Three-Day Course of

Oral Azithromycin vs Topical Oxytetracycline/

Polymyxin in Treatment of Active Endemic Trachoma
Mustafa Guzey,* Gonul Aslan,
Ilyas Ozardali, Emel Basar, Ahmet Satici* and Sezin Karadede*
Departments of *Ophthalmology, Clinical Microbiology,
Pathology, Harran University School of Medicine, Sanliurfa, Turkey; Department
of Ophthalmology, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey

Purpose: The aim of this study on endemic trachoma was to carry out a comparison of
azithromycin (3-day course, oral dose of 10 mg/kg per day) with conventional treatment
(topical oxytetracycline/polymyxin ointment; twice a day for 2 months) in a rural area near
Sanliurfa, Turkey.
Methods: Ninety-six subjects with active trachoma were randomly assigned conventional or
azithromycin treatment. Subjects were examined 1, 2, 3, and 6 months after the start of treatment. Clinical findings were recorded for each eye. Swabs were taken from upper eyelids
3 and 6 months after the start of treatment for direct fluorescein antibody test.
Results: By six-month follow-up, trachoma had resolved clinically in 43 (89.58%) of the 48
subjects who received azithromycin, compared with 33 (68.75%) of the 48 who were treated
conventionally. Microbiological success rates (direct fluorescein antibody test negativity)
were 83.33% in the azithromycin group and 62.50% in the conventional therapy group.
Compliance with both treatments was good. By 6 months, 14.58% of the subjects in azithromycin group and 33.33% of the subjects in the topical treatment group were reinfected.
There were significant differences in the efficacy of the treatment effects and the re-emergence of disease between the two treatment groups. Azithromycin was well-tolerated.
Conclusions: These results indicate that azithromycin may be an effective alternative for patients with active trachoma. As a systemic treatment, a 3-day course oral dose has important
potential for trachoma control. Jpn J Ophthalmol 2000;44:387391 2000 Japanese
Ophthalmological Society
Key Words: Azithromycin, oxytetracycline/polymyxin, trachoma.

Introduction
Trachoma, an ocular infection caused by Chlamydia
trachomatis, is the second leading cause of blindness
worldwide. Active trachoma occurs predominantly in
children in hyperendemic communities, with the risk
of blinding complications occurring in middle-aged
and older adults.1,2 Although trachoma has been
controlled in some areas, predictions based on de-

Received: June 16, 1999

Correspondence and reprint requests to: Mustafa GUZEY,
MD, Forsa Sok. Guney Apt. No. 21 Daire 1 Senesenevler,
Bostanci, Istanbul, Turkey
Jpn J Ophthalmol 44, 387391 (2000)
2000 Japanese Ophthalmological Society
Published by Elsevier Science Inc.

mographic trends suggest that the burden of both infection and blindness is likely to increase.3 There is a
need for effective intervention to control ocular
Chlamydia trachomatis infections.
The currently recommended treatment of trachoma
is topical tetracycline eye ointment for at least 6 weeks,
or on 5 consecutive days a month for 6 months.4 It is
suggested that subjects with a severe form of the disease should, in some circumstances, receive systemic
therapy. There is a wide spectrum of opinion among
trachoma experts about the effectiveness of these recommendations, reflecting a scarcity of data from controlled trials in endemic areas on which rational decisions about therapy can be based.5,6
0021-5155/00/$see front matter
PII S0021-5155(00)00167-2

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There are several reasons why this treatment is

