Japanese journal of ophthalmology vol.44 no.4

Three-Day Course of
Oral Azithromycin vs Topical Oxytetracycline/
Polymyxin in Treatment of Active Endemic Trachoma
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 treat-
ment. 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 azithro-
mycin 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-emer-
gence of disease between the two treatment groups. Azithromycin was well-tolerated.
Conclusions: These results indicate that azithromycin may be an effective alternative for pa-
tients with active trachoma. As a systemic treatment, a 3-day course oral dose has important
potential for trachoma control.
Jpn J Ophthalmol 2000;44:387–391
Key Words:
Azithromycin, oxytetracycline/polymyxin, trachoma.
Introduction
mographic trends suggest that the burden of both in-fection and blindness is likely to increase.3 There is a Trachoma, an ocular infection caused by Chlamydia need for effective intervention to control ocular trachomatis, is the second leading cause of blindness Chlamydia trachomatis infections.
worldwide. Active trachoma occurs predominantly in The currently recommended treatment of trachoma children in hyperendemic communities, with the risk is topical tetracycline eye ointment for at least 6 weeks, of blinding complications occurring in middle-aged or on 5 consecutive days a month for 6 months.4 It is and older adults.1,2 Although trachoma has been suggested that subjects with a severe form of the dis- controlled in some areas, predictions based on de- ease should, in some circumstances, receive systemictherapy. There is a wide spectrum of opinion amongtrachoma experts about the effectiveness of these rec- ommendations, reflecting a scarcity of data from con- Correspondence and reprint requests to: Mustafa GUZEY, trolled trials in endemic areas on which rational deci- MD, Forsa Sok. Guney Apt. No. 21 Daire 1 Senesenevler,Bostanci, Istanbul, Turkey Jpn J Ophthalmol 44, 387–391 (2000) 2000 Japanese Ophthalmological Society There are several reasons why this treatment is less than satisfactory. It is difficult to apply ointmentto the eyes of young children. The ointment cancause discomfort or blurring of vision and melts un-der conditions of high ambient temperature. Manyinfected children have no symptoms and even in cir-cumstances where ointment is given free it can bedifficult to motivate parents to continue treatmentfor the stipulated period. A systemic treatmenteffective in a short period would thus represent asubstantial advance in the chemotherapy of activetrachoma.
Azithromycin is a recently approved azalide anti- Figure 1. Chemical structure of azithromycin.
biotic with the molecular formula of C38H72N2O12,and a molecular weight of 749.00. It is a derivative oferythromycin, containing an extra methyl-substi- papillary hypertrophy of the upper tarsal conjunctiva tuted nitrogen at position 9a in the lactone ring (Fig- with discharge, redness, irritation and burning-stinging ure 1). This modification confers good bioavailabil- ity, with sustained high tissue concentrations after an Ninety-six patients were randomly assigned con- oral dose. Azithromycin achieves high concentra- ventional or azithromycin treatment. Randomiza- tions in phagocytic cells and in fibroblasts. It appears tion was by room, all active cases within a room re- that fibroblasts serve as a reservoir of azithromycin ceiving the same treatment. Baseline eye swabs were in tissues, allowing activity against organisms and taken from all patients before treatment.
possibly transferring the antibiotic to phagocytic Expected effects, side effects, advantages, and dis- cells for activity against intracellular pathogens and advantages of both treatment methods were ex- delivery to infection sites.7 The high macrophage plained to patients who participated in the study and tissue concentration of the drug and prolonged and/or their parents, and informed consent was half-life suggest that azithromycin could potentially be used in shorter treatment regimens.8,9 The present Azithromycin suspension (200 mg/5 mL, Zitro- study compared the clinical and microbiological effi- max; Pfizer, Istanbul, Turkey) administered as a cacy and safety of a 3-day course of azithromycin 3-day course (10 mg/kg per day) by mouth; a syringe with a conventional 8-week course of topical oxytet- was used for measurement and administration. Sub- racycline/polymyxin for the treatment of young pa- jects randomized for conventional treatment were tients with active ocular Chlamydia trachomatis in- administered 0.5% oxytetracycline HCl/polymyxin eye ointment (Terramycin, 5 mg/g oxytetracyclineHCl, 1 mg/g/polymyxin B sulfate; Pfizer) to each eyetwice daily for 8 weeks.
