464
Diloxanide Furoate for Treating Asymptomatic Entamoeba histolytica Cyst Passers: 14 Years' Experience in the United States James B. McAuley, Barbara L. Herwaldt, Susan L. Stokes, John A. Becher, Jacqueline M. Roberts, Marco K. Michelson, and Dennis D. Juranek
From the Division of Parasitic Diseases and Scientific Resources Program. National Center for Infectious Diseases. Centers for Disease Control, Public Health Service. Department of Health and Human Services. Atlanta. Georgia
u.s.
Entamoeba histolytica has a worldwide distribution and is endemic in many developing countries [1]. Although most infected persons are asymptomatic, the worldwide incidence of colitis and liver abscess due to E. histolytica infection is extensive [2]. The prevalence of infection in the United States is not known but is probably < 1%. Three groups of persons are at particularly high risk for infection: immigrants from or travelers to areas in which E. histolytica is endemic, male homosexuals, and mentally retarded persons in chronic-care facilities [3]. With the substantial increase in world travel, the number of high-risk persons in the United States is likely to increase [4, 5]. The available antiamebic drugs can be classified according to their efficacy against replicating amebae in the intestinal lumen, the submucosa of the bowel, and extraintestinal sites. Three luminal amebicides that eradicate intestinal carriage by achieving high concentrations in the lumen of the colon are currently available in the United States: iodoquinol (Yo-
Received 31 January 1992; revised 10 April 1992. This work was presented in part at the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy held 29 September-2 October 1991 in Chicago. Informed consent was obtained from the patients or from their parents or guardians. and the guidelines for human experimentation ofthe U.S. Department of Health and Human Services were followed in the conduct of this study. The use of specific trade names is for identification only and does not imply endorsement by the U.S. Public Health Service. Reprints or correspondence: Dr. Barbara L. Herwaldt, Centers for Disease Control, 1600 Clifton Road. Mailstop F 13. Atlanta. Georgia 30333.
Clinical Infectious Diseases
1992;15:464-8
This article is in the public domain.
doxin, a halogenated hydroxyquinoline; Glenwood, Tenafly, NJ), diloxanide furoate (Furamide; Boots, Nottingham, England), and paromomycin (Hurnatin, an aminoglycoside; Parke-Davis, Morris Plains, NJ). Paromomycin is also active against amebae in the intestinal mucosa. Metronidazole, the only nitroimidazole available in the United States, achieves good tissue levels but has variable efficacy in the lumen of the intestine, presumably because it is so well absorbed that the residual intraluminal drug concentration may be inadequate. Dehydroemetine is effective in the intestinal wall, liver, and other tissues but not in the intestinal lumen. Chloroquine is active only in the liver. Diloxanide furoate, which was first synthesized in 1956, is a substituted acetanilide [6, 7]. Since its release in 1960, this drug has been used widely outside the United States for treating asymptomatic or mildly symptomatic persons passing E. histolytica cysts. In general, it is less effective in persons with invasive intestinal amebiasis and should not be used as the primary drug for treating persons with acute amebic dysentery [8-10]. It is of no value in treating extraintestinal amebiasis. Numerous case series and treatment trials involving from four to 136 patients have reported efficacy rates of 57% to 100% among asymptomatic or mildly symptomatic persons passing E. histolyttca cysts [11-21]. The rate ofgastrointestinal adverse effects ranged from 0 to 87%, but no severe toxicities were reported. We used yearly summaries (1977-1983) and expanded individual patient report forms (1984-1990) to review the efficacy and toxicity of diloxanide furoate, We then compared these findings with published data on diloxanide furoate, paromomycin, and iodoquinol to determine which
Downloaded from http://cid.oxfordjournals.org/ at Monash University on June 15, 2015
Diloxanide furoate is used for treating asymptomatic or mildly symptomatic persons who are passing cysts of Entamoeba histolytica. The Centers for Disease Control (Atlanta) released this drug for 4,371 treatment courses from 1977 through 1990. Of the 2,815 report forms (64%) returned, 656 adverse effects were reported for 390 treatment courses (14%); they included flatulence (260), diarrhea or cramping (100), nausea (93), headache (17), disorientation or dizziness (9), and diplopia (4). During 1984-1990 uniform collection of data allowed more detailed analysis of toxicity and efficacy; fewer adverse effects were reported for persons aged 20 months to 10 years than for persons aged> 10 years (6 of 206 [3%] vs. 89 of 763 [12%], relative risk = 0.27, 95% confidence interval = 0.12 < relative risk < 0.61). Parasitological cures were achieved during 497 (86%) of the 575 treatment courses (52%) administered to asymptomatic persons who were passing cysts, who had received a fulll0-day treatment course, and for whom results of a follow-up stool examination (~14 days post-treatment) were available. Diloxanide furoate is safe and effective for treating asymptomatic persons who are passing E. histolytica cysts and may be particularly well tolerated in children.
CID 1992: 15 (September)
Diloxanide Furoate Use in the United States
drug should be considered the treatment of choice in the United States for asymptomatic persons passing cysts of E. histolytica.
Methods
Results The CDC released 4,371 treatment courses of diloxanide furoate from 1977 through 1990: 2,836 (65%) from 1977 through 1983 and 1,535 (35%) from 1984 through 1990.
