Therapeutic options for infections with Enterobacteriaceae producing carbapenem-hydrolyzing enzymes

Enterobacteriaceae that produce serine carbapenemases or metallo-beta-lactamases, such as KPC, OXA-48, VIM or NDM, respectively, are spreading mostly as nosocomial pathogens worldwide. Such strains are typically resistant to most if not all available antimicrobials. Specific relevant clinical data are scarce to guide the determination of the most appropriate treatment options. Data on antimicrobial susceptibility, resistance development, synergy, pharmacokinetic and pharmacodynamic parameters of the candidate regimens, as well as the experience from the treatment of infections with nonfermenting Gram-negative pathogens, can aid in this regard. Colistin and tigecycline are most likely to be active in vitro against Enterobacteriaceae producing carbapenem-hydrolyzing beta-lactamases, but resistance development is of concern. Individual members of the aminoglycoside class can also be active in vitro, while carbapenems or aztreonam (specifically for metallo-beta-lactamase producers) can have low minimum inhibitory concentrations. Current data do not reliably support the use of these agents as monotherapy for systemic infections. Several expanded-spectrum cephalosporins, such as ceftazidime, may be active against OXA-48 type producers. Fosfomycin might be useful as a last-resort option as part of combination regimens. Combination antimicrobial therapy with agents exhibiting synergy might also be of benefit, until novel effective agents could become clinically available.