INTRODUCTION
Nitroimidazole compounds such as metronidazole, tinidazole, secnidazole, and ornidazole have remained the mainstay of treatment of amebiasis, for both the intestinal and extraintestinal forms.1,2 Most cases of amebiasis can be treated successfully with oral nitroimidazoles because of their high rates of bioavailability. However, not all patients are able to tolerate oral medication, particularly those with more severe illness. Individuals with fulminant amebic colitis or acute necrotizing colitis, the most serious form of intestinal amebiasis, can develop colonic perforation, panperitonitis, and ileus with a resulting high case fatality rate.3,4 Treatment of amebic liver abscess with oral medication can also be hampered, especially if the abscess ruptures. Previously cited underlying conditions for developing severe illness include pregnancy, diabetes, excessive alcohol consumption, and corticosteroid use.2 In addition, HIV infection seems to be associated with a severe manifestation of the illness.5 Thus, a need for an effective and safe parenteral anti-amebial agent is growing.
Previously, dehydroemetine had been used parenterally in amebiasis, mostly for amebic liver abscess but occasionally also for intestinal amebiasis.6 However, this agent frequently gives rise to treatment-limiting adverse effects such as gastrointestinal reactions, muscle weakness, and myalgia; of graver concern is cardiotoxicity, manifesting as a fall in blood pressure, tachycardia, and electrocardiographic changes in the T-waves.7 Its use is therefore no longer recommended in industrialized countries and is not shown on a U.S. treatment guide for parasitic diseases.8 Several studies have reported intravenous metronidazole to be safe and highly effective when used in uncomplicated amebic liver abscess.9–11 This is not unexpected because of the comparable pharmacokinetic parameters, i.e., the peak serum concentration (Cmax) and the area under the serum concentration-time curve (AUC), between oral and intravenous administration of metronidazole.12 However, the literature is scarce on its use in moderate-to-severe amebiasis, especially in its intestinal form.
The Research Group on Chemotherapy of Tropical Diseases, Japan, was founded in 1980. It is responsible for importing and distributing throughout the country medicines for tropical and parasitic diseases that are not licensed in Japan, with the aim of making optimal treatments available to the patients.13 Since intravenous metronidazole was first introduced by the research group in 2000, it has been used to treat amebiasis, primarily moderate-to-severe infections. In this study, we analyzed data on the use of this agent to delineate its role in these clinical settings.
MATERIALS AND METHODS
Research group and the use of unlicensed medicines.
After the medicines were imported into Japan by the research group, they were examined at the National Institute of Health Sciences, Tokyo, to check their chemical composition and ensure that they meet the Japanese regulatory standards for Good Manufacturing Practice.13 The medicines were distributed to nearly 20 designated medical facilities throughout Japan so that they were readily available and dispatched throughout the country without undue delay.
Approval for participation in this program was gained from the ethics committee for each designated medical facility. In principle, the medicines were administered at these facilities only, after written informed consent has been obtained from individual patients. A medicine was given outside of a designated center only in exceptional circumstances, e.g., if a patient was too ill to be treated elsewhere. After treatment, the physician in charge was asked to complete and return a structured patient record devised by the research group.
Supplies of intravenous metronidazole were manufactured by Rhône-Poulenc Rorer (Kent, United Kingdom) as a 0.5% (wt/vol) drip infusion bag and purchased from a British pharmacy.
Patients and data analysis.
Twenty-eight patients who were treated with intravenous metronidazole for intestinal amebiasis, amebic liver abscess, or both between April 2001 and June 2006 were enrolled in the study. The use of and dose of the drug was decided mainly by the physician in charge of the patient, although advice was available from specialists in the research group. For the majority of patients, a deterioration in their condition left them unable to tolerate oral metronidazole, and treatment with intravenous metronidazole was instituted instead. Patient records were used to collect the following data for analysis: underlying disease/condition, complication of amebiasis, surgical operation (colectomy), oral administration of metronidazole, dose of intravenous metronidazole given, any adverse effects associated with the use of intravenous metronidazole, and the clinical outcome. The physicians were asked to classify the clinical outcome as “cured,” “improved,” “worsened,” or “died.” The physicians were contacted for any additional information or clarification of data as necessary.
RESULTS
The clinical details, surgical and pharmacologic treatments, and results of the treatment of the 28 cases that received intravenous metronidazole are described in Table 1.
