The free-living amoebae that cause human infections include Acanthamoeba, Naegleria, Balamuthia mandrillaris, and, rarely, Sappinia. All 4 genera cause serious CNS or ocular infections. Distinct from enteric pathogenic protozoa, they all are usually soil/water commensals, have no human carrier state, involve no insect vector, and cause sporadic disease associated with specific behaviors and exposures.[1]
Acanthamoeba are among the most prevalent environmental protozoa and have been classified by 18s rDNA sequencing into at least 20 genotypes, designated T1-T20. The most common environmental and human pathogens belong to the T4 genotype, and correlate to the A. castellanii complex. Groups T1, T2a, T3-6, T10-12, and T15 have been associated with human disease.[2]
The life cycle of Acanthomeba consists of an active form, the trophozoite (which is 14-40 µm in diameter), and an inactive but environmentally resistant form, the cyst (which has a double-layered wall with a diameter of 12-16 µm).
Acanthamoeba was first established as a cause of human disease in the 1970s. This genus causes 3 clinical syndromes: granulomatous amebic encephalitis (GAE), disseminated granulomatous amebic disease (eg, skin, sinus, and pulmonary infections), and, most commonly, amebic keratitis. Individuals who develop GAE or disseminated disease usually are immunocompromised, whereas those with keratitis usually are immunocompetent. Disseminated disease and GAE carry a poor prognosis, and treatment strategies are not well defined; Acanthamoeba keratitis is a sight-threatening infection with a favorable prognosis when diagnosed and treated early, though surgical intervention and/or corneal transplantation may occasionally be necessary.
Clinicians must be aware of the increased risk for ocular keratitis among contact lens wearers and those with corneal trauma. Historically, contamination of contact lenses has been linked to Acanthamoeba keratitis; however, cases have also occurred in persons with appropriate contact lens hygiene. As Acanthamoeba persists in warmer temperatures, the incidence increases during warmer months.
Early recognition of the signs of amoebic keratitis, including pain (often out of proportion to clinical findings), tearing, photophobia, and foreign body sensation, warrant aggressive diagnostic and therapeutic intervention.
GAE should be suspected in severely immunosuppressed patients with subacute onset of headache, cognitive impairment, and focal neurologic signs. On imaging of the brain, single or multiple ring-enhancing lesions may be appreciated that can resemble brain abscesses, Toxoplasma infection, or other diseases, and as such biopsy may be required for definitive diagnosis. Patients with GAE may also have skin nodules or ulcers that may be biopsied.[3, 4, 5]
The amoeba enters the body through the skin or respiratory tract; individuals swimming with contact lenses are at increased risk for amoebic keratitis. Acanthamoeba can enter the circulation and disseminate in immunocompromised individuals, manifesting as GAE or disseminated disease.
Acanthamoeba can be found in soil, fresh and brackish water, cooling towers, and heating or air conditioning units.[5] Most persons appear to have been exposed to this organism during their lifetime, as 50%-100% of healthy people have serum antibodies directed against Acanthamoeba, but whether this leads to protective immunity is unknown. Acanthamoeba has caused disease worldwide and appears of increasing interest, particularly in Asia.[6, 7, 8]
Acanthamoeba keratitis can develop sporadically among people who wear water-contaminated contact lenses or have had corneal trauma. Outbreaks are possible owing to manufacturing and distribution of lens cleaning solutions that are either contaminated or impotent.[9] Keratitis has been associated with wearing nondisposable contact lenses, using homemade sodium chloride solution to clean the lenses, and wearing lenses while swimming and showering. The isolation of Acanthamoeba cysts from swimming pool water is not unusual, as they resist chlorination. A higher percentage of isolates from swimming pools have been shown to be pathogenic than those isolated from natural fresh water.
