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Chronic osteomyelitis is a difficult to treat infection of the bone, which requires a combined medical and surgical approach and often persists intermittently for years, with relapses and failures. The optimal type, route of administration, and duration of antibiotic treatment remain controversial, and the emergence of multi-drug resistant organisms poses major therapeutic challenges. Identification of the causative agent and subsequent targeted antibiotic treatment has a major impact on patients' outcome. In this review, we summarize which intravenous and oral antibiotics are the best options available for the treatment of chronic osteomyelitis, according to specific aetiologies.