Selective pressures generated by the indiscriminate use of β-lactam antibiotics have resulted in increased bacterial resistance across all β-lactams classes. In particular, the use of third-generation cephalosporins has been associated with the emergence of extended-spectrum β-lactamase—producing and AmpC β-lactamase—producing Enterobacteriaceae and vancomycin-resistant enterococci. Conversely, β-lactams (e.g., cefepime, piperacillin-tazobactam, and ampicillin-sulbactam) have not demonstrated such strong selective pressures. Chief among institutional strategies to control outbreaks of multidrug-resistant bacteria are infection-control measures and interventional programs designed to minimize the use of antimicrobial agents that are associated with strong relationships between use and resistance. Successful programs include antimicrobial stewardship programs (prospective audit and feedback), formulary interventions (therapeutic substitutions), formulary restrictions, and vigilant infection control. Fourth-generation cephalosporins, such as cefepime, have proven to be useful substitutes for third-generation cephalosporins, as a part of an overall strategy to minimize the selection and impact of antimicrobial-resistant organisms in hospital settings.