The common causes of ventilator-associated pneumonia (Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter spp) are frequently resistant to multiple antibiotic classes. S aureus develops resistance to all beta-lactam antibiotics by producing a modified penicillin-binding protein. Linezolid resistance arises by way of mutations in the 23S ribosomal subunit. Antibiotic resistance in gram-negative bacilli usually arises by way of beta-lactamase production, upregulation of efflux pumps, or loss of outer membrane proteins. The ability of bacteria to develop and disseminate new mechanisms of antibiotic resistance may outstrip the availability of new antibiotic classes.