The Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Authorsvan Rijn, Sander P
Wessels, Mireille A
van Soolingen, Dick
Alffenaar, Jan-Willem C
MetadataShow full item record
TitleThe Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing.
Published inAntimicrob Agents Chemother 2017, 61(9) pii: e02039-16
PubliekssamenvattingCarbapenems are now being explored for treatment of multidrug-resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day and the lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once-a-day dose for clinical use. We utilized the hollow-fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid maximum-effect (Emax) modeling was used to identify the relationship between total bacterial burden and the drug exposure and to identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose fractionation hollow-fiber study, efficacy was linked to percentage of the 24-h dosing interval of ertapenem concentration persisting above MIC (%TMIC). We performed 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed a %TMIC of ≥40%. We identified an intravenous dosage of 2 g once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC of 2 mg/liter was identified for that dose. An ertapenem dosage of 2 g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.
- Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis.
- Authors: van Rijn SP, Zuur MA, van Altena R, Akkerman OW, Proost JH, de Lange WC, Kerstjens HA, Touw DJ, van der Werf TS, Kosterink JG, Alffenaar JW
- Issue date: 2017 Apr
- Meropenem-clavulanate has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis.
- Authors: Davies Forsman L, Giske CG, Bruchfeld J, Schön T, Juréen P, Ängeby K
- Issue date: 2015 Mar
- Amikacin Optimal Exposure Targets in the Hollow-Fiber System Model of Tuberculosis.
- Authors: Srivastava S, Modongo C, Siyambalapitiyage Dona CW, Pasipanodya JG, Deshpande D, Gumbo T
- Issue date: 2016 Oct
- A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.
- Authors: Deshpande D, Srivastava S, Nuermberger E, Pasipanodya JG, Swaminathan S, Gumbo T
- Issue date: 2016 Nov 1
- Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis.
- Authors: Srivastava S, Magombedze G, Koeuth T, Sherman C, Pasipanodya JG, Raj P, Wakeland E, Deshpande D, Gumbo T
- Issue date: 2017 Aug