- Free-living amoeba known to infection humans: Acanthamoeba spp, Naegleria fowleri, Balamuthia mandrillaris and Sappinia pedata.
- Ubiquitous, isolated worldwide from soil, air, fresh & salt water.
- 2 stage life cycle:
- Actively feeding & dividing trophozoite
- Dormant cyst (double-walled, wrinkled cyst) which is resistant to chlorine and antibiotics. Encystation occurs under stress.
- Described as “Trojan horses,” they can also harbor intracellular bacteria.
- Serologic surveys detect antibodies in 50-100% of healthy people.
- In immunocompetent patients → keratitis.
- AK occurs in pts who use contact lenses, history of eye trauma, exposure to contaminated water source.
- In immunocompromised patients → presentations include:
- Granulomatous amebic encephalitis (GAE, about 200 cases described)
- Disseminated acanthameobiasis
- Leukocytoclastic vasculitis
- Sub-acute granulomatous dermatitis.
- GAE: space-occupying or ring-enhancing lesions on CT and MRI; if lumbar puncture is deemed safe (i.e., no increased ICP), the CSF has normal to slightly low glucose, elevated protein, and elevated WBCs with lymphocyte predominance.
- Keratitis: chronic corneal ulcers that have not responded to routine antibiotic therapy, may resemble HSV lesions.
- Direct exams:
- Wet mount: e.g., fresh CSF in encephalitis; trophozoites resemble macrophages.
- H&E: fixed specimens.
- Calcofluor white: fluorescently stains cysts and trophozoites in tissue sections.
- Immunofluorescent staining with monoclonal antibodies
- Transmission electron microscopy
- Culture: can grow in special growth medium or cell cultures.
- Real time PCR: validated for diagnosis of keratitis.
SITES OF INFECTION
- Eye: acanthamoeba keratitis (AK), corneal pain and photophobia; vision-threatening infection associated with amoeba-contaminated saline solution or contact lens case; corneal scrapes or bx needed for dx; may also culture contact lenses and saline solution. WILL LEAD TO VISUAL LOSS IF RX DELAYED
- CNS: chronic granulomatous amebic encephalitis - associated w/ confusion, stiff neck, HA, irritability over wks to months; may be associated with pulmonary symptoms. Portal of entry is either lungs or skin.
- May present as multifocal lesions in midbrain, brain stem, & cerebellum; rarely abscess-like; cyst-like lesions can occur. Trophozoites tend to be angiotropic.
- Occurs in immunocompromised hosts: ETOH, steroids, chemotherapy, organ transplantation, lupus, AIDS.
- Skin: occurs in patients with AIDS and transplant recipients; painful ulcerated nodules on trunk or extremities; 73% mortality rate. Leukocytoclastic vasculitis reported.
- Bone: osteomyelitis reported; usually from cutaneous focus.
- Disseminated: acanthameobiasis involving skin, bone, lungs and CNS reported in immunocompromised host.
CNS, skin, lung & disseminated disease
- Combination therapy for skin, CNS and disseminated disease is the rule.
- Pentamidine 4 mg/ kg IV qd
- pentamidine-associated side effects are nephrotoxicity, leukopenia, elevated LFTs, and hypoglycemia.
- Sulfadiazine 1.5 g PO q6h
- Flucytosine 37.5 mg/kg PO q6h (max 150 mg/kg/d)
- Fluconazole 12 mg/kg IV qd
- Miltefosine < 45 kg: 100 mg PO qd (in 2 divided doses); ≥45 kg: 150 mg PO qd (in 3 divided doses)
- CDC offers expanded access investigational new drug (IND) protocol for miltefosine (see drug module).Contraindicated in pregnancy and breastfeeding.
- Voriconazole and miltefosine combined therapy of GAE reported in immunocompetent and immunosuppressed hosts.
- Test for drug sensitivity. All non-ocular treatment regimens are based on case reports; no prospective studies available.
- Drugs must be cysticidal to prevent recurrence from dormant cysts.
- IV pentamidine + topical chlorhexidine + topical ketoconazole successful for cutaneous disease without CNS involvement.
- Fluconazole + sulfadiazine + surgery in AIDS pt with localized CNS involvement.
- Due to high rates of mortality and delays in diagnosis, a described combination regimen should be started and surgical intervention considered.
- Earliest sign, dendriform pattern on corneal epithelium.
