Acanthamoeba species
Authors: Govinda S. Visvesvara, Hsin-Yun Sun, M.D., Stan Deresinski, M.D.
Among the hundreds of free-living amebae that thrive in the environment members of only three genera, namely Acanthamoeba, Balamuthia, and Naegleria are known to cause disease in humans and other animals. Recently, however, another free-living ameba -Sappinia - has been identified as causing encephalitis in a young man indicating that there are probably other free-living amebae that may also cause human disease given appropriate conditions and the opportunity (24, 41). According to the classical taxonomic classificationAcanthamoeba, Balamuthia and Sappinia were classified under Phylum Protozoa, sub phylum Sarcodina, Super Class Rhizopodea, Class Lobosea, Order Amoebida; and Naegleria under Order Schizopyrenida; Family Vahlkampfiidae (41). Since the older hierarchical system was based solely on the morphology of the organisms the International Society of Protistologists recently replaced it with a new classification that included modern morphological approaches, biochemical pathways and molecular phylogenetics. According to this new schema the Eukaryotes have been classified into six clusters or “Super Groups” namely, Amoebozoa, Opisthokonta, Rhizaria, Archaeplastida, Chromalveolata and Excavata. Acanthamoeba, Balamuthia and Sappinia are included under Super Group Amoebozoa and Naegleria fowleriunder Super Group Excavata (1).
Acanthamoeba, Balamuthia, and Naegleria infect the central nervous system (CNS) of humans and other animals. Acanthamoeba and Balamuthia cause chronic granulomatous amebic encephalitis whereas N. fowleri causes an acute, fulminant primary amebic meningoencephalitis. Acanthamoeba and Balamuthia also cause cutaneous infection in humans. Additionally, Acanthamoeba causes infection of the eye, Acanthamoeba keratitis. Infections also occur naturally in a variety of animals, including gorillas, monkeys, cattle, sheep, dogs, turkeys and toucans (23, 24, 41).
Parasitology
More than 20 species of Acanthamoeba, included in three groups (Group I, II and III) based on size and cyst morphology, has been described. Recently, however, based on the sequences of the genomic DNA Acanthamoeba spp. have been identified as belonging to 15 genotypes (T1-T15). Nine species (A. castellanii, A. culbertsoni, A. divionensis, A. griffinii, A. hatchetti, A. healyii, A. lenticulata, A. polyphaga, A. rhysodes) have been associated with human disease with genotype T4 as the most commonly identified genotype in both ocular and CNS infections (4, 41). Acanthamoeba and Balamuthia are morphologically dissimilar in culture. However, in fixed tissue sections they look similar and hence the differentiation is made by indirect immunohistology or PCR (11, 29, 41).
Acanthamoeba has two stages, a trophozoite and a cyst, in its life cycle. Both the trophic and cyst stages are usually uninucleate with the nucleus possessing a large densely staining nucleolus. The trophozoites feed in nature upon Gram negative bacteria and reproduce by binary fission. Under unfavorable conditions the trophozoites encyst to produce double-walled cysts. The outer cyst wall is wrinkled and the inner cyst wall is stellate, polygonal, round or oval (7).
Acanthamoeba has attracted attention recently because of its ability to act as host for a number of human pathogenic bacteria such as Legionella, Mycobacterium, Burkholderia, Escherichia coli serotype 0157, Chlamydia, Chlamydia-like bacteria, Francisella tularensis, Listeria monocytogenes, Helicobacter pylori. Pure cultures of Acanthamoeba have been used as a “selective medium” to isolate L. pneumophila, L. anisa, Mycobacterium massiliense from human clinical specimens such as sputum, liver, lung abscesses and even human feces. Recently, Mimi virus, a virus about the size of a small bacterium with a 1.2 megabase genome has been discovered in A. polyphaga. Further, bacteria which are present within the amebae can evade harmful agents like antibacterial pharmaceuticals and disinfectants like chlorine. Because of these features the public health importance of Acanthamoeba is understated (41).
