Am. J. Trop. Med. Hyg., 77(2), 2007, pp.

381–385
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

Experience with Intravenous Metronidazole to Treat Moderate-to-Severe Amebiasis

in Japan
Mikio Kimura,* Tetsuya Nakamura, and Yukifumi Nawa for the Research Group on Chemotherapy of Tropical
Diseases, Japan
Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan; Department of Infectious Diseases and
Applied Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; University of Miyazaki, Miyazaki, Japan

Abstract. Twenty-eight cases of either intestinal amebiasis, amebic liver abscess, or both, most of which were of
moderate-to-severe intensity, were treated with intravenous metronidazole, pioneered by the Research Group on
Chemotherapy of Tropical Diseases, Japan. This study was not conducted as a formal clinical trial, and all patients either
underwent colectomy for intestinal amebiasis, received oral metronidazole, or both. Despite these limitations, intrave-
nous metronidazole was shown to be well tolerated and seemed to be very effective. This agent should be more widely
recommended than previously thought for treating moderate-to-severe amebiasis, especially its intestinal form.

INTRODUCTION porting and distributing throughout the country medicines for

Nitroimidazole compounds such as metronidazole, tinida-
zole, secnidazole, and ornidazole have remained the mainstay
of treatment of amebiasis, for both the intestinal and extraint-
estinal forms.1,2 Most cases of amebiasis can be treated suc-
cessfully with oral nitroimidazoles because of their high rates
of bioavailability. However, not all patients are able to toler-
ate oral medication, particularly those with more severe ill-
ness. Individuals with fulminant amebic colitis or acute nec-
rotizing 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, ex-
cessive alcohol consumption, and corticosteroid use.2 In ad-
dition, 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 gas-
trointestinal 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), be-
tween oral and intravenous administration of metronida-
zole.12 However, the literature is scarce on its use in moder-
ate-to-severe amebiasis, especially in its intestinal form.
The Research Group on Chemotherapy of Tropical Dis-
eases, Japan, was founded in 1980. It is responsible for im-
* Address correspondence to Mikio Kimura, Infectious Disease Sur-
veillance Center, National Institute of Infectious Diseases, Toyama
1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. E-mail: kimumiki@
abox3.so-net.ne.jp
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 intro-
duced 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 distrib-
uted to nearly 20 designated medical facilities throughout Ja-
pan 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 desig-
nated center only in exceptional circumstances, e.g., if a pa-
tient was too ill to be treated elsewhere. After treatment, the
physician in charge was asked to complete and return a struc-
tured 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 phar-
macy.
Patients and data analysis. Twenty-eight patients who were
treated with intravenous metronidazole for intestinal amebia-
sis, 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 metro-
nidazole, 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),

381
382 KIMURA AND OTHERS

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 epi-
sodes of amebic liver abscess, three were diagnosed by the
detection of E. histolytica in drainage fluids, five had a posi-
tive antibody response, and the remaining one through imag-
ing only.
Effectiveness of treatment. Intravenous metronidazole
was administered to the 19 cases who had intestinal ame-
biasis alone. Of those, five were known to be HIV positive,
and 18 had complications of intestinal amebiasis such as
ileus, colonic perforation, peritonitis, disseminated intravas-
cular coagulation, and multiple organ failure. Twelve under-
went 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 it-
self.

TABLE 1
Clinical details, surgical and pharmacologic treatments, and the results of treatment with intravenous metronidazole for patients with amebiasis

Lesion

Age/ Intestinal Amebic liver

No. sex amebiasis abscess Underlying disease/condition Complication Colectomy

1 49/M + − Acute renal failure (steroid therapy) − −

2 58/M + − − Ileus −

3 53/M + − HIV infection (AIDS) MOF, renal failure, DIC, paralytic ileus, −
megacolon
4 61/M + − Gastric Ca. (operated, cancer s/o colonic perforation −
chemotherapy)
5 76/F + − − Ileus −

6 49/M + − HIV infection Paralyitc ileus −

7 32/M + − HIV infection Intra-abdominal abscess, colonic −
perforation
8 31/M + − HIV infection (AIDS) Colonic perforation, peritonitis +
9 40/M + − − Colonic perforation +
10 72/M + − − Colonic perforation +
11 51/M + − HIV infection (AIDS) Appendiceal abscess, cecal fistula, total +
colonic necrosis
12 44/M + − Nephrotic syndrome, ulcerative colitis Perforating peritonitis +
(steroid therapy)
13 71/M + − Rectal Ca. (operated) Ileus, colonic perforation, panperitonitis +
14 62/M + − − Appendiceal perforation, panperitonitis, +
necrotizing colitis
15 68/M + − Rectal Ca. s/o acute abdomen +
16 21/F + − − Peritonitis, cecal abscess +
17 48/M + − − Abdominal wall abscess, colonic +
perforation, sepsis, MOF
18 39/F + − Depression Ileus +

19 ?/M + − − Necrotizing colitis +

20 26/F − + − − −
21 52/M − + − Pneumonia, DIC, panperitonitis −
22 50/M − + − ARDS (mechanical ventilation), paralytic −
ileus
23 30/F − + − Pneumonia, edema (hypoalbuminemia) −
24 55/M − + Male homosexual − −
25 57/M − + − ARDS (mechanical ventilation) −
26 34/M + + Male homosexual Paralytic ileus −
27 63/M + + Malnutrition, male homosexual Colonic perforation, intra-thoracic rupture −