- Aggressive surgical and medical management include debridement and high concentration of topical drugs.
- Test for drug sensitivity to guide therapy; do not wait for results; initiate therapy, then modify based on results.
- Topical 0.02% chlorhexidine and polyhexamethylene biguanide (PHMB, 0.02%) either alone or in combination. Treatment with either chlorhexidine or PHMB is often combined with propamidine isethionate (Brolene) or hexamidine (Desmodine).
- Penetrating keratoplasty has been used in combination with chemotherapy, especially in more advanced disease.
- Reserve topical steroids for severe pain or inflammation after sterilization.
- The diagnosis can be very difficult because of the resemblance of trophozoites to macrophages/histiocytes in tissue specimens. A high level of suspicion is necessary.
- There are no prospective controlled trials for therapeutic options: combination therapy is the rule.
- Mortality for non-ocular disease is >70% in most cases despite aggressive combination therapy.
- AK occurs in pts who use contact lenses, history of eye trauma, exposure to contaminated water source. Immediate ophthalmology consultation warranted.
Basis for recommendation
- Clarke B et al: Advances in the diagnosis and treatment of acanthamoeba keratitis. J Ophthalmol 2012:, 2012 [PMID:23304449]
Comment: Recent review of AK, stages of infection: epithelial adhesion and desquamation, stromal invasion, and neuritis. Authors recommend topical biguanides and diamidines hourly for first 48 hours then taper to reduce epithelial toxicity. Role of triazoles briefly discussed. Steroids may be added as an adjunct therapy after sterilization. Treatment duration is in the range of 6 months.
- Hammersmith KM: Diagnosis and management of Acanthamoeba keratitis. Curr Opin Ophthalmol 17:327, 2006 [PMID:16900022]
Comment: Comprehensive review of the management of Acanthamoeba keratitis.
- Schuster FL, Guglielmo BJ, Visvesvara GS: In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J Eukaryot Microbiol 53:121, 2006 Mar-Apr [PMID:16579814]
Comment: Because miltefosine and voriconazole cross the blood–brain barrier and concentrate in brain tissue, they were tested in vitro against trophic stages of several clinical isolates of Balamuthia mandrillaris, Acanthamoeba spp. and Naegleria fowleri. Voriconazole was found to have a potent inhibitory effect when tested against Acanthamoeba spp. Concentrations of miltefosine >40 μM killed Acanthamoeba. These data serve as the in vitro basis for use of miltefosine to treat GAE caused by Acanthamoeba spp.
The Medical Letter on Drugs and Therapeutics. Drugs for Parasitic Infections, 3rd Edition. New Rochelle, NY; 2013. www.medicalletter.org.
Comment: Recommended treatment for GAE updated to include recommended dosing for pentamidine, sulfadiazine, flucytosine, fluconazole, and miltefosine. Miltefosine is contraindicated in pregnancy and breastfeeding. AK treatment recommendations discuss use of topical or oral voriconazole in patients who fail PHMB, chlorhexidine and hexamidine.
- Venkatesan A et al: Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 57:1114, 2013 [PMID:23861361]
Comment: Consensus statement on case definitions and diagnostic algorithms in encephalitis includes comment on role of free-living amoeba and treatments undergoing investigation, Table 5.
- Visvesvara GS: Infections with free-living amebae. Handb Clin Neurol 114:153, 2013 [PMID:23829906]
Comment: Comprehensive review of biology of free-living amebae includes clinical data, diagnostic data, and epidemiology. Detailed discussion of granulomatous amebic encephalitis and other manifestations of Acanthamoeba infection.
- Centers for Disease Control and Prevention website; Accessed 10/9/13, http://www.cdc.gov/parasites/acanthamoeba/biology.html
Comment: Life cycle of Acanthamoeba spp. illustrations include the double walled cyst. Further data provide details on Groups I, II, and III with respect to morphology and epidemiology can be accessed at: http://www.cdc.gov/parasites/acanthamoeba/health_professionals/acanthamoeb...
- Ikeda Y et al: Assessment of real-time polymerase chain reaction detection of Acanthamoeba and prognosis determinants of Acanthamoeba keratitis. Ophthalmology 119:1111, 2012 [PMID:22381810]
Comment: Data show high sensitivity of quantitative real-time PCR for Acanthamoeba keratitis and correlation between copy numbers of Acanthamoeba spp. and stage of AK based on slit-lamp biomicroscopy. AK was divided into 5 stages of disease severity: (1) epitheliitis, (2) epitheliitis with radial neuritis, (3) anterior stromal disease, (4) deep stromal keratitis, and (5) ring infiltrate or extra corneal inflammation.
