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Vancomycin as the drug of choice for treatment of methicillin‐resistant Staphylococcus aureus (MRSA) pneumonia has been called into question on the basis of therapeutic failures. In patients with MRSA pneumonia, treatment failures are probably due to the complex interplay of variables affecting the host‐antimicrobial‐pathogen interrelationship. However, it has been suggested that decreased penetration of vancomycin into the lungs may contribute. This review explores physiochemical and physiologic variables that affect pulmonary penetration and describes methods used in quantifying pulmonary vancomycin concentrations. Most important, findings are evaluated in the clinical context of the chemotherapeutic options available for treatment of MRSA pneumonia. The possibility of increased serum vancomycin concentrations as a method to optimize current treatment outcomes is also explored.