less than satisfactory. It is difficult to apply ointment
to the eyes of young children. The ointment can
cause discomfort or blurring of vision and melts under conditions of high ambient temperature. Many
infected children have no symptoms and even in circumstances where ointment is given free it can be
difficult to motivate parents to continue treatment
for the stipulated period. A systemic treatment
effective in a short period would thus represent a
substantial advance in the chemotherapy of active
trachoma.
Azithromycin is a recently approved azalide antibiotic with the molecular formula of C38H72N2O12,
and a molecular weight of 749.00. It is a derivative of
erythromycin, containing an extra methyl-substituted nitrogen at position 9a in the lactone ring (Figure 1). This modification confers good bioavailability, with sustained high tissue concentrations after an
oral dose. Azithromycin achieves high concentrations in phagocytic cells and in fibroblasts. It appears
that fibroblasts serve as a reservoir of azithromycin
in tissues, allowing activity against organisms and
possibly transferring the antibiotic to phagocytic
cells for activity against intracellular pathogens and
delivery to infection sites.7 The high macrophage
and tissue concentration of the drug and prolonged
half-life suggest that azithromycin could potentially
be used in shorter treatment regimens.8,9 The present
study compared the clinical and microbiological efficacy and safety of a 3-day course of azithromycin
with a conventional 8-week course of topical oxytetracycline/polymyxin for the treatment of young patients with active ocular Chlamydia trachomatis infection.

Materials and Methods

In April 1998, an ocular survey was done in four
villages of Sanliurfa by a trained observer (MG).
The everted upper lids of both eyes were examined
with a binocular magnifying loupe. Findings were
graded according to the simplified World Health Organization grading system.10 Ninety-six subjects with
bilateral active trachoma or showing the symptoms
given below were selected. The existence of an active trachoma was clinically characterized by the
presence of at least 5 follicles associated with a papillary hypertrophy of the upper tarsal conjunctiva and
microbiologically characterized by the presence of at
least 5 elementary bodies per direct fluorescein antibody test slide. Clinical signs and symptoms taken
into consideration were follicular conjunctivitis and

Figure 1. Chemical structure of azithromycin.

papillary hypertrophy of the upper tarsal conjunctiva

with discharge, redness, irritation and burning-stinging
sensation and eyelid swelling.
Ninety-six patients were randomly assigned conventional or azithromycin treatment. Randomization was by room, all active cases within a room receiving the same treatment. Baseline eye swabs were
taken from all patients before treatment.
Expected effects, side effects, advantages, and disadvantages of both treatment methods were explained to patients who participated in the study
and/or their parents, and informed consent was
obtained.
Azithromycin suspension (200 mg/5 mL, Zitromax; Pfizer, Istanbul, Turkey) administered as a
3-day course (10 mg/kg per day) by mouth; a syringe
was used for measurement and administration. Subjects randomized for conventional treatment were
administered 0.5% oxytetracycline HCl/polymyxin
eye ointment (Terramycin, 5 mg/g oxytetracycline
HCl, 1 mg/g/polymyxin B sulfate; Pfizer) to each eye
twice daily for 8 weeks.
Possible side effects were investigated in both
groups by means of a standard interview, 7 days after
treatment started. The interview protocol contained
both specific questions about gastrointestinal symptoms in the preceding 7 days and open questions
about the general health of the subjects. At subsequent follow-up, mothers were questioned about the
general health of the subjects and any adverse events
recorded.
The following laboratory tests for safety evaluation were obtained at baseline and at weeks 2 and 4:
complete blood count with differential and platelet
counts, prothrombin time, activated partial thromboplastin time, gamma glutamyl transferase, alanine
aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum bilirubin, lactate dehydro-

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M. GUZEY ET AL.
ORAL AZITHROMYCIN VS TOPICAL OXYTETRACYCLINE

genase, blood urea nitrogen, serum creatinine, serum calcium and phosphorus, electrolytes, total
protein, albumin, blood glucose, uric acid, serum
cholesterol, and urinalysis.
Conventional treatment was applied by the patients mothers, supervised by a trained nurse. Compliance with conventional treatment was assessed by
a system of witnessed treatments; the subjects name
was written on a form each time a treatment was witnessed. More than 95% of scheduled treatments
were witnessed.
Subjects were examined 1, 2, 3, and 6 months after
the start of treatment. Clinical findings were recorded for each eye. Swabs were taken from upper
eyelids 3 and 6 months after the start of treatment. A
dacron swab was rubbed on the everted upper tarsal
conjunctiva, after which it was rolled on a slide for
the direct antibody immunofluorescence test. Methanol-fixed slides were stained with monoclonal-fluorescein isothiocyanate antibody conjugate to the
major outer membrane protein. Smears were considered positive if 5 or more elementary bodies per
slide were seen.11
Noticeable symptomatic relief and considerable
resolution of clinical signs (disappearance of papillary hypertrophy, decrease in the number and size of
follicles) were considered as clinical success, and a
negative direct fluorescein antibody test was accepted as microbiological success.
In cases where this test was negative in the third
month, a positive test result obtained in the sixth
month was considered as the establishment of a reinfection, whether a noticeable re-appearance of clinical signs and symptoms was present or not. For statistical analysis of the results, the chi-square test was
used to compare the treatment groups.