More than 90% of the approximately 150 reported cases of GAE have occurred among immunocompromised persons, including those with AIDS,[10] organ transplantation, systemic lupus erythematosus, diabetes mellitus, individuals receiving steroid therapy, and persons with cancer who are receiving chemotherapy.[11] Likewise, persons with disseminated disease without CNS involvement usually are immunocompromised; this condition is most common among AIDS patients with low CD4 counts (eg, < 200 cells/µL), patients who have undergone organ transplantation, and those with long-term steroid use.[12, 13] Rarely, disseminated disease can develop in immunocompetent children and adults. The incidence of GAE and disseminated disease appears to be rising, likely mirroring the increased number of individuals worldwide who are living with immunocompromising conditions.
Acanthamoeba keratitis cases substantially increased in the 1980s with the introduction of disposable soft contact lenses.[14] Some evidence shows that the rate has subsequently declined, especially with the introduction of multipurpose cleaning solutions. The estimated rate of Acanthamoeba keratitis is 1 per 250,000 people in the United States, although rates vary among studies: from 1.65-2.01 per million population up to 1 per 10,000 people who wear contact lenses.[15, 16] Worldwide, the annual incidence ranges from 0.15 per million to 1.4 per million.
GAE and disseminated Acanthamoeba infections are very rare, but rates may be increasing given the rising number of persons living with immunocompromising conditions. Data on the incidence of GAE and disseminated disease caused by Acanthamoeba are not available, as these are not reportable diseases.
Acanthamoeba keratitis is a local infection that may be complicated by progressive visual loss, ulceration, secondary anterior uveitis with hypopyon, abscess formation, scleritis, glaucoma, cataract, and corneal melt and perforation. Ocular prognosis is worsened by delay in therapy for more than 3 weeks, use of steroids, and development of extracoronal manifestations.[17] Current drugs have limited efficacy unless used early in the clinical course.
GAE carries a very high mortality rate (nearly 100%). GAE tends to progress slowly, leading to death several weeks to months after onset of symptoms. Survivors of GAE have been described; these patients were treated with combination antimicrobial therapies. Disseminated disease also carries a high mortality rate, which is increased in cases of CNS involvement.
The prognosis of Acanthamoeba keratitis depends on the timing of recognition and therapy. Patients with symptoms that last for more than 3 weeks have a higher risk of long-term visual loss and complications.
The prognosis of GAE and disseminated disease is very poor, and worsened by late diagnosis, degree of immunosuppression, and marginally effective therapies. GAE carries a high mortality rate (nearly 100%). Most cases are fatal in 7-120 days (mean, 39 days).
Disseminated disease with skin involvement (no CNS disease) is associated with a high mortality rate (73%).
Patients who wear contact lenses should be educated about the risks of improper use and management of contact lenses. Contact lens wearers should avoid using homemade sodium chloride solutions and swimming while wearing contact lenses. Patients should consult manufacturer's guidelines regarding cleaning instructions.
Acanthamoeba keratitis usually is associated with a history of excessively long lens wear and/or contamination of the lens with unsterile water. Typical sources include swimming, showering, using nonsterile lens cleaners, contaminating lenses and cases by "topping off" or other unhygienic practices, and handling lenses with wet hands.[18, 19] The incubation period for Acanthamoeba keratitis is unknown but thought to range from several days to several weeks.[5] Keratitis typically begins with a unilateral foreign-body sensation followed by pain, tearing, photophobia, blepharospasm, and blurred vision.[18, 17] . Although pain out of proportion to inflammation in early keratitis has been observed, it can present as a painless keratitis, so lack of pain should not be used to rule out this disease process.[16] Bilateral involvement has been described in up to 11% of cases.[20]
Granulomatous amebic encephalitis (GAE) is a subacute to chronic meningoencephalitis. The incubation period is unknown but is probably weeks to months. The duration of illness until death ranges from 7-120 days (average, 39 days). Patients with GAE may have concurrent sinus, lung, or skin disease. Most patients present with focal neurologic deficits coupled with signs of increased intracranial pressure; other symptoms may include confusion, seizures, headache, focal weakness or ataxia, visual disturbances, and fever.
