Download Amebic meningoencephalitides and keratitis: challenges

Amebic meningoencephalitides and keratitis: challenges in
diagnosis and treatment
Govinda S. Visvesvara
Centers for Disease Control and Prevention, Atlanta,
Georgia, USA
Correspondence to Govinda S. Visvesvara, PhD,
Centers for Disease Control and Prevention, Roybal
Campus, M.S.-D66, 1600 Clifton Road, Atlanta,
GA 30333, USA
Tel: +1 404 718 4159; e-mail: [email protected]
This article is dedicated to the memory of Dr Frederick
L. Schuster, a good friend and an often collaborator.
Current Opinion in Infectious Diseases 2010,
23:590–594
Purpose of review
Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri, although freeliving amebae, also cause devastating diseases in humans leading to death.
Acanthamoeba spp. and B. mandrillaris cause granulomatous amebic encephalitis,
cutaneous and nasopharyngeal as well as disseminated infection. Acanthamoeba also
causes a vision-threatening infection of the cornea, Acanthamoeba keratitis, principally
in contact lens wearers. N. fowleri causes an acute, fulminating infection of the
central nervous system, primary amebic meningoencephalitis, in healthy children and
young adults who indulge in aquatic activities in fresh water. This review focuses on
the recent developments in the diagnosis and treatment and clinical management of the
diseases caused by these amebae.
Recent findings
Development of a multiplex real-time PCR test has made it possible to simultaneously
detect all the three free-living amebae in a sample. It is a rapid assay with a short turnaround time of just 4–5 h. An early diagnosis would be helpful in initiating potentially
effective treatment. A recent study reported exciting results indicating that loading of
rokitamycin in chitosan microspheres improves and prolongs the in-vitro antiAcanthamoeba activity of the drug.
Summary
Diagnoses of these infections are challenging and antimicrobial therapy is empirical,
which often results in fatalities. Further research is needed to explore the possibility of a
better drug delivery system that crosses the blood–brain barrier and effectively reach
the central nervous system.
Keywords
Acanthamoeba keratitis, Acanthamoeba spp., Balamuthia mandrillaris, granulomatous
amebic encephalitis, Naegleria fowleri, primary amebic meningoencephalitis
Curr Opin Infect Dis 23:590–594
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7375
Introduction
Free-living amebae belonging to the genera Acanthamoeba, Balamuthia, and Naegleria cause infections of the
central nervous system (CNS) of humans [1–5]. Acanthamoeba and Naegleria are ubiquitous in nature and occur
worldwide. They feed on bacteria and multiply by binary
fission. The environmental niche of Balamuthia is not
well known. It has been isolated from soil and dust
[1,3,5,6] and it is possibly present in water. Balamuthia
does not feed on bacteria but may feed on small amebae
and/or small yeasts.
Several species of Acanthamoeba cause a chronic granulomatous infection leading to death, principally in immunocompromised persons, whereas the only known species
of Balamuthia (B. mandrillaris) causes a chronic granulomatous infection in both immunocompromised and
0951-7375 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
immunocompetent persons. Additionally, both Acanthamoeba spp. and B. mandrillaris cause disseminated infections including skin, sinuses, lungs, prostate, and uterus
[1–3]. Acanthamoeba spp. also causes an infection of the
eye, Acanthamoeba keratitis, principally in contact lens
wearers [1,2,5,7 –9]. Among the 40 species that belong
to the genus Naegleria, only one species, Naegleria fowleri,
causes an acute, fulminating and a necrotizing hemorrhagic meningoencephalitis called primary amebic
meningoencephalitis (PAM) in otherwise healthy children and young adults [1,4,5]. Additionally, another
ameba belonging to the genus Sappinia (Sappinia pedata)
has been identified as a cause of encephalitis in a human
[10]. Although, hundreds of infections have been caused
by Acanthamoeba spp., B. mandrillaris, and N. fowleri, only
a few persons have survived these infections because of
delay in diagnosis due to lack of knowledge, and empirical treatment due to lack of optimal therapy. The basic
DOI:10.1097/QCO.0b013e32833ed78b
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Amebic meningoencephalitides and keratitis Visvesvara 591
biology of the amebae and available information on the
therapy used will be discussed.
Acanthamoeba spp.
Acanthamoeba has two stages in its life cycle; a trophozoite
stage in which the ameba feeds and reproduces by binary
fission, and a double-walled cyst stage that is resistant
to environmental pressures [1,2,11], probably due to the
presence of complex carbohydrates in the cyst wall [12].
