Plasmid-mediated resistance in Enterobacteriaceae: changing landscape and implications for therapy

Antimicrobial resistance is increasing worldwide, and pathogenic microorganisms that are resistant to all available antimicrobial agents are increasingly reported. Emerging plasmid-encoded extended-spectrum β-lactamases (ESBLs) and carbapenemases are increasingly reported worldwide. Carbapenemase production encoded by genes located on mobile genetic elements is typically accompanied by genes encoding resistance to other drug classes, often but not necessarily located on the same mobile element. Multiple plasmid-mediated mechanisms of resistance against the fluoroquinolones and aminoglycosides have been described, and the combination of plasmid-mediated resistance with chromosomally encoded resistance mechanisms of multiple drug classes now results in strains that are resistant to all of the main classes of commonly used antimicrobial drugs. Clinical studies of antimicrobial therapy and outcome of patients infected with ESBL- or carbapenemase-producing strains of Enterobacteriaceae compared with patients infected with susceptible strains are limited in their design but suggest a worse outcome after infection with resistant strains. Alternative options for the treatment of infections caused by carbapenem-resistant strains of Enterobacteriaceae are limited. Current strategies include colistin, fosfomycin, tigecycline and temocillin. Although in vitro testing suggests strong activity for each of these drugs against a large proportion of carbapenem-resistant strains of Enterobacteriaceae, clinical evaluations do not provide strong evidence for equivalent or improved outcome. Oral treatment with fosfomycin tromethamine is effective against lower urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli. Intravenous fosfomycin may be beneficial and safe for patients when used as part of a combination therapy in the management of severe infections caused by carbapenem-resistant Klebsiella pneumoniae. Tigecycline is only indicated for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections in Europe, and is also approved for treatment of community-acquired pneumonia in the US. Clearly, further research on the clinical and safety outcomes in the treatment of multidrug-resistant Enterobacteriaceae with these existing alternative drugs, and the development of new and unrelated drugs, are urgently warranted.