Agenda Item 2: Applications for Addition (azithromycin)
(Updated version received from MSF 27 February 2003)
Application for Inclusion of
Azithromycin in the
WHO Model List of Essential Medicines
From
Médecins sans Frontières
Application for Inclusion of Azithromycin in the
WHO Model List of Essential Medicines
Médecins sans Frontières
Contents
1.Summary statement of the proposal for inclusion, change or deletion4
2.Name of the focal point in WHO submitting the application4
3.Name of the organization(s) consulted and/or supporting the application4
4.International Nonproprietary Name (INN, generic name) of the medicine4
5.Whether listing is requested as an individual medicine or as an example of a
therapeutic group4
6.Information supporting the public health relevance4
6.1.Genital Chlamydia burden4
6.2.Trachoma burden4
7.Treatment details5
7.1.Azithromycin general5
7.2.Genital Chlamydia infection5
7.2.1.WHO Guideline5
7.2.2.Diagnostic tests for Chlamydia6
7.2.3.Syndromic treatment of urethral discharge6
7.2.4.Studies7
7.3.Trachoma8
7.3.1.Studies8
7.3.2.WHO guideline9
8.Summary of comparative effectiveness in a variety of clinical settings:9
8.1.Identification of clinical evidence10
8.1.1.Genital chlamydia infection10
8.1.2.Trachoma10
8.2.Summary of available data11
8.3.Summary of available estimates of comparative effectiveness11
9.Summary of comparative evidence on safety12
9.1.Estimate of total patient exposure to date12
9.2.Description of adverse effects/reactions12
9.3.Identification of variation in safety due to health systems and patient factors12
9.4.Summary of comparative safety against comparators13
Contents (continued)
10.Summary of available data on comparative cost and cost-effectiveness within
the pharmacological class or therapeutic group13
10.1.Range of costs of the proposed medicine15
10.1.1.Donation programme15
10.2.Comparative cost-effectiveness presented as range of cost per routine outcome16
11.Summary of regulatory status of the medicine16
12.Availability of pharmacopoeial standards17
13.Proposed text for the WHO Model Formulary17
14.References18
1
Application for Inclusion of Azithromycin in the
WHO Model List of Essential Medicines
Médecins sans Frontières
1.Summary statement of the proposal for inclusion, change or deletion
Azithromycin is proposed for inclusion into the core WHO Model list of essential medicines for the treatment of genital Chlamydial infection and trachoma.
2.Name of the focal point in WHO submitting the application
Submitted by MSF via WHO/EDM. MSF asked WHO/STI for collaboration.
3.Name of the organization(s) consulted and/or supporting the application
Médecins sans Frontières
4.International Nonproprietary Name (INN, generic name) of the medicine
Azithromycin (rINN, BAN, USAN)
5.Whether listing is requested as an individual medicine or as an example of a therapeutic group
Azithromycin is the prototype of a subclass of macrolide antibiotics known as the azalides. Listing as an individual medicine. If other equivalent molecules are developed, azithromycin can become an example of the therapeutic group.
6.Information supporting the public health relevance
6.1.Genital Chlamydia burden
Incidence: 92 million infections worldwide per year (WHO/CDS/CSR/EDC/2001.10).
6.2.Trachoma burden
Trachoma, caused by Chlamydia Trachomatis infection, is the world’s leading cause of preventable blindness. WHO estimates that there are 146 million cases of active disease, in need of treatment to prevent blindness. 590 million people worldwide are at risk of acquiring the infection. 6 million people are irreversibly blinded by trachoma or at immediate risk of blindness. Trachoma is responsible for at least 15.5% of blindness worldwide.
7.Treatment details
7.1.General infections
Azithromycin is effective in treating uncomplicated skin infections, upper and lower urinary tract infections, atypical and community acquired pneumonia. A major advantage over erythromycin is the clinical efficacy of single-dose azithromycin in uncomplicated urethritis or cervicitis due to Chlamydia trachomatis. An additional advantage includes a well-tolerated adverse-effect profile. Azithromycin is also effective for primary prophylaxis and treatment of Mycobacterium avium complex infection in patients with HIV infection.
Azithromycin is active against the following organisms as demonstrated by in vitro and clinical studies: Gram-positive: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes; Gram-negative: Haemophilus ducreyi, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae; Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae
Comprehensive reviews on azithromycin have been published1,2,3, including specific reviews on paediatric patients4,5. Other review articles discuss the selection of the right macrolide antibiotic6.
The above information is for reference only; listing of azithromycin is not requested for general infections.