Diagnosis of amebiasis.
Of the 22 episodes of intestinal amebiasis, 21 were diagnosed by the demonstration of Entamoeba histolytica in the stool, in biopsied or resected colonic or appendiceal materials, or from intra-abdominal abscess fluids. The remaining one episode was diagnosed by the presence of anti-amebic antibodies. Of the nine episodes of amebic liver abscess, three were diagnosed by the detection of E. histolytica in drainage fluids, five had a positive antibody response, and the remaining one through imaging only.
Effectiveness of treatment.
Intravenous metronidazole was administered to the 19 cases who had intestinal amebiasis alone. Of those, five were known to be HIV positive, and 18 had complications of intestinal amebiasis such as ileus, colonic perforation, peritonitis, disseminated intravascular coagulation, and multiple organ failure. Twelve underwent colectomy, and 13 received oral metronidazole. Most received a dosage of intravenous metronidazole of 1,500 mg/d (in three doses), given for 3 days to 4 weeks. The clinical outcome was classified as cured in five (26%), improved in eight (42%), and died in six (32%). Even in four of the six fatal cases, the physicians judged intravenous metronidazole as moderately effective for the ongoing amebic infection itself.
Six patients with amebic liver abscess alone were given intravenous metronidazole. None of these had a known underlying disease; however, four had complications of amebic liver abscess. All had received oral metronidazole. Intravenous metronidazole was given at a dosage of 1,500 mg/d (in three doses) for 6–14 days. The clinical outcome was classified as cured in four (67%) and improved in two (33%).
Three patients with both intestinal amebiasis and amebic liver abscess were given intravenous metronidazole. Of these, two had an underlying disease, and all suffered complications of amebiasis. One underwent colectomy, and all received oral metronidazole. Intravenous metronidazole 1,500 mg/d (in three doses) was given for 10–14 days. The clinical outcome was classified as improved in two (67%) and died in one (33%). Even in the fatal case, the physician judged intravenous metronidazole as highly effective for the ongoing amebic infection itself.
Adverse effects of treatment.
Adverse drug effects were reported in nine (32%) individuals. In four patients (Cases 1, 2, 8, and 21), the adverse effects subsided or disappeared after intravenous metronidazole was discontinued and were therefore considered to be drug-associated. All of the fatalities were considered to be caused by either intractable complications of amebiasis or deterioration of an underlying disease, with no definitive link found between the deaths and adverse effects of intravenous metronidazole.
DISCUSSION
The interpretation of our study results is limited by a number of factors, partly because of the study design, because this was not a formal clinical trial. First, the opinion of individual physicians may have resulted in inconsistencies in the assessment of the effectiveness and safety of intravenous metronidazole. Second, the follow-up periods after treatment varied and may have been shorter than adequate. However, the follow-up periods described on the patient records often reflected those conducted during hospitalization only and did not include follow-ups at the outpatient clinics after discharge. In addition, a deterioration in the patient’s condition or delayed adverse drug effect is likely to have been identified and reported to the research group because the physicians developed a close relationship with the majority of patients undergoing this treatment. Third, none of the patients were treated with intravenous metronidazole alone; they underwent colectomy, received oral metronidazole, or both. This makes it difficult to fully evaluate the effectiveness of intravenous metronidazole alone. Despite these limitations, it was remarkable that many patients with moderate-to-severe amebiasis undergoing the treatment were eventually cured or improved. Furthermore, even in some of the fatal cases, intravenous metronidazole seemed to be effective for the ongoing amebic infection itself.
Intravenous metronidazole was shown to be highly effective in the treatment of uncomplicated amebic liver abscess during the 1970s and 1980s.9–11 The first study reported all nine cases cured using intravenous metronidazole (two doses of 1,000 mg, 24 hours apart) followed by oral metronidazole.9 The second was a comparative study of intravenous metronidazole with (N = 22) and without (N = 14) concurrent intramuscular emetine, which yielded a 100% cure rate in both treatment arms.10 The third study compared intravenous metronidazole (N = 18), 1,500 mg/d in three doses for 7 days, and intramuscular dehydroemetine (N = 18), 60 mg daily for 10 days, and yielded successful treatment rates of 100% and 72%, respectively.11 None of those three studies reported significant adverse effects with intravenous metronidazole use, whereas dehydroemetine-treated patients did experience adverse effects (nausea, vomiting, hypertension, and tachycardia).11 Furthermore, there have been two anecdotal reports of the effectiveness of intravenous metronidazole in the treatment of amebic liver abscess after a rupture14 or an imminent rupture of the abscess.15 Our study results reinforce the effectiveness of this agent in the treatment of moderate-to-severe amebic liver abscess. In contrast, there has been only one report of intravenous metronidazole used to treat intestinal amebiasis (fulminant amebic colitis), for which the clinical efficacy of this agent was not clearly shown.16 Our study involves the largest ever reported number of intestinal amebiasis cases and may be the first to encourage the use of this agent in this clinical setting.