Results
There were 96 subjects aged from 2 to 18 years
(Table 1). The treatment groups did not differ significantly in age or sex distribution.
Symptoms of diarrhea, vomiting, and abdominal
pain occurred in the azithromycin group (Table 2).
There were no serious adverse reactions and both
treatments were well-tolerated. No abnormalities
were determined in the laboratory test results. All
symptoms resolved spontaneously and none required
treatment. Compliance with conventional treatment
was extremely good. Local adverse reactions were
not seen in the conventional therapy group.
At 3 months, the clinical signs of 44 (91.67%) subjects in the azithromycin group and the clinical signs

Table 1. Baseline Comparisons of

Treatment Groups
Age (year)
and Sex
5
58
912
13
M/F

Azithromycin*
(n 48)

Conventional*
(n 48)

10 (20.83)
23 (47.92)
12 (25)
3 (6.25)
22/26

12 (25)
21 (43.75)
10 (20.83)
5 (10.42)
25/23

*Values in parentheses are percentages.

of 36 (75.00%) subjects in the conventional treatment group had resolved (P .029). These rates
were 89.58% and 68.75% at 6 months, respectively
(P .012) (Table 3). The rate of reinfection by 6
months was 33.33% in the conventional treatment
group, as opposed to 14.58% in the azithromycin
group, and the difference was statistically significant
(P .027). Antigen positivity at baseline and severe
or moderate disease were associated with persistence of clinical signs, and there was a tendency for
younger patients to have more persistent clinical
signs.
There were significant differences in the prevalence of direct fluorescein antibody test positivity in
ocular swabs between the therapy modalities (Table 4).

Discussion
Trachoma is a common disease that has disappeared in many parts of the world because of improved living conditions and hygiene. In trachomaendemic areas, severe disease leading to scarring and
blindness may be the result of frequent reinfection
or persistent infection in those whose immune system does not mount an adequate response to clear
the infection. Trachoma continues to be a serious
public health threat in southeast Turkey.12,13 Chlamydia trachomatis is an intracytoplasmic parasite and
has a unique, long, life cycle. Chlamydia shows two

Table 2. Adverse Events Survey 7 Days After

Azithromycin Treatment
Adverse Events
Abdominal pain
Diarrhea
Vomiting
Headache/body pain
Poor appetite
Fever

Number of Cases*
10 (20.83)
5 (10.42)
3 (6.25)
2 (4.17)
2 (4.17)
1 (2.08)

*Values in parentheses are percentages.

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Jpn J Ophthalmol
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Table 3. Clinical Success Rate (Resolution of Clinical

Signs) in Azithromycin and Conventional Treatment
Groups 3 and 6 Months After Start of Treatment
Time
3 months
6 months

Azithromycin*
(n 48)
44 (91.67)
43 (89.58)

Conventional*
(n 48)
36 (75.00)
33 (68.75)

Table 4. Microbiological Success Rate (Direct Fluorescein

Antibody Test Negativity) in Azithromycin and
Conventional Treatment Groups 3 and 6 Months After
Start of Treatment

Chi-Square
4.80
6.32

*Values in parentheses are percentages.

P .029.