7.2.Genital Chlamydia infection
7.2.1.WHO Guideline
The current WHO/STI guideline7 recommends either:
-doxycycline 100mg orally, twice daily, for 7 days, OR
-azithromycin 1 g orally, in a single dose for adults >45kg, and 20 mg/kg single dose for <45kg.
Alternative regimens are:
-amoxicillin, 3 x 500mg for 7 days
-erythromycin 4 x 500mg, for 7 days
-ofloxacin, 2 x 300mg, for 7 days
-tetracycline, 4 x 500mg, for 7 days.
Azithromycin has the clear advantage that it is easy to administer (just 1 single dose); all other antibiotics need a 7-day course with 2-4 doses per day, which might reduce effectiveness through poor compliance.
For genital chlamydial infections in pregnancy, WHO recommends erythromycin or amoxicillin, as the safety of Azithromycin in pregnancy has not yet been established.
7.2.2.Diagnostic tests for Chlamydia
There are often no obvious clinical manifestations of genital Chlamydia infection. If infection with chlamydia is not properly diagnosed, it can result in sterility in some women or in mother-to-child infection during childbirth, leading to conjunctivitis or eye inflammation in the baby. In men it can cause urethritis with possible infection of the ductus deferens and the testicles (epididymitis).
Existing rapid diagnostic tests for gonorrhoea and chlamydial infection are based on antigen detection, and are in the form of IC strips or cassettes. However, they are not simple because they require a number of steps to obtain results and their cost is high at approximately US$7 per test. Their sensitivity is 60% to 70% compared to amplification tests. Research on alternative tests is ongoing.
WHO is developing a model as a tool for estimating the required sensitivity for a rapid test. Different scenarios are considered depending on the population (sex workers, women with multiple casual partners, women with long term regular partnerships), number of sex acts and partners, prevalence of gonorrhoea and chlamydial infections and consistency of condom use. The major variable in the model is the return rate and delay of return of the patients. Cost analysis indicate that a strategy including a rapid test could be half as expensive as a strategy using a gold standard (slow) test.
For symptomatic patients with urethral discharge, WHO recommends a syndromic approach with a treatment for both gonorrhoea and Chlamydia infection, as determining the exact cause requires expensive tests and takes time. Patients with urethral discharge should be treated immediately.
7.2.3.Syndromic treatment of urethral discharge
Azithromycin is effective in the empiric treatment of nongonococcal urethritis. A 1-gram dose has been shown to be as effective as doxycycline given for 7 days. For patients where a single dose regimen would be advantageous, azithromycin is an effective alternative to doxycycline.8
Single dose therapy with either azithromycin (1 gram) or ciprofloxacin (500 milligrams) was effective in the treatment of urethral gonorrhea or cervical gonorrhea.9 However, WHO/STI guidelines prefer a 2g single dose for gonococcal infections, as the 1g dose provides protracted sub-therapeutic levels which may precipitate the emergence of resistance.
If a specific diagnosis is not possible, patients should be treated using the syndromic approach.
For urethral discharge, WHO recommends a syndromic treatment of gonorrhoea AND Chlamydia.
WHO also recommends the following treatments for uncomplicated gonorrhoea:
-ciprofloxacin 500mg orally, single dose (contraindicated in pregnancy and adolescents) OR
-azithromycin 2g orally, single dose, OR
-ceftriaxone 125mg IM injection, single dose, OR
-cefixime, 400mg orally, single dose, OR
-spectinomycin 2g IM inj, single dose.
This means that a 2g single dose would be sufficient treatment for the syndrome “urethral discharge”. Alternatively, countries can choose another gonorrhoea treatment, and combine it with a single dose of 1g azithromycin (or 7 days doxycycline twice daily 100mg) for Chlamydia.
7.2.4.Studies
Three groups of treatment were created to determine the efficacy of treating Chlamydia trachomatis in pregnant women. Everyone in group 1 (n = 17 pairs) received azithromycin (1 gram single dose); in group 2 (n = 21 pairs) the patient received erythromycin (500 milligrams (mg) three times daily for seven days) and the partner took tetracycline (500 mg four times daily for seven days); in group 3 (n = 10 pairs) the woman took azithromycin (1 gram single dose) and the partner received tetracycline as described in group 2. No pregnant women and/or their partners in group 3 had a positive culture four weeks after therapy, compared to 20% of patients and partners in group 2 and 7.1% of those in group 1. For all participants given azithromycin, only 4.5% had positive cultures four weeks after starting therapy, compared to 21.1% of participants given either erythromycin or tetracycline (P=0.018). Azithromycin produced significantly less adverse effects and resulted in better compliance compared with erythromycin or tetracycline10.
