In Journal of Antimicrobial Chemotherapy Mike Ruth, Jakko van Ingen and colleagues showed, using the hollow fiber pharmacodynamic model, that minocycline may be useful to treat pulmonary diseases caused by Mycobacterium avium complex bacteria. This opportunistic infection is increasing in prevalence and outcomes of current treatment regimens are very poor. Minocycline is an old, safe and well tolerated antibiotic that may improve treatment outcomes.Abstract
Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose.
Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10 000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients.
The MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments.
Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.
Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models.
Ruth MM, Magombedze G, Gumbo T, Bendet P, Sangen JJN, Zweijpfenning S, Hoefsloot W, Pennings L, Koeken VACM, Wertheim HFL, Lee PS, van Ingen J, Deshpande D.
Mike Ruth and Jakko van Ingen are members of theme Infectious disease and global health.
Want to know more about these subjects? Click on the buttons below for more news.
RIMLSNanomedicine Cancer development and immune defenseRare cancersTumors of the digestive tract Urological cancersWomen's cancersInfectious diseases and global healthInflammatory diseases Mitochondrial diseasesReconstructive and regenerative medicineRenal disorders Vascular damage
Related news items
4,8 million euros for prevention of tuberculosis among people with diabetes in Africa16 July 2019
Reinout van Crevel and Lindsey te Brake have received European funding of 4.8 million euros to lead an international consortium to screen thousands of people with diabetes in Uganda and Tanzania for TB, and investigate the effect and costs of 3 months preventive treatment for TB.read more
Handbook of biomarkers and precision medicine a new publication by Alain van Gool12 July 2019
Alain van Gool published a new handbook on biomarkers and applications in (pre)clinical drug development for precision medicine.read more
The real impact of menstrual complaints on work and school productivity8 July 2019
Menstrual period symptoms may be linked to nearly nine days of lost productivity every year, through presenteeism, suggests the largest study of its kind, published in the journal BMJ Open. But the real impact on women and society is underestimated and poorly appreciated, say the researchers.read more
Walking for science Research by Radboud university medical center and Radboud University during the Vierdaagse (Four Day Marches)5 July 2019
The Vierdaagse is a unique opportunity to conduct research into physical activity and healthy lifestyle.read more
Prostate cancer theranostics imaging, surgical guidance, and targeted photodynamic therapy5 July 2019
In Theranostics, Mark Rijpkema and colleagues present the development of a novel multimodal tracer that targets both preoperative imaging, surgical guidance, and targeted photodynamic therapy of PSMA-expressing prostate cancer.read more