Materials and Methods
Possible side effects were investigated in both In April 1998, an ocular survey was done in four groups by means of a standard interview, 7 days after villages of Sanliurfa by a trained observer (MG).
treatment started. The interview protocol contained The everted upper lids of both eyes were examined both specific questions about gastrointestinal symp- with a binocular magnifying loupe. Findings were toms in the preceding 7 days and open questions graded according to the simplified World Health Or- about the general health of the subjects. At subse- ganization grading system.10 Ninety-six subjects with quent follow-up, mothers were questioned about the bilateral active trachoma or showing the symptoms general health of the subjects and any adverse events given below were selected. The existence of an ac- tive trachoma was clinically characterized by the The following laboratory tests for safety evalua- presence of at least 5 follicles associated with a papil- tion were obtained at baseline and at weeks 2 and 4: lary hypertrophy of the upper tarsal conjunctiva and complete blood count with differential and platelet microbiologically characterized by the presence of at counts, prothrombin time, activated partial throm- least 5 elementary bodies per direct fluorescein anti- boplastin time, gamma glutamyl transferase, alanine body test slide. Clinical signs and symptoms taken aminotransferase, aspartate aminotransferase, alka- into consideration were follicular conjunctivitis and line phosphatase, serum bilirubin, lactate dehydro- ORAL AZITHROMYCIN VS TOPICAL OXYTETRACYCLINE genase, blood urea nitrogen, serum creatinine, se- Table 1. Baseline Comparisons of
rum calcium and phosphorus, electrolytes, total protein, albumin, blood glucose, uric acid, serum Conventional treatment was applied by the pa- tients’ mothers, supervised by a trained nurse. Com- pliance with conventional treatment was assessed by a system of witnessed treatments; the subject’s name was written on a form each time a treatment was wit- nessed. More than 95% of scheduled treatments *Values in parentheses are percentages.
Subjects were examined 1, 2, 3, and 6 months after the start of treatment. Clinical findings were re- of 36 (75.00%) subjects in the conventional treat- corded for each eye. Swabs were taken from upper ment group had resolved (P ϭ .029). These rates eyelids 3 and 6 months after the start of treatment. A were 89.58% and 68.75% at 6 months, respectively dacron swab was rubbed on the everted upper tarsal (P ϭ .012) (Table 3). The rate of reinfection by 6 conjunctiva, after which it was rolled on a slide for months was 33.33% in the conventional treatment the direct antibody immunofluorescence test. Meth- group, as opposed to 14.58% in the azithromycin anol-fixed slides were stained with monoclonal-fluo- group, and the difference was statistically significant rescein isothiocyanate antibody conjugate to the (P ϭ .027). Antigen positivity at baseline and severe major outer membrane protein. Smears were consid- or moderate disease were associated with persis- ered positive if 5 or more elementary bodies per tence of clinical signs, and there was a tendency for younger patients to have more persistent clinical Noticeable symptomatic relief and considerable resolution of clinical signs (disappearance of papil- There were significant differences in the preva- lary hypertrophy, decrease in the number and size of lence of direct fluorescein antibody test positivity in follicles) were considered as clinical success, and a ocular swabs between the therapy modalities (Table 4).
negative direct fluorescein antibody test was ac-cepted as microbiological success.
Discussion
In cases where this test was negative in the third month, a positive test result obtained in the sixth Trachoma is a common disease that has disap- month was considered as the establishment of a rein- peared in many parts of the world because of im- fection, whether a noticeable re-appearance of clini- proved living conditions and hygiene. In trachoma- cal signs and symptoms was present or not. For sta- endemic areas, severe disease leading to scarring and tistical analysis of the results, the chi-square test was blindness may be the result of frequent reinfection used to compare the treatment groups.
or persistent infection in those whose immune sys-tem does not mount an adequate response to clearthe infection. Trachoma continues to be a serious public health threat in southeast Turkey.12,13 Chlamy-dia trachomatis is an intracytoplasmic parasite and There were 96 subjects aged from 2 to 18 years has a unique, long, life cycle. Chlamydia shows two (Table 1). The treatment groups did not differ signif-icantly in age or sex distribution.
