A model of cefoperazone tissue penetration: diffusion coefficient and protein binding

Meulemans, A.

doi:10.1128/aac.36.2.295

Cited by 8 publications

(3 citation statements)

References 16 publications

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“…It is widely accepted that only the free fraction can act against bacteria, but the direct effects of protein binding have not been clearly established (25). However, it may be that the protein-bound fraction, although not directly active, may act as a readily available reservoir, as has been suggested for other antibiotics (16).…”

Section: Discussionmentioning

confidence: 99%

Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients

Lamer

Beco

Stolzmann

et al. 1993

Antimicrob Agents Chemother

273

173

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Vancomycin penetration into the fluid lining the epithelial surface of the lower respiratory tract was studied by performing fiberoptic bronchoscopy with bronchoalveolar lavage on 14 critically ill, ventilated patients who had received the drug for at least 5 days. The apparent volume of epithelial lining fluid (ELF) recovered by bronchoalveolar lavage was determined by using urea as an endogenous marker. Vancomycin levels in ELF ranged from 0.4 to 8.1 ,ug/ml (mean, 4.5 ,iglml), while the mean simultaneous level of the drug in plasma was 24 ,ug/ml (range, 9 to 37.4 ,ug/ml). There was a significant relationship (r = 0.64, P < 0.02) between vancomycin levels in plasma and those in ELF, with a correlation whose slope (0.15) indicated that the blood-to-ELF ratio of drug penetration was 6:1. Using the albumin concentration in ELF as a marker of lung inflammation, we found that vancomycin penetration was higher in patients with ELF albumin values of >3.4 mg/ml than in patients with normal values (<3.4 mg/ml) (P < 0.02). These results suggest that the vancomycin distribution includes the ELF of the lower respiratory tract at a concentration that is dependent upon the levels in blood and the alveolar capillary membrane protein permeability. These concentrations were well above the MICs for most staphylococci and enterococci.Vancomycin, a glycopeptide antibiotic, is used worldwide to treat deep-seated gram-positive bacterial infections caused by staphylococci or enterococci resistant to 1-lactams or patients with significant allergy to ,B-lactams (18, 29). These pathogens may be responsible for nosocomial pneumonia, which is a common and life-threatening problem complicating the management of patients receiving mechanical ventilation (24). Successful treatment of bacterial pneumonia will, however, depend upon adequate delivery of the antibiotic to the area of infection. Unfortunately, little is known about the penetration of vancomycin into lung tissue.With the advent of the technique of bronchoalveolar lavage (BAL), it is now possible to directly obtain a sample of the fluid and cells lining the epithelial surface of the human lower respiratory tract (4, 21). Therefore, in an attempt to quantify the penetration of vancomycin into lung alveoli, we obtained both BAL fluid and blood samples from critically ill patients who were receiving this antibiotic as part of their therapy. In addition, we investigated whether vancomycin penetration was modified by the inflammatory status of the lung.( chanically ventilated and, because of the presence of a new pulmonary infiltrate with fever and/or purulent tracheal secretions, underwent flexible fiberoptic bronchoscopy with a protected specimen brush (PSB) and BAL a few days later, after the initiation of treatment with vancomycin. For each patient, the following clinical variables were recorded: age, sex, weight, disease severity score on admission (as assessed by the APACHE II score) (13), creatinine clearance, and lung injury score as previously described by Murray et al. (17). E...

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Section: Discussionmentioning

confidence: 99%

Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients

Lamer

Beco

Stolzmann

et al. 1993

Antimicrob Agents Chemother

273

173

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“…Another study (418) used enzyme-modified carbon fiber microelectrodes and RTP to measure choline diffusion in the rat caudate (striatum) and hypothalamus, obtaining λ ~ 1.8; however, this slice study suffered from technical limitations (see 150). Finally, we note that Meulemans (227, 228) used voltammetric methods to attempt to measure concentration profiles for an antibiotic and for nitric oxide (NO) in rat brain tissue and estimate effective diffusion coefficients. Quantitative measurements of NO are difficult but Zacharia and Deen (424) have established values for D in water and saline solutions.…”

Section: Methods Of Measurementmentioning

confidence: 99%

Diffusion in Brain Extracellular Space

Syková

Nicholson²

2008

Physiological Reviews

1,240

1,452

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Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix, and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is ∼20% and the tortuosity is ∼1.6 (i.e., free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge, and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases, and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties is valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.

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“…In a healthy and well vascularized tissue, the inter-capillary distance is about 100-200 µm (Casley- Smith et al 1976), and so the infection site cannot be further than x % 100 µm from the nearest capillary (drug source). The estimates on the diffusion constants of antibiotics in tissues vary (Meulemans 1992;Meulemans et al 1989), but the lower limit is D ¼ 10 À7 cm 2 =s ¼ 10 lm 2 =s. 4 The mutation probability µ ranges from 10 À9 to 10 À7 , depending on the antibiotic and bacterial strain (Lee et al 2012;Oliver et al 2000).…”

Section: Real Infectionsmentioning

confidence: 99%

Evolution of Drug Resistance in Bacteria

Waclaw

2016

Advances in Experimental Medicine and Biology

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Resistance to antibiotics is an important and timely problem of contemporary medicine. Rapid evolution of resistant bacteria calls for new preventive measures to slow down this process, and a longer-term progress cannot be achieved without a good understanding of the mechanisms through which drug resistance is acquired and spreads in microbial populations. Here, we discuss recent experimental and theoretical advances in our knowledge how the dynamics of microbial populations affects the evolution of antibiotic resistance . We focus on the role of spatial and temporal drug gradients and show that in certain situations bacteria can evolve de novo resistance within hours. We identify factors that lead to such rapid onset of resistance and discuss their relevance for bacterial infections.

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A model of cefoperazone tissue penetration: diffusion coefficient and protein binding

Cited by 8 publications

References 16 publications

Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients

Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients

Diffusion in Brain Extracellular Space

Evolution of Drug Resistance in Bacteria

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