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The Significance of Serum vs Tissue Levels of Antibiotics in the Treatment of Penicillin-Resistant Streptococcus pneumoniae and Community-Acquired Pneumonia*: Are We Looking in the Wrong Place?

Robert E. Siegel, MD, FCCP
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*From the Pulmonary Section, Bronx Veterans Affairs Medical Center, Bronx, NY.

Correspondence to: Robert E. Siegel, MD, FCCP, Associate Chief, Pulmonary Section, Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468; e-mail: siegel.robert@bronx.va.gov



Chest. 1999;116(2):535-538. doi:10.1378/chest.116.2.535
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Extract

Abbreviations: CAP = community-acquired pneumonia; MDRSP = multidrug-resistant Streptococcus pneumoniae; MIC = minimal inhibitory concentration; PRSP = penicillin-resistant Streptococcus pneumoniae

When treating serious infections, the emphasis has traditionally been placed on establishing and sustaining serum antimicrobial levels above the minimal inhibitory concentration (MIC) for likely infecting pathogens, in order to eradicate the infection. This is particularly true withβ -lactam and macrolide antibiotics, which kill on the basis of time-dependent kinetics, or on time-serum levels that are maintained above the MIC. These antibiotics do not exhibit concentration-dependent killing or sustained killing when serum levels fall below the MIC, as seen with aminoglycosides and fluoroquinolones. The issue of maintaining high serum levels is crucial in intravascular infections, such as endocarditis, or in infections in tissues in which antibiotic penetration is poor, such as meningitis. The lung is a highly vascular organ in which many antibiotics concentrate above serum levels. Antibiotics follow a concentration gradient from serum to extracellular fluid to intracellular site. Macrolides, in particular, as well as fluoroquinolone antibiotics accumulate in lung tissue, in macrophages, and in neutrophils at levels above those in the serum.1 For intracellular pathogens, such as Legionella, intracellular antibiotic concentrations may be the most important determinant of outcome. For extracellular pathogens, such as pneumococci, the most crucial sites for antibiotic accumulation may be the extracellular fluid and the alveolar-lining fluid. Studies that utilize bronchial mucosal biopsies or animal infection models demonstrate that β-lactam antibiotics accumulate in lung tissue at levels that are close to or slightly below serum levels. However, models of inflammation and infection have not been adequately studied to determine the antibiotic penetration into the site of infection.1 In addition, the clearance of antibiotics from the alveolar-lining fluid has also not been studied sufficiently to determine the effect of infection on local drug levels.2 Clinical results in pneumonia may depend more on tissue penetration and accumulation in the infected lung than on serum levels. This might explain two recent observations in the treatment of pneumonia: (1) the lack of clinically observed treatment failures with β-lactam or macrolide antibiotic therapy despite an epidemic of penicillin-resistant Streptococcus pneumoniae (PRSP) and multidrug-resistant Streptococcus pneumoniae (MDRSP); and (2) the success of ultrashort IV antibiotic treatment regimens, with rapid oral switch, for hospitalized patients with moderately severe community-acquired pneumonia (CAP).

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