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Chlamydial STD Treatment

Bandolier was taken to task recently about the article in issue 26 on treatment of fungal nail infections. A long course of griseofulvin was compared with a short course of terbinafine, and the latter shown to be better. Our GP reader made the point that because terbinafine treatment was much shorter duration, possible adverse events were less likely; it was the treatment any sensible practitioner would prescribe for their grandmother, so why was Bandolier suggesting the use of griseofulvin?

The point about simplicity of shorter duration antibiotic regiments is well made, exactly the point the Bandolier article was making, perhaps with insufficient force.

STD treatment guidelines 1993

The point about single dose oral therapy for sexually transmitted diseases (STD) was also made by a panel of experts from the Centres for Disease Control (CDC) in the USA, judging systematically amassed information. These guidelines [1] recommend a 1g single oral dose of azithromycin for chlamydial infections; the previously recommended regimen of oral doxycycline 100 mg twice daily for seven days remains an alternative treatment.

They mention that an important research issue is whether non-compliance with the 7-day doxycycline regimen results in treatment failures sufficiently high to warrant routine use of the more expensive single-dose azithromycin.

Bandolier thought that it would be worth looking at the evidence since chlamydia is the commonest curable cause of sexually transmitted disease in England & Wales. Data on new cases of infection from 1993 shows that men and women between the ages of 16 and 24 years are most often affected. We did a simple search of MEDLINE from 1990 using azithromycin and chlamydia trachomatis as search terms. This was a sensitive strategy that brought up a number of papers, whose abstracts were examined to see if they were randomised trials or studies of cost-effectiveness.

Azithromycin and doxycycline compared

For randomised trials, the search was for studies which compared directly a 1g single oral dose of azithromycin with 100 mg oral doxycycline twice daily for seven days in chlamydial infections. The search identified nine trials with about 1,800 patients. Details of the trials are summarised in the table, with clinical or microbial cures reported at two weeks to allow comparison between the trials.
Summary of trials comparing single-dose azithromycin with one-week doxycycline
Reference Setting Design Azithromycin cure Doxycycline cure Azithromycin adverse events Doxycycline adverse events
Steingrimsson et al, J Antimicrob Chemother 1990, 25 Supp A: 109-114. (Iceland) 181 men and 1 woman attending STD clinic, in two phases with different antimicrobial regimens random, blind, culture positive, attending follow-up for efficacy. Pfizer support Microbial cure 55/6190% Microbial cure 54/58 93% 10/118 given azithromycin in any regimen data not given
Whatley et al, Int J STD & AIDS 1991, 2: 248-51. (UK) 62 men aged over 18 attending STD clinic. random, open, 19 given azithromycin, 22 doxycycline. Pfizer support Symptomatic and microbial cure 76.4% Symptomatic and microbial cure 83.4% no data no data
Martin et al, N Engl J Med, 1992, 327: 921-5. (USA) 299 female and 158 male patients with clinical symptoms and positive chlamydia antigen test random, open, multi-centre - 141 azithromycin, 125 doxycycline attended follow-up Clinical or microbial cure 109/111 98% Clinical or microbial cure 96/96 100% 35 day survey all patients 41/237 17% 35 day survey all patients 43/220 20%
Nilsen et al, Genitourin Med 1992, 68: 325-7. (Norway) 130 men with clinical signs & symptoms of urethritis, chlamydia antigen positive random, double-blind, double-dummy, multicentre, attending follow-up. Pfizer support Clinical cure 31/35 (89%) Microbial cure 35/35 (100%) Clinical cure 32/34 (94%) Microbial cure 34/34 (100%) 35 day survey all patients 20/66 30% 35 day survey all patients 14/64 22%
Hammerschlag et al, Ped Pharmacol Ther 1993, 122: 961-5. (USA) 65 female and 8 male adolescents positive for chlamydia random, open Microbial cure 35/37 (95%) Microbial cure 18/18 (100%) 35 day survey all patients 9/46 20% 35 day survey all patients 9/27 33%
Lauharanta et al, J Antimicrob Chemother 1993, 31 Supp E, 177-83. (Finland) 120 men with symptoms of non-gonococcal urethritis random, open microbial response in chlamydia positive, clinical response in chlamydia negative Microbial cure 24/26 (92%) Clinical cure 19/20 (95%) Microbial cure 26/26 (100%) Clinical cure 14/21 (67%) 35 day survey all patients 11/60 18% 35 day survey all patients 9/59 16%
Lister et al, J Antimicrob Chemother 1993, 31 Supp E, 185-92. (UK) 143 men with symptoms of non-gonococcal urethritis random, open clinical cure for chlamydia positive and negative tests Clinical cure pos 12/16 (75%) Clinical cure neg 21/23 (91%) Clinical cure pos 11/12 (92%) Clinical cure neg 30/30 (100%) 5/62 8% 9/66 14%
Steingrimsson et al, Sex Trans Dis 1994, 21;43-6. (Iceland) 183 men attending an STD clinic for symptoms or contact tracing random, partial blind, microbial cure for three pathogens. Pfizer support Microbial cure 130/142 (92%) Microbial cure 111/117 (95%) 2/100 2% 2/83 2%
Stamm et al, JAMA 1995, 274: 545-9. (USA) 452 men with symptomatic non-gonococcal urethritis less than 14 days duration random, double-blind, double-dummy. Pfizer support Clinical cure 222/248 (90%) (95%CI 85-93%) Clinical cure 110/123 (89%) (95%CI 82-94%) 23% 29%
The main differences between trials were those that treated or included patients only with proven chlamydial infections, and those which treated all patients with appropriate symptoms. Two trials used a double-blind, double-dummy technique where patients took the same number of tablets or capsules over a week to maintain blinding. Numbers of patients analysed were often fewer than those enrolled, and analysis usually involved patients who tested positive for chlamydia and who attended follow up visits.

