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To study microbial and susceptibility patterns and antimicrobial treatment responses in patients with severe, acute exacerbations of chronic obstructive pulmonary disease requiring mechanical ventilation.Microbial investigation using tracheobronchial aspirates, bronchoscopy with a protected specimen brush, and bronchoalveolar lavage, as well as paired serologies. Evaluation of antimicrobial treatment by results of the initial investigation, susceptibility testing, and a repeated microbial investigation (tracheobronchial aspirates, bronchoscopy with a protected specimen brush, and bronchoalveolar lavage) after 72 hrs.A respiratory intensive care unit of a 1,000-bed teaching hospital.Fifty severely exacerbated and mechanically ventilated patients with chronic obstructive pulmonary disease.Initial empirical antimicrobial treatment according to clinical judgment.Overall, 36 of 50 patients (72%) had evidence of a microbial origin. Community-acquired endogenous pathogens were present in 70% of patients, and Gram-negative enteric bacilli andPseudomonas/Stenotrophomonasspecies were present in 30%. All five isolates ofStreptococcus pneumoniaewere resistant to penicillin (three intermediately and two highly), and three were resistant to multiple antibiotics.Pseudomonasspecies revealed multiresistance in four of nine isolates (44%), andStenotrophomonas maltophiliarevealed multiresistance in one of two isolates. Antimicrobial treatment was modified according to diagnostic results in 11 of 31 patients (36%) with potentially pathogenic microorganisms. In patients who underwent a repeat investigation after 72 hrs, 24% of the initially present and potentially pathogenic microorganisms persisted. Inappropriate initial antimicrobial therapy was associated significantly with bacterial persistence (p< .002).Considering the diversity of microbial pathogens and the resistance rates especially toS. pneumoniaein this patient population, antimicrobial treatment should be based on the constant study of local microbial and susceptibility patterns along with routine microbial investigation of the individual patient.