The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How

The recent expansion of multidrug resistant and pan-drug-resistant pathogens poses significant challenges in the treatment of healthcare associated infections. An important advancement, is a handful of recently launched new antibiotics targeting some of the current most problematic Gram-negative pathogens, namely carbapenem-producing Enterobacteriaceae (CRE) and carbapenem-resistant <i>P. aeruginosa</i> (CRPA). Less options are available against carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) and strains producing metallo-beta lactamases (MBL). Ceftazidime-avibactam signaled a turning point in the treatment of KPC and partly OXA- type carbapenemases, whereas meropenem-vaborbactam was added as a potent combination against KPC-producers. Ceftolozane-tazobactam could be seen as an ideal beta-lactam backbone for the treatment of CRPA. Plazomicin, an aminoglycoside with better pharmacokinetics and less toxicity compared to other class members, will cover important proportions of multi-drug resistant pathogens. Eravacycline holds promise in the treatment of infections by CRAB, with a broad spectrum of activity similar to tigecycline, and improved pharmacokinetics. Novel drugs and combinations are not to be considered "panacea" for the ongoing crisis in the therapy of XDR Gram-negative bacteria and colistin will continue to be considered as a fundamental companion drug for the treatment of carbapenem-resistant Enterobacteriaceae (particularly in areas where MBL predominate), for the treatment of CRPA (in many cases being the only <i>in vitro</i> active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and <i>P. aeruginosa</i>, deserves a greater attention. Optimal conditions for monotherapy and the "when and how" of combination treatments integrating the novel agents will be discussed.