A randomized controlled trial of azithromycin versus doxycycline/ciprofloxacin for the syndromic management of sexually transmitted infections in a resource-poor setting

Roxana Rustomjee1,*, A. B. M. Kharsany2, C. A. Connolly3 and S. S. Abdool Karim4

1Unit for Clinical and Biomedical Tuberculosis Research, Medical Research Council, King George V Hospital, PO Box 19494, Domerton 4015; 2Department of Medical Microbiology, Nelson R. Mandela School of Medicine, Durban; 3Medical Research Council, Durban; 4University of Natal, Durban, South Africa

Received 10 August 2001; returned 20 November 2001; revised 16 January 2002; accepted 18 February 2002.


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A randomized controlled trial was carried out to assess the effectiveness of azithromycin versus a standard regimen with doxycycline/ciprofloxacin in the treatment of sexually transmitted infections in a resource-poor environment. Infection with Chlamydia trachomatis was cured in 23/24 (95.8%) of women in the azithromycin arm versus 19/21 (90.5%) in the doxycycline arm (P = 0.6), resulting in three treatment failures. Gonorrhoea was cured in 55/56 (98.2%) women, with one treatment failure in a patient with concomitant C. trachomatis infection. These results indicate that a single oral dose of azithromycin may prove to be a more effective and convenient treatment for sexually transmitted infections in women in a resource-poor environment

Keywords: azithromycin, Chlamydia trachomatis, gonorrhoea, sexually transmitted disease


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Current sexually transmitted disease (STD) treatment protocols are based on syndromic management principles1 or targeted specifically at the causative organisms.1 In either case the antibiotic of choice for treating non-gonococcal cervicitis has been a tetracycline, such as doxycycline 200 mg daily or 100 mg twice daily for 7 days. It is not surprising that multiple doses per day and 7 day regimens have associated problems of reduced compliance and side effects.2 The availability of azithromycin, which has proven efficacy against Chlamydia trachomatis infection,2 provides an opportunity to treat C. trachomatis infections with one single dose.2

Azithromycin has the potential to revolutionize the treatment of STDs. In addition to its effect on C. trachomatis infection, high in vitro activity has been demonstrated against Neisseria gonorrhoeae and Haemophilus ducreyi, and it has been shown to be active against Treponema pallidum.3,4 Azithromycin has properties useful for the treatment of STDs, as it can be administered orally and has pharmacokinetic properties permitting single dose therapy for certain indications.2

Attendees at an STD clinic, Durban, South Africa, have chlamydial infection rates of 12–38%, tend to be young and have poor follow-up attendence.5 This scenario is a strong argument for the use of a drug that is effective in a single dose. For these reasons we undertook a randomized controlled trial to compare the effectiveness of azithromycin with that of doxycycline/ciprofloxacin in the syndromic management of women presenting with a muco-purulent cervical discharge.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Approval for this study was obtained from the Ethics Committee of the Faculty of Medicine, University of Natal. Informed consent was obtained from all participants.

First-visit, non-pregnant, female, clinic attendees at an STD clinic in Durban, from 16 August to 7 November 1999, were invited to participate in the trial if they had a muco-purulent cervical discharge with a diagnosis of non-gonococcal cervicitis (NGC), based on a routine vaginal wet mount and cervical Gram stain.

Participants (n = 89) were randomly assigned to either Intervention A (single dose of azithromycin, administered under direct observation) or Intervention B (the clinic’s current standard therapy of doxycycline 100 mg twice daily for 7 days), and followed up weekly for 2 weeks. Seven patients were lost to follow-up.

‘First-catch’ urine specimens were obtained at each visit to diagnose C. trachomatis and N. gonorrhoeae infection using ligase chain reaction (LCR) (Abbott Laboratories, Chicago, IL, USA).

Appropriate specimens were collected at enrolment/baseline, week 1 and week 2 in order to diagnose gonorrhoea (culture), trichomoniasis, bacterial vaginosis, candidiasis and syphilis, as described previously.5 At each visit clinical signs and symptoms, adherence to treatment and side effects were recorded. Participants were counselled on safer sex practices, supplied with partner notification cards and male condoms. Other STDs were treated as described previously.5

In a subgroup of patients where infection with N. gonorrhoeae was concomitantly (n = 19) or independently (n = 37) detected, ciprofloxacin 250 mg was added to the treatment regimen in the doxycycline arm at the first follow-up visit. These patients were followed for an additional week. The results were compared with those patients who received azithromycin (1 g stat) at enrolment.

Patients with persistent positive LCR results for C. trachomatis at the second follow-up visit were considered as treatment failures. Gonorrhoea cure was defined as culture and LCR negative. Statistical comparisons were performed using the {chi}2 test, Wilcoxson non-parametric test or Fisher’s exact test, as appropriate.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of the women followed up (n = 82), 26 were infected with C. trachomatis only, 19 had concomitant infection with N. gonorrhoeae and 37 were infected with N. gonorrhoeae only. After randomization 45 women in treatment arm A (single-dose azithromycin) and the 37 women in treatment arm B (doxycycline/ciprofloxacin) were comparable in terms of socio-demographic characteristics and prevalence of other STDs (Table 1).


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Table 1.  Baseline characteristics of study population after randomization
 
Treatment cure rates

The overall treatment cure rate for C. trachomatis infection, at the second follow-up visit was 23/24 (95.8%) and 19/21 (90.5%), in the azithromycin and doxycycline arms of the trial, respectively (P = 0.6). One treatment failure occurred in the azithromycin arm and two in the doxycycline arm based on LCR test results (Figure 1).



