Bacterial lower respiratory tract infection (BLRTI) is relatively common in patients requiring mechanical ventilation. Antibiotics have been used prophylactically and therapeutically for BLRTIs, including for ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT)., The pulmonary concentration of antibiotics is an important factor influencing clinical outcomes and the emergence of resistance. Meta-analyses of trials evaluating tigecycline have shown increased mortality relative to comparator antibiotics, including studies of hospital-associated pneumonia. The use of off-label high-dose tigecycline (100 mg every 12 hours) has been shown to achieve greater clinical cure rates when compared with both approved dosing and the comparator imipenem-cilastin, suggesting that underdosing of tigecycline contributed to the poor outcomes observed in prior studies. Similarly, ceftobiprole was compared with linezolid and ceftazidime in patients with hospital-acquired pneumonia/VAP and was found to be inferior, which was thought in large part to be due to underdosing in critically ill patients. Moreover, in vitro studies suggest that antibiotic concentrations less than a specific threshold, termed the mutation prevention concentration (MPC), can be associated with greater emergence of antibiotic resistance, which is particularly important in the lung, given the variable penetration of antibiotics into the epithelial lining fluid (Fig 1)., Taken together, these data support the premise that antibiotic delivery to the lung is a key determinant of clinical cure and emergence of resistance.