Penetration of Anti-Infective Agents into Pulmonary Epithelial Lining Fluid
University of Illinois at Chicago, USA.Clinical Pharmacokinetics (Impact Factor: 5.05). 10/2011; 50(10):637-64. DOI: 10.2165/11594090-000000000-00000
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.
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- "Contemporary thought on the newer 'longer acting' injectable macrolides in veterinary medicine is that the most important index is AUC/MIC. However, intense debate remains whether this should be measured and reported for plasma (Toutain, 2009; Papich, 2014), at the site of infection (Amsden, 2001; Evans, 2005) or both (Rodvold et al., 2011). Although not statistically significant, the marginally significant association between plasma PKPD indices and treatment outcome (P = 0.10) would seem to substantiate the claims of using plasma drug concentrations. "
ABSTRACT: The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran(®) ) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362-592 lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M. haemolytica (n = 287) and P. multocida (n = 257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16 μg/mL. A two-compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time-concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC24 /MIC, AUC∞ /MIC, CMAX /MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M. haemolytica and P. multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. A significant association was found between treatment success and PELF AUC0-24 /MIC for P. multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes.Journal of Veterinary Pharmacology and Therapeutics 10/2015; DOI:10.1111/jvp.12267 · 1.19 Impact Factor
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- "a widely used technique for collecting the ELF to determine sufficient drug concentrations achieved at the infected site. This technique has been commonly applied to antibacterial agents (Rodvold et al., 2011a) and is also recently applicable to other anti-infective agents, such as antifungal, antitubercular, antiparasitic, and antiviral agents (Rodvold et al., 2011b). In the case of LO as well, it is likely that the ELF is a relevant site to determine drug concentrations from the standpoint of pharmacokinetic/pharmacodynamic relationship, considering viral surface location of the neuraminidase enzyme. "
ABSTRACT: Laninamivir octanoate (LO) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro in order to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 μmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 h post-dose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14)C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 μM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h(-1), which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery.Drug metabolism and disposition: the biological fate of chemicals 10/2012; 41(1). DOI:10.1124/dmd.112.048280 · 3.25 Impact Factor
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ABSTRACT: The critical role of pharmacokinetics and pharmacodynamics in the selection and dosing of antimicrobial therapeutics, including antifungal agents, has gained increasing recognition [1–4]. The study of pharmacokinetics involves understanding the interaction of a drug with the host, including measurements of absorption, distribution, metabolism, and elimination. The study of antimicrobial pharmacodynamics provides insight into the link between drug pharmacokinetics, in vitro susceptibility, and treatment outcome. Knowledge of the pharmacokinetic/pharmacodynamic index and magnitude associated with efficacy can be helpful for clinicians to predict therapeutic success/failure, guide optimal dosing levels and intervals, aid in susceptibility breakpoint development, guide therapeutic drug monitoring, and limit potential adverse outcomes, including toxicity and the development of resistance [5–8]. Numerous in vitro, animal, and clinical studies have been instrumental in characterizing the pharmacodynamic activity of the clinically available antifungal drug classes, including triazoles, polyenes, flucytosine, and echinocandins [6–18]. The analyses of data with these antifungal drug classes have identified distinct pharmacodynamic characteristics that result in different optimal dosing strategies. Accumulating clinical data have also become available with several antifungals that allow pharmacodynamic data analyses [19–25]. Most often the results of these investigations have corroborated information from experimental models. The following chapter outlines the pharmacodynamic characteristics of antifungals and presents evidence of the clinical relevance of these concepts.Cold Spring Harbor Perspectives in Medicine 01/2011; 5(5). DOI:10.1007/978-1-4419-6640-7_8 · 9.47 Impact Factor
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