Epidemiology
Acanthamoeba species have been recovered from diverse habitats including soil, fresh, brackish and sea water, dust in air, sewage, swimming pools, Jacuzzis, filters of heating, air-conditioning and ventilating units, humidifiers, dialysis units, home aquaria, cell cultures, contact lens paraphernalia, and nasal passages of sick as well as healthy individuals. Despite widespread distribution, systemic infection occurs only in debilitated or immunocompromised individuals. Acanthamoeba keratitis however occurs in healthy individuals and is associated with corneal trauma and/or contact lens use (23, 41). Corneal infection occurs because of improper maintenance of the lenses and wearing lenses while swimming. A dramatic increase in the keratitis cases in the Chicago (Illinois) area occurred in 2003 and 2006 (16). Therefore, CDC conducted a survey of 22 ophthalmology centers, which revealed a national increase in the number of keratitis cases starting in 2004 and continuing through 2007 (6). A subsequent investigation identified the use of a commercial multipurpose contact lens solution as a primary risk factor leading to an international recall by the manufacturer (16).
Clinical Manifestations
Acanthamoeba causes granulomatous amebic encephalitis, pneumonitis, cutaneous infection leading to disseminated disease, paranasal sinusitis, and, in contact lens users, keratitis. All but keratitis occur predominantly in immunocompromised individuals. CNS and disseminated infections are believed to be the result of hematogenous dissemination from the lungs, paranasal sinuses or skin (41).
CNS, Disseminated, and Other Non-Ocular Infections
Granulomatous amebic encephalitis occurs in humans with compromised immunologic functions because of HIV/AIDS, or who are chronically ill, diabetic, have undergone organ transplantation or are otherwise debilitated with no recent history of exposure to freshwater. Onset of granulomatous amebic encephalitis is slow and insidious and develops as a chronic disease and may last from several weeks to months. The salient features of granulomatous amebic encephalitis are headache, stiff neck, and mental status abnormalities as well as nausea, vomiting, low-grade fever, lethargy, cerebellar ataxia, visual disturbances, hemiparesis, seizures and coma. Computerized tomography (CT) scans of the brain show large, low-density abnormality mimicking a single or multiple space-occupying mass. Magnetic resonance imaging (MRI) with enhancement shows multiple, ring-enhancing lesions in the brain (41). Since granulomatous amebic encephalitis has a long incubation period, the portal of entry is difficult to establish. BecauseAcanthamoeba has been isolated from nasal passages of humans it is thought that air-borne cysts may enter the nasal passages and cause sinusitis and other nasopharyngeal infections and subsequently cause granulomatous amebic encephalitis in HIV/AIDS patients. Amebae may also enter the body through breaks in the skin, resulting in hematogenous dissemination to the lungs and brain (23, 24, 41). CSF examination in general reveals lymphocytic pleocytosis with mild elevation of protein and normal or slightly depressed glucose. Although several case reports have described culturing of Acanthamoeba from CSF of patients with granulomatous amebic encephalitis it is not usually found in the CSF (24, 41). Acanthamoeba has been detected in the CSF of a patient without CNS disease and the authors speculate that the amebae apparently entered the CSF from the nasopharynx through a fistula (31). Acanthamoeba DNA has also been found in the CSF (46). Biopsy/autopsy results clearly show multifocal sites of encephalomalacia and hemorrhagic necrosis, most often in the posterior fossa, midbrain, thalamus, brainstem, corpus callosum and cerebellum (24, 41). Both trophozoites and cysts are usually seen.
Laboratory Diagnosis
The diagnosis is usually made by visualization of the trophozoites that measure 10 to 30 µm diameter and/or cysts measuring 10 to 20 µm in biopsy or autopsy specimens. The cysts are double-walled with an outer wrinkled and an inner stellate or polygonal cyst walls. In tissue, the Acanthamoeba is readily visualized with hematoxylin and eosin staining and can be seen to have basophilic cytoplasm with a single large eccentrically located nucleus containing a prominent nucleolus. Since Acanthamoeba and Balamuthia look similar in tissue sections, immunohistochemical tests, or PCR, or realtime PCR can distinguish Acanthamoeba from Balamuthia. (11, 29, 41, 46). Acanthamoeba may also be isolated into culture by inoculating pieces of infected tissue (brain, lung, skin, nasopharyngeal) on nonnutrient agar plate coated with Gram negative bacteria.