Results

Overall clinical cure rates were identical between the treatments at two weeks - 414 of 453 (91.4%) patients given azithromycin were cured, as were 293 of 316 (92.7%) of patients given doxycycline (odds ratio 0.91{95%CI 0.53 - 1.58}).

At two weeks there was no difference between the microbial cure rates - 279 of 301 (92.7%) patients given azithromycin compared with 243 of 253 (96.0%) of patients given doxycycline (odds ratio 0.53 {0.26 - 1.09}).
There was a trend for azithromycin cure rates to be higher than those of doxycycline at five weeks due to more frequent relapse in the latter group. Adverse events were mild and similar between treatments, though trials reported widely varying rates of adverse events. Reported events were 145 of 819 (17.7%) of patients given azithromycin compared with 19.0%) of patients given doxycycline (odds ratio 0.85{0.64 - 1.12}).
The most recent paper, that of Stamm et al [2], is the most detailed, and probably of the highest methodological quality, and worth reading, together with the accompanying editorial [3].

Efficacy and effectiveness

The editorial makes the point about patients in trials generally being compliant in taking their tablets, while "real-world" patients may not. This is the difference between efficacy (how well drugs work under ideal conditions) and effectiveness (how well drugs work under routine practice conditions). The authors of the editorial provide some interesting references about compliance, including a report that compliance with a 7-day treatment regimen in an STD clinic was only about 63%.

Cost effectiveness

The CDC has also recently published a cost effectiveness study comparing single-dose azithromycin compared with a one-week course of doxycycline [4] in women. It was based on a four times higher cost of azithromycin, and a high (80%) compliance rate with doxycycline. It included scenarios of treating only chlamydia positive women, or presumptive treatment based on clinical signs and symptoms.

The results showed that from the perspective of the health care system, the higher medicine costs of azithromycin were offset by lower costs associated with pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy and tubal infertility. Treating chlamydia-positive women with azithromycin would save four times as much as the additional cost. Treating women only presumed to be have chlamydial infection with azithromycin was broadly neutral in cost.

For both scenarios, compliance rates for doxycycline which fell below 80%, or lower medicine costs of azithromycin compared with doxycycline made the azithromycin choice even more cost effective.

References:

  1. WC Levine, AO Berg, RE Johnson et al. Development of sexually transmitted diseases treatment guidelines, 1993. Sexually Transmitted Diseases 1994; 21, Suppl;S96-S101.
  2. WE Stamm, CB Hicks, DH Martin et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. Journal of the American Medical Association 1995;274:545-9.
  3. GP Schmid, PB Fontanarosa. Evolving strategies for management of the nongonococcal urethritis syndrome. Journal of the American Medical Association 1995;274:577-9.
  4. AC Haddix, SD Hillia, WJ Kassler. The cost effectiveness of azithromycin for chlamydia trachomatis infections in women. Sexually Transmitted Diseases 1995 22:274-80.



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