Multidrug-resistant gram-negative bacilli are emerging threats in the intensive care unit setting worldwide. Extended-spectrum β-lactamases, AmpC β-lactamases, and carbapenem-resistant Enterobacteriaceae are increasing at an alarming rate, leaving limited therapeutic options. In addition, multidrug resistance among Pseudomonas aeruginosa and Acinetobacter baumannii has widely disseminated and become a frequent cause of nosocomial infections within many intensive care units. Therefore, resistance is increasing to all currently available antibiotics, including cephalosporins, penicillins, aztreonam, carbapenems, fluoroquinolones, and aminoglycosides. Some multidrug-resistant gram-negative bacteria remain susceptible to only a few antibiotics such as tigecycline, fosfomycin, and polymyxins. The steady trend of increasing resistance coupled with the lack of novel antibiotics targeting resistant gram-negative bacilli has forced clinicians to increasingly apply more aggressive dosing strategies, such as prolonged and continuous infusion of β-lactam antibiotics to address the challenges associated with these difficult-to-treat pathogens. Nurses who have a thorough understanding of antibiotic resistance patterns, infection control procedures, and appropriate antibiotic use and dosing regimens, particularly the method of administration, are essential in the battle to preserve the usefulness of antibiotics and prevent further antibiotic resistance.