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


METHODS
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.


CONCLUSIONS
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.
Hygeia General Hospital, 6th Department of Internal Medicine , Erythrou Stavrou Str & Kifisias Avenue, Marousi, Athens, 15123 , Greece.
Ilias
I
Karaiskos
Helen
H
Giamarellou
D040981:Acinetobacter baumannii / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D002986:Clinical Trials as Topic; D024901:Drug Resistance, Multiple, Bacterial; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects
D000900:Anti-Bacterial Agents; D015507:Drugs, Investigational
avibactam; carbapenem resistance; carbapenem-producing β-lactamases; ceftolozane; colistin; eravacycline; extended spectrum β lactamase; extensively drug-resistant; fosfomycin; multidrug-resistant; pandrug-resistant; plazomicin; tigecycline