Off-label use versus formal recommendations of conventional and novel antibiotics for the treatment of infections caused by multidrug-resistant bacteria

The infections caused by multidrug- and extensively drug-resistant (MDR, XDR) bacteria, including Gram-positive cocci (GPC, including methicillin-resistant Staphylococcus aureus, MDR-Streptococcus pneumoniae and vancomycin-resistant enterococci) and Gram-negative bacilli (GNB, including carbapenem-resistant [CR] Enterobacterales, CR-Pseudomonas aeruginosa and XDR/CR-Acinetobacter baumannii complex) can be quite challenging for physicians with respect to treatment decisions. Apart from complicated urinary tract and intra-abdominal infections (cUTIs, cIAIs), bloodstream infections and pneumonia, these difficult-to-treat bacteria also cause infections at miscellaneous sites (bones, joints, native/prosthetic valves and skin structures, etc.). Antibiotics like dalbavancin, oritavancin, telavancin and daptomycin are currently approved for the treatment of acute bacterial skin and skin structural infections (ABSSSIs) caused by GPC. Additionally, ceftaroline, linezolid and tigecycline have been formally approved for the treatment of community-acquired pneumonia and ABSSSI. Cefiderocol and meropenem-vaborbactam are currently approved for the treatment of cUTIs caused by XDR-GNB. The spectra of ceftazidime-avibactam and imipenem/cilastatin-relebactam are broader than that of ceftolozane-tazobactam, but these three antibiotics are currently approved for the treatment of hospital-acquired pneumonia, cIAIs and cUTIs caused by MDR-GNB. Clinical investigations of other novel antibiotics (including cefepime-zidebactam, aztreonam-avibactam and sulbactam-durlobactam) for the treatment of various infections are ongoing. Nevertheless, evidence for adequate antibiotic regimens against osteomyelitis, arthritis and infective endocarditis due to several GPC and MDR-GNB is still mostly lacking. A comprehensive review of PubMed publications was undertaken and the formal indications and off-label use of important conventional and novel antibiotics against MDR/XDR-GPC and GNB isolates cultured from miscellaneous sites are presented in this paper.