A Single Dose Oral Azithromycin versus Intramuscular Benzathine Penicillin for the Treatment of Yaws-A Randomized Non Inferiority Trial in Ghana

Abstract

BackgroundYaws is a treponemal infection that was almost eradicated fifty years ago; however, the disease has re-emerged in a number of countries including Ghana. A single-dose of intramuscular benzathine penicillin has been the mainstay of treatment for yaws. However, intramuscular injections are painful and pose safety and logistical constraints in the poor areas where yaws occurs. A single center randomized control trial (RCT) carried out in Papua New Guinea in 2012 demonstrated the efficacy of a single-dose of oral azithromycin for the treatment of yaws. In this study, we also compared the efficacy of a single oral dose of azithromycin as an alternative to intramuscular benzathine penicillin for the treatment of the disease in another geographic setting.MethodologyWe conducted an open-label, randomized non-inferiority trial in three neighboring yaws-endemic districts in Southern Ghana. Children aged 1–15 years with yaws lesions were assigned to receive either 30mg/kg of oral azithromycin or 50,000 units/kg of intramuscular benzathine penicillin. The primary end point was clinical cure rate, defined as a complete or partial resolution of lesions 3 weeks after treatment. The secondary endpoint was serological cure, defined as at least a 4-fold decline in baseline RPR titre 6 months after treatment. Non- inferiority of azithromycin treatment was determined if the upper bound limit of a 2 sided 95% CI was less than 10%.FindingsThe mean age of participants was 9.5 years (S.D.3.1, range: 1–15 years), 247(70%) were males. The clinical cure rates were 98.2% (95% CI: 96.2–100) in the azithromycin group and 96.9% (95% CI: 94.1–99.6) in the benzathine penicillin group. The serological cure rates at 6 months were 57.4% (95% CI: 49.9–64.9) in the azithromycin group and 49.1% (95% CI: 41.2–56.9) in the benzathine penicillin group, thus achieving the specified criteria for non-inferiority.ConclusionsA single oral dose of azithromycin, at a dosage of 30mg/kg, was non-inferior to a single dose of intramuscular benzathine penicillin for the treatment of early yaws among Ghanaian patients, and provides additional support for the WHO policy for use of oral azithromycin for the eradication of yaws in resource-poor settings.Trial RegistrationPan African Clinical Trials Registry PACTR2013030005181 http://www.pactr.org/

Factors associated with cutaneous ulcers among children in two yaws-endemic districts in Ghana

“…In a cluster randomized study by Marks et al, in the Solomon Islands, Treponema pallidum particle agglutination assay (TPPA) positivity and dual sero-positivity were associated with increased number of dual positive household contacts [13]. Similar studies have also found this significant association of yaws and environmental factors such as overcrowding [20,[26][27][28]. The choice of case-control study design could amount to recall bias particularly among the controls.…”

“…WHO launched the Morges Yaws Eradication Strategy in 2012, with a target of eradication by 2020. A major component of the new strategy was the change from the injectable benzathine penicillin to oral azithromycin [7]. The new treatment strategy was piloted in three countries including Ghana [8][9][10] and though the strategy had significant impact on disease burden, it did not achieve elimination targets in high endemic communities [11].…”

Complete genome sequences of two strains of Treponema pallidum subsp. pertenue from Ghana, Africa: Identical genome sequences in samples isolated more than 7 years apart

“…In 2012, the WHO launched a plan for eradication of yaws using macrolide antibiotic azithromycin [ 47 ]. So far, azithromycin was found to be effective in treatment of yaws [ 48 – 51 ], although in syphilis-causing strains, two mutation were associated with macrolide resistance [ 52 – 53 ]. Since resistance to azithromycin is caused by point mutation in the 23S rRNA gene and since both copies of the 23S rRNA genes need to be mutated, we have previously estimated the probability of emergence of macrolide-resistant yaws treponemes to be a rather rare event (with probability 10 −4 –10 −5 per infected patient) [ 54 ].…”

Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials

“…averting injections in a low-resource setting). 41 Tradeoff decisions are also relevant in affluent settings. Several NI-RCTs have been carried out for ascertaining whether antibiotics could be a reasonable alternative to current surgical SoC for acute appendicitis.…”