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CURRENT
THERAPEUTIC
RESEARCH
VOL. 56, NO. 7, JULY 1995
EFFICACY AND SAFETY OF METRONIDAZOLE VERSUS A
COMBINATION OF METRONIDAZOLE AND
DIIODOHYDROXYQUINOLINE FOR THE TREATMENT OF
PATIENTS WITH INTESTINAL AMEBIASIS: A PRIMARY CARE
PHYSICIAN RESEARCH GROUP STUDY
CHANDRAMOHAN H. ASRANI, SHYAM S. DAMLE, VINOD V. GHOTGE,
ANAND S. GOKHALE, MANGESH JALGAONKAR, PUNDALIK R. PAI KAKODE,
ANIL KUMAR, MEHMOOD A. MERCHANT, ARVIND PEDNEKAR,
NARENDRA VAIDYA, ZAINUDDIN ZAINUDDIN, AND SUBHASH J. PHATERPEKAR~2
Private Practice and Searle I ndia) Limited, Bombay, I ndia
ABSTRACT
An open-label, multicenter study to compare the efficacy and safety of
a combination of metronidazole and diiodohydroxyquinoline with
metronidazole alone for treatment of patients with intestinal amebi-
asis was conducted by primary care physicians
in India. Parasitologic
cure rates were 97 for the combination drug group and 87 for the
metronidazole group at the end of 10 days, with a statistically signif-
icant difference (P < 0.05) in favor of the combination drug regimen
Side effects were similar in both groups. Eighty-six percent of patients
in the combination drug group and 67 of those in the metronidazole
group were graded as good-to-excellent responders clinically by the
investigators. The results indicate that a systemic amebicide and a
luminal amebicide can complement each other to effectively eradicate
the amebic infection and enhance the cure in patients with intestinal
amebiasis.
INTRODUCTION
Intestinal amebiasis and use of antiamebics is routine in primary care
practice, especially in developing countries, where unhygienic conditions
predispose a large fraction of the population to this infection. Although
amebiasis commonly presents with intestinal or abdominal symptoms, it
can also present with systemic symptoms when it spreads to other organs,
most commonly the liver.
Because there are many other diseases that mimic intestinal amebi-
asis, study results found in the literature suggest a confirmatory diagnosis
by using multiple, serial, stool examinations,2 which is a practical diffi-
Address correspondence to: Dr. S. J. Phaterpekar, Searle (India) Limited, 21, D.S. Marg, P.O. Box 233,
Bombay, 400 001, India.
Received
for
ubli cation on May 16.1995. Pri nted in the U.S.A.
Reproduction in whole or part is not permitted.
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C.H. ASRANI ET AL.
culty in day-to-day primary care practice. The different sites and different
stages of the amebic life cycle make it difficult to treat patients with this
disease by using a single drug, although many effective drugs are avail-
able.3*4Such a therape utic hurdle, along with an unhygienic environment,
contribute to reoccurrence and reinfection.
It has been therefore suggested that use of antiamebic agents acting at
different sites concomitantly is advisable to eradicate amebiasis at all sites
and in all stages of the life cycle.4 To our knowledge, there are no published
studies comparing monotherapy with such combination therapy. There-
fore, this study was undertaken by a group of primary care physicians at
different centers to compare the efficacy and safety of therapeutically
recommended doses of a well-established systemic amebicide, metronida-
zole, with a combination of systemic and luminal amebicides, metroni-
dazole and diiodohydroxyquinoline, in treating patients with intestinal
amebiasis.
P TIENTS NDMETHODS
A total of 100 primary care physicians from different cities in India par-
ticipated in this open-label, comparative, parallel-group study, with an
intention to recruit a total of 1000 patients in 1 year. A randomization
schedule was prepared for a group of 120 patients in advance. Each coor-
dinator used the same randomization schedule. Enrollment of patients was
stopped at the end of a predetermined time period, and the data collected
were pooled for analyses. Male and nonpregnant female patients older
than 12 years of age suspected to be suffering from amebiasis were re-
cruited. In view of the difficulty of performing serial stool examinations,
attempts to examine at least one stool sample to confirm the diagnosis
before starting therapy were made. Patients with a history of alcohol abuse
or hypersensitivity, or contraindications to any of the study drugs, and
those with systemic amebiasis, severe illness, and/or persistent vomiting
were not enrolled into the study. Patients whose stool samples could not be
examined were excluded from the parasitologic efficacy assessment.
