REVIEW
Update on Acanthamoeba Keratitis: Diagnosis,
Treatment, and Outcomes
Nicholas J. R. Maycock, BSc (Hons), MBBS, FRCOphth, and
Rakesh Jayaswal, MBChB, FRCOphth, FRCS(Ed)
Purposes: A literature review to describe the current diagnosis and
management of Acanthamoeba keratitis.
Results: Acanthamoeba is a ubiquitous protozoan: 8 species, 5
genotypic classes have been reported to cause keratitis. It is potentially
a sight-threatening infection, and there is often a poor prognosis
because of a significant delay in diagnosis and frequently a lack of
effective medical management. Main risk factors are contact lens
wear, poor hygiene, and contact with contaminated water. Current
methods of diagnosis include corneal scrapings for histopathologic
analysis, tissue culture, confocal microscopy, and polymerase chain
reaction (PCR), each are reviewed in turn. Treatment options include
medical (biguanides, diamidines, and corticosteroids) and surgical
(epithelial debridement, amniotic membrane transplant, and penetrat-
ing keratoplasty).
Conclusions: Earl diagnosis and treatment are required to
effectively manage this condition.
Key Words: Acanthamoeba, keratitis, review article, cornea
(Cornea 2016;0:1–8)
A canthamoeba keratitis (AK) is a potentially sight-
threatening infection of the ocular surface that is
produced by several amebas of the genus Acanthamoeba.
First described in the 1970’s as an ocular pathogen,1 it
causes a chronic keratitis that is often refractory to
traditional antibiotic therapy. There is often a poor prog-
nosis because of a significant delay in diagnosis and
frequently a lack of effective medical treatment. AK has
been increasing in prevalence in recent years; causes seem
to be multifactorial but outbreaks have been recorded
because of the use of certain contact lenses (CL) and their
cleaning solutions.2–6 New and improved methods of
diagnosis and treatment are needed to effectively manage
this condition.
Received for publication September 17, 2015; revision received January 10,
2016; accepted January 14, 2016.
From the Eye Department, Queen Alexandra Hospital, Portsmouth, Hants,
United Kingdom.
The authors have no funding or conflicts of interest to disclose.
Reprints: Nick Maycock, Department of Eye, Queen Alexandra Hospital,
Portsmouth, Hants PO6 3LY, United Kingdom (e-mail: nickmaycock@
yahoo.com).
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THE PATHOGEN
Acanthamoeba spp. are ubiquitous, free-living proto-
zoans that have been isolated from a variety of habitats
including air, soil, dust, water, and the nasopharyngeal
mucosa of healthy individuals.7,8 They are known to thrive
in ponds, swimming pools, hot tubs, and CL solutions and
exist in either an active trophozoite or dormant cystic form
(Fig. 1). Over 20 unique species of Acanthamoeba have been
identified with 8 reported to cause keratitis, the most common
of which are Acanthamoeba castellani and Acanthamoeba
polyphaga.8,9 There are 15 genotypic classes designated T1 to
T15 with T3, 4, 5, 6, and 11 documented as causing AK.10
Acanthamoeba has 2 stages to its life cycle (Fig. 2), an
active trophozoite stage that exhibits growth and a dormant
cystic stage with minimal metabolic activity. The trophozoite
is capable of slow locomotion via pseudopodia.11,12 It feeds
on yeast, small bacteria, other protozoans, and in the cornea,
keratocytes.13 They reproduce asexually via binary fission and
are 25 to 50 mm in size.
The cyst is the dormant form and is 15 to 30 mm in size.
Encystment occurs under adverse conditions such as food
deprivation, desiccation, and changes in temperature and pH. It
allows the organism to survive extreme conditions, and cysts are
resistant to biocides, chlorination, antibiotics, and low temper-
atures.12 Excystment occurs when the trophozoite emerges from
the cyst under favorable environmental conditions. There is
a seasonal trend toward disease onset in the summer months.14,15
Epidemiology
Acanthamoeba keratitis is most common in CL wearers,
with reported rates in the range of 1 to 33 cases per million
CL wearers.16 The wide variation is thought to be because of
the prevalence of CL use, the contamination of domestic and
swimming pool water, the amebicidal efficacy of CL cleaning
systems, the use of reusable soft CLs, and the use of
diagnostic tests for AK.17,18
Pathogenesis
Our understanding of how Acanthamoeba invades
the cornea comes from animal studies.8,19 Adhesion is an
important first step and has been shown to be controlled by
a number of adhesion proteins and cell surface molecules.
