Amebiasis is transmitted by oral ingestion of the transmissible cystic form of E. histolytica in human stool. This transmission occurs by ingestion of fecally contaminated food and water, mainly in developing countries. The pathogen can also be transmitted directly from human to human, with clustering of E. histolytica strains due to sexual contact. [1, 2] Over the past 2 decades, amebic infection has been increasingly reported as a sexually transmitted infection (STI) in developed countries of East Asia and in Australia. [3] E. histolytica has also been recently recognized as a comorbidity among HIV-infected men or as a domestic STI in developed European countries. [4, 5] Neither of our 2 patients had a history of travel to a developing country in their lifetime. Additionally, we performed genotyping of 6 short tandem repeat (STR) loci in transfer RNA lesions of E. histolytica in stool samples from both patients. [6] Interestingly, the STR genotypes showed different patterns at all 6 loci between the 2 patients. However, both genotypes were identical to previously reported genotypes of Japanese origin (S2 Fig; J8 in patient 1 and J13 in patient 2). Therefore, we could not identify the transmission route of the patients’ infection. Additionally, because samples were not available at referral, we did not know the reason (reinfection, treatment failure by poor adherence, or drug resistance) why patient 1 repeatedly developed E. histolytica infection before referral.

Noninvasive infections (described as asymptomatic intestinal colonization [7]) can be treated using a lumen-active agent, such as paromomycin [8], without a tissue-active agent. Tissue-active agents, such as metronidazole, should be administered before a lumen-active agent for invasive intestinal diseases (amebic colitis). However, in clinical settings similar to the 2 present patients, the difference between intestinal colonization and invasive colitis is often uncertain. [9–12] Our patients had minimal symptoms but showed macroscopically visible intestinal ulcers upon colonoscopy and microscopically identified inflammation caused by E. histolytica in biopsy samples. This difference is presumably because disease severity (colonization or colitis) in amebiasis is not currently determined using pathophysiological criteria but is based on patients’ symptoms. Furthermore, colonoscopy is not routinely recommended for asymptomatic cyst passers who may have ulcerative lesions in their large intestine, such as patient 2 (cystic form of Entamoeba in the stool and visible ulcers identified by colonoscopy). However, these cases are commonly treated by a lumen-active agent without a tissue-active agent. [7] These results raise the unresolved issue that monotherapy by a lumen-active agent can be inadequate treatment for asymptomatically infected patients with E. histolytica who are diagnosed by stool tests, such as microscopy or PCR. Additionally, as warranted in our cases, extra-intestinal lesions, such as liver abscess, should be ruled out before determining their treatment for all asymptomatically infected cases. However, imaging studies before treatment with a lumen-active agent are currently not recommended for these cases. [7] At a minimum, close follow-up is required when a tissue-active agent is not administered prior to a lumen-active agent. Additionally, nitroimidazole agents, especially metronidazole, often show toxicity in patients, such as drug hypersensitivity, neurological disorders, and sometimes Stevens–Johnson syndrome. [13, 14] Another problem in the clinical settings is that there are no available alternative regimens for invasive diseases for patients who are unable to tolerate a nitroimidazole agent. In our cases, we did not use tissue-active agents before paromomycin because of concern about adverse effects. Both patients achieved complete healing of ulcerative lesions after paromomycin monotherapy (Fig 1C and 1D). A study from Japan reported that 11 of 143 cases of amebiasis were treated with paromomycin monotherapy, although symptoms and outcomes of the treatment were unclear from the report. [15] Additionally, older reports published before the era of PCR differentiation of E. histolytica from nonpathogenic Entamoeba described the effectiveness of a single dose or 5 days of paromomycin, even for symptomatic amebic colitis. [16, 17] However, 6.3% to 44.0% of the cases experienced recurrence within 10 weeks of follow-up. Tissue-active agents are generally used for initial treatment, according to recent case reports of endoscopically diagnosed, asymptomatic amebic colitis. [9, 18] Furthermore, paromomycin is not systemically absorbed, and 100% is excreted in an unchanged form from stool. Taken together, these results suggest that the best treatment regimen for endoscopically diagnosed asymptomatic ulcers in the large intestine due to E. histolytica remains undetermined. Paromomycin monotherapy, which might be considered only for patients who are intolerant to nitroimidazole after excluding extraintestinal involvement, will not adequately treat all cases of intestinal amebiasis. Further investigations are required to determine appropriate treatment for asymptomatically infected patients with E. histolytica who are diagnosed via colonoscopy or stool tests.