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.