Pathogenesis
Pathogenesis of Acanthamoeba encephalitis is poorly understood. The immunity is predominantly T-lymphocyte-mediated and therefore depletion of CD4+ and T-helper cells allows replication of amebae. The route of invasion is the bloodstream, and the trophozoites and cysts are often seen around blood vessels and in necrotic CNS tissue. Acanthamoeba trophozoites invade and cause damage to the host tissue (a) by ingesting host cells through food cups or amebastomes; and (b) producing enzymes such as lysosomal hydrolases, aminopeptidases phospholipases, proteinases, metalloporoteinases, plasminogen activators and mannose-binding protein (MBP). Acanthamoeba expresses an MBP on its surface which adheres to mannose glycoproteins on the surface of the epithelial cells thus contributing to the pathogenic potential of Acanthamoeba (8, 18, 41). In vitro studies have shown that the microglial cells produce a variety of interleukins (IL-1a and b, and tumor necrosis factor) when cultured with Acanthamoeba and the interleukins together with macrophage play a role in killing the amebae. The macrophage-mediated killing is probably contact-dependent (8, 23).
SUSCEPTIBILITY IN VITRO AND VIVO
Antiparasitic Agents
Acanthamoebae are susceptible in vitro to sulfadiazine and to pentamidine, as well as to the topical agents, chlorhexidine and propamidine (32). The benzimidazoles, mebendazole, flubendazole and fenbendazole are inactive against A. polyphaga (17). The minimal inhibitory concentration of azithromycin against Acanthamoeba spp. was 0.1 µg/mL, while erythromycin and clarithromycin were ineffective (32). Azithromycin was amebastatic, but not amebicidal. Chlorpromazine, chlorprothexine, and triflupromazine inhibited growth by up to 90% at concentrations of 5 µg/mL to 10 µg/mL, although toxicity for rat glioma cells was noted at the higher concentration. Voriconazole, a triazole compound derived from fluconazole has been found to be a potent inhibitor of four strains of Acanthamoebaisolated from patients with keratitis, cutaneous lesions and encephalitis even at a concentration of 1 μg/ml. Miltefosine, an alkylphosphocholine compound used in cancer treatment, has been found to be active against 4 strains of Acanthamoeba at a concentration of 40 μM (33).
Topical Agents
While there is variability between species in the susceptibility to individual agents, Acanthamoeba are usually susceptible in vitro to both propamidine and chlorhexidine, agents which have an additive effect in vitro (13, 34). In vitro studies utilizing five strains of Acanthamoeba found that 0.02% solution eradicated all trophozoites and 0.1% chlorhexidine eradicated all cysts (45). Chlorhexidine was more consistently active than either polyhexamethylene biguanide or propamidine isethionate. Encystation is associated with resistance to these and other biocides (22). The most active agents among those studied in a rabbit model of keratitis were propamidine and polyhexamethylene biguanide (30). Pentamidine, hexamidine, chlorhexidine, and chloroxylenol had intermediate activity; neomycin, amphotericin B and povidone-iodine had poor activity.
ANTIPARASITIC THERAPY
Treatment of granulomatous amebic encephalitis and disseminated disease (Table 1 & (2) is problematic because of several factors: (a) lack of clear-cut symptoms, (b) lack of a good reliable diagnostic test premortem, and (c) lack of knowledge by the physician. Diagnosis is often made at the time of postmortem examination. Published case reports, although limited in number, provide us with the most useful information on the therapy of this infection. Repeat brain biopsy in a single patient treated with miconazole and 5-fluorocytosine(5-FC) demonstrated an apparently decreased number of trophozoites together with an increase in cysts and enhanced granulomatous inflammation (44).
Treatment for at least 13 cases of AIDS patients with disseminated Acanthamoeba infection or encephalitis have been reported (1-8). More than 80% presented with cutaneous lesions followed by sinusitis and encephalitis (5, 14, 19, 25, 27, 37, 39, 40). Combination therapy with 2 or more drugs was prescribed, and greater than 80% of the patients recovered after treatment. The commonly used drugs were pentamidine, 5-flucytocine (5-FU), and itraconazole. Other drugs included fluconazole, ketoconazole, amphotericin B, metronidazole,rifampin, azithromycin, sulfadiazine, pyrimethamine and efficacy was variable. The regimens were adjusted in more than half of the patients due to poor response to their initial regimen. Only one patient underwent surgery for a brain lesion.
