Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches

Abstract

Introduction: In the era of multidrug-resistant, extensively drug-resistant (XDR) and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the threat of untreatable infections particularly those caused by carbapenemase-producing bacteria, that is, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Therefore, all the presently available antibiotics, as well as for the near future compounds, are presented and discussed.

Areas covered: Current knowledge concerning mechanisms of action, in vitro activity and interactions, pharmacokinetic/pharmacodynamics, clinical efficacy and toxicity issues for revived and novel antimicrobial agents overcoming current resistance mechanisms, including colistin, tigecycline, fosfomycin, temocillin, carbapenems, and antibiotics still under development for the near future such as plazomicin, eravacycline and carbapenemase inhibitors is discussed.

Expert opinion: Colistin is active in vitro and effective in vivo against XDR carbapenemase-producing microorganisms in the critically ill host, whereas tigecycline, with the exception of P. aeruginosa, has a similar spectrum of activity. The efficacy of combination therapy in bacteremias and ventilator-associated pneumonia caused by K. pneumoniae carbapenemase producers seems to be obligatory, whereas in cases of P. aeruginosa and A. baumannii its efficacy is questionable. Fosfomycin, which is active against P. aeruginosa and K. pneumoniae, although promising, shares poor experience in XDR infections. The in vivo validity of the newer potent compounds still necessitates the evaluation of Phase III clinical trials particularly in XDR infections.

Keywords: avibactam; carbapenem resistance; carbapenem-producing β-lactamases; ceftolozane; colistin; eravacycline; extended spectrum β lactamase; extensively drug-resistant; fosfomycin; multidrug-resistant; pandrug-resistant; plazomicin; tigecycline.

Figure 1.

Graphical representation of CMS and colistin concentrations observed at a dose 3 MU q8 h and with a loading dose of 6 MU and 9 MU (infusion over 0.5 h and 1 h).