Efficacy Data
For the 1,535 treatment courses released from 1984 through 1990, 1,100 report forms (72%) were returned and analyzed for safety and efficacy. Sixty-one persons had more than one course oftherapy (range, 2-6 courses). Thus, report forms were returned for 1,013 different persons. The data are presented with the number of treatment courses as the denominator, since the report forms did not indicate whether retreatments were needed because of nonresponse to therapy or reinfection. The mean age of persons treated was 26 years (median, 25 years), with a range of 20 months to 89 years. Six hundred seventy-three patients (61 %) were male and 387 (35%) were female; the gender was not reported for 40 (4%). Five hundred seventy-five patients (52%) were Caucasian, 296
(27%) were Asian, 96 (9%) were black, and 10 (I %) were American Indian. The specific ethnic group was provided for 480 foreign-born persons (44%), of whom 200 (42%) were Hispanic, 101 (21 %) were Laotian, 96 (20%) were Cambodian, 78 (16%) were Vietnamese, and 5 (l %) were Haitian. The suspected route by which infection was acquired was reported for 895 treatment courses (81 %). Ingesting contaminated food or water was the probable cause of 620 infections (56%). However, 163 infections (15%) were reported to have been acquired by nonsexual person-to-person spread, 84 (8%) to have been sexually acquired (83 men and 1 woman), and 28 (3%) to have been the result ofthe pica syndrome. For 624 infections (57%), recent travel was indicated as a probable factor in exposure. The length of therapy was 10 days for 981 (97%) of the 1,011 treatment courses for which duration was reported. Twenty courses (2%) were for 10 days (range, 11-58 days). The results of the pretreatment stool examination either were not provided or were listed as unknown for 204 ( 19%) of the treatment courses. Results of the 896 reported stool examinations revealed both cysts and trophozoites of E. histolytica in 51 (6%), only cysts in 802 (90%), only trophozoites in 40 (4%), and no demonstrable parasites in 3 (0.3%). Of the 890 treatment courses (81 %) for which clinical outcome was reported, 768 (86%) were classified as cures and 122 (14%) as failures. No clinical outcome was given for 210 treatment courses (19%). The courses of eight persons were classified as clinical failures despite negative results ofa posttreatment stool examination at least 14 days after completion of therapy. The treatment courses of 16 persons were classified as clinical cures despite positive results of a posttreatment stool examination. No association was found among age, sex, race, ethnic group, and clinical outcome. Results of posttreatment stool examinations performed at least 14 days after therapy was completed were negative for 639 (58%) of the treatment courses, positive for 93 (8%), and unavailable for 368 (33%). Female patients were more likely to have a parasitological failure than were male patients (43 of 265 [16%] vs. 46 of 447 [l0%], relative risk [RR] = 1.36, 95% CI = 1.07 < RR < 1.72). No association was found among age, race, ethnic group, and parasitological cure. Persons with trophozoites in their pretreatment stool specimens were not more likely to have a parasitological failure than were persons with only cysts (7 of 49 [14%] vs. 70 of 576 [12%], P> .05). Five hundred seventy-five treatment courses (52%) were administered to 539 asymptomatic persons passing cysts of E. histolytica who had received a full 10-day treatment course and for whom results of follow-up stool examination (~14 days post-treatment) were available. Parasitological cures were reported following 497 (86%) of these treatment courses.
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The Centers for Disease Control (CDC~ Atlanta) Drug Service provides to physicians diloxanide furoate and other essential antiparasitic drugs that are difficult to obtain in the United States. The drugs are provided under investigational new drug protocols from the U.S. Food and Drug Administration (FDA). Physicians are requested to supply pretreatment and follow-up information on persons treated with these drugs. Data from 1977-1983 did not include the outcome oftherapy and, therefore, were used to determine only adverse effects. Data from the second study period, 1984 through 1990, were used to determine both efficacy and safety. The expanded form ( 1984-1990) includes information on age, race, sex, ethnicity, travel history, pretreatment stool examination, posttreatment stool examinations at 1 and 4 weeks, drug-related adverse effects, and response to therapy. Because of instances in which the drug was not used for various reasons, the number of drug releases is greater than the number of treatment courses actually administered. Data were analyzed with use of the statistical computer package Epi Info, version 5.0 (USD, Stone Mountain, GA). Statistical differences were determined with use of X2 and Fisher's exact tests when appropriate and expressed with use of Cornfield 95% confidence intervals (CIs).
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CID 1992; 15 (September)
Table 1. Adverse effects of diloxanide furoate during 1977-1990. Severity rating Adverse effect
Mild
Moderate
Severe
Total
51 23 6 12 9 6 6 10
101 51 33 19 12 21 5 4 8 6 3 3 4 3 2
70 13
38 6 2 7 2
260 93 52 48 31 30 19 18 17 8 8 6 6 6 5 4 4
I
0 4 I I
2 3 I
2
I I
II
10 8 2 5 3 5 2 0 2 0 0 0 2 I
Total
I
3 I
3 0 I
0 I I
0 0 0
656*
NOTE. There were a total of 2.815 treatment courses. * Total includes disorientation. indigestion. insomnia. paresthesia, and urticaria (each reported three times); alopecia. bleeding (rectal), depression. fever. malaise. muscle tremor, myasthenia. nervousness. and perirectal pruritus (each reported twice); and drowsiness. myalgia, joint pain. burning sensation. irritability. forgetfulness, impotence, and nightmares (each reported once).
Toxicity Data For the 2,836 treatment courses released from 1977 through 1983, the CDC received 1,833 responses (65%) in the form of returned reports (1,715) or unused courses of drug (118). Of the 1,715 report forms returned, at least one adverse effect was reported for 295 treatment courses (17%), no adverse effects were reported for 1,147 (67%), and the section on adverse effects was not completed for 273 (16%). A total of 504 adverse effects were reported for 295 treatment courses. The most commonly reported effects were flatulence (207), nausea (70), abdominal cramping (44), diarrhea (34), pruritus (29), and abdominal pain (24) (table I). No deaths were reported. Available data did not indicate whether therapy was stopped because of adverse effects. For the period 1984 through 1990, 131 (12%) ofthe I, 100 patients who were treated and whose treatment courses were reported on were not available for follow-up. For the remaining 969 treatment courses, no information concerning adverse effects was recorded for 135 (12%), no adverse effects were reported for 739 (67%), and 153 adverse effects were reported for 95 (9%) (table I). Nine (9%) of the 95 treatment courses were not completed because of adverse effects. Persons aged 20 months to 10 years reported fewer adverse effects than did persons aged ~ 10 years (6 of206 [3%] vs. 89 of 763 [12%], RR = 0.27, 95% CI = 0.12 < RR < 0.61). Female patients were more likely than male patients to report
adverse effects (45 of 350 [13%] vs. 49 of 590 [8%], RR = 1.55, 95% CI = 1.06 < RR < 2.27) even when differences in age and duration oftherapy were accounted for. The percentage of persons reporting adverse effects varied significantly by racial group, with the highest rate for American Indians (3 of8 [38%]), followed by Caucasians (64 of514 [12%]), blacks (6 of90 [7%],and Asians (10 of265 [4%]) (P < .00 I, Fisher's exact test [four-by-two table]). The percentage of reported adverse effects did not vary by ethnic group. Although most reported adverse effects were gastrointestinal complaints, potentially more serious effects were reported; these included headache (17), lethargy (10), dizziness (6), diplopia (4), and paresthesia (3) (table 1).