It could be argued that intravenous metronidazole alone might not be sufficient for treating intestinal amebiasis and that the positive findings reported in this study could be caused partly by the intra-luminal activity of oral metronidazole. Interestingly, however, an initial cure rate of 100% was obtained by using intramuscular dehydroemetine as the sole agent in the treatment of intestinal amebiasis.6 Therefore, treatment with intravenous metronidazole alone might be sufficient, although a luminal amebicide such as diloxanide furoate or paromomycin may be required afterward. An opportunity to study this would only arise if patients presented with severe disease initially and treatment with oral metronidazole was not appropriate.
Intravenous metronidazole has been considered safe when used extensively for treating anaerobic bacterial infections since the 1970s.17,18 Our results are largely consistent with this notion. We should, however, be aware of the possibility that adverse effects of this drug could be masked by the severity of the patient’s medical condition. Recently, encephalopathy with ataxic gait of transient nature was reported in a patient receiving intravenous metronidazole.19 Conceivably, this may be caused by metronidazole itself rather than its intravenous administration, because similar toxicity has been described in those receiving oral medication.19–21 Consistent with this, metronidazole has been shown to cross the blood–brain barrier in humans.20
In conclusion, intravenous metronidazole should be more widely recommended than previously thought for treating moderate-to-severe amebiasis, especially its intestinal form.
Clinical details, surgical and pharmacologic treatments, and the results of treatment with intravenous metronidazole for patients with amebiasis
| Lesion | Metronidazole | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| No. | Age/sex | Intestinal amebiasis | Amebic liver abscess | Underlying disease/condition | Complication | Colectomy | Oral use (timing)* | Intravenous use | Adverse effect | Clinical outcome |
| * Before, during, or after intravenous metronidazole. MOF, multiple organ failure; DIC, disseminated intravascular coagulation; ARDS, acute respiratory distress syndrome; MRSA, methicillin-resistant Staphylococcus aureus. | ||||||||||
| 1 | 49/M | + | − | Acute renal failure (steroid therapy) | – | − | + (before and after) | 1,500 mg/d for 7 days | Erythema multiforme exudativum | Improved |
| 2 | 58/M | + | − | – | Ileus | − | + (before and after) | 2,000 mg/d, then 1,500 mg/d, totally for 7 days | Tremor, insomnia, incoordination, bone marrow suppression | Died (ileus, toxic megacalon, perforating peritonitis) |
| 3 | 53/M | + | − | HIV infection (AIDS) | MOF, renal failure, DIC, paralytic ileus, megacolon | − | + (before) | 1,500 mg/d for 7 days | – | Improved |
| 4 | 61/M | + | − | Gastric Ca. (operated, cancer chemotherapy) | s/o colonic perforation | − | + (before) | 1,500 mg/d for 3 days | – | Cured |
| 5 | 76/F | + | − | – | Ileus | − | + (before) | 500 mg/d for 5 days | – | Died (pneumonia, renal failure, hepatic failure, sepsis, DIC) |
| 6 | 49/M | + | − | HIV infection | Paralyitc ileus | − | + (before) | 2,000 mg/d for 12 days | – | Improved |
| 7 | 32/M | + | − | HIV infection | Intra-abdominal abscess, colonic perforation | − | + (before) | 1,500 mg/d for 7 days | – | Improved |
| 8 | 31/M | + | − | HIV infection (AIDS) | Colonic perforation, peritonitis | + | − | 1,500 mg/d for 5 days | Consciousness disturbance | Improved |
| 9 | 40/M | + | − | – | Colonic perforation | + | − | 1,500 mg/d for 7 days | – | Cured |
