ArticlesSingle-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial
Introduction
Yaws—an endemic treponematosis and, as such, a neglected tropical disease—is re-emerging. 40 years after a worldwide control programme almost eradicated the disease, it has re-emerged in children in poor, rural, and marginalised populations in parts of Africa, Asia, and South America. Yaws is caused by Treponema pallidum subsp pertenue, and affects mainly skin, bones, and cartilage. The disease has a natural history in primary, secondary, and tertiary stages. Unless diagnosed and treated at an early stage, yaws can become a chronic, relapsing disease, and can lead to severe deforming bone lesions in the long term.1
Between 1952, and 1964, WHO and UNICEF led a worldwide campaign to control and eventually eradicate yaws and other endemic treponematoses.2 Yaws became the second disease targeted for eradication, after smallpox. Control programmes were established in 46 countries and, by the end of 1964, the number of cases had reduced by 95%, from 50 million to 2·5 million. However, control efforts were gradually abandoned in most countries3 and the disease re-emerged in the late 1970s, prompting the adoption of WHO's assembly resolution 38·58.4 According to the last estimate by WHO in 1995, more than 500 000 children were still affected in Africa, Asia, and South America.5
Penicillin remains the drug of choice to treat endemic treponematoses.6, 7 WHO guidelines recommend one intramuscular injection of long-acting benzathine benzylpenicillin at a dose of 1·2 MU for adults and 0·6 MU for children;8 however, other guidelines recommend higher doses.9 This treatment is effective and has several advantages, as described for venereal syphilis.10 Although this treatment is cheap and well tolerated, it has drawbacks, including the operational and logistical difficulties related to treatment with drug injection, the potential risk of transmission of blood-borne pathogens with unsafe injection practices, the pain related to deep intramuscular injection of a large volume (4 mL), and a high rate of self-reported allergy to penicillin.
Oral phenoxymethylpenicillin for 7–10 days (50 mg/kg daily in four doses; maximum dose 300 mg four times a day) was effective in a yaws control programme.11 Such a regimen overcomes the disadvantages of intramuscular drug administration, but poor adherence to a multiday treatment regimen is a risk. In pilot studies of the potential of oral, single-dose treatment against several infectious disorders, azithromycin—a macrolide antibiotic with a long half-life in tissue—seemed to be a valuable drug against Chlamydia trachomatis,12 Neisseria gonorrhoeae,13 and Haemophilus ducreyi14 infections. Promising results were also reported from a large-scale study10 done in Tanzania, with two regimens to treat early syphilis: one oral dose (2 g) of azithromycin and one intramuscular dose of benzathine benzylpenicillin 2·4 MU. A multicentre trial15 in North America and Madagascar had similar findings.
The immediate-release formulation of azithromycin given in one oral dose of 30 mg per kg of bodyweight has been approved and widely used to treat acute otitis media in children since 2001.16, 17 The product is available as an oral tablet or as syrup, which is easier to administer to very young children.
We assessed the efficacy of a single oral dose of azithromycin compared with the standard single intramuscular dose of benzathine benzylpenicillin to treat yaws.
Section snippets
Study setting and patients
We undertook a prospective, open-label, non-inferiority, randomised controlled trial at Lihir Medical Centre in Papua New Guinea between Sept 1, 2010, and Feb 24, 2011. The Lihir islands are geographically remote, and despite being host to a major gold-mining operation since 1995, the living conditions and sanitation remain basic in most areas. Yaws is still a substantial cause of morbidity in Papua New Guinea.18, 19 Monthly reports for monitoring several indicators of infectious diseases and
Results
Figure 1 shows the trial profile. 250 patients with serologically confirmed yaws were randomly assigned to receive either azithromycin or benzathine benzylpenicillin. Baseline clinical and serological characteristics of the two treatment groups were similar (table 1). Mean age of the participants was 8·8 years (SD 3·6; range 8 months to 15 years). 42% of patients had primary yaws (table 1). The rapid plasma reagin titre was less than 1 in 32 in 107 (43%) participants and 1 in 64 or more in 143
Discussion
Our findings show that azithromycin was non-inferior to benzathine benzylpenicillin for the primary composite endpoint of serological cure at 6 months and healing of ulcers. Furthermore, the two treatment groups had similar rates of cure at 3 month follow-up and in subgroups defined according to demographic and biological characteristics. These results add to previous evidence of the suitability of use of a single dose of a drug such as azithromycin to treat various infectious diseases (panel).
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