Discussion Amebiasis remains a major health concern worldwide. Although ""-' I0% of the world's population is thought to be infected with E. histolytica, 90% of these persons will remain asymptomatic [2]. When and how to treat persons who are asymptomatic and passing E. histolytica cysts remain controversial [22-27]. Several authors have suggested that persons who need therapy can be differentiated from those who do not on the basis ofzymodeme status [3,23-27]. which can be tested only in a research laboratory. This strategy would prevent persons from being treated multiple times for commensal infections. In countries where E. histolytica is not
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Flatulence Nausea Cramps Diarrhea Abdominal pain Pruritus Lethargy Other (not specified) Headache Anorexia Vomiting Constipation Vertigo/dizziness Abdominal distention Rash Dry mouth Diplopia
Not rated
CID 1992; 15 (September)
Diloxanide Furoate Use in the United States
[39-41]. In each instance, the dose and duration of therapy were much greater than were typically indicated for the treatment of amebiasis. The findings that children were less likely to report adverse effects and women were more likely to do so may represent a reporting phenomenon as opposed to a physiological difference. The racial difference in the percentage of persons reporting adverse effects may also represent a reporting phenomenon, either by the patient or by the physician who completed the form. These issues can be resolved in only a prospective study in which the pretreatment diagnosis and follow-up evaluations are performed in a uniform manner. Although diloxanide furoate is effective and minimally toxic, it is unlikely to become licensed for use in the United States because the financial incentive is too small for a pharmaceutical company to pursue. Because the efficacies of the two licensed luminal agents are comparable, the treating physician must weigh other factors such as toxicity, duration of therapy (7 days for paromomycin and 20 days for iodoquinol), and cost (a standard course of paromomycin costs three times that ofiodoquinol). Paromomycin is also effective in persons with mild or moderately symptomatic amebiasis and thus may be advantageous in certain cases. At the present time, we see no great advantage of diloxanide furoate over the other luminal drugs; duration of therapy with paromomycin is comparable, iodoquinol is relatively inexpensive, and both drugs are well tolerated, have comparable efficacy rates to diloxanide furoate, and can be more conveniently obtained in the United States.
References I. Walsh JA. Problems in recognition and diagnosis ofamebiasis: estimation of the global magnitude of morbidity and mortality. Rev Infect Dis 1986;8:228-38. 2. Guerrant RL. Amebiasis: introduction, current status. and research questions. Rev Infect Dis 1986;8:2 I8-27. 3. Weinke T. Friedrich-Janicke B. Hopp P. Janitschke K. Prevalence and clinical importance of Entamoeba histolvtica in two high-risk groups: travelers returning from the tropics and male homosexuals. J Infect Dis 1990;1 61: 1029-3 I. 4. Steffen R. Lobel HO. Haworth J. Bradley DJ. eds. Travel medicine. Berlin: Springer-Verlag. 1989:v-vi. 5. Keller P. Koch K. World tourism: facts and figures. In: Steffen R. Lobel HO. Haworth J. Bradley OJ. eds. Travel medicine. Berlin: SpringerVerlag. 1989:10-5. 6. Main PT. Bristow NW. Oxley P, et al. Entamide. Annals of Biochernistry and Experimental Medicine 1960;20:441-8. 7. Geoffroy H. Zniber A. Schwarz R. Kouhen C. Abitol E. A new amoebicide: diloxanide furoate. Maroc Medical t 962;4 1:98- I04. 8. DharlwaJ RKS. Singh Verma NP. Nloguy C. et al. Clinical trial with entamide furoate in acute amoebic dysentery. Indian J Med Sci 1963: J7:825-6. 9. Krishna Das KV. Pai KN. Clinical trials with Furamide in patients with acute and chronic intestinal amoebiasis. Indian Pract 1962; 15:98390.
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endemic and reinfection is unlikely to occur, it is common practice to treat asymptomatic persons who are passing cysts of E. histolytica. Until a rapid diagnostic test that can distinguish pathogenic from nonpathogenic strains of E. histolytica is available, most authorities would agree that asymptomatic infections be treated on the assumption that the parasite is a potential pathogen. Once the decision has been made to treat the patient, the choice of luminal agents must be made. Only two luminal agents, iodoquinol and paromomycin, are currently licensed in the United States. A third luminal agent, diloxanide furoate, has been reported to have efficacy rates comparable with those of iodoquinol and paromomycin [ 10-21, 28-36]. Our data are not ideal for demonstrating efficacy because pretherapy and posttherapy stool examinations were not performed in a uniform manner in a single laboratory. However, it is encouraging that in general practice the efficacy is similar to that documented in clinical trials [10-21]. Contrary to the results of several published clinical trials [8-10], we did not find that the efficacy of diloxanide furoate was significantly lower for persons with trophozoites in their pretreatment stool than for persons with only cysts. This discrepancy may indicate that most of the persons who were passing trophozoites were infected with a nonpathogenic (noninvading) strain. The minimal toxicity of diloxanide furoate that has been documented in small clinical trials was confirmed by our large study. The most frequently reported adverse effect was flatulence. However, as noted above, several potentially more serious adverse effects were reported. Because this was not a placebo-controlled trial and the rate at which these symptoms occur in the general population is not known, it is difficult to determine the degree to which diloxanide furoate contributed to these symptoms. We cannot be certain that the persons were not receiving other medications that may have contributed to the reported adverse effects. Despite these reservations, patients should be warned about these potentially serious adverse effects. For comparison, we reviewed spontaneous reports received by the FDA of adverse effects related to the use of acetaminophen. Of note is that numerous neurological complaints were listed; these included somnolence, headache, dizziness, confusion, anxiety, depression, and psychosis. Most of these adverse effects occurred in persons who were receiving numerous other drugs known to have neurological adverse effects. The FDA has received two reports of adverse effects related to paromomycin: irreversible deafness in a person receiving high doses of both paromomycin and neomycin for hepatic encephalopathy [37] and mild gastrointestinal disturbance in a second individual. An additional report of reversible malabsorption in an individual who received paromomycin was published in 1970 [38]. By comparison, the FDA has a record of three persons who developed optic atrophy and one who developed permanent blindness following the use of iodoquinol
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10. Botero DR. Treatment of acute and chronic intestinal amoebiasis with entamide furoate. Trans R Soc Trop Med Hyg 1964;58:419-21.
