Treatment of MDR-Gram negative infections in the 21st century: a never ending threat for clinicians

•Currently the best alternative to carbapenems for ESBL related infections are BLBLI.•Combination therapy is advisable for CRE infections.•Microbiological adequacy not combination drives the outcome in PA related infections.•Colistin is the key drug for the treatment of carabapenem-resistant-Ab infections.•Use of aerosolized drugs along with systemic administration should be encouraged.

The spread of antimicrobial resistance among Gram negative bacteria has dramatically reduced the current therapeutic opportunities and hampered the perspectives of drug discovery pipeline. Several unmet needs concerning the optimal therapeutic approaches to severe infections caused by the leading multi-drug-resistant GNB are still unresolved, mainly in relationship with the difficulty in the design of prospective comparative studies. Therefore a perspective of how the main resistance patterns and the related infections can be managed in the absence of more definitive data is mandatory.