Given these caveats, one important lesson from recent studies is that antibiotic coverage should be given early after infection is suspected, and the spectrum of this agent(s) should address all reasonably suspected pathogens. Several studies57,69,71 have demonstrated that the need to change antibiotic drugs after culture data becomes available identifies a subgroup of patients with higher mortality. Moreover, Luna and colleagues58 noted that the mortality benefit of appropriate antibiotic coverage pertained only to that treatment present before invasive diagnostic testing, suggesting that an important time window exists after which antibiotic treatment, regardless of activity, is less effective. As such, the single most important management decision after a clinical diagnosis of pneumonia is whether antimicrobial activity against potentially resistant organisms such as Pseudomonas aeruginosa, Acinetobacter species, and Stenotrophomonas maltophilia is warranted. These organisms occur later in the course of mechanical ventilation,82 usually in the presence of previous antibiotic therapy,69,83,84 and are independently associated with poor outcome.4,8,9,57,62,72,73 Trouillet and coworkers75 prospectively studied 135 patients with ventilator-associated pneumonia, comparing episodes caused by these high-risk bacteria (including methicillin-resistant Staphylococcus aureus) with those secondary to other pathogens. By multivariate analysis, duration of ventilation before pneumonia onset and previous broad spectrum antibiotic drug use were the only factors associated with high-risk organisms. Moreover, in 84 patients ventilated for 7 days or longer with previous antibiotic exposure, an empirical triple-drug regimen including vancomycin was required to obtain acceptable antimicrobial activity in 88% of episodes. With this sort of data in mind, the American Thoracic Society guidelines85 recommend expanded coverage for these organisms in the presence of 5 days or more of hospitalization before pneumonia onset, previous antibiotic treatment, corticosteroid use, structural lung disease, and immunosuppression.