1963;71: 125"':'6. 21. Padaria FT, Patel LR. Clinical evaluation of furamide in the treatment of amoebiasis. Current Medical Practice 1963;7:612-5. 22. Kean BH. The treatment of amebiasis: a recurrent agony. JAMA 1976;235: 50 I. 23. Gathiram V, Jackson TFHG. A longitudinal study of asymptomatic carriers of pathogenic zymodemes of Entamoeba histolvtica. S Afr Med J 1987;72:669-72. 24. Allason-Jones E, Mindel A, Sargeaunt P, Katz D. Outcome of untreated infection with Entamoeba histolvtica in homosexual men with and without HIV antibody. BMJ 1988;297:654-7. 25. Allason-Jones E, Mindel A, Sargeaunt P, Williams P. Entamoeba histolvtica as a commensal intestinal parasite in homosexual men. N Engl J Med 1986;315:353-6.
26. Sargeaunt PG, Jackson TFHG, Wiffen S, et al. The reliability of Entamoeba histolytica zymodemes in clinical laboratory diagnosis. Arch Invest Med (Mex) 1987;18:69-75. 27. Nanda R, Baveja U, Anand BS. Entamoeba histolytica cyst passers: clinical features and outcome in untreated subjects. Lancet
1984;2:301-3. 28. Wagner ED, Burnett HS. Paromomycin in the treatment of amoebiasis in Nyasaland. Trans R Soc Trop Med Hyg 1961;55:428-30. 29. Moffett HF, Toh SH. The treatment ofamebic dysentery with paromomycin (Humatin). Antibiotic Medicine and Clinical Therapy
1960;7:569-70. 30. Dooner HP. The treatment ofamebiasis with paromomycin (Humatin). Antibiotic Medicine and Clinical Therapy 1960;7:486-89. 31. Shafei AZ. The treatment ofamebic dysentery with paromomycin. Antibiotic Medicine and Clinical Therapy 1959;6:275-8. 32. Bell S, Woodruff AW. Humatin in intestinal amebiasis. Am J Trop Med Hyg 1960;9: 155- 7. 33. Courtney KO, Thompson PE, Hodgkinson R, Fitzsimmons JR. Paro-
34.
35.
36. 37. 38. 39.
momycin as a therapeutic substance for intestinal amebiasis and bacterial enteritis. In: Marti-Ibanez F, ed. Antibiotics annual 19591960. New York: Antibiotica, 1960:304-9. Lopez-Elias F, Oliver-Gonzalez J. Treatment of intestinal amebiasis with paromomycin (Humatin). Antibiotic Medicine and Clinical Therapy 1959;6:584-5. Fisher MW, Thompson PE. Antibiotics with specific affinities. Part 3: paromomycin. In: Schnitzer RJ, Hawking F, eds. Experimental chemotherapy. Vol 3. New York: Academic Press, 1964:329-45. Coffey GL, Anderson LE, Fisher MW, et al. Biological studies ofparomomycin. Antibiot Chemother 1959;9:730-8. Boston Collaborative Drug Surveillance Program. Drug induced deafness. JAMA 1973;224:515-6. Keusch GT, Troncale FJ, Buchanan RD. Malabsorption due to paromomycin. Arch Intern Med 1970;125:273-6. American Academy of Pediatrics Committee on Drugs. Blindness and neuropathy from diiodohydroxyquin-like drugs. Pediatrics 1974;54:
378-9. 40. Oakley GP. The neurotoxicity of the halogenated hydroxyquinolines. JAMA 1973;225:395-7. 41. Behress MM. Optic atrophy in children after diiodohydroxyquin therapy. JAMA 1974;228:693-4.
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II. Wolfe MS. Nondysenteric intestinal amebiasis treatment with diloxanide furoate. JAMA 1973;224: 1601-4. 12. Marsden PD. Clinical trials with entamide furoate, entamide piperazine sulphate, and emetine bismuth iodide in a tropical environment. Trans R Soc Trop Med Hyg 1960;54:396-9. 13. Schapiro MM. Intestinal amebiasis: a preliminary clinical trial of Furamide Tic. Am J Trop Med Hyg 1967;16:704-7. 14. Woodruff AW, Bell S. Clinical trials with entamide furoate and related compounds in a non-tropical environment. Trans R Soc Trop Med Hyg 1960;54:389-95. 15. Shaldon S. Entamide furoate in the treatment of acute amoebic dysentery. Trans R Soc Trop Med Hyg 1960;54:469-70. 16. Suchak NG, Satoskar RS, Sheth UK. Entamide furoate in the treatment of intestinal amoebiasis. Am J Trop Med Hyg 1962;11:330-2. 17. Nevill LB. Entamide and furamide in the treatment of amoebic infection in Nakuru, Kenya. Trans R Soc Trop Med Hyg 1962;56:81-4. 18. Sankale M, Brodu C. Intestinal amoebiasis treated with furamide (with reference to 34 patients observed at Dakar). Medecine 0 Afrique Noire 1963; 10: 189-91. 19. Dubey MP, Gupta PS, Chuttani HK. Entamide furoate in the treatment of intestinal amoebiasis. J Trop Med Hyg 1965;68:63-6. 20. Darbon A, Portal A, Girier L, Tach-Toan. Clinical study of a new contact amoebicide: diloxanide (entamide) furoate. Presse Med
CID 1992; 15 (September)
Diloxanide Furoate for Treating Asymptomatic Entamoeba histolytica Cyst Passers: 14 Years' Experience in the United States James B. McAuley, Barbara L. Herwaldt, Susan L. Stokes, John A. Becher, Jacqueline M. Roberts, Marco K. Michelson, and Dennis D. Juranek
From the Division of Parasitic Diseases and Scientific Resources Program. National Center for Infectious Diseases. Centers for Disease Control, Public Health Service. Department of Health and Human Services. Atlanta. Georgia
u.s.
