Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents.

University of Illinois at Chicago, USA.
Clinical Pharmacokinetics (Impact Factor: 5.49). 10/2011; 50(10):637-64. DOI: 10.2165/11594090-000000000-00000
Source: PubMed

ABSTRACT The exposure-response relationship of anti-infective agents at the site of infection is currently being re-examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial activity against lung infections caused by extracellular pathogens. There have been an extensive number of studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug concentrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1. Potential explanations (e.g. drug transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration occur among antibacterial classes need further investigation. The relationship between ELF concentrations and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pathogens and to explain why selected anti-infective agents (e.g. those with ELF to plasma concentration ratios of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques have also allowed further examination of drug doses and differences in the time courses of ELF and plasma concentrations as potential explanations for clinical and microbiological effects seen in clinical trials. Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic parameters.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: To discuss controversies surrounding antimicrobial use in critically ill horses. PubMed searches from 1970-present for terms including, but not limited to: "horse," "foal," "antimicrobial," "prophylaxis," "infection," "surgery," "sepsis," and "antimicrobial resistance." Increasing bacterial antimicrobial resistance has changed first-line antimicrobial choices and prompted shortening of the duration of prophylactic and therapeutic treatment. The need to decrease bacterial resistance development to critically important antimicrobials has been highlighted. Veterinary medicine has followed a similar trend but often without a high-level evidence. Common dilemmas include diseases in which the theoretically most effective drug is a reserved antimicrobial, the inability to differentiate infectious from noninfectious disease, the duration and necessity of prophylactic antimicrobials and use of antimicrobials in primary gastrointestinal disease. These problems are illustrated using examples of purulent infections, neonatal sepsis, colic surgery, and treatment of colitis. Although enrofloxacin, cephalosporins, and doxycycline, in contrast to gentamicin, reach therapeutic concentrations within the lungs of healthy horses, the first two should not be used as first line treatment due to their reserved status. Due to the high risk of bacterial sepsis, antimicrobial treatment remains indispensable in compromised neonatal foals but shortening the length of antimicrobial treatment might be prudent. One prospective randomized study demonstrated no difference between 3 and 5 days of perioperative antimicrobial treatment in colic surgery but shorter durations were not evaluated. High-level evidence to recommend antimicrobial treatment of adult horses with undifferentiated diarrhea does not exist. Few evidence-based recommendations can be made. Commonly used antimicrobial combinations remain the mainstay for treating purulent infections. Antimicrobial treatment for compromised foals should not extend beyond recovery. Continuation of prophylactic antimicrobials >3 days is likely unnecessary after colic surgery; shorter durations might be equally effective. Antimicrobial prophylaxis in adult horses with diarrhea is unlikely to be beneficial. © Veterinary Emergency and Critical Care Society 2015.
    01/2015; 25(1). DOI:10.1111/vec.12275
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of the study was to develop a drug-unspecific approach to pharmacometric modeling for predicting the rate and extent of distribution from plasma to epithelial lining fluid (ELF) and alveolar cells (AC) for data emanating from studies involving bronchoalveolar lavage (BAL) sampling, using rifampicin (RIF) as an example. Data consisting of RIF plasma concentrations sampled at approximately 2 and 4 h postdose and ELF and AC concentrations quantified from one BAL sample, taken at approximately 4 h postdose, in 40 adult subjects without tuberculosis was used as an example for model development. This study emphasized the usage of drug-specific plasma pharmacokinetics (PK) for a correct characterization of plasma to pulmonary distribution. As such, RIF PK was described using absorption transit compartments and a one compartment distribution model coupled with an enzyme turn-over model. The ELF and AC distribution model consisted of characterization of the rate of distribution of drug from plasma to ELF and AC by two distribution rate constant, k ELF and k AC, respectively. The extent of distribution to ELF and AC was described by unbound ELF/plasma concentration ratio (R ELF/unbound-plasma) and unbound AC/plasma concentration ratio (R AC/unbound-plasma) which typical values were predicted to be 1.28 and 5.5, respectively. The model together with a drug-specific plasma PK description provides a tool for handling data from both single and multiple BAL sampling designs and directly predicts the rate and extent of distribution from plasma to ELF and AC. The model can be further used to investigate design aspects of optimized BAL studies.
    European Journal of Clinical Pharmacology 01/2015; 71(3). DOI:10.1007/s00228-014-1798-3 · 2.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Staphylococcus aureus, including methicillin-susceptible (MSSA) and resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1g q12h), ceftaroline (600mg q12h and q8h), and ceftriaxone (2g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72h with a starting inoculum of ∼10(6) CFU/mL. Time-kill curves were constructed and microbiological response (change in log10CFU/mL from 0h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72h log10CFU/mL was largest for ceftaroline q8h (> 3 log10CFU/mL-reductions against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log10CFU/mL, while the activity of ceftaroline q12h was more variable (0.2 to 2.3 log10CFU/mL-reductions against 3 of 4 strains). Ceftriaxone (both regimens) were poorly active against MSSA tested (0.1 reduction to 1.8 log10CFU/mL increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600mg q8h exhibited improved antibacterial activity compared with ceftaroline 600mg q12h and vancomycin, and deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia.
    Antimicrobial Agents and Chemotherapy 10/2014; 58(12). DOI:10.1128/AAC.03742-14 · 4.45 Impact Factor