| 10 | 72/M | + | − | – | Colonic perforation | + | − | 1,500 mg/d for 7 days | – | Cured |
| 11 | 51/M | + | − | HIV infection (AIDS) | Appendiceal abscess, cecal fistula, total colonic necrosis | + | − | 1,500 mg/d for 14 days | – | Died (AIDS) |
| 12 | 44/M | + | − | Nephrotic syndrome, ulcerative colitis (steroid therapy) | Perforating peritonitis | + | − | 1,500 mg/d for 21 days | – | Cured |
| 13 | 71/M | + | − | Rectal Ca. (operated) | Ileus, colonic perforation, panperitonitis | + | − | 1,500 mg/d for 3–4 days | – | Died (ARDS, hepatic failure, MOF) |
| 14 | 62/M | + | − | – | Appendiceal perforation, panperitonitis, necrotizing colitis | + | + (before) | 1,500 mg/d for 4 days | Renal failure? | Died |
| 15 | 68/M | + | − | Rectal Ca. | s/o acute abdomen | + | + (after) | 1,500 mg/d for 7 days | Slight increase in GOT and GPT | Improved |
| 16 | 21/F | + | − | – | Peritonitis, cecal abscess | + | + (after) | 1,500 mg/d for 9 days | – | Cured |
| 17 | 48/M | + | − | – | Abdominal wall abscess, colonic perforation, sepsis, MOF | + | + (before and during) | 1,500 mg/d for 7 days | ? | Died (MOF, brain hemorrhage, brain edema, brain herniation) |
| 18 | 39/F | + | − | Depression | Ileus | + | + (during and after) | 1,500 mg/d for 24 days | Consciousness disturbance (drowsiness), deterioration of depression, abnormal MRI findings | Improved |
| 19 | ?/M | + | − | – | Necrotizing colitis | + | + (before) | 1,500 mg/d for 7 days | – | Improved |
| 20 | 26/F | − | + | – | – | − | + (before) | 1,500 mg/d for 10 days | – | Cured |
| 21 | 52/M | − | + | – | Pneumonia, DIC, panperitonitis | − | + (before) | 1,500 mg/d for 7 days | Dark urine, diarrhea | Cured |
| 22 | 50/M | − | + | – | ARDS (mechanical ventilation), paralytic ileus | − | + (before) | 1,500 mg/d for 10 days | – | Cured |
| 23 | 30/F | − | + | – | Pneumonia, edema (hypoalbuminemia) | − | + (after) | 1,500 mg/d for 6 days | – | Improved |
| 24 | 55/M | − | + | Male homosexual | – | − | + (before and after) | 1,500 mg/d for 7 days | – | Improved |
| 25 | 57/M | − | + | – | ARDS (mechanical ventilation) | − | + (after) | 1,500 mg/d for 14 days | – | Cured |
| 26 | 34/M | + | + | Male homosexual | Paralytic ileus | − | + (before) | 1,500 mg/d for 10 days | – | Improved |
| 27 | 63/M | + | + | Malnutrition, male homosexual | Colonic perforation, intra-thoracic rupture | − | + (before and after) | 1,500 mg/d for 14 days | Renal dysfunction, electrolyte abnormality, CO2 narcosis | Died |
| 28 | 64/M | + | + | Multiple myeloma (complete remission) | Perforating peritonitis, sepsis, bacterial/hemorrhagic shock, acute circulatory failure | + | + (before) | 1,500 mg/d for 14 days | Watery diarrhea (MRSA colitis) | Improved |
Address correspondence to Mikio Kimura, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. E-mail: kimumiki@abox3.so-net.ne.jp
Authors’ addresses: Mikio Kimura, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan, Telephone: 81-3-5285-1111, ext. 2043, Fax: 81-3-5285-1129. Tetsuya Nakamura, Department of Infectious Diseases and Applied Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639, Japan, Telephone: 81-3-5449-5337, Fax: 81-3-5449-5427. Yukifumi Nawa, University of Miyazaki, Gakuen-Kibanadai-Nishi 1-1, Miyazaki 889-2192, Japan, Telephone: 81-985-58-7100, Fax: 81-985-58-2818.
Acknowledgments: We are indebted to all the member physicians of the Research Group on Chemotherapy of Tropical Diseases, Japan, for treating the patients.
Financial support: This study was conducted as a “Research on Health Sciences Focusing on Drug Innovation” (KH42075 and KHA2031) funded by the Japan Health Sciences Foundation.
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