Entamoeba histolytica has a worldwide distribution and is endemic in many developing countries [1]. Although most infected persons are asymptomatic, the worldwide incidence of colitis and liver abscess due to E. histolytica infection is extensive [2]. The prevalence of infection in the United States is not known but is probably < 1%. Three groups of persons are at particularly high risk for infection: immigrants from or travelers to areas in which E. histolytica is endemic, male homosexuals, and mentally retarded persons in chronic-care facilities [3]. With the substantial increase in world travel, the number of high-risk persons in the United States is likely to increase [4, 5]. The available antiamebic drugs can be classified according to their efficacy against replicating amebae in the intestinal lumen, the submucosa of the bowel, and extraintestinal sites. Three luminal amebicides that eradicate intestinal carriage by achieving high concentrations in the lumen of the colon are currently available in the United States: iodoquinol (Yo-
Received 31 January 1992; revised 10 April 1992. This work was presented in part at the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy held 29 September-2 October 1991 in Chicago. Informed consent was obtained from the patients or from their parents or guardians. and the guidelines for human experimentation ofthe U.S. Department of Health and Human Services were followed in the conduct of this study. The use of specific trade names is for identification only and does not imply endorsement by the U.S. Public Health Service. Reprints or correspondence: Dr. Barbara L. Herwaldt, Centers for Disease Control, 1600 Clifton Road. Mailstop F 13. Atlanta. Georgia 30333.
Clinical Infectious Diseases
1992;15:464-8
This article is in the public domain.
doxin, a halogenated hydroxyquinoline; Glenwood, Tenafly, NJ), diloxanide furoate (Furamide; Boots, Nottingham, England), and paromomycin (Hurnatin, an aminoglycoside; Parke-Davis, Morris Plains, NJ). Paromomycin is also active against amebae in the intestinal mucosa. Metronidazole, the only nitroimidazole available in the United States, achieves good tissue levels but has variable efficacy in the lumen of the intestine, presumably because it is so well absorbed that the residual intraluminal drug concentration may be inadequate. Dehydroemetine is effective in the intestinal wall, liver, and other tissues but not in the intestinal lumen. Chloroquine is active only in the liver. Diloxanide furoate, which was first synthesized in 1956, is a substituted acetanilide [6, 7]. Since its release in 1960, this drug has been used widely outside the United States for treating asymptomatic or mildly symptomatic persons passing E. histolytica cysts. In general, it is less effective in persons with invasive intestinal amebiasis and should not be used as the primary drug for treating persons with acute amebic dysentery [8-10]. It is of no value in treating extraintestinal amebiasis. Numerous case series and treatment trials involving from four to 136 patients have reported efficacy rates of 57% to 100% among asymptomatic or mildly symptomatic persons passing E. histolyttca cysts [11-21]. The rate ofgastrointestinal adverse effects ranged from 0 to 87%, but no severe toxicities were reported. We used yearly summaries (1977-1983) and expanded individual patient report forms (1984-1990) to review the efficacy and toxicity of diloxanide furoate, We then compared these findings with published data on diloxanide furoate, paromomycin, and iodoquinol to determine which
Downloaded from http://cid.oxfordjournals.org/ at Monash University on June 15, 2015
Diloxanide furoate is used for treating asymptomatic or mildly symptomatic persons who are passing cysts of Entamoeba histolytica. The Centers for Disease Control (Atlanta) released this drug for 4,371 treatment courses from 1977 through 1990. Of the 2,815 report forms (64%) returned, 656 adverse effects were reported for 390 treatment courses (14%); they included flatulence (260), diarrhea or cramping (100), nausea (93), headache (17), disorientation or dizziness (9), and diplopia (4). During 1984-1990 uniform collection of data allowed more detailed analysis of toxicity and efficacy; fewer adverse effects were reported for persons aged 20 months to 10 years than for persons aged> 10 years (6 of 206 [3%] vs. 89 of 763 [12%], relative risk = 0.27, 95% confidence interval = 0.12 < relative risk < 0.61). Parasitological cures were achieved during 497 (86%) of the 575 treatment courses (52%) administered to asymptomatic persons who were passing cysts, who had received a fulll0-day treatment course, and for whom results of a follow-up stool examination (~14 days post-treatment) were available. Diloxanide furoate is safe and effective for treating asymptomatic persons who are passing E. histolytica cysts and may be particularly well tolerated in children.
CID 1992: 15 (September)
Diloxanide Furoate Use in the United States
drug should be considered the treatment of choice in the United States for asymptomatic persons passing cysts of E. histolytica.
Methods
Results The CDC released 4,371 treatment courses of diloxanide furoate from 1977 through 1990: 2,836 (65%) from 1977 through 1983 and 1,535 (35%) from 1984 through 1990.