P .012.

distinctive forms during its life cycle: the elementary

body and the reticulate body. The elementary body
is an infectious particle that initiates its infectious cycle by attaching to the surface of a susceptible cell.
Over a period of 68 hours, the particle enlarges,
and undergoes reorganization to become a reticulate
body. The reticulate body is noninfectious but metabolically active. Anti-chlamydial agents are only effective against reticulate bodies. These agents must
penetrate into the cell, cytoplasmic inclusions, and finally into the reticulate body itself. Moreover, they
must be maintained at high concentrations in tissues
for a long period of time. Effective anti-chlamydial
agents include tetracyclines, macrolides, and some of
the fluoroquinolones.14
Recent advances in diagnostic and screening technology and azithromycin therapy will likely have a
significant impact on the efficacy of disease control
programs and the opportunity for eventual disease
eradication. Azithromycin, with a half-life of 5 to 7
days, has excellent pharmacokinetic characteristics,
such as increased bioavailability, lower incidence of
gastrointestinal tract side effects, and increased concentration in mucus, macrophages, and tissues.15
These characteristics allow for short course or single
dosing, which alleviates the problem of patient noncompliance with multi-day regimens. The difficulty
of applying ointment to the eyes of young children,
the discomfort associated with its use, and the frequency of symptomless infection are other reasons
for the failure of control programs based on topical
therapy.
In this study, the 3-day course oral dose of azithromycin cured 83.33% of subjects with active trachoma
by 6 months and was more effective than the conventional treatment. Possible adverse effects of the
treatment were not serious and compliance was good
in azithromycin-treated subjects. These observations
have important implications for the control of
trachoma.
Chumbley et al16 suggested that there were no sta-

Time
3 months
6 months

Azithromycin*
(n 48)

Conventional*
(n 48)

Chi-Square

42 (87.50)
40 (83.33)

34 (70.83)
30 (62.50)

4.04
5.28

*Values in parentheses are percentages.

P .045.

P .022.

tistically significant differences between the trachoma cure rates of tetracycline eye ointment-, oral
doxycycline-, and oral sulfamethoxypyridazinetreated groups. Dawson et al17 reported that 16
doses of azithromycin were equivalent to 30 days of
topical oxytetracycline/polymyxin ointment and may
offer an effective alternative means of controlling
endemic trachoma. Tabbara et al18 reported that single-dose azithromycin is as effective as a 6-week
course of topical tetracycline ointment in the treatment of active trachoma. These findings, when implemented, may help establish high compliance in
treating trachoma and could contribute to the control of trachoma.
Bailey et al19 reported that there were no significant differences in treatment effect, baseline
characteristics, and re-emergent disease between tetracycline eye ointment and single oral dose azithromycin.
Malaty et al20 suggested that there may be an extraocular reservoir of Chlamydia trachomatis infection in trachoma-endemic communities, for example,
in the gut or nasopharynx of infected children, which
may contribute to ocular infection. Systemic therapy,
such as oral azithromycin, would be more likely to
eradicate such a reservoir than would topical tetracycline.
Our finding of a significant difference between
azithromycin and conventional treatment indicates
that the two treatments have unequal efficacy.
In our study, reinfection rates were different for
azithromycin and conventional treatment. The high
rates of reinfection probably reflect the treatment
strategy we adopted, the treatment of only active
cases. It has been shown that subclinically infected
individuals are an important source of reinfection in
a rural area. Mass treatment of the whole community, which would be feasible with single-dose
azithromycin could reduce the rate of reinfection
through elimination of the reservoir of infection.

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ORAL AZITHROMYCIN VS TOPICAL OXYTETRACYCLINE

Rates of reinfection would then depend largely on

migration patterns into and out of the communities
treated, and on the success of behavioral interventions, such as face washing, which might reduce the
rate of transmission.16,21,22
The high efficacy rate, low incidence of side effects, and shorter treatment duration suggest that
azithromycin at a dosage of 10 mg/kg per day for 3
days is a viable alternative for the treatment of ocular Chlamydia trachomatis infections. The shorter
treatment duration is likely to improve patient compliance. We believe that azithromycin given at this
dosage represents a potential alternative for the
treatment of active trachoma.

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