• Cornea/External Disease

    Early treatment of Acanthamoeba keratitis reduces long-term visual sequelae.  Unfortunately, treatment of well-established Acanthamoeba keratitis remains frustrating, since diagnosis of the condition is frequently elusive.  Too frequently, patients endure weeks of topical steroid therapy prior to diagnosis. The possibility of visual loss despite months of continued topical therapy is an unfortunate potential outcome.  While emerging therapies such as alkylphosphocholines (Miltefosine), new guanadines, other antibiotics, and other chemotherapeutics offer promise for difficult to treat infections (Eye. 2003;17:893-905), many of these remedies have not been well described, nor are they currently available to the practicing ophthalmologist.  Consequently, a combination of topical biguanide and diamidine therapy remains the mainstay of Acanthamoeba keratitis treatment.

    Diagnosis

    The emergence of Acanthamoeba keratitis as a serious pathogen in ophthalmology coincided with the expansion of soft contact lens use in the 1980s.  Acanthamoeba usually gains access to the cornea secondary to contact lens associated epithelial compromise and has been shown to grow in contact lens cases and some contact lens solutions. Acanthamoeba has been detected in contaminated water supplies, hot tubs and swimming pools.  

    Culture, staining, confocal microscopy, polymerase chain reaction, and clinical suspicion can be used to achieve a diagnosis.  Although scrapings and cultures may be negative in disease largely limited to the stroma, epithelial debridement is nevertheless extremely useful.  When confined to the epithelium, debridement with a Kimura spatula or other suitable instrument decreases amebic load and is therapeutic. Because a portion of initial biopsies and cultures are inconclusive, larger specimens aid in diagnosis. Specimens should be cultured on non-nutrient agar with E. coli (or other coliform) overlay. Corneal scrapings should also be sent for microscopy. Scrapings can be stained with Giemsa or calcafour white. Topical therapy begins immediately after debridement. When questioning if the endpoint of treatment has been reached, repeat cultures and scrapes are invaluable.

    Medical Therapy: Cationic Antiseptics and Diamidines

    Trophozoites, the active and mobile form of the protozoan, are responsive to many therapies.  On the other hand, cysts, the dormant form of Acanthamoeba , are encased in a tough proteoglycan coat, making them difficult to treat.  Cysts can remain viable almost indefinitely in extremely adverse conditions; treatment should therefore be cysticidal.  A combination of cationic antiseptics and diamidines has been shown to be most effective in treating Acanthamoeba keratitis (Expert Rev Anti Infect Ther. 2003;1:205-208). Commonly used in dental preparations, the cationic antiseptics (chlorhexidine digluconate and polyhexamethyline biguanide [PHMB]) are essentially swimming pool sanitizers.  Meanwhile, the diamidines (propamadine isethionate and hexamidine isethionate) are available outside the United States as over-the-counter remedies for conjunctivitis and red eye.  Neither the cationic antiseptics nor the diamidines are commercially available in the U.S.

    PHMB and chlorhexidine are known collectively as steric biguanides. They are prepared for medical use by compounding pharmacists. Various concentrations of biguanides are used.  Starting strength is usually 0.02% of chlorhexidine or PHMB; this can be decreased, if toxicity develops, or increased, if there is an inadequate response to therapy.  Use of chlorhexidine and PHMB in concentrations greater than 0.02% is untested, so higher concentrations should be used carefully.  In the event that the above therapy fails, Charles Leiter, Pharm.D. has said that the medications may be increased from a starting dose of 0.02% up to 0.06% for chlorhexidine or PHMB.

    Both chlorhexidine and PHMB are effective against trophozoites with variable efficacy against cysts.  While PHMB and chlorhexidine have both been used to effectively treat Acanthamoeba keratitis (Expert Rev Anti Infect Ther. 2003;1:205-208), emerging evidence has shown a disconnect between in vivo and in vitro sensitivities (Ophthalmology. 2003;110:1593-1600). Specifically, PHMB is more effective in vitro than in vivo.

    Initial therapy for Acanthamoeba keratitis should begin with diagnostic epithelial debridement for culture and staining followed by immediate topical therapy (Table 1).   Topical dual therapy should start with chlorhexidine 0.02%  and propamidine 0.1% every hour around the clock for 2-3 days.  Following this, the treatment can be reduced to waking hours only for approximately 3 days.  Therapy is then tapered to 4 times a day.  For disease limited to the epithelium, therapy may be discontinued after 2-4 weeks.  With frequent use, propamidine is relatively toxic, but in combination therapy with biguanides toxicity is usually limited to reversible epitheliopathy.

    Table 1.  Guidelines for treatment of Acanthamoeba keratitis.

