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Pathogen-directed therapy targeting multidrug-resistant bacteria in pneumonia can be a challenge. We reviewed the recent literature on bacterial resistance, diagnostic methods, and treatment strategies to guide pathogen-directed therapy of respiratory infections.Antibiotic resistance is a growing problem in both community and nosocomial settings. Macrolide resistance in Streptococcus pneumoniae varies geographically, ranging from 45 to 88%, and has been associated with prior antibiotic use. Methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative bacilli remain the main targets for pathogen-directed therapy in patients with hospital-acquired and ventilator-associated pneumonia. Rapid molecular tests show promise to facilitate pathogen-directed therapy. Improved antibiotic use with the right drug and optimal dose is a key strategy in tackling antimicrobial resistance. Evidence supporting de-escalation for hospital-acquired and ventilator-associated pneumonia has been increasing. To date, no convincing evidence exists to support combination therapy for severe infections due to carbapenem-resistant Gram-negative bacilli. Aerosolized therapy might provide additive benefits to parenteral therapy, but requires further study.Pathogen-directed therapy guided by in-vitro microbiological data is a safe approach for the treatment of respiratory infections due to antibacterial-resistant bacteria. Further research should focus on the role of rapid diagnostic tools, new antibiotics, and novel immunotherapy for respiratory infection.