Efficacy Data
For the 1,535 treatment courses released from 1984 through 1990, 1,100 report forms (72%) were returned and analyzed for safety and efficacy. Sixty-one persons had more than one course oftherapy (range, 2-6 courses). Thus, report forms were returned for 1,013 different persons. The data are presented with the number of treatment courses as the denominator, since the report forms did not indicate whether retreatments were needed because of nonresponse to therapy or reinfection. The mean age of persons treated was 26 years (median, 25 years), with a range of 20 months to 89 years. Six hundred seventy-three patients (61 %) were male and 387 (35%) were female; the gender was not reported for 40 (4%). Five hundred seventy-five patients (52%) were Caucasian, 296
(27%) were Asian, 96 (9%) were black, and 10 (I %) were American Indian. The specific ethnic group was provided for 480 foreign-born persons (44%), of whom 200 (42%) were Hispanic, 101 (21 %) were Laotian, 96 (20%) were Cambodian, 78 (16%) were Vietnamese, and 5 (l %) were Haitian. The suspected route by which infection was acquired was reported for 895 treatment courses (81 %). Ingesting contaminated food or water was the probable cause of 620 infections (56%). However, 163 infections (15%) were reported to have been acquired by nonsexual person-to-person spread, 84 (8%) to have been sexually acquired (83 men and 1 woman), and 28 (3%) to have been the result ofthe pica syndrome. For 624 infections (57%), recent travel was indicated as a probable factor in exposure. The length of therapy was 10 days for 981 (97%) of the 1,011 treatment courses for which duration was reported. Twenty courses (2%) were for 10 days (range, 11-58 days). The results of the pretreatment stool examination either were not provided or were listed as unknown for 204 ( 19%) of the treatment courses. Results of the 896 reported stool examinations revealed both cysts and trophozoites of E. histolytica in 51 (6%), only cysts in 802 (90%), only trophozoites in 40 (4%), and no demonstrable parasites in 3 (0.3%). Of the 890 treatment courses (81 %) for which clinical outcome was reported, 768 (86%) were classified as cures and 122 (14%) as failures. No clinical outcome was given for 210 treatment courses (19%). The courses of eight persons were classified as clinical failures despite negative results ofa posttreatment stool examination at least 14 days after completion of therapy. The treatment courses of 16 persons were classified as clinical cures despite positive results of a posttreatment stool examination. No association was found among age, sex, race, ethnic group, and clinical outcome. Results of posttreatment stool examinations performed at least 14 days after therapy was completed were negative for 639 (58%) of the treatment courses, positive for 93 (8%), and unavailable for 368 (33%). Female patients were more likely to have a parasitological failure than were male patients (43 of 265 [16%] vs. 46 of 447 [l0%], relative risk [RR] = 1.36, 95% CI = 1.07 < RR < 1.72). No association was found among age, race, ethnic group, and parasitological cure. Persons with trophozoites in their pretreatment stool specimens were not more likely to have a parasitological failure than were persons with only cysts (7 of 49 [14%] vs. 70 of 576 [12%], P> .05). Five hundred seventy-five treatment courses (52%) were administered to 539 asymptomatic persons passing cysts of E. histolytica who had received a full 10-day treatment course and for whom results of follow-up stool examination (~14 days post-treatment) were available. Parasitological cures were reported following 497 (86%) of these treatment courses.
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The Centers for Disease Control (CDC~ Atlanta) Drug Service provides to physicians diloxanide furoate and other essential antiparasitic drugs that are difficult to obtain in the United States. The drugs are provided under investigational new drug protocols from the U.S. Food and Drug Administration (FDA). Physicians are requested to supply pretreatment and follow-up information on persons treated with these drugs. Data from 1977-1983 did not include the outcome oftherapy and, therefore, were used to determine only adverse effects. Data from the second study period, 1984 through 1990, were used to determine both efficacy and safety. The expanded form ( 1984-1990) includes information on age, race, sex, ethnicity, travel history, pretreatment stool examination, posttreatment stool examinations at 1 and 4 weeks, drug-related adverse effects, and response to therapy. Because of instances in which the drug was not used for various reasons, the number of drug releases is greater than the number of treatment courses actually administered. Data were analyzed with use of the statistical computer package Epi Info, version 5.0 (USD, Stone Mountain, GA). Statistical differences were determined with use of X2 and Fisher's exact tests when appropriate and expressed with use of Cornfield 95% confidence intervals (CIs).
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Table 1. Adverse effects of diloxanide furoate during 1977-1990. Severity rating Adverse effect
Mild
Moderate
Severe
Total
51 23 6 12 9 6 6 10
101 51 33 19 12 21 5 4 8 6 3 3 4 3 2
70 13
38 6 2 7 2
260 93 52 48 31 30 19 18 17 8 8 6 6 6 5 4 4
I
0 4 I I
2 3 I
2
I I
II
10 8 2 5 3 5 2 0 2 0 0 0 2 I
Total
I
3 I
3 0 I
0 I I
0 0 0
656*
NOTE. There were a total of 2.815 treatment courses. * Total includes disorientation. indigestion. insomnia. paresthesia, and urticaria (each reported three times); alopecia. bleeding (rectal), depression. fever. malaise. muscle tremor, myasthenia. nervousness. and perirectal pruritus (each reported twice); and drowsiness. myalgia, joint pain. burning sensation. irritability. forgetfulness, impotence, and nightmares (each reported once).
Toxicity Data For the 2,836 treatment courses released from 1977 through 1983, the CDC received 1,833 responses (65%) in the form of returned reports (1,715) or unused courses of drug (118). Of the 1,715 report forms returned, at least one adverse effect was reported for 295 treatment courses (17%), no adverse effects were reported for 1,147 (67%), and the section on adverse effects was not completed for 273 (16%). A total of 504 adverse effects were reported for 295 treatment courses. The most commonly reported effects were flatulence (207), nausea (70), abdominal cramping (44), diarrhea (34), pruritus (29), and abdominal pain (24) (table I). No deaths were reported. Available data did not indicate whether therapy was stopped because of adverse effects. For the period 1984 through 1990, 131 (12%) ofthe I, 100 patients who were treated and whose treatment courses were reported on were not available for follow-up. For the remaining 969 treatment courses, no information concerning adverse effects was recorded for 135 (12%), no adverse effects were reported for 739 (67%), and 153 adverse effects were reported for 95 (9%) (table I). Nine (9%) of the 95 treatment courses were not completed because of adverse effects. Persons aged 20 months to 10 years reported fewer adverse effects than did persons aged ~ 10 years (6 of206 [3%] vs. 89 of 763 [12%], RR = 0.27, 95% CI = 0.12 < RR < 0.61). Female patients were more likely than male patients to report
adverse effects (45 of 350 [13%] vs. 49 of 590 [8%], RR = 1.55, 95% CI = 1.06 < RR < 2.27) even when differences in age and duration oftherapy were accounted for. The percentage of persons reporting adverse effects varied significantly by racial group, with the highest rate for American Indians (3 of8 [38%]), followed by Caucasians (64 of514 [12%]), blacks (6 of90 [7%],and Asians (10 of265 [4%]) (P < .00 I, Fisher's exact test [four-by-two table]). The percentage of reported adverse effects did not vary by ethnic group. Although most reported adverse effects were gastrointestinal complaints, potentially more serious effects were reported; these included headache (17), lethargy (10), dizziness (6), diplopia (4), and paresthesia (3) (table 1).