Symptoms of diarrhea, vomiting, and abdominal pain occurred in the azithromycin group (Table 2).
Table 2. Adverse Events Survey 7 Days After
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%) sub- jects in the azithromycin group and the clinical signs *Values in parentheses are percentages.
Table 3. Clinical Success Rate (Resolution of Clinical
Table 4. Microbiological Success Rate (Direct Fluorescein
Signs) in Azithromycin and Conventional Treatment Antibody Test Negativity) in Azithromycin and Groups 3 and 6 Months After Start of Treatment Conventional Treatment Groups 3 and 6 Months After Start of Treatment *Values in parentheses are percentages.
†P ϭ .029.
*Values in parentheses are percentages.
†P ϭ .045.
‡P ϭ .022.
distinctive forms during its life cycle: the elementarybody and the reticulate body. The elementary body tistically significant differences between the tra- is an infectious particle that initiates its infectious cy- choma cure rates of tetracycline eye ointment-, oral cle by attaching to the surface of a susceptible cell.
doxycycline-, and oral sulfamethoxypyridazine- Over a period of 6–8 hours, the particle enlarges, treated groups. Dawson et al17 reported that 1–6 and undergoes reorganization to become a reticulate doses of azithromycin were equivalent to 30 days of body. The reticulate body is noninfectious but meta- topical oxytetracycline/polymyxin ointment and may bolically active. Anti-chlamydial agents are only ef- offer an effective alternative means of controlling fective against reticulate bodies. These agents must endemic trachoma. Tabbara et al18 reported that sin- penetrate into the cell, cytoplasmic inclusions, and fi- gle-dose azithromycin is as effective as a 6-week nally into the reticulate body itself. Moreover, they course of topical tetracycline ointment in the treat- must be maintained at high concentrations in tissues ment of active trachoma. These findings, when im- for a long period of time. Effective anti-chlamydial plemented, may help establish high compliance in agents include tetracyclines, macrolides, and some of treating trachoma and could contribute to the con- Recent advances in diagnostic and screening tech- Bailey et al19 reported that there were no sig- nology and azithromycin therapy will likely have a nificant differences in treatment effect, baseline significant impact on the efficacy of disease control characteristics, and re-emergent disease between tet- programs and the opportunity for eventual disease racycline eye ointment and single oral dose azithro- eradication. Azithromycin, with a half-life of 5 to 7 days, has excellent pharmacokinetic characteristics, Malaty et al20 suggested that there may be an ex- such as increased bioavailability, lower incidence of traocular reservoir of Chlamydia trachomatis infec- gastrointestinal tract side effects, and increased con- tion in trachoma-endemic communities, for example, centration in mucus, macrophages, and tissues.15 in the gut or nasopharynx of infected children, which These characteristics allow for short course or single may contribute to ocular infection. Systemic therapy, dosing, which alleviates the problem of patient non- such as oral azithromycin, would be more likely to compliance with multi-day regimens. The difficulty eradicate such a reservoir than would topical tetracy- of applying ointment to the eyes of young children, the discomfort associated with its use, and the fre- Our finding of a significant difference between quency of symptomless infection are other reasons azithromycin and conventional treatment indicates for the failure of control programs based on topical that the two treatments have unequal efficacy.
In our study, reinfection rates were different for In this study, the 3-day course oral dose of azithro- azithromycin and conventional treatment. The high mycin cured 83.33% of subjects with active trachoma rates of reinfection probably reflect the treatment by 6 months and was more effective than the con- strategy we adopted, the treatment of only active ventional treatment. Possible adverse effects of the cases. It has been shown that subclinically infected treatment were not serious and compliance was good individuals are an important source of reinfection in in azithromycin-treated subjects. These observations a rural area. Mass treatment of the whole commu- have important implications for the control of nity, which would be feasible with single-dose azithromycin could reduce the rate of reinfection Chumbley et al16 suggested that there were no sta- through elimination of the reservoir of infection.