This leads to phagocytosis and release of enzymes
and toxins such as ecto-ATPase, neuraminidase, superox-
ide dismutase, elastase, protease, phospholipases,
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Maycock and Jayaswal
FIGURE 1. Pictures of Acanthamoeba cyst and trophozoite.
glycosidases, and acanthaporin.20 The resulting stromal
degradation allows deep penetration into the cornea.
Acanthamoeba trophozoites are able to penetrate Descemet
membrane, but intraocular infection rarely occurs because
of the intense neutrophil response in the anterior
chamber.21
CL use causes microtrauma to the epithelium and an
upregulation of glycoproteins. Soft lenses have a more
adherent surface than hard lenses, which allows the tropho-
zoite to bind and thereby gain access to the corneal surface.
Trophozoites bind to glycoproteins on the corneal epithelium,
triggering the release of a number of cytopathic factors
including mannose-induced protein 133. Corneal epithelial
destruction and apoptosis allow invasion of the stroma. The
release of multiple proteases allows the organism to penetrate
deep into the stroma,12,22–24 causing direct cytolysis, phago-
cytosis, and apoptosis.8 They cluster around corneal nerves
leading to radial keratoneuritis,25 and it is thought that
trophozoite-derived proteases contribute to nerve damage
and the severe pain associated with AK.8
A thorough understanding of the immune response is
important for management of the condition. Topical cortico-
steroids, which are widely used in ophthalmology, are known
to suppress the activity of neutrophils and macrophages
in vivo. Interestingly, they have been shown to accelerate
trophozoite excystment and proliferation, which may poten-
tially increase their susceptibility to antiamebic therapy.13
However, caution must be urged in their use in any infectious
keratitis because of the potential risk of worsening
the condition.
Risk Factors
The main risk factor is CL wear.3,13,26–30 Although lens
hygiene is often poor, patients who regularly disinfect with
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Cornea  Volume 0, Number 0, Month 2016
multipurpose solution and hydrogen peroxide solution still
contract AK. It has been shown that most commercially
available multipurpose solutions are ineffective against
Acanthamoeba,31–35 suggesting other factors are at play and
further research is required. Other documented causes include
swimming and showering with CLs in situ, inadequate
CL disinfection, exposure to contaminated water, and
corneal trauma.
Most cases occur in CL wearers, and AK prevalence
can be reduced by strict contact lens hygiene. Typically,
amebas inhabit the lens case via tap water, rapidly multiply if
the case is not cleaned properly and regularly, and then infect
the eye via the CLs.36
DIAGNOSIS
It is important to remember and consider AK in all
cases of CL keratitis, especially where onset is insidious and
features are atypical as early diagnosis and treatment is
essential to ensure a good visual outcome.37–41 Clinical
features are often mistaken for fungal or herpes simplex
infection, which may lead to a delay in diagnosis and
appropriate treatment. It is important to remember that AK
is polymicrobial or coinfected with herpes simplex virus in
10% to 23% of cases.13
Clinical Features
The disease is usually unilateral and should be consid-
ered in any case of keratitis or trauma contaminated with soil
or water. There is a spectrum of disease with a progression of
symptoms and signs from epithelial to stromal disease: the
pain is often severe and disproportionate to the clinical
signs, whereas some may be pain free. Photophobia, pain,
epiphora, and reduced visual acuity are commonly the first
reported symptoms.
Early findings include an epitheliopathy with punctate
keratopathy, pseudodendrites (Fig. 3), epithelial or subepi-
thelial infiltrates, and perineural infiltrates. Tu et al38,42
described 5 levels of AK severity: epitheliitis, epitheliitis
with radial neuritis, anterior stromal disease, deep stromal
keratitis, or ring infiltrate. The characteristic ring infiltrate is
only seen in approximately 50% of patients (Fig. 4). In the
early stage, it can easily be confused with Herpes simplex
keratitis, whereas in the advanced stage, the infection
resembles the clinical picture of a fungal keratitis or a corneal
ulcer.20 Perineural infiltrates are highly suggestive for AK and
have been reported in up to 63% of cases at 6 weeks.13
Although certain features are pathognomic for the condition,
they are not always present, and the clinician must therefore
have a high index of suspicion in cases where the history and
other features are suggestive.
