The goal of this clinical trial is to test the non inferiority of linezolid compared with azithromycin as a treatment for yaws . The main questions it aims to answer are: can linezolid cure active yaws, and can linezolid cure latent yaws. Participants with serologically confirmed yaws will be randomized to receive linezolid (experimental) or azithromycin (control group) treatment and followed up to assess clinical resolution.

The current principle of yaws eradication is based on a single round of mass drug administration of azithromycin (AZI) called total community treatment (TCT) followed by targeted treatment of active cases and close contacts every 6 months called total targeted treatment (TTT). Studies done in Papua New Guinea have shown that 3 rounds of TCT are preferable to 1 TCT followed by TTT rounds because it results in higher overall coverage, particularly of latent cases. In the context of repeated rounds of TTT and multiple rounds of TCT, resistance to AZI has ben detected on 5 patients with yaws Recent studies have been successful on the culture of Treponema pallidum (syphilis and yaws), therefore investigators are now able to identify more potential treatment for yaws and syphilis.

Yaws is one of the major causes of the Cutaneous Ulcer Disease (CUD) syndrome. The CUD syndrome is a painful and debilitating condition, endemic to remote tropical regions with poor sanitation and limited health care access affecting children mainly. In Papua New Guinea it is caused by a range of unknown and some known pathogens besides yaws that are not easily distinguished on clinical diagnosis. New information on the causative agents of the CUD syndrome is needed to facilitate its management with an integrated approach.

The aim of the project is to provide evidence supporting (or rejecting) the hypothesis that the use of linezolid (LZD) can be an alternative treatment to cure yaws corroborated by clinical, serological, and molecular methods. LZD is a very safe drug that has been delivered to adults and children for the treatment of cutaneous infections all over the world. Investigators will compare two different treatments: (A) linezolid (LZD) and (B) azithromycin (AZI). In addition, the investigators plan to contribute to characterize the etiology of the CUD syndrome. The study will be implemented in selected wards of the Islands Region of Papua New Guinea.

Inclusion Criteria:

1. Participants 5-18 years identified during an active case search program at the elementary, primary and secondary schools in the Islands Region.
2. CUD syndrome suspected due to yaws: one or more ulcerative or nodular or papilloma skin lesion of more than 1.5 cm in diameter.
3. Positive treponemal (T1) and non-treponemal (T2) serology by Chembio dual path platform (DPP) syphilis screen & confirm assay (DPP test).
4. Accepted and signed informed consent.
5. Ability to comply with the requirements of the study protocol including follow up visits.

Exclusion Criteria:

1. Children younger than 5 years old.
2. Clinical late-stage possible yaws: destructive osteitis (rhinopharyngitis gangosa, sabre shins) or gummous nodules.
3. Known allergy to LZD or AZI antibiotics.
4. Pregnant or breastfeeding women.
5. Refusal at ward level or village chief (for village inclusion), or refusal of individual or guardian (for individual inclusion).
6. Have taken any antibiotics with potential activity against TPE within the last 7 days prior to randomization (i.e., beta lactams, cephalosporines, macrolides, tetracyclines).
7. Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, incapacitating psycho-affective disturbance, acute confusional state.
8. Renal function impairment requiring hemodialysis.
9. Current treatment with any drugs likely to interact with the study medication
10. Symptomatic concomitant infection requiring antibiotic treatment potentially active against TPE.
11. Having received treatment for yaws in the last 6 months.
12. Patients who are unable to take oral medication or having a gastrointestinal disease likely to interfere with drug absorption (including malnutrition and stomach flu).

Protocol and anonymised data will be made available upon reasonable request

Investigator will not be present for treatment nor for outcome assessment, and data analysis (statistics) will be blinded.