Discussion Amebiasis remains a major health concern worldwide. Although ""-' I0% of the world's population is thought to be infected with E. histolytica, 90% of these persons will remain asymptomatic [2]. When and how to treat persons who are asymptomatic and passing E. histolytica cysts remain controversial [22-27]. Several authors have suggested that persons who need therapy can be differentiated from those who do not on the basis ofzymodeme status [3,23-27]. which can be tested only in a research laboratory. This strategy would prevent persons from being treated multiple times for commensal infections. In countries where E. histolytica is not
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Flatulence Nausea Cramps Diarrhea Abdominal pain Pruritus Lethargy Other (not specified) Headache Anorexia Vomiting Constipation Vertigo/dizziness Abdominal distention Rash Dry mouth Diplopia
Not rated
CID 1992; 15 (September)
Diloxanide Furoate Use in the United States
[39-41]. In each instance, the dose and duration of therapy were much greater than were typically indicated for the treatment of amebiasis. The findings that children were less likely to report adverse effects and women were more likely to do so may represent a reporting phenomenon as opposed to a physiological difference. The racial difference in the percentage of persons reporting adverse effects may also represent a reporting phenomenon, either by the patient or by the physician who completed the form. These issues can be resolved in only a prospective study in which the pretreatment diagnosis and follow-up evaluations are performed in a uniform manner. Although diloxanide furoate is effective and minimally toxic, it is unlikely to become licensed for use in the United States because the financial incentive is too small for a pharmaceutical company to pursue. Because the efficacies of the two licensed luminal agents are comparable, the treating physician must weigh other factors such as toxicity, duration of therapy (7 days for paromomycin and 20 days for iodoquinol), and cost (a standard course of paromomycin costs three times that ofiodoquinol). Paromomycin is also effective in persons with mild or moderately symptomatic amebiasis and thus may be advantageous in certain cases. At the present time, we see no great advantage of diloxanide furoate over the other luminal drugs; duration of therapy with paromomycin is comparable, iodoquinol is relatively inexpensive, and both drugs are well tolerated, have comparable efficacy rates to diloxanide furoate, and can be more conveniently obtained in the United States.
References I. Walsh JA. Problems in recognition and diagnosis ofamebiasis: estimation of the global magnitude of morbidity and mortality. Rev Infect Dis 1986;8:228-38. 2. Guerrant RL. Amebiasis: introduction, current status. and research questions. Rev Infect Dis 1986;8:2 I8-27. 3. Weinke T. Friedrich-Janicke B. Hopp P. Janitschke K. Prevalence and clinical importance of Entamoeba histolvtica in two high-risk groups: travelers returning from the tropics and male homosexuals. J Infect Dis 1990;1 61: 1029-3 I. 4. Steffen R. Lobel HO. Haworth J. Bradley DJ. eds. Travel medicine. Berlin: Springer-Verlag. 1989:v-vi. 5. Keller P. Koch K. World tourism: facts and figures. In: Steffen R. Lobel HO. Haworth J. Bradley OJ. eds. Travel medicine. Berlin: SpringerVerlag. 1989:10-5. 6. Main PT. Bristow NW. Oxley P, et al. Entamide. Annals of Biochernistry and Experimental Medicine 1960;20:441-8. 7. Geoffroy H. Zniber A. Schwarz R. Kouhen C. Abitol E. A new amoebicide: diloxanide furoate. Maroc Medical t 962;4 1:98- I04. 8. DharlwaJ RKS. Singh Verma NP. Nloguy C. et al. Clinical trial with entamide furoate in acute amoebic dysentery. Indian J Med Sci 1963: J7:825-6. 9. Krishna Das KV. Pai KN. Clinical trials with Furamide in patients with acute and chronic intestinal amoebiasis. Indian Pract 1962; 15:98390.
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endemic and reinfection is unlikely to occur, it is common practice to treat asymptomatic persons who are passing cysts of E. histolytica. Until a rapid diagnostic test that can distinguish pathogenic from nonpathogenic strains of E. histolytica is available, most authorities would agree that asymptomatic infections be treated on the assumption that the parasite is a potential pathogen. Once the decision has been made to treat the patient, the choice of luminal agents must be made. Only two luminal agents, iodoquinol and paromomycin, are currently licensed in the United States. A third luminal agent, diloxanide furoate, has been reported to have efficacy rates comparable with those of iodoquinol and paromomycin [ 10-21, 28-36]. Our data are not ideal for demonstrating efficacy because pretherapy and posttherapy stool examinations were not performed in a uniform manner in a single laboratory. However, it is encouraging that in general practice the efficacy is similar to that documented in clinical trials [10-21]. Contrary to the results of several published clinical trials [8-10], we did not find that the efficacy of diloxanide furoate was significantly lower for persons with trophozoites in their pretreatment stool than for persons with only cysts. This discrepancy may indicate that most of the persons who were passing trophozoites were infected with a nonpathogenic (noninvading) strain. The minimal toxicity of diloxanide furoate that has been documented in small clinical trials was confirmed by our large study. The most frequently reported adverse effect was flatulence. However, as noted above, several potentially more serious adverse effects were reported. Because this was not a placebo-controlled trial and the rate at which these symptoms occur in the general population is not known, it is difficult to determine the degree to which diloxanide furoate contributed to these symptoms. We cannot be certain that the persons were not receiving other medications that may have contributed to the reported adverse effects. Despite these reservations, patients should be warned about these potentially serious adverse effects. For comparison, we reviewed spontaneous reports received by the FDA of adverse effects related to the use of acetaminophen. Of note is that numerous neurological complaints were listed; these included somnolence, headache, dizziness, confusion, anxiety, depression, and psychosis. Most of these adverse effects occurred in persons who were receiving numerous other drugs known to have neurological adverse effects. The FDA has received two reports of adverse effects related to paromomycin: irreversible deafness in a person receiving high doses of both paromomycin and neomycin for hepatic encephalopathy [37] and mild gastrointestinal disturbance in a second individual. An additional report of reversible malabsorption in an individual who received paromomycin was published in 1970 [38]. By comparison, the FDA has a record of three persons who developed optic atrophy and one who developed permanent blindness following the use of iodoquinol
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10. Botero DR. Treatment of acute and chronic intestinal amoebiasis with entamide furoate. Trans R Soc Trop Med Hyg 1964;58:419-21.