Single-dose azithromycin (1 gram) is as effective as multi-dose doxycycline (100 milligrams twice daily) in the treatment of Chlamydia Trachomatis infection. At 1 month following treatment, the incidence of persistence or recurrence of Chlamydia Trachomatis infection was 5.1% and 4.1% for those treated with single-dose and multi-dose therapy, respectively. According to relative risk (RR) calculations (RR, 1.2, 95% confidence interval 0.35 to 4.5), the two dosing regimens are similar in efficacy. Of the 73 women on the multi-dose regimen, 94.5% were compliant, that is taking doxycycline for 5 or more days (7 days = 67; 5 days = 2). Similar compliance was noted in the male partners. Since compliance is a limitation in multi-dose treatment regimens, azithromycin may be favoured in the treatment of C trachomatis. However, this study demonstrated that compliance was not a limitation and that doxycycline is still a viable treatment option. In patients where compliance will be problematic, azithromycin is an alternative11.
Azithromycin, as a single dose, is as effective as multiple dose regimens of tetracycline, doxycycline and erythromycin in the treatment of C trachomatis infections. The azithromycin regimen has an advantage because compliance is increased substantially by single-dose therapy12,13.
Azithromycin administered as a single dose was effective in the empiric treatment of nongonococcal urethritis associated with both Chlamydia trachomatis and Ureaplasma urealyticum14. In this large study, involving 452 men, patients were randomized to either azithromycin 1 gram as a single dose or doxycycline 100 milligrams twice daily for 7 days. Both regimens were equally effective, regardless of the infecting organism. Though the cost of azithromycin is substantially greater, the increased compliance with a single-dose regimen may warrant its use.
Single-dose azithromycin has been used in the treatment of sexually transmitted diseases related to Neisseria gonorrhoeae, Chlamydia trachomatis, or Ureaplasma urealyticum. In this randomized study, involving 182 patients, regimens of doxycycline 100 milligrams orally twice daily for 7 days, azithromycin 500 milligrams orally twice daily for 1 day, azithromycin 1 gram as a single oral dose, and azithromycin 500 milligrams on day 1 followed by 250 milligrams twice daily for 2 further days (3 day course) were similarly effective. Failure rates were higher with all regimens that were used to treat ureaplasma infections15.
7.3.Trachoma
In 1996, a WHO Expert Committee concluded that Azithromycin 20mg/kg was as effective as 6-7 weeks of topical tetracycline eye ointment, and that it was well tolerated with good patient compliance. The only problem was its high cost, and the committee urged the manufacturer to “consider all possible means of making azithromycin available on a sustainable basis to all those in need, to prevent blindness from trachoma.”16
A single oral dose (1g stat or 20mg/kg if <45kg) is as effective as 6-week course of daily tetracycline ointment in clearing ocular chlamydial infection and in resolving the signs of trachoma17. The protocol is simple to follow due to its particular pharmacokinetics: the oral dose is rapidly absorbed, time to peak plasma level is 2-3 hours, and the bioavailability of 37% is not affected by co-administration of food. Azithromycin levels in the tissues are up to 50 times higher than in plasma, and the terminal elimination T1/2 is > 40 hours after a single dose.18,19
For control of trachoma in entire communities, a short course of oral azithromycin is more effective than the standard 6-weeks course of daily tetracycline ointment. Community-wide treatment with oral azithromycin markedly reduces C Trachomatis infection and clinical trachoma in endemic areas and may be an important approach to control of trachoma.20
The formulation is well accepted by the population and easier to administer than the topical tetracycline eye ointment, specially to small children21.
Oral azithromycin therefore appears to offer a means for controlling blinding trachoma. It is easy to administer and higher coverages may be possible than have been achieved hitherto.22
7.3.1.WHO guideline
WHO Guideline: Primary Health Care Management of Trachoma, HSC/PBD PBL/93.33, 1993.
WHO recommends the 'SAFE' strategy: surgery, antibiotics, facial cleanliness and environmental improvement. The antibiotic is thus only 1 of the 4 components needed for trachoma control.
Azithromycin is also mentioned in the 1994 FCH/HIS sexually transmitted diseases Management of sexually transmitted diseases, GPA/TEM/94.1
7.3.2.Studies
Single dose azithromycin (20 milligrams/kilogram) was 100% effective in 13 school-age children with active trachoma. This study suggest that azithromycin tear concentrations are adequate to eradicate Chlamydia trachomatis, the causative organisms of trachoma. A follow-up ophthalmologic examination at 6 months demonstrated all patients were disease free23.
Single dose azithromycin (20 milligram/kilogram) was as effective as a six-week course of topical tetracycline opthalmic ointment in the treatment of conjunctivitis caused by Chlamydia trachomatis in a group of children (aged 6 to 14 years). Infection was resolved in 63.3% and 65.4% of patients treated with azithromycin and tetracycline, respectively24.