After the physicians obtained oral informed consent and recorded
proper medical history and all symptoms and signs, the patients were
given either a combination of metronidazole 200 mg plus diiodohy-
droxyquinoline 325 mg* (two tablets, three times daily) or metronidazole
200 mg (two sugar-coated tablets, three times daily), for a period of 5 days.
At the end of 5 days of treatment, the patients stools were examined
for the presence of trophozoites and/or cysts. Patients showing no evidence
of
Entamoeba histolytica
in either form were advised to discontinue their
* Trademark: Qugyl @IL PHABMA, Bombay, India).
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METRONIDAZOLE AND DIIODOHYDROXYQUINOLINE IN TREATING AMEBIASIS
treatment. Those with evidence of the parasite were advised to continue
the same treatment for another 5 days and were examined again at the end
of 10 days of therapy.
All patients were assessed clinically during the follow-up at the end of
day 5 and day 10 of treatment. All patients except those who withdrew
from the study were included for clinical evaluation and for investigator
assessment. Of these, only those who were originally microbiologically
positive for the parasite were included for parasitologic cure evaluation.
Disappearance of cysts and/or trophozoites of
histolyticu
in microscopic
stool examination was considered as the criteria for success of therapy.
Any concomitant medications administered were recorded on the case
record forms. Side-effect monitoring (as solicited by physicians) was car-
ried out throughout the study period. At the end of the treatment period,
the physicians rated the overall response of the patients to the study drugs
as poor (~25 relief and not tolerated), fair (25 to 49 relief and not well
tolerated), good (50 to 74 relief and well tolerated), or excellent (75 to
100 relief and well tolerated).
Statistical Analysis
The Kolmogorov-Smirnov test was used to determine statistical dif-
ferences between the two patient groups for stool consistency, abdominal
pain, and flatulence. Students
t
test was used for determining statistical
differences in average stool frequency and age, while the chi-square test
was used to detect differences in sex, parasitologic cure rate, and investi-
gators assessment. Appropriate parametric and nonparametric statistical
tests were used to compare the two groups; the differences were labeled as
statistically significant when the
P
value was less than 0.05 (95 confi-
dence level).
RESULTS
The 100 primary care physicians participating in this study recruited a
total of 961 patients. The baseline profile of the study population is shown
in Table I.
Patients who received other antiamebics and those who met exclusion
criteria during the study period were treated as protocol violators and not
included for efficacy analysis. Only 591(62 ) patients who showed a stool
smear positive for histolytica at admission were evaluated separately for
microbiologic cure. One patient from the combination drug group who
developed an allergic reaction on the first day of treatment was withdrawn
from the study.
The stool examinations done at the end of 5 days of treatment showed
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C H ASRANI ET AL
Table I. Patient demographics. There were no statistically significant differences between
the study groups at baseline.
Treatment Gmup
Meimnid8zolr nd
ilodobydmxyquinollne
No. of patients enrolled
No. of patients lost to fol low-up/protocol violations
No. of assessable tients
No. of patients w
tIY
stools showing EnfamoeI~ his
to
%I?:
r
ca
trophozoiteskysts
Female
Not recorded
Average age (y)
Y
421
510 3::
342
249
312
lg:
::
34
IG
a parasitologic cure rate of 73 in the combination drug group, and of 64
in the metronidaxole alone group. The cumulative parasitologic cure rate
at the end of 10 days of treatment was 97 in the combination drug group
and 87 in the metronidaxole alone group (Table II). The difference in the
parasitologic eradication rate at both 5 days and 10 days of treatment was
in favor of the combination drug group (P < 0.05 at 5 days and P < 0.01 to
0.015 at 10 days).
The remission of clinical symptoms is shown in Table III. Although a
favorable trend was seen in remission of symptoms in the combination
drug group, no statistically significant difference was found between the
two study groups.