As the disease progresses, ring infiltrates, ulceration,
and a secondary sterile anterior uveitis with hypopyon are
common. Perineural infiltrates regress, but the condition may
lead to iris damage with a permanently dilated pupil, abscess
formation, scleritis, glaucoma, cataract, corneal melt, and
perforation. Advanced disease with perforation can lead to
a cataract, which is a poor prognostic sign. Bacterial
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Cornea  Volume 0, Number 0, Month 2016 Diagnosis, Treatment, and Outcomes of AK

FIGURE 2. Life cycle of Acanthamoeba spp. in humans (from Centers for Disease Control 2010: http://www.cdc.gov/parasites/
acanthamoeba/biology.html). Adaptations are themselves works protected by copyright. So in order to publish this adaptation,
authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the
translation or adaptation.

superinfection should always be considered, especially if
there is no response to treatment.
Culture
Amebic cultures should be included in any corneal
scrape in suspected infective keratitis. Acanthamoeba feeds
readily on inactivated E. coli agar plates, and cultures need to
be reviewed daily under a light microscope for trails that
indicate migration of Acanthamoeba. Cultures are often used
in conjunction with a smear slide or small lamellar disc
biopsy for microscopy. A number of stains are used for the
detection of cysts: Lactophenol-cotton blue, acridine orange,
calcofluor white, silver, immunoperoxidase, and hematoxylin
and eosin.20,43 Acanthamoeba has been cultured from CLs,
lens cases, and lens cleaning solutions when corneal biopsies
were negative.12,21,44,45 It is imperative that clinicians ask
patients to surrender their most recent CLs and lens cases for
microbiological investigation.
Immunohistological staining with monoclonal antibodies
has improved detection, but techniques are invasive, time-
consuming, and reliant on the technician’s skill. Consequently,
they are often delayed until there is a high index of suspicion or
when there has been no response to treatment. Repeat testing is
required if initial investigations are negative, and it has limited
use in assessing treatment response. The effectiveness of
isolating Acanthamoeba in cultures has been reported as
between 30% and 60%,37,46 and it may require weeks to obtain
final results from the laboratory.47 Therefore, clinicians must be
primarily guided by the history and clinical findings.
Confocal Microscopy
Confocal microscopy allows examination of corneal
structures at a cellular level in real time.46–53 Previously
limited by low resolution, newer systems and computer
software allow a more rapid and detailed examination and
permit monitoring of the disease course. It is noninvasive and

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Maycock and Jayaswal
FIGURE 3. Clinical features of Acanthamoeba keratitis: early
disease showing linear epitheliopathy and pseudodendrite.
has a spatial resolution of 2 to 4 mm, allowing the analysis of
individual corneal cells and the inflammatory response.54
Because of a small field of view, it is limited in its ability
to confirm a complete absence of Acanthamoeba cysts.47
There is some concern that the high sensitivity and specificity
values for the diagnosis of AK (.90%) may lead to a number
of false-positive or false-negative results.13
FIGURE 4. Clinical features of Acanthamoeba keratitis: classic
ring infiltrate.
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Polymerase Chain Reaction
Polymerase chain reaction (PCR) can identify the
presence of amebic DNA in a tissue sample. The process is
technical and expensive38,42 but has significant potential
diagnostic properties. However, a diagnosis of AK is not
confirmed unless there is a corresponding positive tissue
sample: in 2 UK National Surveys, a tissue diagnosis was
only obtained in 177/349 cases (50%).26,55
A frequently used PCR technique involves amplification
of a fragment of the 18S recombinant RNA gene and was first
described by Schroeder et al56 in 2001. Several studies have
reported the use of real-time PCR to diagnose AK.57–61 Real-
time PCR can quantitate DNA at the site of infection making it
possible to make an accurate diagnosis, start a tailored
antiamebic regimen early, and monitor treatment success.
PREVENTION
It is important to minimize risk factors for Acantha-
moeba infection. Strict CL and storage case hygiene are
essential with the use of appropriate disinfecting solutions; no
overnight wear of CLs, no topping-off of solutions, and no
homemade saline. It is also important to avoid contact with
contaminated water such as swimming or showering with CL
in situ. Any corneal trauma, however trivial, is a potential
portal for infection and must be minimized.
