As a general rule, first line treatment of intracardiac prosthetic material related endocarditis consists of surgical prosthesis removal, combined with appropriate antimicrobial therapy. The exception encompasses uncomplicated prosthetic valve endocarditis (PVE). PVE actually has a fair chance of successful medical treatment alone (>50%), depending on the causative micro-organism. Although there is evidence and consensus with regard to the first line treatment, surgical removal is not always possible because of its associated high risk, technical limitations, or unwillingness of patients to undergo an invasive surgical procedure. Second and third line treatments do not include surgery, and consist of antimicrobial therapy with biofilm-penetrating agents during a predetermined timespan (second line) or as life-long suppressive antimicrobial therapy (third line). These treatments are the alternative in situations wherein first line treatment is not feasible or is unwanted. Although not extensively investigated, these treatments are considered suboptimal.