28 64/M + + Multiple myeloma (complete Perforating peritonitis, sepsis, bacterial/ +

remission) hemorrhagic shock, acute circulatory
failure
 INTRAVENOUS METRONIDAZOLE IN MODERATE-TO-SEVERE AMEBIASIS 383

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 metronida-
zole. Intravenous metronidazole was given at a dosage of
1,500 mg/d (in three doses) for 6–14 days. The clinical out-
come 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 intrave-
nous 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 there-
fore considered to be drug-associated. All of the fatalities
were considered to be caused by either intractable complica-
tions 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 num-
ber 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 assess-
ment of the effectiveness and safety of intravenous metro-
nidazole. Second, the follow-up periods after treatment var-
ied and may have been shorter than adequate. However, the
follow-up periods described on the patient records often re-
flected those conducted during hospitalization only and did
not include follow-ups at the outpatient clinics after dis-
charge. In addition, a deterioration in the patient’s condition

TABLE 1
Continued

Metronidazole

Oral use Intravenous

(timing)* use Adverse effect Clinical outcome

+ (before and after) 1,500 mg/d for 7 days Erythema multiforme exudativum Improved
+ (before and after) 2,000 mg/d, then 1,500 mg/d, Tremor, insomnia, incoordination, bone Died (ileus, toxic megacalon,
totally for 7 days marrow suppression perforating peritonitis)
+ (before) 1,500 mg/d for 7 days − Improved

+ (before) 1,500 mg/d for 3 days − Cured

+ (before) 500 mg/d for 5 days − Died (pneumonia, renal failure,

hepatic failure, sepsis, DIC)
+ (before) 2,000 mg/d for 12 days − Improved
+ (before) 1,500 mg/d for 7 days − Improved
− 1,500 mg/d for 5 days Consciousness disturbance Improved
− 1,500 mg/d for 7 days − Cured
− 1,500 mg/d for 7 days − Cured
− 1,500 mg/d for 14 days − Died (AIDS)

− 1,500 mg/d for 21 days − Cured

− 1,500 mg/d for 3–4 days − Died (ARDS, hepatic failure, MOF)
+ (before) 1,500 mg/d for 4 days Renal failure? Died

+ (after) 1,500 mg/d for 7 days Slight increase in GOT and GPT Improved
+ (after) 1,500 mg/d for 9 days − Cured
+ (before and during) 1,500 mg/d for 7 days ? Died (MOF, brain hemorrhage,
brain edema, brain herniation)
+ (during and after) 1,500 mg/d for 24 days Consciousness disturbance (drowsiness), Improved
deterioration of depression, abnormal
MRI findings
+ (before) 1,500 mg/d for 7 days − Improved
+ (before) 1,500 mg/d for 10 days − Cured
+ (before) 1,500 mg/d for 7 days Dark urine, diarrhea Cured
+ (before) 1,500 mg/d for 10 days − Cured
+ (after) 1,500 mg/d for 6 days − Improved
+ (before and after) 1,500 mg/d for 7 days − Improved
+ (after) 1,500 mg/d for 14 days − Cured
+ (before) 1,500 mg/d for 10 days − Improved
+ (before and after) 1,500 mg/d for 14 days Renal dysfunction, electrolyte Died
abnormality, CO2 narcosis
+ (before) 1,500 mg/d for 14 days Watery diarrhea (MRSA colitis) Improved
* Before, during, or after intravenous metronidazole. MOF, multiple organ failure; DIC, disseminated intravascular coagulation; ARDS, acute respiratory distress syndrome; MRSA,
methicillin-resistant Staphylococcus aureus.
384 KIMURA AND OTHERS
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 under-
went colectomy, received oral metronidazole, or both. This
makes it difficult to fully evaluate the effectiveness of intra-
venous metronidazole alone. Despite these limitations, it was
remarkable that many patients with moderate-to-severe ame-
biasis undergoing the treatment were eventually cured or im-
proved. Furthermore, even in some of the fatal cases, intra-
venous metronidazole seemed to be effective for the ongoing
amebic infection itself.
Intravenous metronidazole was shown to be highly effec-
tive 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 metron-
idazole 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 sig-
nificant adverse effects with intravenous metronidazole use,
whereas dehydroemetine-treated patients did experience ad-
verse effects (nausea, vomiting, hypertension, and tachycar-
dia).11 Furthermore, there have been two anecdotal reports of
the effectiveness of intravenous metronidazole in the treat-
ment of amebic liver abscess after a rupture14 or an imminent
rupture of the abscess.15 Our study results reinforce the ef-
fectiveness 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 intes-
tinal amebiasis (fulminant amebic colitis), for which the clini-
cal efficacy of this agent was not clearly shown.16 Our study
involves the largest ever reported number of intestinal ame-
biasis 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 metronida-
zole. 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 suf-
ficient, although a luminal amebicide such as diloxanide fu-
roate or paromomycin may be required afterward. An oppor-
tunity 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 bar-
rier 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.
Received January 17, 2007. Accepted for publication April 13, 2007.
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.
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 Infec-
tious Diseases and Applied Immunology, Institute of Medical Sci-
ence, 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.
Reprint requests: Mikio Kimura, Infectious Disease Surveillance
Center, National Institute of Infectious Diseases, Toyama 1-23-1,
Shinjuku-ku, Tokyo 162-8640, Japan.
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