TREATMENT
Medical
Acanthamoeba trophozoites are sensitive to a number
of available medications: antibiotics, antiseptics, antifungals,
and antiprotozoals, including metronidazole, antivirals, and
antineoplastic therapies. Acanthamoeba cysts may lead to
prolonged or resistant infection as most of the above treat-
ments are ineffective, and only those that are cysticidal will
stand any chance of success. Cysts have shown a high
resistance in vitro to imidazoles and antifungals such as
voriconazole. The diamidines and biguanides are the most
effective cysticidal antiamebics, and their use has been well
documented.13,41
Biguanides
Polyhexamethylene biguanide (PHMB) 0.02% to
0.06% (200–600 mg/mL) and chlorhexidine 0.02% to 0.2%
(200–2000 mg/mL) are commonly used biguanides.41,62 They
disrupt the cytoplasmic membrane and damage cell compo-
nents and respiratory enzymes. PHMB and chlorhexidine
have low minimal cysticidal concentrations of 2 mg/mL,
although there have been some reports of clinically resistant
organisms.63,64 Both have low levels of corneal epithelial
toxicity,13 which support their use as first-line therapy. When
used in combination with diamidines, there is evidence of
a synergistic effect.13,65 PHMB is most frequently used at
a concentration of 0.02% but can be increased to 0.06% in
unresponsive or severe infection. Similarly, chlorhexidine is
commenced at 0.02% but increased to 0.2% if required.
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Cornea  Volume 0, Number 0, Month 2016
Diamidines
Propamidine isethionate 0.1% (1000 mg/mL) and
hexamidine 0.1% (1000 mg/mL) are commonly used diami-
dines. Their antimicrobial effect comes from their ability to
alter the cell membrane structure and its permeability. They
penetrate into the cytoplasm causing denaturation of cyto-
plasmic proteins, and enzymes and have been shown to be
effective against both trophozoite and cyst. They are well
tolerated but prolonged therapy may lead to ocular surface
toxicity. Hexamidine has been shown to have a faster
amebicidal effect against both cyst and trophozoites.
Treatment Regimens
The goals of therapy are (1) the removal of Acantha-
moeba cysts and trophozoites from the corneal tissue and (2)
resolution of the host inflammatory response. It is thought that
early intensive therapy is more effective as the cysts have not
had time to penetrate deep into the corneal tissue or mature
fully.13 Failure to kill or eradicate all cysts will result in
recurrence of the disease.
Patients are usually commenced on a biguanide and
a diamidine as combination therapy. For the first 48 hours
these are given hourly (day and night) before being reduced to
hourly (daytime only) for a number of days or weeks. It is
important that the treatment regimen is reduced and tailored
to each clinical case to minimize any epithelial toxicity. The
aim is to reduce therapy to 4 times a day, but patients may
need to be on therapy for up to 6 months.55 Further research is
required to assess the effectiveness of available treatments
and different regimens; despite low MMC’s and reports of
success, there has been some variation in outcomes.13,66,67
Extracorneal manifestations of AK may be present in
both early and late disease and indicate a poor prognosis.
Treatment with oral nonsteroidal anti-inflammatory medica-
tion, high-dose systemic steroids, or other systemic immuno-
suppressive drugs such as cyclosporine may need to be
continued for several months13,68 to control the inflammation
and eradicate the pathogen. Further work is required to better
understand this aspect of the disease and find new and
improved treatments.
Controversy of Topical Steriods
The use of topical corticosteroids remains controversial
in AK. They are usually not required in cases that are
diagnosed early and responsive to antiamebic drugs. How-
ever, when there is significant anterior segment inflammation,
steroids may facilitate a rapid resolution of symptoms but
must be used judiciously because of the potential risk of
worsening the condition by damping down the host inflam-
matory response. It is essential that anti-amoebic therapy is
continued for a number of weeks after the steroids have been
stopped to eradicate the disease.13,69–71 The condition may be
considered cured once the eye has been free of inflammation
after 4 weeks of tapered biguanide monotherapy.13 Particular
care must be taken as recent evidence suggests that steroid use
may result in increased pathogenicity of the amebas.72 Further
work is required to investigate this phenomenon.