Six patients were immunocompetent, and 4 (66.7%) were children (4, 21, 31, 36). All had central nervous system involvement with meningitis in 4 patients and brain tumors in 2. Five patients improved after treatment and one died of Acanthamoeba infection. Treatment was combination therapy with multiple drugs; rifampin (66.7%), trimethoprim-sulfamethoxazole (66.7%), ketoconazole (50%) were the most commonly-used drugs. Other agents included fluconazole (33.3%), amphotericin B (33.3%), amikacin (33.3%), metronidazole (33.3%), sulfadiazine (33.3%)streptomycin (16.7%), and 5-FU (16.7%). Similarly, the regimens were adjusted in half of the patients due to poor response. One underwent surgery for a brain lesion. Treatment for Acanthamoeba infection was reported in 4 transplant patients (2 lungs, 1 liver, and 1 kidney) (13-16). Three of them presented with multiple cutaneous lesions and one with brain tumor (9, 28, 38, 42). All the patients improved after combination therapy. Itraconazole (75%) and pentamidine (50%) were the most commonly-used drugs prescribed. Other drugs leading to a good response included rifampin (25 %), trimethoprim-sulfamethoxazole (25%), amphotericin B (25%), Abelcet (25%), 5-FU (25%), voriconazole (25%), azithromycin (25%), and clarithromycin (25%). Drugs that did not improve clinical course included sulfadiazine (25%), pyrimethamine (25%), and metronidazole (25%). Again, regimens were adjusted due to poor response in half of the patients, and only one patient underwent surgery for a brain lesion.
These reports indicate the great uncertainty that must accompany any recommendation for treatment of granulomatous amebic encephalitis or disseminated acanthamoebiasis. In a few cases, biopsy or surgical removal of abscessed areas, have also helped in the ultimate recovery of the patient possibly as a result of the elimination or a decrease in parasite load.
Our estimation, based on this limited data, is that patients with granulomatous amebic encephalitis or disseminated Acanthamoeba infection should be treated with pentamidine isethionate IV 4 mg/kg body weight/24 hrs, sulfadiazine 500 mg four times a day, pyrimethamine 50 mg, once a day, voriconazole 200 mg bid and miltefosine. Topical chlorhexidine and/or miltefosine may be placed on ulcerated cutaneous lesions. Murakawa and colleagues have recommended a regimen of pentamidine, sulfadiazine, fluconazole and 5-FC, together with topical skin care (27).
Consideration may be given to surgical excision of cerebral mass lesions due to granulomatous amebic encephalitis. Treatment should be continued for at least several weeks after clinical evidence of cure. Patients who remain severely immunocompromised may require long-term suppressive therapy. Note: pentamidine is highly toxic and needs close monitoring.
Keratitis: Polyhexamethylene biguanide has also been administered together with propamidine isethionate with clinical success (2, 15). An open nonrandomized prospective trial found evidence of success in 50 of 60 (83%) evaluable eyes treated with 0.1% propamidine isethionate together with neomycin-polymyxin B-gramicidin ophthalmic solution (12). Chlorhexidine was effective in six of six infected eyes (20).
One recommended regimen is 0.02% chlorhexidine digluconate drops in 0.9% physiological saline in combination with 0.1% propamidine isetihionate drops, each administered hourly around the clock for 72 hours, then every 2 hours during the day for 4 weeks, 3 hourly during the day for 4 weeks and every 4 hours during the day for a final 4 months (35). Care must be taken, however, since the bis-biguanide chlorhexidine is toxic to corneal epithelium of experimental animals at concentration of 0.05% (10). PHMB, a polymeric biguanide, is safe at concentrations as high as 20% (3).
ADJUNCTIVE THERAPY
Surgical excision of cerebral mass lesions due to granulomatous amebic encephalitis should be considered if possible. Debridement of cornea, penetrating keratoplasty and corneal grafting, have led to good results in Acanthamoeba keratitis. Dexamethasone increases the pathogenicity of Acanthamoeba in vitro and in an animal model of keratitis (26), and hence is not recommended.
ENDPOINTS FOR MONITORING THERAPY
Clinical endpoints for treating granulomatous amebic encephalitis have not yet been determined. Patients may need therapy for many months after clinical response.
VACCINES
There are no vaccines for Acanthamoeba infections.
PREVENTION
Acanthamoeba keratitis can be prevented by proper care of contact lenses, and avoiding use of contact lenses while swimming.