1963;71: 125"':'6. 21. Padaria FT, Patel LR. Clinical evaluation of furamide in the treatment of amoebiasis. Current Medical Practice 1963;7:612-5. 22. Kean BH. The treatment of amebiasis: a recurrent agony. JAMA 1976;235: 50 I. 23. Gathiram V, Jackson TFHG. A longitudinal study of asymptomatic carriers of pathogenic zymodemes of Entamoeba histolvtica. S Afr Med J 1987;72:669-72. 24. Allason-Jones E, Mindel A, Sargeaunt P, Katz D. Outcome of untreated infection with Entamoeba histolvtica in homosexual men with and without HIV antibody. BMJ 1988;297:654-7. 25. Allason-Jones E, Mindel A, Sargeaunt P, Williams P. Entamoeba histolvtica as a commensal intestinal parasite in homosexual men. N Engl J Med 1986;315:353-6.
26. Sargeaunt PG, Jackson TFHG, Wiffen S, et al. The reliability of Entamoeba histolytica zymodemes in clinical laboratory diagnosis. Arch Invest Med (Mex) 1987;18:69-75. 27. Nanda R, Baveja U, Anand BS. Entamoeba histolytica cyst passers: clinical features and outcome in untreated subjects. Lancet
1984;2:301-3. 28. Wagner ED, Burnett HS. Paromomycin in the treatment of amoebiasis in Nyasaland. Trans R Soc Trop Med Hyg 1961;55:428-30. 29. Moffett HF, Toh SH. The treatment ofamebic dysentery with paromomycin (Humatin). Antibiotic Medicine and Clinical Therapy
1960;7:569-70. 30. Dooner HP. The treatment ofamebiasis with paromomycin (Humatin). Antibiotic Medicine and Clinical Therapy 1960;7:486-89. 31. Shafei AZ. The treatment ofamebic dysentery with paromomycin. Antibiotic Medicine and Clinical Therapy 1959;6:275-8. 32. Bell S, Woodruff AW. Humatin in intestinal amebiasis. Am J Trop Med Hyg 1960;9: 155- 7. 33. Courtney KO, Thompson PE, Hodgkinson R, Fitzsimmons JR. Paro-
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momycin as a therapeutic substance for intestinal amebiasis and bacterial enteritis. In: Marti-Ibanez F, ed. Antibiotics annual 19591960. New York: Antibiotica, 1960:304-9. Lopez-Elias F, Oliver-Gonzalez J. Treatment of intestinal amebiasis with paromomycin (Humatin). Antibiotic Medicine and Clinical Therapy 1959;6:584-5. Fisher MW, Thompson PE. Antibiotics with specific affinities. Part 3: paromomycin. In: Schnitzer RJ, Hawking F, eds. Experimental chemotherapy. Vol 3. New York: Academic Press, 1964:329-45. Coffey GL, Anderson LE, Fisher MW, et al. Biological studies ofparomomycin. Antibiot Chemother 1959;9:730-8. Boston Collaborative Drug Surveillance Program. Drug induced deafness. JAMA 1973;224:515-6. Keusch GT, Troncale FJ, Buchanan RD. Malabsorption due to paromomycin. Arch Intern Med 1970;125:273-6. American Academy of Pediatrics Committee on Drugs. Blindness and neuropathy from diiodohydroxyquin-like drugs. Pediatrics 1974;54:
378-9. 40. Oakley GP. The neurotoxicity of the halogenated hydroxyquinolines. JAMA 1973;225:395-7. 41. Behress MM. Optic atrophy in children after diiodohydroxyquin therapy. JAMA 1974;228:693-4.
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II. Wolfe MS. Nondysenteric intestinal amebiasis treatment with diloxanide furoate. JAMA 1973;224: 1601-4. 12. Marsden PD. Clinical trials with entamide furoate, entamide piperazine sulphate, and emetine bismuth iodide in a tropical environment. Trans R Soc Trop Med Hyg 1960;54:396-9. 13. Schapiro MM. Intestinal amebiasis: a preliminary clinical trial of Furamide Tic. Am J Trop Med Hyg 1967;16:704-7. 14. Woodruff AW, Bell S. Clinical trials with entamide furoate and related compounds in a non-tropical environment. Trans R Soc Trop Med Hyg 1960;54:389-95. 15. Shaldon S. Entamide furoate in the treatment of acute amoebic dysentery. Trans R Soc Trop Med Hyg 1960;54:469-70. 16. Suchak NG, Satoskar RS, Sheth UK. Entamide furoate in the treatment of intestinal amoebiasis. Am J Trop Med Hyg 1962;11:330-2. 17. Nevill LB. Entamide and furamide in the treatment of amoebic infection in Nakuru, Kenya. Trans R Soc Trop Med Hyg 1962;56:81-4. 18. Sankale M, Brodu C. Intestinal amoebiasis treated with furamide (with reference to 34 patients observed at Dakar). Medecine 0 Afrique Noire 1963; 10: 189-91. 19. Dubey MP, Gupta PS, Chuttani HK. Entamide furoate in the treatment of intestinal amoebiasis. J Trop Med Hyg 1965;68:63-6. 20. Darbon A, Portal A, Girier L, Tach-Toan. Clinical study of a new contact amoebicide: diloxanide (entamide) furoate. Presse Med
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