The side effects encountered during the treatment period are detailed
in Table IV. The overall incidence of the side effects was not statistically
significant between the two groups, with the rate of incidence of most
symptoms being very similar. The investigators overall assessment is
shown in Table V. A total of 439 (66 ) patients in the combination drug
group had a good-to-excellent response, compared with 260 (67 ) in the
metronidaxole alone group
P C
0.001).
Table II. Evaluation of efficacy, by ueing microecopic stool examination, in patients with
intestinal amebiasis.
Metnmldezele Plw
Dbdohgd~~~nol l ne
m rtkude
(n= 249)
5 Days
5
Days 10
Days
Parasitologic.cure
O. Of pabents
217
87
P < 0.05 versus metro nidazole alone.
t P < 0.01 to 0.015 versus metronidazole alone.
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METRONIDAZOLE AND DIlODOHYDROXYQUINOLINB IN TRE TING AMEBIASIS
Table III. Remission of clinical symptoms in patients with intestinal amebiasis. Table values
are numbers of patients.
Variable in
Remiuion Admklon
End of End of
Day 5 Day 10
AveDrage aily frequency of stool
Str I consis tency (watery to semisolid )
;
Abpinal pain
FlalClence
;
DISCUSSION AND CONCLUSION
Amebiasis manifests with various clinical symptoms. However, it is diffr-
cult to establish the microscopic diagnosis of E histolytica due to the need
for serial stool examinations. Although systemic amebicides such as met-
ronidazole are considered potent and capable of eradication of E histolytica
at
all sites, its success in intestinal amebiasis has not been well docu-
mented. This is probably due to the rapid absorption of these drugs in the
proximal part of the gastrointestinal tract, resulting in reduced concen-
trations of drug in the distal portions of intestine.5 This leads to dimin-
ished activity at the primary site of proliferation of amebae, where they
thrive and lodge themselves to produce either an active intestinal or sys-
temic amebiasis, or an asymptomatic carrier state.
The luminal amebicides such as diiodohydroxyquinoline are not ap-
preciably absorbed from the gastrointestinal tract, and reach the distal
portions of intestine in amebicidal concentrations.5 The combination of
Table IV. Incidence of side effects in oatienta with intestinal amebiasis.
Si de
Ef f ect
Metronidazole Plus
Ol l odoh d~~~~nol i ne
Mettnn;ezole
(n= 421)
Metallic taste
Abdominal pain
Headache
gg
Diarrhea
Drowsiness
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C H ASRANI ET AL
Table V. Investigatory aaseasmentof treatment results in patienta with intestinal amebiasis.
Mstmnld8zolsPlut
Mstrol:Fs
Grades (n = 368)
Good to excellent
Poor to fair
P c 0.001 versus metronidazole alone.
these two types of antiamebic drugs should, therefore, complement each
other and effectively eradicate the infection.
This study has demonstrated that the parasitologic cure rate with the
recommended dosage of a combination of systemic and luminal amebicides
was better than metronidazole, a systemic amebicide, alone. This study
also found that, although metronidazole tablets with sugar coating were
administered to the patients, the popular myth about the metallic taste
being masked was proven wrong, as the side effect of metallic taste was
reported by patients in the metronidazole alone group with an incidence
similar to that reported in the combination drug group, for which the
tablets were not sugar coated. There was a possible limitation in the study
design. This was an open-label study and the investigators were not
blinded. Hence, there can be a bias in collection of historic data like stool
frequency and consistency, abdominal pain, and flatulence.
References:
1. Holtan N. Amebiasis. Postgrad
Med
1988;83:65.
2. Parija SC. Laboratory diagnosis of amoebiasis. Antiseptic. 1991;88:506-510.
3. Wolfe MS. The treatment of intestinal protozoan infections.Med Clin North Am. 1982;
66:707-710.
4. Drug Evaluations Annual 1995. Chicago: American Medical Association: 1995:1752.
5. Webster LT. Amebiasis, giardiasis, and trichomoniasis.
Goodman and Gihnuns The
Pharmacological Basis of Therapeuti cs. New York: Pergamon Press; 1990999,1002.
683