
0 to < 5 mg/L .............................................. 0 % successful
5 to < 10 mg/L ............................................ 69 % successful
10 to < 15 mg/L .......................................... 79 % successful
15 to < 20 mg/L .......................................... 95 % successful
20 to < 25 mg/L ......................................... 100 % successful
The adult dose of atovaquone is 750 mg taken orally three times daily
for 21 days, but the optimal dosing regimen has yet to be established.
The dosage should be adjusted to achieve average steady-state plasma levels
of atovaquone greater than 10 mg/L, because lower values are more likely
to be associated with therapeutic failures.
Data on appropriate doses for immunocompromised pediatric patients are
sparse; doses of 40 mg/kg once daily yielded therapeutic plasma levels,
but lower doses may be satisfactory. Although patients with AIDS may display
reduced steady-state plasma levels of atovaquone, the reason for this is
unclear (see Haile and Flaherty, 1993).
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.
Manifestations of underlying disease and adverse effects directly attributable
to atovaquone have not been readily distinguished in severely debilitated
and immunocompromised patients such as those with AIDS.
Atovaquone has been the source of few side effects that require withdrawal
of therapy. The most common reactions are
In case of vomiting and diarrhea therapeutic failure may be due to decreased
Maculopapular rashes (dose dependent) occur in about 20% of patients, but
are mostly mild and not progressing during continuing therapy.
In histories of allergic skin reactions atovaquone should not be given
nor in cases of possible allergy to the drug.
On occasion abnormalities of serum transaminase and amylase levels have
Atovaquone has no proven efficacy against bacterial, viral, as well as
most opportunistic infections commonly afflicting immunocompromised persons.
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.
pediatric patients, and
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
After a single oral dose, absorption of the drug is slow and erratic; it
is increased about threefold by the presence of fatty food and is dose-limited
above 750 mg.
Plasma level-time profiles show a double peak, albeit with considerable
the first peak appears in 1 to 8 hours while
the second occurs 1 to 4 days after a single dose.
This pattern suggests an enterohepatic circulation, as does the
long half-life of
2 to 3 days (Goodman & Gilman's)
(62.5 +- 35.3) hr after iv,
(67.0 +- 33.4 ... 77.6 +- 23.1) hr MEPRON Suspension, Physicians'
Indeed, over 94% of the drug is recovered unchanged in human feces, and
only traces appear in the urine.
Metabolites of atovaquone have yet to be identified in human beings.
99.9% of the drug is bound to plasma proteins over the concentration range
1 ... 90 mg/L, so that its concentration in cerebrospinal fluid is less
than 1% of that found in plasma.
Absorption: The suspension formulation provides an approximately 2-fold
increase in atovaquone bioavailablity in the fasting or fed state, compared
to the previously marketed tablet formulation.The absolute bioavailablitiy
a 750 mg dose of MEPRON Suspension administered under fed conditions in
9 HIV infected (CD4 > 100 cells/mm3) volunteers was (47 +- 15)
a 750 mg dose of the previously marketed tablet formulation was (23 +-
Administrering atovaquone with food enhances its absorption by approx.
In one study, 16 healthy volunteers received a single
dose of 750 mg Suspension after an overnight fast (AUC = (324 +- 115) hr
mg/L) and following a standard breakfast (23 g fat: 610 kcal)(AUC = (801
+- 320) hr mg/L).
Table: Dose non-proportionality in adults, weights in mg atovaquone
|average steady state
||11.7 +- 4.8
||15.1 +- 6.1 (*)
8.8 +- 3.7 (2*)
||12.5 +- 5.8
||15.3 +- 7.6
|3 x 750 (Tablets)
||13.9 +- 6.9 (3*)
||13.5 +- 5.1
||16.8 +- 6.4
(*) = healthy and HIV, food, AUC = (280 +- 114)
(2*) = HIV, no food, AUC = (169 +- 77) hr mg/L.
(3*) = HIV.
Costs in Germany
250 ml Suspension -with 750 mg atovaquone per 5 ml. Price: 1449 DM.
12 Tablets with 250 mg atovaquone per Tablet. Price: 109 DM
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.,
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.
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
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.
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
Serological studies for Borrelia, Babesia and Ehrlichia should be combined
where appropriate with
antigen assay for Borrelia and
PCR studies for Borrelia and Babesia.
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
in evaluating the seronegative patient,
in evaluating those still ill or relapsing after therapy, and
in sorting out individual contributions of each organism.
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.
Flu-like symptoms rapidly evolve to include shaking chills, high fevers,
Fatalities have been reported.
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
this acute presentation is much less common, and
it is rare to see parasite forms on smear.
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.
Babesia smear (very low yield),
serologies (IgG and IgM) and
if necessary, PCR of peripheral blood.
Pentamidine is a treatment given as daily IM shots- very
painful, they cause sterile abscesses and permanent fibrous scars on the
buttocks. More importantly, response is poor, and the patient risks development
of glucose intolerance. Clearly, not a first choice.
Clindamycin, 600 mg qid plus Quinine, 650 mg qid has been
the published standard but the suggested two week course is nearly impossible
to tolerate (hearing loss, rash, fever, headache) and treatment failures
have been reported.
Gentamicin in combination with either penicillin or a first
generation cephalosporin is used in treating livestock infected with piroplasms.
There are only anecdotal reports of efficacy in humans and the dose and
duration of therapy (14+days) has not been well worked out. The main side
effect is hearing loss from the gentamicin, and the need for IM or IV doses.
Mepron (atovaquone), 750 mg bid, has demonstrated efficacy, but should
be given concurrently with azithromycin, 250 to 600 mg daily, or resistance
Efficacy is by far the best with this combination, but
surprisingly, Herxheimer-like reactions are almost always seen at the fourth
day, and at the fourth week of therapy. Does this represent a newly described
phenomenon in treating Piroplasms, or does this combination have heretofore
unrecognized efficacy in killing Bb? Although I do not have the answer,
I suspect the latter simply based on the (in Bb) familiar four-week cycle.
In late, longstanding cases, one month of treatment is the minimum, and
four or more months are often needed.
Problems during therapy include
the expense of Mepron ($600.00 per bottle- enough for one month of treatment),
rarely, a temporary greenish discoloration of the vision.
Regular blood counts and liver panels are recommended during any prolonged
course of therapy.
in Medicine16(5):319-320, 326, 1999
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
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
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
"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
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
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
Goodman & Gilman's Pharmacological Basis of Therapeutics,
1996, 9th edition
Physicians' Desk Reference (1996),
Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA, Medical
Microbiology, 3rd. ed., Mosby-Year Book, Inc., St. Louis, 1998 and
Burrascano JJ, The
New Lyme Disease: Diagnostic Hints And Treatment Guidelines For Tick
Borne Illnesses, 1998.
Bug Vectors: Ticks and Human Babesiosis,
Jerome Goddard, PhD
A mechanism for the synergistic antimalarial
action of atovaquone and proguanil, Srivastava IK, Vaidya AB
version: July 8, 2010