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Effective antibiotic drug dosing for Pneumonia – beyond plasma levels
Pneumonia remains a global healthcare challenge associated with substantial morbidity and mortality. Antimicrobial therapy is the primary intervention used by clinicians, but variable effectiveness exists which in part can be related sub-optimal dosing. To be maximally effective, antimicrobial dosing should ensure therapeutic concentrations at the site of infection, which in the context of pneumonia, is measured in the epithelial lining fluid (ELF). Of course, defining which concentration is ‘therapeutic’ is affected by the susceptibility of the pathogen to the antimicrobial (pharmacodynamics). Concentrations in the ELF for most antimicrobial are affected by typical factors like renal function and body size, as well as sickness severity, lung inflammation and presence of fibrosis from chronic pathologies like chronic obstructive airways disease. Careful interpretation of data is also important as concentration-time profiles in the lung do not match plasma and so singular time-point comparisons can provided misleading estimates of drug penetration. Available data demonstrates highly variable antimicrobial exposures in ELF, both between antimicrobials and between patients receiving the same antimicrobial. Antimicrobials considered to have consistently adequate penetration into the lung include linezolid and macrolides like azithromycin. Beta-lactams have variable penetration (e.g. meropenem ELF exposure is <5% to >200% in ventilator associated pneumonia patients). Other drugs have low and variable penetration including glycopeptides, whilst the aminoglycosides have such low penetration that they are considered not a clinical option in monotherapy. The importance of antimicrobial penetration into the lung is being recognized by pharmaceutical industry, with some drugs like ceftolozane-tazobactam now having a pneumonia-specific dose which is twice the urinary tract and intra-abdominal infection doses to account for ~50% lung penetration.