Skin disease may precede the onset of CNS manifestations by weeks to months and may include ulcers, nodules, or subcutaneous abscesses. Disseminated disease without CNS involvement may manifest as skin lesions, sinusitis, and/or pneumonitis. Other unusual manifestations of Acanthamoeba infection include osteomyelitis, adrenalitis, and vasculitis.
Early physical findings in amebic keratitis include punctate keratopathy, pseudodendrites, epithelial or subepithelial infiltrates, and perineural infiltrates.[17] Confocal microscopy assists in identifying 5 stages of keratopathy, as described by Tu[21] : epitheliitis, epitheliitis with radial neuritis, anterior stromal disease, deep stromal keratitis, and ring infiltrates. Ring infiltrates are characteristic, but are found in only 50% of cases. Early infection can mimic herpes keratitis, and late infection can mimic fungal keratitis. Perineural infiltrates are also highly suggestive of amebic keratitis.
The physical findings of GAE are highly dependent on location of lesions and result from increased intracranial pressure and focal neurological damage. These include abnormal mental status examination results, focal weakness or ataxia, and papilledema.
Disseminated disease without GAE may manifest as skin lesions that are typically hard, erythematous nodules or skin ulcers.
In keratitis, amebic cysts and trophozoites are found within the cornea. An acute or mixed inflammatory infiltrate may contain giant cells. Corneal revascularization may occur.
Individuals with GAE have moderate-to-severe cerebral edema. Necrotizing granulomas that contain perivascular trophozoites and cysts are usually located in the cerebellum, mid brain, and brain stem. Multinucleated giant cells may be present within the granulomas. Granulomas are usually noted among immunocompetent patients. On biopsy specimens, angiitis with perivascular cuffing with lymphocytes may be seen. The leptomeninges are spared except when they directly overlie areas of cortical involvement.
Based on animal models, polymerase chain reaction (PCR) testing appears to be a promising method of rapid keratitis diagnosis.[22]
Effective medical therapy for Acanthamoeba infection is not well established, particularly in cases of GAE, where diagnosis is often made postmortem. Medical success rates of Acanthamoeba keratitis range from 75%-84% with early diagnosis and aggressive management. Listed below are treatments that have been reported in the literature.
Acanthamoeba keratitis
Medical treatment consists of topical antimicrobial agents, which can achieve high concentrations at the site of the infection. Because the cyst form may be highly resistant to therapy, a combination of agents generally is used.[17, 23]
Many authorities recommend a combination of chlorhexidine (0.02%) and polyhexamethylene biguanide (PHMB, 0.02%) for treating both the trophozoites and cysts.[24, 23]
These topical antimicrobials are administered every hour immediately after corneal debridement or for the first several days of therapy. These agents are then continued hourly during waking hours for a minimum of 3 days (at least 9 times/day is recommended) depending on clinical response. The frequency is then reduced to every 3 hours for a minimum of 3-4 weeks. Two weeks may be required before a response is observed. Some advocate treating for 6-12 months. When therapy is discontinued, close observation is warranted to rule out recurrent disease.
No clear consensus exists about use of steroids. Most authorities recommend avoiding use of steroids, however there may be a benefit if anterior-chamber inflammation is present.[17] Patients receiving steroids should continue antiamebic therapy for several weeks after the steroids are stopped.
Granulomatous amebic encephalitis (GAE) and Disseminated Disease
Treatment is not standardized, and data is limited. Among the successfully treated patients with GAE and disseminated disease, all but 2 were given a combination of antimicrobials. The 2 patients [FT1] treated with single agent therapy received sulfamethazine or trimethoprim-sulfamethoxazole (TMP-SMX). If possible, immunosuppression should be reversed. A combination of pentamidine, an azole (fluconazole or itraconazole), a sulfadiazine, and flucytosine can be considered.
Combination regimens used include:
Two immunocompetent children survived with treatment that consisted of ketoconazole, rifampin, and trimethoprim-sulfamethoxazole. A recent case utilizing this regimen reported the patient ultimately relapsed and died of progressive leukemia.[25] . A heart transplant recipient was successfully treated with a combination of flucytosine, fluconazole, miltefosine, and decreased immunosuppression.[26] A case of disseminated disease that involved only the skin was treated with intravenous pentamidine, topical chlorhexidine gluconate, and 2% ketoconazole cream, followed by oral itraconazole.
