Multidrug-resistant nonfermenters are a worldwide threat. Pseudomonas aeruginosa and Acinetobacter baumannii have been associated with high mortality and treatment failures. In addition, therapeutic options are increasingly narrowed, mainly due to widespread resistance in these pathogens and a shortage of new antimicrobial compounds. Hence, old, potent but toxic antibiotics such as the polymyxins are re-emerging as therapeutic options. Maximizing pharmacokinetics/pharmacodynamics with existing agents is also a worthwhile approach to explore. This problem exemplifies the critical need for new drug development for multidrug-resistant Gram-negative microorganisms.