- Khairnar K et al: Comparison of molecular diagnostic methods for the detection of Acanthamoeba spp. from clinical specimens submitted for keratitis. Diagn Microbiol Infect Dis 70:499, 2011 [PMID:21658877]
Comment: Cross-sectional study of 128 patients and 11 specimen types evaluated performance of 2 gel-based PCR assays and 2 quanitative real-time PCR assays (QPCR) compared to direct microscopy and culture. Both QPCR techniques performed with high sensitvity (82 and 89%) and specificity (98 and 89%). Although QPCR was more expensive per test ($14.80), the increased sensitivity reduced false negative results based on microscopy ($2.50) and culture ($2.50).
- Centers for Disease Control and Prevention (CDC): Investigational Drug Available Directly from CDC for the Treatment of Infections with Free-Living Amebae. MMWR Morb Mortal Wkly Rep 62:, 2013 [PMID:23965830]
Comment: Miltefosine (hexadecylphosphocholine), an antineoplastic agent also used to treat leishmaniasis, is available via an expanded access investigational new drug (IND) protocol from CDC for treatment of free-living amebae infections. Miltefosine is generally well-tolerated, gastrointestinal adverse effects are reported. CDC Emergency Operations Center offers diagnostic assistance, specimen collection and shipping directions, and treatment recommendations. Contact at 770-488-7100.
- Alkhunaizi AM et al: Acanthamoeba encephalitis in a patient with systemic lupus treated with rituximab. Diagn Microbiol Infect Dis 75:192, 2013 [PMID:23265295]
Comment: Case report of 51 yo man with lupus nephritis treated with steroids, mycophenolate mofetil (MMF), and rituximab. Authors comment on the presumed role of rituximab, an anti-CD20 chimeric antibody, in the aggressive course of encephalitis. Due to the combined effects of drugs used to establish immunosuppression, both the cellular and antibody-mediated immune responses were impaired.
- Satlin MJ et al: Fulminant and fatal encephalitis caused by Acanthamoeba in a kidney transplant recipient: case report and literature review. Transpl Infect Dis Sep 9 [PMID:24010955]
Comment: Case report of 58 year old man s/p kidney transplant 2 yrs prior to admission with 2 recent episodes of rejection on immunosuppressive therapy admitted with dx of pneumonia. Day 4 of hospitalization, he developed fulminant encephalitis. MRI demonstrated multiple well-defined lesions with signs of intralesional hemorrhage attributed to angioinvasive fungal infection. Post-mortem exam revealed necrotizing encephalitis without granuloma formation. Trophozoites were abundant around blood vessels. Indirect immunofluorescence testing on brain tissue using rabbit antisera performed by the CDC was positive for Acanthamoeba species. Amoeba were not identified in the lungs.
- Schuster FL, Visvesvara GS: Opportunistic amoebae: challenges in prophylaxis and treatment. Drug Resist Updat 7:41, 2004 [PMID:15072770]
Comment: Detailed listing of successful antimicrobial treatments includes dosages and references.
- Webster D et al: Treatment of granulomatous amoebic encephalitis with voriconazole and miltefosine in an immunocompetent soldier. Am J Trop Med Hyg 87:715, 2012 [PMID:22869634]
Comment: Case report of an immunocompetent soldier with deployments to Bosnia, Kosovo, and Afghanistan who presented with a right temporal lobe lesion. Despite gross total excision, symptoms progressed and lesion size increased. Serology revealed Acanthamoeba titer of 1:1024 with ameba-like organisms on H&E staining, and quantitative realtime PCR confirmed GAE due to Acanthamoeba. Treatment with voriconazole 100 mg po bid and miltefosine 100 mg po bid x 3 mos. Course was complicated by acute renal insufficiency that resolved after discontinuation of treatment.
- Yoder JS et al: Acanthamoeba keratitis: the persistence of cases following a multistate outbreak. Ophthalmic Epidemiol 19:221, 2012 [PMID:22775278]
Comment: CDC report of multistate outbreak of AK in 2007-2009 that lead to a recall of contact lens disinfecting solution.