Infection in the intensive care unit: beta-lactamase-mediated resistance among Enterobacteriaceae and optimal antimicrobial dosing.

Class I beta-lactamase-mediated resistance in Enterobacteriaceae is increasingly common, clinically important, and often associated with previous use of third-generation cephalosporins. Extended-spectrum beta-lactamases that confer resistance to third-generation cephalosporins are also becoming more widespread. Beta-lactamase-producing organisms often display multiresistance, and this has been associated with increased mortality among patients. For all beta-lactam antimicrobials, the time that the plasma concentration exceeds the minimum inhibitory concentration (MIC) is the principal factor determining antibacterial activity. For concentration-dependent antimicrobials such as aminoglycosides and fluoroquinolones, the area under the plasma-concentration time curve:MIC ratio is the variable that has the strongest link to clinical outcome, particularly when relatively low peak: MIC values (< 10:1) are achieved. Peak concentration is of major concern for suppression of resistance. When high peak: MIC ratios (> or = 10:1) are achieved, this may suppress resistance and become the primary variable linked to outcome. When designing antimicrobial dosage regimens, it is important to take into account the pharmacodynamics of the drug in order to maximize the potential for achieving a positive clinical outcome and suppressing the emergence of bacterial resistance.