As many as 24 species are included in three groups based
on morphology and 16 sequence types based on sequencing of the 18S rRNA gene [2,13]. Although several
different species and several genotypes cause infections,
the most prevalent amebae that cause infections are
included in group II and sequence type T4 [2].
Therapy used for systemic Acanthamoeba
infections
Although a number of antimicrobials have been used in
the past to treat CNS as well as nasopharyngeal infections
no drug has been found to be useful. A few patients have
recovered after a combination of multiple drugs including
fluconazole, itraconazole, ketoconazole, pentamidine
isethionate, trimethoprim–sulfamethoxazole (co-trimoxazole), sulfadiazine, and 5-fluorocytosine (flucytosine),
but the outlook for most patients remains hopeless
especially because of HIV/AIDS and other opportunistic
infections [2,14,15]. Recently, however, several patients
recovered after treatment with a combination of drugs
partly because of early diagnosis [16–21]. Treatment of
cutaneous infections without spreading to CNS has fared
better. Some successful treatment regimens have
included topical chlorhexidine and ketoconazole cream
followed by pentamidine isethionate, 5-fluorocytosine,
and itraconazole [1,2,14,18,22].
A number of antimicrobials have been tested in vitro,
against different Acanthamoeba isolates [2,23]. For
example, miltefosine (hexadecylphosphocholine) was
found to be effective in vitro against Acanthamoeba
isolates [24,25] and was found to be useful in systemic
infections [21] and amebic keratitis [26]. In a recent
article, Walochnik et al. [27] have demonstrated that
Acanthamoeba penetrates the recently developed organ
system culture of a skin equivalent within 24 h and
that miltefosine at 50 mmol/l concentration neutralizes
Acanthamoeba in such a system and that it is nontoxic to
mammalian cells. In vivo, even a 6% (150 mmol/l)
solution is well tolerated by human skin [27]. Miltefosine is also stable for at least 1 year and it is also much less
toxic than chlorhexidine gluconate, an anti-Acanthamoeba
drug used currently for Acanthamoeba keratitis. Mechanisms of efficacy are probably due to inhibition of lipid
remodeling, phospholipid biosynthesis, intracellular sig-
naling, targeting of cellular membranes, and/or induction
of apoptosis [27,28]. Further, a number of factors such
as the virulence of the amebae, the infectious dose, time
at which therapeutic intervention started, the immune
status of the host, and the use of steroids during the
course of the infection contribute to the success or
otherwise of the intervention program.
Delivery of drugs to the affected areas,
specifically the brain
Many of the drugs that are currently used to target the
infectious agents do not cross the blood–brain barrier;
hence suitable antiamebic concentrations are unavailable
in the CNS to neutralize the amebae. An effort has been
made recently to mitigate this by using inert polymers
such as chitosan microspheres as vehicles for antimicrobials. Chitosan particles loaded with pharmaceuticals
could be useful in transporting the drug to the ocular
surface or to the brain when sprayed into the nasal
epithelium. Loading of rokitamycin in chitosan microspheres improves and prolongs the anti-Acanthamoeba
activity when compared with the free drug [29].
Further research has shown that the chitosan derivative,
diethylaminomethyl(diethyldimethylene ammonium) nmethylchitosan has better properties in regard to size,
mucoadhesiveness, and in-vitro release of rokitamycin
and thus is more suitable for ocular or nasal administration. Additionally, this chitosan derivative had no toxic
effect in vitro to human umbilical vein endothelial cells
[30].
Treatment for Acanthamoeba keratitis
Prognosis for Acanthamoeba keratitis is better and has
considerably improved during the past few years. This
is probably due to improvement in diagnosis, better
awareness, and understanding of the infection by the
eye care providers (especially with regard to the association of Acanthamoeba keratitis and contact lenses) resulting in the timely initiation of antimicrobials. Therefore,
prospects for the recovery are excellent. The drawback
however is the possibility of conversion of the trophic
stage to the cyst stage (reviewed in [9]), leading to the
recurrence of infection. The cyst, because of its double
wall and the presence of cellulose in the inner wall, is
resistant to drugs (reviewed in [6,12]). The drugs currently recommended for the treatment of Acanthamoeba
keratitis are two biguanides, polyhexamethylene biguanide (PHMB) and chlorhexidine, and two diamidines,
propamidine isethionate (Brolene; Sanofi-Aventis, Paris,
France) and hexamidine (Desomedine; Chauvin-Blache,
Montpellier, France): PHMB (0.02%) or chlorhexidine
(0.02%) along with a diamidine (either 0.1% propamidine
or 0.1% hexamidine). These are used hourly as drops day
and night for 48 h initially followed by hourly drops by
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592 Antimicrobial agents
day only for another 72 h. Because of epithelial toxicity
this schedule is reduced to 2 h by day 5 for 3–4 weeks
and then tapered off [6]. Although use of topical corticosteroids is controversial, it is necessary to control
corneal inflammation, severe pain, and scleritis [6].
