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The widespread use of broad-spectrum antibiotics has led to emergence of antibiotic-resistant strains of many Gram-negative organisms. This problem is particularly serious in critically ill patients, especially those with ventilator-associated pneumonia. Extensive antibiotic resistance has developed in Gram-negative bacteria, due both to innate resistance in some species and the fact that they are highly adept at acquiring antibiotic-resistant determinants from each other. Antibiotic resistance develops through the following three basic mechanisms: alteration of the drug target, prevention of drug access to the target (including actively removing the drug from the bacteria), and drug inactivation. Certain Gram-negative microorganisms are particular problems in the intensive care unit, including Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, and the Enterobacteriaceae. The combination of an increasing population at risk, and the natural virulence and adaptability of Gram-negative bacteria guarantees that critical care physicians will face a persistent and increasing challenge from these pathogens.