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I have read studies in which antibiotic concentrations in human lung are
measured by performing BAL during
bronchoscopy procedures. Is there an acceptable, less invasive way to
determine antibiotic levels in the
lung?
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Name: alexandra stirling
E-mail: alexandra stirling
Date: 07/29/98
Time: 14:18:10
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Date: Thu, 30 Jul 1998 16:41:43 -0400
From: ZHIHONG MENG
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: PharmPK Antibiotic concentrations in lung -Reply
Mime-Version: 1.0
yes, I think it is best way to do it. you can separate BAL whole fluid into
supernatant and pellet to measure the concentration inside of whole
fluid, supernatant and cells respectively.
meng
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From: "David Nix"
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Date: Thu, 30 Jul 1998 14:41:12 MST7
Subject: Re: PharmPK Antibiotic concentrations in lung
Priority: normal
Antimicrobial agent concentrations have been measured in sputum and
trachial aspirates, but the results are basically useless. These
samples contain nasal and oropharyngeal secretions in addition to
pulmonary secretions. Sputum may also remain in the lung for
prolonged periods of time before collection. There are also many
technical issues in the analytical handling of the samples.
In the past, lung tissue concentrations were frequently obtained
during surgical procedures, but these concentrations are difficult to
interpret since the concentration is measured from a tissue
homogenate. The ability of antimicrobials to enter cells greatly
influences the result. Whole tissue is not the site of infection.
BAL procedures allowed determination of more relavent concentrations
including concentrations in endothelial lining fluid (presumed site
of infection in pneumonia), bronchial mucosa (site of infection for
bronchitis), and alveolar macrophages (relevant for
bacteria that grow and survive in intracellular sites).
Unfortunantly, there is no easier way to measure concentration in the
lung that are relevant to antimicrobial therapy.
David Nix
The University of Arizona
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From:
Date: Thu, 30 Jul 1998 18:06:15 EDT
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Mime-Version: 1.0
Subject: Re: PharmPK Antibiotic concentrations in lung
Hi,
Yes there is, but is both expensive and technically demanding. It also only
(really) works for fluoroquinolones or other drugs with groups which have a
nice, clear NMR signal to allow distinction from the hydrogen background.
The group at Mass General/MIT/BI (Bob Rubin's group) have examined non-
invasive penetration into many tissues using an MRI technique. These studies
have been reported in Antimicrobial Agents and Chemotherapy.
I'm sorry, but I don't know of an other way to examine the issue of lung
penetration. Also, even when perfrming BAL, one has to be very careful to
simultaneously measure BAL and plasma urea to determine the drug dilution with
BAL. Further, one has to realize that many drugs commonly examined this way
have significant intracellular partitioning (particularly into WBC's) and some
(like azithromycin, for example) actually use theWBC as a "conduit" to
penetration to the infection site. This, of course, means that penetration
will differ significantly with an infection or other cause of local
inflammation. As most oftese studies are performed in normal volunteers, it
makes interpretation of the normal volunteer studies chalenging.
All the best.
George Drusano
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A microdialysis model has been established at our facility and I have just
started a project to measure the amount of a new antibiotic which penetrates
the lung. I think that microdialysis is well suited for antimicrobial levels
in any tissue because it measures free drug... which is what kills the bugs.
The problem comes with calibrating the probes... you need to know how well
the molecule crosses the probe membrane to accurately predict how much is in
the lung (compared to what you measure).
In vitro calibration is simple, but most certainly is not equivalent to in
vivo activity. Calibrating in vivo by loss (putting the drug in the
dialysate) is possible, but there is a difference between in vitro
calibration by loss and by gain (drug in surrounding fluid, dialysate clear)
so there is most certainly a difference in vivo. Drug availability limits
possibility of in vivo infusion to create constant levels for in vivo
calibration by gain.
Thus the utility of microdialysis seems limited, but at the discovery level
we are interested in the significance of pulmonary distribution, not the
actual levels. In vivo calibration and demonstration that lung levels are
significantly high compared to blood levels and/or muscle levels should be
sufficient to prove our claim of pulmonary infection efficacy (to push the
drug candidate to development).
Dave
dhellis.-at-.erinet.com
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In the past, our group has used microdialysis to measure free
concentrations of antibiotics in other tissues.
* Kovar, A., T. Dalla Costa, et al. (1996). "Comparison of Plasma
and Free Tissue Levels of Ceftriaxone in Rats by Microdyalisis."
J. of Pharm. Sci. 86(1): 52-56.
* Kovar, A., A. Nolting, et al. (1997). "[Microdialysis for the
determination of free drugs in tissues]." Pharm Unserer Zeit
26(1): 17-23.
* Muller, M., B. Rohde, et al. (1997). "Relationship between
serum and free interstitial concentrations of cefodizime and
cefpirome in muscle and subcutaneous adipose tissue of healthy
volunteers measured by microdialysis." J Clin Pharmacol 37(12):
1108-13.
* Nolting, A., T. Dalla Costa, et al. (1996). "Determination of
Free Extracellular Concentrations of Piperacillin by
Microdialysis." J Pharm Sci 85(4): 369-72.
Using microdialysis, we have actually measured concentrations of
antibiotics in both lung and muscle tissue in rats. The levels in
both tissues were almost identical. These results are going to be
presented at the AAPS meeting in the Symposium:
"Pharmacokinetic/Pharmacodynamic Evaluation of Anti-Infective
Therapy" (11/17/98) and also probably in a poster.
What seems a little more complicated is to do this in humans,
because the procedure involves puncturing the lung to introduce
the microdialysis probe.
Amparo de la Pe=F1a
University of Florida
email: adelap.-a-.grove.ufl.edu
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