Some of the earlier studies also included topical
neomycin although it has no activity against cysts of
Acanthamoeba. Recent in-vitro testing of voriconazole, a
triazole compound, showed some activity against the
trophozoites of several Acanthamoeba isolates indicating
that this triazole may be of use therapeutically [25].
Indeed, it has been shown that use of 1% voriconazole
in three eyes of two patients as a second-line treatment
of Acanthamoeba keratitis cleared the infection which was
previously unresponsive to treatment with chlorhexidine and hexamidine [31].
Balamuthia mandrillaris
B. mandrillaris was isolated in 1986 from the brain of a
pregnant mandrill baboon that died of encephalitis. It was
initially described as a leptomyxid ameba but was later
recognized as distinct and different from the leptomyxids
and was described as a new genus and species, B. mandrillaris [1,3,5]. An immunofluorescent test developed
using an antibody made in rabbits against this ameba
identified a number of human infections as caused by B.
mandrillaris, although they were previously erroneously
identified as either due to Acanthamoeba or an unknown
ameba. B. mandrillaris causes granulomatous amebic
encephalitis (GAE) similar to that caused by Acanthamoeba and can occur at any time of the year. Diagnosis is
difficult and most cases are recognized postmortem
[1,3,5].
B. mandrillaris has only two stages in its life cycle. The
trophozoite is pleomorphic, large and measures from 12 to
60 mm. The cysts are more or less round and measure 12–
30 mm. Both the trophozoites and cysts are uninucleate
and contain a large, centrally located dense nucleolus.
Occasionally, the nucleus of trophozoites, especially in
infected tissue sections, may have two or three nucleoli.
Cysts appear to be double walled with a wavy outer wall
and a round inner wall, just like those of Acanthamoeba,
when viewed under an optical microscope. Ultrastructurally, however, they are tripartite with an outer thin and
irregular ectocyst, an inner thick endocyst, and a middle
amorphous fibrillar mesocyst [1,3].
Treatment for Balamuthia infections
Of the more than 100 cases of balamuthiasis that have
been reported, only seven patients have survived
[1,3,5,32–35,36,37,38]. Of these seven, four patients
were treated with a combination of pharmaceuticals
including pentamidine isethionate, sulfadiazine, azithro-
mycin/clarithromycin, flucytosine, and fluconazole. This
regimen was based on the efficacy of some of these drugs
after they were tested in vitro [3]. Pentamidine had to be
discontinued because of toxicity [34,35,36,37]. Some of
the patients also received thioridazide or trifluoperazine
for a short time. A macrolide antibiotic like azithromycin
was initially started but was switched to clarithromycin
because of poor penetration of the former into the cerebrospinal fluid (CSF) [34]. Currently, four more patients,
three in the USA and one in Australia, have been treated
successfully. Two of the US patients were treated with
miltefosine, which has been shown to have some activity
in vitro against Balamuthia [25]. The regimen included
fluconazole 400 mg intravenously (i.v.) twice daily (b.i.d.),
pentamidine 380 mg i.v. daily (q.d.), sulfadiazine 150 mg
four times daily (q.i.d.), flucytosine 2000 mg orally (p.o.)
q.d., and miltefosine 150 mg p.o. q.d. Azithromycin that
was given previously was discontinued because of
toxicity (M. Volmer, K. Kokko, personal communication).
An Australian patient with balamuthiasis also received
i.v. pentamidine 300 mg q.d., oral azithromycin 600 mg
q.d., oral itraconazole 200 mg b.i.d., oral sulfadiazine
1.5 mg q.i.d., oral fluconazole 1 g q.d., and corticosteroid
weaned early. This patient underwent a complete excision of the brain abscess, which may be a significant
factor according to the doctor who treated this patient
(Doyle, personal communication). Thus, it appears that if
balamuthiasis can be recognized early in its course,
interventional therapy can be instituted that may result
in medical cure.