Single dose azithromycin was comparable to oxytetracycline/polymyxin eye ointment in the treatment of active endemic trachoma. This study was conducted in 168 rural Egyptian children. Azithromycin suspension was administered in 1 of the following 3 dosing regimens: a single 20 milligrams/kilogram (mg/kg) dose (n=40); one dose (20 mg/kg) weekly for 3 weeks (n=43); one dose (20 mg/kg) every 4 weeks for a total of 6 doses (n=42). The eye ointment (1% oxytetracycline with 10000 units/gram polymyxin) was administered once daily for 5 consecutive days every 28 days for a total of six 5-day periods (n=43). After 1 year, the clinical cure rate was not statistically different between any of the treatment groups and was approximately 47%. Azithromycin may represent a treatment alternative for endemic trachoma25.
8.Summary of comparative effectiveness in a variety of clinical settings
Drugs that have been proposed by WHO for the treatment of C Trachomatis include:
Genital infections:
doxycycline 100mg orally, twice daily for 7 days (recommended)
amoxycillin 500mg orally, 3 times daily for 7 days (alternative)
erythromycin 500mg orally, 4 times daily for 7 days (alternative)
ofloxacin 300mg orally twice daily, for 7 days (alternative)
tetracycline 500mg orally, four times daily for 7 days (alternative)
Trachoma:
tetracycline eye ointment
An advantage with azithromycin is its activity against Chlamydia trachomatis and proven efficacy when administered as a single 1 gram dose26. Azithromycin only needs to be taken once (single dose) which improves patient compliance, compared to all other antibiotics which require multiple dosages for 7 days.
Azthromycin can be used in pregnancy, but the safety of amoxicillin and erythromycin has been better established. Erythromycin and amoxicillin are therefore preferred treatments in pregnant women.
Doxycycline is equally effective and more affordable in the treatment of genital CT, but must be taken twice daily for 7 days. Doxycycline is contraindicated in pregnancy.
Azithromycin has several distinct advantages over erythromycin: it is better tolerated; there is better tissue penetration; and there are favourable pharmacokinetics.
Ofloxacin is expensive, and often reserved for MDR/TB programmes?
Oral tetracycline is as effective, but has more side-effects than azithromycin. It is also contra-indicated in pregnancy and children.
Azithromycin is equally effective to tetracycline eye ointment, but can be given in a single dose, whereas tetracycline eye ointment needs to be given for 6weeks, causes visibility problems and may suffer from stability problems in tropical climates.
The short duration of treatment used, once daily dosing, and the acceptable taste to most children make azithromycin a good first choice in paediatric infections.
The price of Azithromycin may be a stumbling block, especially in countries where the patent is still valid. However, generics are available at acceptable prices, and could be imported under compulsory licenses.
8.1.Identification of clinical evidence
8.1.1.Genital chlamydia infection
The BMJ Clinical Evidence rates single dose Azithromycin as “likely to be beneficial” in men, non-pregnant women and pregnant women.27
A meta-analysis of short term RCTs has found that a single dose of Azithromycin may be as effective in achieving microbiological cure of C Trachomatis as a 7 day course of doxycycline. Rates of adverse effects were similar28.
One systematic review of RCTs has found that a single dose of Azithromycin is as effective in achieving microbiological cure of C Trachomatis as a 7 day course of erythromycin in pregnant women29.
8.1.2.Trachoma
Trachoma is a public health problem which requires more than drugs alone: WHO recommends the integrated “SAFE” strategy: Surgery, Antibiotics, Face-washing and Environmental change.
The existing Cochrane Review searched The Cochrane Controlled Trials Register - CENTRAL/CCTR, which contains the Cochrane Eyes and Vision Group specialised register (Cochrane Library Issue 3, 2001), MEDLINE (1966 to August 2001), and EMBASE (1980 to September 2001). They used the Science Citation Index to look for articles that cited the included studies, searched the reference lists of identified articles and contacted authors and experts for details of further relevant studies
The systematic review found 15 studies that randomised a total of 8678 participants. For both outcomes (active trachoma and laboratory evidence of infection) the results of the chi-square tests suggested that there was significant statistical heterogeneity among the trials. There was also marked clinical heterogeneity. No summary statistics were calculated and we therefore present a narrative summary of the results. For the comparisons of oral or topical antibiotic against placebo/no treatment, the data are consistent with there being no effect of antibiotics but are suggestive of a lowering of the point prevalence of relative risk of both active disease and laboratory evidence of infection at three and 12 months after treatment. For the comparison of oral against topical antibiotics the results suggest that oral treatment is neither more nor less effective than topical treatment..30