Linked Life Data

20231389

Source:http://linkedlifedata.com/resource/pubmed/id/20231389

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-4-20
pubmed:abstractText
Ethambutol, together with a macrolide, is the backbone for treatment of disseminated Mycobacterium avium disease. However, at the standard dose of 15 mg/kg of body weight/day, ethambutol efficacy is limited. In addition, susceptibility breakpoints have consistently failed to predict clinical outcome. We performed dose-effect studies with extracellular M. avium as well as with bacilli within human macrophages. The maximal kill rate (E(max)) for ethambutol against extracellular bacilli was 5.54 log(10) CFU/ml, compared to 0.67 log(10) CFU/ml for intracellular M. avium, after 7 days of exposure. Thus, extracellular assays demonstrated high efficacy. We created a hollow-fiber system model of intracellular M. avium and performed microbial pharmacokinetic-pharmacodynamic studies using pharmacokinetics similar to those of ethambutol for humans. The E(max) in the systems was 0.79 log(10) CFU/ml with 7 days of daily therapy, so the kill rates approximated those encountered in patients treated with ethambutol monotherapy. Ratio of peak concentration to MIC (C(max)/MIC) was linked to microbial kill rate. The C(max)/MIC ratio needed to achieve the 90% effective concentration (EC(90)) in serum was 1.23, with a calculated intramacrophage C(max)/MIC ratio of 13. In 10,000 patient Monte Carlo simulations, doses of 15, 50, and 75 mg/kg achieved the EC(90) in 35.50%, 76.81%, and 86.12% of patients, respectively. Therefore, ethambutol doses of >or=50 mg/kg twice a week would be predicted to be better than current doses of 15 mg/kg for treatment of disseminated M. avium disease. New susceptibility breakpoints and critical concentrations of 1 to 2 mg/liter were identified for the determination of ethambutol-resistant M. avium in Middlebrook broth. Given that the modal MIC of clinical isolates is around 2 mg/liter, most isolates should be considered ethambutol resistant.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1098-6596
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
54
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1728-33
pubmed:dateRevised
2010-11-2
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Ethambutol optimal clinical dose and susceptibility breakpoint identification by use of a novel pharmacokinetic-pharmacodynamic model of disseminated intracellular Mycobacterium avium.
pubmed:affiliation
Division of Infectious Diseases, UT Southwestern Medical Center, Dallas, TX 75390-9113, USA.
pubmed:publicationType
Journal Article