    Initial Therapy

    Concentration

    Frequency

    Chlorhexadine combined with Brolene

    0.02% (200 ug/ml)

    0.1% (1000 ug/ml)

    q1 hour x 2-3 days around the clock, then q1 hour while awake x 3 days, then tapered to qid.

    Second Line Therapies

    Concentration

    Frequency

    PHMB

    0.02%-0.06%

    q1 hour x 2-3 days around the clock, then q1 hour while awake x 3 days, then tapered to qid.

    Hexamidine

    0.1%

    Pentamadine

    0.1%

    Third Line Therapies

    Concentration

    Frequency

    Imidazoles

    1% (10,000 mg/l) and po

    Anti-fungals are used as frequently as q1 hour initially. 

    Neomycin

    10 mg/ml

    Neomycin must be titrated based on toxicity and response.

    Adjunctive Therapies

    Concentration

    Frequency

    NSAIDs

    Topical and po

    bid-qid

    Predniselone

    1%

    Avoid if possible


    Stromal disease requires longer therapy.  Realizing that response to therapy, especially in established infections, can take 2 weeks to be appreciated, therapy may be reduced to every 4 hours while awake once control is established.  For extensive disease, topical therapy may continue from 3 weeks to 6 months or longer depending on patient response.  Serial photographs are helpful in following response to therapy.

    Alternative Medical Therapies

    Hexamadine 0.1%  or pentamidine isethionate 0.1% (Pentam 300) may be substituted for propamadine.  Anti-fungals have been used with some success, but concentrations of itraconazole and ketoconazole may not reach cysticidal levels in the cornea (Eye . 2003;17:893-905).  If attempted, topical ketaconazole or fluconazole should be used at a 1% concentration but only in combination with PHMB or chlorhexidine. Topical neomycin (10mg/ml) was once used as a primary therapy.  Unfortunately, it is rarely cysticidal, can be severely toxic, incite hypersensitivity, and is of limited therapeutic value (Eye. 1994;8:555-563).

    Secondary keratoneuritis, scleritis, or episcleritis can be extremely painful.  An inflammatory response after initiation of therapy further complicates this picture. Topical cycloplegics may be appropriate.  Pain control may be necessary with topical or oral non-steroidal anti-inflammatory drugs (NSAIDs) and possibly oral narcotics.  Topical steroids, when used with great caution, may be helpful in relieving otherwise intractable pain.

    Steroids: Use Great Caution

    The use of topical steroids to treat Acanthamoeba keratitis is controversial and strongly discouraged by many clinicians.  Acanthamoeba cysts exposed to dexamethasone have increased pathogenicity with increased numbers of trophozoites through excystment and proliferation (Invest Ophthalmol Vis Sci. 2001;42:2885-2893.)  Not surprisingly, topical steroids have been associated with longer treatment times (Cornea. 1997;16:277-283).  Caution must be exercised in cases where steroids are used.  They should only be employed while the patient is using antiamoebic therapy, and antiamoebic therapy should continue for 2-4 weeks after discontinuing steroids.

    Surgical Therapy

    In rare instances when a patient is unresponsive to medical therapy with impending perforation, combined penetrating keratoplasty and medical therapy may be employed.  The surgeon must remain cognizant that the remaining host bed is likely inundated with organisms and will certainly require a long therapeutic course.  As suggested above, the need for post-operative steroids will increase the pathogenicity of the organism.  Ideally, surgical therapy should be postponed until the disease is under sufficient medical control.

    References

    1. Seal D. Treatment of Acanthamoeba keratitis. Expert Rev Anti Infect Ther. 2003;1:205-208.
    2. Perez-Santonja JJ, Kilvington S, Hughes R, Tufail A, Matheson M, Dart JK. Persistently culture positive Acanthamoeba keratitis: in vivo resistance and in vitro sensitivity. Ophthalmology. 2003;110:1593-1600.
    3. Seal DV. Acanthamoeba keratitis update-incidence, molecular epidemiology and new drugs for treatment. Eye. 2003;17:893-905.
    4. Hay J, Kirkness CM, Seal DV, Wright P. Drug resistance and Acanthamoeba keratitis: the quest for alternative antiprotozoal chemotherapy. Eye. 1994;8 ( Pt 5):555-563.
    5. McClellan K, Howard K, Niederkorn JY, Alizadeh H. Effect of steroids on Acanthamoeba cysts and trophozoites. Invest Ophthalmol Vis Sci. 2001;42:2885-2893.
    6. Park DH, Palay DA, Daya SM, Stulting RD, Krachmer JH, Holland EJ. The role of topical corticosteroids in the management of Acanthamoeba keratitis. Cornea. 1997;16:277-283.

    Author Disclosure

    The author states that he has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service. He would like to thank Erica C. Tryon, MA for her help in editing this manuscript.