Are epidemiologic cut-off values predictors of the in vivo efficacy of azoles in experimental aspergillosis?

2012 ◽  
Vol 74 (2) ◽  
pp. 158-165 ◽  
Author(s):  
Enrique Calvo ◽  
F. Javier Pastor ◽  
Deanna A. Sutton ◽  
Anette W. Fothergill ◽  
Michael G. Rinaldi ◽  
...  
Keyword(s):  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pierre Santucci ◽  
Daniel J. Greenwood ◽  
Antony Fearns ◽  
Kai Chen ◽  
Haibo Jiang ◽  
...  

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.


2021 ◽  
Author(s):  
L Giacani ◽  
A Haynes ◽  
M Vall Mayans ◽  
M Ubals Cazorla ◽  
C Nieto ◽  
...  

Author(s):  
Jerzy Karczewski ◽  
Christine M Brown ◽  
Yukari Maezato ◽  
Stephen P Krasucki ◽  
Stephen J Streatfield

Abstract Objectives To evaluate the efficacy of a novel lantibiotic, CMB001, against MRSA biofilms in vitro and in an in vivo experimental model of bacterial infection. Methods Antibacterial activity of CMB001 was measured in vitro after its exposure to whole blood or to platelet-poor plasma. In vitro efficacy of CMB001 against a Staphylococcus aureus biofilm was studied using scanning electron microscopy. The maximum tolerable dose in mice was determined and a preliminary pharmacokinetic analysis for CMB001 was performed in mice. In vivo efficacy was evaluated in a neutropenic mouse thigh model of infection. Results CMB001 maintained its antibacterial activity in the presence of blood or plasma for up to 24 h at 37°C. CMB001 efficiently killed S. aureus within the biofilm by causing significant damage to the bacterial cell wall. The maximum tolerable dose in mice was established to be 10 mg/kg and could be increased to 30 mg/kg in mice pretreated with antihistamines. In neutropenic mice infected with MRSA, treatment with CMB001 reduced the bacterial burden with an efficacy equivalent to that of vancomycin. Conclusions CMB001 offers potential as an alternative treatment option to combat MRSA. It will be of interest to evaluate the in vivo efficacy of CMB001 against infections caused by other pathogens, including Clostridioides difficile and Acinetobacter baumannii, and to expand its pharmacokinetic/pharmacodynamic parameters and safety profile.


2019 ◽  
Vol 25 (18) ◽  
pp. 5686-5701 ◽  
Author(s):  
Fernanda Faião-Flores ◽  
Michael F. Emmons ◽  
Michael A. Durante ◽  
Fumi Kinose ◽  
Biswarup Saha ◽  
...  

ChemInform ◽  
2015 ◽  
Vol 46 (15) ◽  
pp. no-no
Author(s):  
Tim S. Bugni ◽  
et al. et al.
Keyword(s):  

2011 ◽  
Vol 21 (8) ◽  
pp. 2359-2364 ◽  
Author(s):  
Peter J. Manley ◽  
Amy Zartman ◽  
Daniel V. Paone ◽  
Christopher S. Burgey ◽  
Darrell A. Henze ◽  
...  

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