The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid

Abstract

Background: The rising prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) and the recent emergence of community-associated MRSA are major clinical, public health, and economic challenges. MRSA is a leading cause of nosocomial pneumonia and complicated skin and soft-tissue infections (cSSTI). Vancomycin and linezolid are two commonly used antimicrobial agents with activity against Gram-positive pathogens, particularly MRSA, that are used to treat both nosocomial pneumonia and cSSTI. Recently, the therapeutic efficacy of vancomycin in the treatment of hospitalized patients with MRSA infections has been questioned due to the emergence of MRSA strains with reduced susceptibility to vancomycin together with concerns related to inadequate dosing and poor tissue penetration of the drug.

Scope: A literature review was conducted to investigate the pharmacokinetics and pulmonary and tissue penetration of vancomycin and linezolid. Using MEDLINE and EMBASE, the most relevant articles in English published over the past 25 years (up to October 2008) were identified and summarized. Studies in human volunteers and adult patients that measured concentrations of antibiotic in serum, epithelial lining fluid (ELF), and tissue were selected for further review.

Findings: For both drugs, pharmacokinetic studies were conducted in diverse patient populations and employed varying techniques to measure tissue concentrations. Vancomycin concentrations in ELF ranged from 5 to 25% of simultaneous plasma levels, while concentrations in whole homogenized lung tissue were slightly higher (24-41%). Distribution of vancomycin into soft tissue was variable. For linezolid, overall mean concentrations in ELF and in soft tissue were generally similar or higher than simultaneous plasma levels, although variability in tissue penetration across studies in healthy volunteers and patients was seen.

Limitations: The studies included in this review vary greatly in their designs and patient populations; this, together with methodologic difficulties, limits the interpretation of the data.

Conclusions: In the absence of clinical data correlating ELF concentrations and clinical outcome, the clinical significance of differences in pulmonary penetration of vancomycin and linezolid is unknown. Higher vancomycin serum concentrations may be necessary to achieve appropriate lung concentrations to optimize treatment outcomes. Linezolid demonstrates adequate penetration into lung and other soft issues with sustained concentrations above the minimum inhibitory concentrations for susceptible pathogens, including MRSA, for the majority of the dosing interval. Examination of the pharmacokinetic data adds insights not provided by the clinical trial data and together provides clinicians with a more comprehensive basis for selecting appropriate antimicrobial therapy for the treatment of serious MRSA infections.