ORAL AZITHROMYCIN VS TOPICAL OXYTETRACYCLINE Rates of reinfection would then depend largely on multiple doses of suspension. Antimicrob Agents Chemother migration patterns into and out of the communities treated, and on the success of behavioral interven- 9. Taylor KI, Taylor HR. Distribution of azithromycin for the treatment of trachoma. Br J Ophthalmol 1999;83:134–5.
tions, such as face washing, which might reduce the 10. Thylefors B, Dawson CR, Jones BR. A simplified system for the assessment of trachoma and its complications. Bull World The high efficacy rate, low incidence of side ef- fects, and shorter treatment duration suggest that 11. West SK, Rapoza P, Munoz B, Katala S, Taylor HR. Epide- azithromycin at a dosage of 10 mg/kg per day for 3 miology of ocular chlamydial infection in a trachoma-hyperendemic area. J Infect Dis 1991;163:752–6.
days is a viable alternative for the treatment of ocu- 12. Guraksin A, Gullulu G. Prevalence of trachoma in eastern lar Chlamydia trachomatis infections. The shorter Turkey. Int J Epidemiol 1997;26:436–42.
treatment duration is likely to improve patient com- 13. Negrel AD, Minassian DC, Sayek F. Blindness and low vision pliance. We believe that azithromycin given at this in southeast Turkey. Ophthalmic Epidemiol 1996;3:127–34.
dosage represents a potential alternative for the 14. Jones RB. New treatment for Chlamydia trachomatis. Am J 15. Ballow CH, Amsden GW. Azithromycin. The first azalide an- tibiotic. Ann Pharmacother 1992;26:1253–61.
16. Chumbley LC, Viswalingam ND, Thomson IM, Zeidan MA.
References
Treatment of trachoma in the West Bank. Eye 1988;2:471–5.
1. West SK, Munoz B, Turner WM. The epidemiology of tra- 17. Dawson CR, Schachter J, Sallam S, Sheta A, Rubinstein RA, choma in central Tanzania. Int J Epidemiol 1991;20:1088–92.
Washton H. A comparison of oral azithromycin with topicaloxytetracycline/polymyxin for the treatment of trachoma in 2. Thylefors B. Present challenges in the global prevention of children. Clin Infect Dis 1997;24:363–8.
blindness. Aust N Z J Ophthalmol 1992;20:89–94.
18. Tabbara KF, Abu-el-Asrar A, al-Omar O, Choudhury AH, 3. West SK, Munoz B, Lynch M, Kayongoya A, Mmbaga BBO, al-Faisal Z. Single dose azithromycin in the treatment of tra- Taylor HR. Risk factors for constant, severe trachoma among choma. A randomized, controlled study. Ophthalmology preschool children in Kongwa, Tanzania. Am J Epidemiol 19. Bailey RL, Arullendran P, Whittle HC, Mabey DCW. Ran- 4. Salamon SM. Tetracyclines in ophthalmology. Surv Ophthal- domized controlled trial of single-dose azithromycin in treat- ment of trachoma. Lancet 1993;342:453–6.
5. World Health Organization. Strategies for the prevention of 20. Malaty R, Zaki S, Said ME, Vastine DW, Dawson CR, blindness in national programmes: a primary health care ap- Schachter J. Extraocular infections in children in endemic tra- proach. Geneva: World Health Organization, 1984.
choma. J Infect Dis 1981;143:853–7.
6. Dolin PJ, Faal H, Johnson GJ. Reduction of trachoma in a 21. Ward M, Bailey R, Lesley A, Kajbaf M, Robertson J, Mabey sub-Saharan village in absence of a disease control pro- D. Persisting inapparent chlamydial infection in a trachoma endemic community in The Gambia. Scand J Infect Dis 7. McDonald PJ, Pruul H. Phagocyte uptake and transport of azithromycin. Eur J Clin Microbiol Infect Dis 1991;10:828–33.
22. Taylor HR, West SK, Mmbaga BBO. Hygiene factors and in- 8. Nahata MC, Koranyi DI, Gadgil SD. Pharmacokinetics of creased risk of trachoma in central Tanzania. Arch Ophthal- azithromycin in pediatric patients after oral administration of

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