metronidazol dan diodohydroxyquinolon

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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.

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metronidazol dan diodohydroxyquinolon

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