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Diagnosis, Treatment, and Outcomes of AK
Resistant Organism
Persistent keratitis is because of the presence of viable
organisms in the cornea despite treatment with a biguanide
and diamidine. It is important to exclude bacterial superin-
fection or concurrent herpes infection in such cases. In
addition, it is crucial to differentiate those cases that are
caused by persistent inflammation rather than
Acanthamoeba infection.
A persistent epithelial defect may be the first evidence
of a resistant organism. Other causes include epithelial
toxicity from an intensive treatment regimen or severe
anterior segment inflammation, both will usually settle
spontaneously if adequately controlled. Repeated cultures
are necessary to determine whether it is a persistent Acan-
thamoeba infection or cross-infection. Unfortunately, both
confocal microscopy and PCR are unable to distinguish
between viable or nonviable Acanthamoeba cysts, leaving
culture of corneal scrapes or biopsies as the definitive way of
identifying persistent culture-positive disease. Repeated cor-
neal cultures must be performed to identify the persistence of
viable Acanthamoeba and any possible resistance. If unsuc-
cessful, a lamellar keratectomy removing the infected corneal
tissue may be therapeutic and diagnostic.13
In vitro drug sensitivity testing is another possible
option in resistant cases. Recently, a patient with severe AK
responded to personalized treatment with voriconazole after
specific sensitivities to this drug were assayed from amebas in
the patient’s cornea.73
Surgical
Extensive epithelial debridement of the affected area
may be therapeutic as (1) it promotes penetration of topical
therapy74 and (2) if performed early when the pathogen is still
intraepithelial, it may aid in its removal.13 The debrided
epithelium is sent for histology, culture and sensitivities.
Since the introduction of biguanides as medical therapy,
PK is not recommended as a means of removal of organisms
from the cornea.13,34,69,75 Therapeutic keratoplasty should
therefore be reserved for (1) corneal perforation that does
not respond to repeat gluing, (2) significant cataract, or (3)
severe corneal abscess.13,73 Corneal grafts for AK should be
kept to the minimum size required because of the risk of
rejection with large grafts and the potential need for repeat
grafting. Recurrence in the early postoperative period has
reduced significantly since the introduction of biguanides.13,76
Late recurrence several months after surgery may still occur.13
PK is used to improve vision in patients with scarred
corneas or irregular astigmatism after treated/quiescent AK
infection. The long-term outcome is good in these pa-
tients.13,69,75,77 There is evidence to suggest that outcomes
are better if surgery is reserved for visual rehabilitation rather
than therapeutic removal of infected tissue.78
Anterior segment inflammation should be treated
with systemic and topical immunosuppression. Antiamebic
therapy should be used preoperatively and continued post-
operatively to maximize elimination of the organism
and minimize any risk of recurrence. Care should be taken
to use regimens that minimize epithelial toxicity, and
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Maycock and Jayaswal
treatment should be continued until culture results confirm
elimination of the organism. If culture results are positive, it is
sensible to continue antiamebic therapy and steroids for 6
months, as recurrence has been documented up to 3 months
after successful grafting.13 If the culture results are negative, it
is assumed all organisms have been eliminated and anti-
amebic therapy is usually discontinued after several weeks.
In addition, bipedicle conjunctival flaps and cryopre-
served amniotic membrane grafts can restore ocular surface
integrity and provide metabolic and mechanical support for
corneal healing in patients with AK.79 However, in large
corneal perforations, penetrating keratoplasty remains the
only effective surgical option.
Other Procedures
Photorefractive surgery has recently been described in
AK. Kandori et al66 reported 4 cases of AK that developed
large corneal stromal abscesses after treatment with topical
therapy. These were removed using laser phototherapeutic
keratectomy: final acuities were between 20/16 and 20/25
with no disease recurrence. Given the minimal published data
on the use of this procedure in AK, it is difficult to draw firm
conclusions from this limited case series.
Cross-linking (CXL) is another relatively new treatment
option. In vitro studies80,81 have shown no amebicidal effect
of riboflavin combined with UVA exposure, but some clinical
case reports suggest a more promising picture. Garduño-
Vieyra et al82 administered CXL to a patient in Mexico
instead of topical medical therapies. A significant improve-
ment was noted after 24 hours, with symptoms resolving after
3 months. After 5 months, 20/20 vision was reached. Khan
et al83 have since reported 3 similar cases that responded
equally well to CXL, with all ulcers closing within 7 weeks.