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Table 1: Successful Antimicrobial Treatments of Acanthamoeba CNS Infections.
| Systemic Acanthamoeba Infections | ||
|---|---|---|
| Antimicrobials | Dosage | Reference |
| Amebic Encephalitis | ||
Sulfamethazine |
1 g qid |
Cleland et al., 1982 |
Pencillin G |
2 x 106 U q3h (IV) |
Lalitha et al., 1985 |
Cotrimoxazole |
75 mg/kg q12h IV |
Karande et al., 1991 |
Sulfadiazine |
500 mg qid |
Martinez et al., 2000* |
Ketoconazole |
5 mg/kg qd |
Singhal et al., 2001 |
Fluconazole |
400 mg, (parenteral) |
Petry et al., 2006 |
TMP-SMX |
800/600 mg bid (parenteral) |
Walochnik et al., 2008 |
Rifampicin |
600 mg tid |
Fung KT-T et al., 2008 |
Abbreviations used in tables: qxh, every x hours; qd, every day; bid, twice a day; tid, thrice a day qid, four times each day.; IV, intravenous
(Adapted from Schuster FL & Visvesvara GS. Opportunistic amoebae: challenges in prophylaxis and treatment.Drug resistance Updates 2004; 7:41-51).
Table 2. Successful Antimicrobial Treatments of Acanthamoeba Infections Other Than CNS.
Cutaneous, Nasopharyngeal and disseminated Acanthamoeba infection |
||
|---|---|---|
Antimicrobial |
Dosage |
Reference |
Ketoconazole 5-Fluorocytosine |
200 mg q8h IV 40 mg/kg q 8h |
Helton et al. (1993) |
Pentamidine Itraconazole Chlorhexidine (topical) Ketoconazole cream |
4 mg/kg q24h IV 200 mg orally Cleansing bid 2% following cleansing |
Slater et al. (1994) |
5-Fluorocytosine Pentamidine |
2000mg/d/orally 220 mg/d/IV |
Murakawa et al. (1995)
|
Fluconazole 5-Fluorocytosine Sulfapyridine |
*-month old boy, no dosages given |
Murakawa et al. (1995) |
Ketoconazole 5-Fluorocytosine |
200 mg q8h 40 mg/kg/8h |
Sison et al. (1995) |
Pentamidine 5-Fluorocytosine Azithromycin Itraconazole Chlorhexidine (topical) Ketoconazole cream Clarithromycin |
No dosages given |
Oliva et al. (1999) |
Pentamidine Levofloxacin Amphoterecin B 5-Fluorocytosine Rifampin Itraconazole |
4 mg/kg qd IV 500 mg qd IV 550 mg/qd IV 2 g q6h 600 mg bid orally 200 mg bid orally |
Rivera & Padhya (2002) |
Pentamidine 5-Fluorocytosine Itraconazole |
Surgery of the affected area Pentamidine 4mg/kg/d for 4 days, IV 5-Fluorocytosine 75mg/kg/d for one month Itraconazole 200mg/kg/d Chlorhexidine (topical) Ketoconazole cream (topical)
|
Teknos et al. (2000) |
Pentamidine Fluconazole Azithromycin Topical Econazole Topical Chlorhexidine |
No dosages given |
Torno et al. (2000) |
Itraconazole Metronidazole Abelcet Voriconazole Voriconazole
|
7mg/kg/d 4mg/kg/tid IV for 10 wks 200mg bid oral |
Walia et al. 2007 |
Abbreviations used in table: d, day; qxh, every x hours; qd, every day; bid, twice a day; tid, thrice a day qid, four times each day.; IV, intravenous
(Adapted from Schuster FL & Visvesvara GS. Opportunistic amoebae: challenges in prophylaxis and treatment. Drug resistance Updates 2004; 7:41-51).
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Kim EC et al. Bilateral Acanthamoeba Keratitis after Orthokeratology. Cornea. 2010 Jun;29:680-2.
Aichelburg AC, et al. Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine [In process citation]. Emerg Infect Dis 2008;14 (11):1743-1746.
Sriram R., et al. Survival of Acanthamoeba Cysts after Desiccation for More than 20 Years. J Clin Microbiol 2008;46(12):4045-4048.
Mowrey-McKee M, et al. Contact Lens Solution Efficacy Against Acanthamoeba castellani. Eye Contact Lens. 2007;33:211-215.