New and emerging therapies for Acanthamoeba infection
Because of the severity of these infections and the difficulty in killing both cysts and trophozoites without cellular toxicity, a wide range of new therapies are being evaluated in animals and humans.[27] These include both new and old technologies, as well as drugs with new delivery systems, such as liposomes, and new mechanism of action, such as small inhibitory RNA molecules[28] and agents designed to activate programmed death pathways.[29]
Acanthamoeba keratitis: The abnormal epithelium is debrided. Penetrating keratoplasty/corneal transplantation may be necessary in cases that do not respond to medical therapy.[30, 17]
For patients with keratitis, consider obtaining consultations from an infectious disease specialist and an ophthalmologist.
For patients with granulomatous amebic encephalitis, consider obtaining consultations from an infectious disease specialist and a neurologist.
Acanthamoeba keratitis may be prevented by good contact lens hygiene and disinfection practices. Protective eyewear should be worn during high-risk activities to avoid corneal trauma. Only sterile solutions should be used for contact lenses. Patients should avoid swimming and showering while contact lenses are in.
Because of the chronicity of Acanthamoeba diseases, they require long-term monitoring for relapse.
No specific guidelines currently exist for management of amebic keratitis or GAE. A 2015 Cochrane review of medical interventions for keratitis was inconclusive.
The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.
Clinical Context: Imidazole broad-spectrum antifungal agent. Inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
Clinical Context: Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Clinical Context: Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, causing inhibition of protein and phospholipid synthesis.
Clinical Context: Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus and generally used in combination with amphotericin B.
Clinical Context: Nonabsorbable imidazole. Broad-spectrum synthetic antifungal agent that inhibits growth of yeasts and fungal growth by altering cell membrane permeability, which causes fungal cell death.
Therapy is directed at the underlying condition, with the goal of minimizing symptoms and preventing complications.
Clinical Context: Available in oral and parenteral forms. FDA approved for esophageal candidiasis and candidemia. Used clinically for serious candidal infections refractory to amphotericin B. Voriconazole has been found to be active against C glabrata and C krusei, as well as isolates that have developed resistance to fluconazole.
Clinical Context: Inhibits biosynthesis of ergosterol, damaging fungal cell wall membrane, which results in fungal cell death.
Clinical Context: Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles. Daily dose varies with indication.
Fluconazole penetrates the cerebrospinal fluid, kidneys, and liver well. It is concentrated and excreted by the kidneys in its active form so is effective against urinary tract infections.
The mechanism of action of these agents may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.
Clinical Context: Developed as an anti-leishmanial therapy, it appears to have some activity and has been used successfully in a number of cases of GAE. It can be orally administered and has mild to moderate gastrointestinal side effects as major toxicity.
Biochemical pathways in the parasite are sufficiently different from those in the human host to allow selective interference by chemotherapeutic agents in relatively small doses.
Clinical Context: Through a competitive antagonism of para-aminobenzoic acid (PABA), this agent interferes with microbial growth. It is commonly used for meningococcal prophylaxis.
Clinical Context: Trimethoprim-sulfamethoxazole inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. One double-strength tablet contains trimethoprim (TMP) 160 mg and sulfamethoxazole (SMX) 800 mg.
Clinical Context: Also called rifampicin. Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.
Clinical Context: Causes leakage of intracellular components by binding to phospholipids, altering permeability and damaging the bacterial cytoplasmic membrane.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Clinical Context: Binds to negatively charged bacterial cell walls and extramicrobial complexes. It has bacteriostatic and bactericidal effects.
Avoid using homemade sodium chloride solutions and swimming while wearing contacts.
Follow manufacturer's guidelines regarding cleaning contact lenses.
Heat disinfect or use benzalkonium-preserved saline for cleaning contact lenses.
Complications include the following:
Keratitis
Granulomatous amebic encephalitis, disseminated disease