In subsequent PK surgery for scarring, no organisms were
detected in excised tissue. It is possible that the collagen-
stabilizing effect prevents further tissue damage and isolates
and prevents reproduction of the amebas.
Further studies are required to investigate in more detail
the properties of CXL and how it might work in AK and other
infectious keratitis. There is an apparent lack of data to
suggest CXL works consistently. In addition, there are no
significant data to show whether the standard Dresden
protocol is more effective than a pulsed approach, and this
requires more investigation and research. Although individual
case report results seem promising, there are no formal
clinical trials thus far to recommend incorporation into
standard practice.
PROGNOSIS
The most important factors associated with outcome are
the disease severity at presentation and the time taken to start
effective therapy.13,84,85 A delay of more than 3 weeks is
associated with a worse prognosis, and very few patients do
badly if diagnosed and treated within this period.13 Chew
et al15 showed that visual acuity of worse than 20/50 at the
time of diagnosis and stromal involvement had a significantly
worse prognosis. There are no reports in the literature to
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Cornea  Volume 0, Number 0, Month 2016
suggest any difference in prognosis between the Acantha-
moeba subspecies.10
THE FUTURE?
AK remains a challenging condition to diagnose and
treat. Early diagnosis and treatment are reliant on clinical
signs, which may be complicated by secondary coinfection
and compounded by the poor sensitivity of culture or
histology. Confocal microscopy has been recommended, but
it is thought the sensitivity and specificity of this technique
are too low to rely on those for a definitive diagnosis.
Detection of Acanthamoeba DNA via PCR is highly sensitive
and specific but needs further research before uptake is more
widespread. The development of a more streamlined tech-
nique and commercial kit would be a major step forward.
If the disease is severe with recurrent scleritis and
recalcitrant to standard therapies, it may be necessary to try
more than one immunosuppressive agent. Igras and Murphy86
reported a case of 1 patient with severe AK who required
treatment with 4 immunosupressives to bring it under control.
Potential regimens of the future may incorporate the use of
multiple immunosuppressants to limit disease spread.
Other potential areas for further research include
genetic therapy, new markers, new targets for drug therapy,
and stem cell research. Three genes, heat shock protein 70,
actin-I, and elongation factor-1 alpha have been shown to
have varying expression and functions during Acanthamoeba
T4 genotype differentiation.87 In addition, it has recently been
shown that interleukin 17A mediates a protective effect from
Acanthamoeba infection in the cornea. This is in sharp
contrast with other corneal infections such as herpes and
Pseudomonas aeruginosa keratitis where interleukin 17A
exacerbates corneal pathology and inflammation.38,42 Further
understanding and more studies of these different pathways
may be useful in the design of an efficient new therapeutic
strategy in AK.
Autophagy inhibitors are under investigation as poten-
tial future treatments. Moon et al88 evaluated the inhibitors 3-
methyladenine, LY294002, wortmannin, bafilomycin A, and
chloroquine and assessed their ability to reduce Acanthamoe-
ba encystment. In combination with PHMB, they have been
shown to have low cytopathic effects on human corneal cells
and high cytopathic effects on Acanthamoeba cells.
Research suggests that certain bacteria are required for
Acanthamoeba to cause keratitis.89 Nakagawa et al89 showed
that pretreatment of Acanthamoeba with levofloxacin mark-
edly reduced disease activity, suggesting another potential,
and readily available, treatment avenue.
It has been shown that treatment of an Acanthamoeba
neurotrophic ulcer with a topical regenerating agent
[CACICOL20 (1 drop on alternate days) for 8 weeks] led
to rapid resolution of the epithelial defect.90 These agents
require further investigation and randomized controled
studies to assess their efficacy and potential place in the
treatment armamentarium.
A better understanding of the disease process at the
molecular level is essential if we are to provide a faster, more
reliable diagnosis and a more effective treatment. All these
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Cornea  Volume 0, Number 0, Month 2016
new and emerging treatments have the potential to radically
improve the management of Acanthamoeba keratitis but
require further investigation. Clinical practice has changed
little in recent years, and more studies and statistical analysis
are required to validate these potential new treatments. The
condition still presents significant challenges for the clinician,
and new additions to the management armamentarium would
be very welcome.
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