Naegleria fowleri
N. fowleri is also known as an ameboflagellate because of
the presence of a transitory, pear-shaped, nonfeeding,
nondividing flagellate stage in the life cycle in addition
to ameboid trophic and dormant cyst stages. The trophozoite is a slug-like ameba, feeds on Gram-negative bacteria and reproduces by binary fission. It exhibits rapid
sinusoidal movement by producing anterior hemispherical bulges or lobopodia. The posterior end or uroid is
sticky and often has several trailing filaments to which
bacteria may adhere prior to being ingested. The trophozoite measures 10–25 mm and is characterized by a single
nucleus with a prominent, centrally placed nucleolus that
stains densely with chromatic dyes. The cytoplasm contains numerous mitochondria, ribosomes, food vacuoles,
and a contractile vacuole. The trophozoite transforms
into a flagellate stage when changes occur in its environmental niche such as during a rainstorm that might
perturb the ionic concentration of the surrounding
environment. The flagellate usually has two flagella at
the anterior end but three or four flagella may be seen
occasionally. It ranges in length from 10 to 16 mm and
possesses a single nucleus with a large nucleolus. The
flagellate lacks a cytostome and hence cannot feed
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Amebic meningoencephalitides and keratitis Visvesvara 593
and reverts into the ameboid form. The trophozoite
transforms into a resistant cyst during adverse conditions
such as scarcity of food supply or its habitat becomes dry.
The cyst is usually spherical, has a single nucleus with a
large nucleolus and two walls with a thick endocyst and a
closely apposed thinner ectocyst. The wall has pores flush
with its surface that may not be readily seen [1,4].
N. fowleri has been isolated from fresh water, thermal
discharges of power plants, heated swimming pools, hot
springs, hydrotherapy and remedial pools, aquaria, sewage, and even from nasal passages and throats of healthy
individuals. N. fowleri is thermophilic and can tolerate
temperatures of up to 458C; hence, they proliferate
during summer months when the ambient temperature
is high. Therefore, cases of PAM occur in the hot
summer months when large numbers of young people
frequent lakes, ponds, inadequately chlorinated swimming pools, and other warm fresh water bodies for
recreational activities [1,4,39]. Amebae in the water
enter the nasal passages, penetrate the nasal epithelium,
and migrate along the olfactory nerves to the brain.
PAM symptoms include headache, neck stiffness, and
abrupt fever after exposure to fresh water. Because the
disease has a short incubation period, is acute and
fulminating, early diagnosis and initiation of antimicrobial therapy are critical for the survival of the patient
[1–3,40].
Treatment for primary amebic
meningoencephalitis
The drug of choice in treating PAM is the antifungal
antibiotic amphotericin B (AMB). In-vitro testing
indicates that N. fowleri is highly sensitive to the drug,
with a minimal amebicidal concentration of 0.026–
0.078 mg/ml [4]. However, only a few patients have
survived this infection probably because of delayed diagnosis and delay in the initiation of treatment. In one well
documented case, a patient who recovered from PAM
was treated with high doses of AMB simultaneously both
i.v. and intrathecally (i.t.): AMB (i.v. at 1.5 and i.t. at
1.5 mg/kg of body weight/day), and i.v. and i.t. miconazole (i.v. at 350 and i.t. at10 mg/m2 of body surface area/
day), and oral rifampin (10 mg/kg of body weight/day)
[40]. N. fowleri was isolated from the CSF of the patient
and in-vitro testing of the isolate indicated a synergistic or
additive effect of AMB and miconazole. Rifampin was
ineffective [40]. Resistance to AMB has not been
reported [4]. A drawback in the use of the AMB is the
risk of kidney impairment [4,40].
Antifungal drugs in addition to AMB have been tested
against Naegleria isolates in vitro and in mice infected with
the amebae. Schuster et al. [25] examined the in-vitro
activity of miltefosine and voriconazole and found them
to be active against N. fowleri at 40 mg/ml, a dose achievable in the CSF. Recently, Kim et al. [41] examined
the in-vitro and in-vivo activity of AMB, miltefosine,
and chlorpromazine, and found chlorpromazine to be
the most active of the three compounds tested in vivo:
75% of mice infected with N. fowleri survived PAM,
whereas only 55 and 40% of mice treated with miltefosine
and amphotericin B, respectively, survived, indicating
that chlorpromazine may be an effective drug for use
in cases of PAM.
Conclusion
Although progress has been made in the treatment of
amebic encephalitides, these diseases continue to have a
high mortality. This is partly due to difficulty in diagnosis, lack of familiarity of the caregivers with the agents,
initiation of therapy late in the course of infection, and
lack of good therapeutic agents. Acanthamoeba keratitis is
more readily recognized and the infection responds favorably to cationic disinfectants. Fast-acting and efficient
drugs and effective delivery systems to reach the CNS are
urgently needed.
Acknowledgements
The findings and conclusions in this report are those of the authors and
do not necessarily represent the views of the Department of Health and
Human Services or the Centers for Disease Control and Prevention.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 635).
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