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Figure 1. Randomization and treatment outcome. A, azithromycin; B, doxycycline/ciprofloxacin; 1*, same individual.

 
All three treatment failures for C. trachomatis infection occurred in individuals concomitantly infected with N. gonorrhoeae. In this subgroup, 16/19 (84.2%) of patients were cured. One patient, in the azithromycin arm, was clinically and microbiologically cured the first week after treatment, but was LCR positive for C. trachomatis and culture positive for N. gonorrhoeae at week 3. This patient had resumed unprotected coitus with an untreated partner by week 1 after treatment. The cure rate for N. gonorrhoeae was 55/56 (98.2%). One treatment failure occurred as described above.

All the individuals that were cured in the azithromycin arm were LCR negative by the first follow-up examination. In the doxycycline arm, however, six individuals were LCR positive at the first follow-up visit. The delay in becoming LCR negative for C. trachomatis infection in the doxycycline arm as compared with the azithromycin was statistically significant (P = 0.04).

Adherence and side-effect profile

All participants in the azithromycin arm received the treatment under direct observation. Only one participant reported mild diarrhoea (azithromycin arm). Three participants failed to comply with the 7 day course of doxycycline. However, all the above patients were clinically and microbiologically cured.

Resumption of coitus was reported in 40% of participants. Less than 50% of partners presented themselves for treatment and <40% reported condom use. These findings were not different between the two arms of the trial. Neither condom use nor partner treatment was reported for the three treatment failures, despite resumption of coitus.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Worldwide, the appropriate management of STDs should be given a high priority in order to prevent the transmission of HIV.6 Successful management of STDs depends on treatment protocols and patients’ adherence to treatment regimens. Current syndromic management protocols avoid the need for expensive laboratory tests and are beneficial where follow-up and treatment on the basis of subsequent laboratory test results is poor.

In this trial, the cure rates of azithromycin for chlamydial infections, concomitant gonorrhoea, and gonorrhoea only were high (95.8%, 84.2% and 98.2%, respectively), and compared favourably with studies conducted elsewhere.2 As azithromycin therapy was observed directly, compliance was 100% and side effects were few and essentially minor. There is therefore a strong case for the use of single-dose, directly observed oral therapy in order to eradicate both infections. However, due to the small sample and limited evidence from other studies, further investigation is warranted.

This trial used LCR results as an end-point for chlamydial infection. Although this method may show delayed clearance of residual DNA in cured patients,7 the persistence of a positive LCR at week 1 and week 2 after treatment, and persistent signs and symptoms of clinical infection in three patients indicate that these are true treatment failures.7 Whilst antimicrobial susceptibility to the drugs used was not determined, re-infection appears to be the most probable cause.

Treatment with azithromycin resulted in microbiological cures at an earlier time than treatment with doxycycline. This finding has potentially important implications for the transmission dynamics of STDs, particularly HIV. It is possible that shorter infective periods can reduce the transmission of STDs, including HIV.

Some authors1 have questioned the efficacy of azithromycin in the presence of HIV infection. While individual HIV status was not ascertained in this trial, recently reported HIV seroprevalence among female clinic attendees at this clinic was 50%.5 The high cure rates are therefore reassuring against this background of HIV seroprevalence.

For syndromic management in the treatment of STDs, single-dose azithromycin might prove to be a more effective and convenient alternative to the use of both ciprofloxacin and doxycycline in the treatment of cervico-vaginal discharges. It may also provide appropriate therapy where the causative pathogen(s) of a vaginal discharge is unknown, where follow-up is difficult and therapy is required before or without laboratory results.


    Acknowledgements
 
Financial support was received from Pfizer International, South Africa.


    Footnotes
 
* Corresponding author. Tel: +27-31-2071675; Fax: +27-31-2086053; E-mail: roxana.rustomjee{at}mrc.ac.za Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Buve, A., Laga, M. & Piot, P. (1993). Sexually transmitted diseases—where are we now? Health Policy and Planning 8, 277–81.[ISI]

2 . Robinson, A. J. & Ridgway, G. L. (2000). Concurrent gonococcal and chlamydial infection. How best to treat. Drugs 59, 801–13.[ISI][Medline]

3 . Handsfield, H. H. (1993). Sexually transmitted chlamydial infections, gonorrhoea and syphilis. In The New Macrolides, Azalides and Streptogramins, (Neu, H. C., Young, L. S. & Zinner, S., Eds), pp. 167–72. Marcel Dekker, New York.

4 . Ballard, R. C., Ye, H., Matta, A., Dangor, Y. & Radebe, F. (1996). Treatment of chancroid with azithromycin. International Journal of STD and AIDS 7, Suppl. 1, 9–12.

5 . Kharsany, A. B. M., Hoosen, A. A. & Moodley, J. (1997). Bacterial vaginosis and lower genital tract infections in women attending out-patient clinics at a tertiary institution serving a developing community. Journal of Obstetrics and Gynaecology 17, 171–5.[Medline]

6 . Abdool Karim, Q. & Abdool Karim, S. S. (1999). South Africa: host to a new and emerging HIV epidemic. Sexually Transmitted Infections 75, 139–47.[Free Full Text]

7 . Gaydos, C. A., Crotchfelt, K. A., Howell, M. R., Kralian, S., Hauptman, P. & Quinn, T. C. (1998). Molecular amplification assays to detect chlamydial infections in urine specimens from high school female students and to monitor the persistence of chlamydial DNA after therapy. Journal of Infectious Diseases 177, 417–24.[ISI][Medline]