scholarly journals Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model

2006 ◽  
Vol 57 (5) ◽  
pp. 883-890 ◽  
Author(s):  
Hoang Anh Nguyen ◽  
Jean Grellet ◽  
Delphine Paillard ◽  
Véronique Dubois ◽  
Claudine Quentin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Intracellular Activity ◽  
Factors Influencing

scholarly journals Cellular Pharmacokinetics and Intracellular Activity of the Novel Peptide Deformylase Inhibitor GSK1322322 against Staphylococcus aureus Laboratory and Clinical Strains with Various Resistance Phenotypes: Studies with Human THP-1 Monocytes and J774 Murine Macrophages

2015 ◽  
Vol 59 (9) ◽  
pp. 5747-5760 ◽  
Author(s):  
Frédéric Peyrusson ◽  
Deborah Butler ◽  
Paul M. Tulkens ◽  
Françoise Van Bambeke
Keyword(s):  
Staphylococcus Aureus ◽  
Peptide Deformylase ◽  
Cell Fractionation ◽  
Content Type ◽  
Clinical Strains ◽  
Cellular Pharmacokinetics ◽  
Intracellular Activity ◽  
Static Concentration ◽  
Infected Cells

ABSTRACTGSK1322322 is a peptide deformylase inhibitor active againstStaphylococcus aureusstrains resistant to currently marketed antibiotics. Our aim was to assess the activity of GSK1322322 against intracellularS. aureususing anin vitropharmacodynamic model and, in parallel, to examine its cellular pharmacokinetics and intracellular disposition. For intracellular activity analysis, we used an established model of human THP-1 monocytes and tested one fully susceptibleS. aureusstrain (ATCC 25923) and 8 clinical strains with resistance to oxacillin, vancomycin, daptomycin, macrolides, clindamycin, linezolid, or moxifloxacin. Uptake, accumulation, release, and subcellular distribution (cell fractionation) of [14C]GSK1322322 were examined in uninfected murine J774 macrophages and uninfected and infected THP-1 monocytes. GSK1322322 demonstrated a uniform activity against the intracellular forms of allS. aureusstrains tested, disregarding their resistance phenotypes, with a maximal relative efficacy (Emax) of a 0.5 to 1 log10CFU decrease compared to the original inoculum within 24 h and a static concentration (Cs) close to its MIC in broth. Influx and efflux were very fast (<5 min to equilibrium), and accumulation was about 4-fold, with no or a minimal effect of the broad-spectrum eukaryotic efflux transporter inhibitors gemfibrozil and verapamil. GSK1322322 was recovered in the cell-soluble fraction and was dissociated from the main subcellular organelles and from bacteria (in infected cells). The results of this study show that GSK1322322, as a typical novel deformylase inhibitor, may act against intracellular forms ofS. aureus. They also suggest that GSK1322322 has the ability to freely diffuse into and out of eukaryotic cells as well as within subcellular compartments.

scholarly journals Antimicrobial Activity against Intraosteoblastic Staphylococcus aureus

2015 ◽  
Vol 59 (4) ◽  
pp. 2029-2036 ◽  
Author(s):  
Florent Valour ◽  
Sophie Trouillet-Assant ◽  
Natacha Riffard ◽  
Jason Tasse ◽  
Sacha Flammier ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Ex Vivo ◽  
Joint Infection ◽  
Treatment Strategies ◽  
Bactericidal Effect ◽  
Infection Model ◽  
Content Type ◽  
Intracellular Activity ◽  
Mg63 Cells ◽  
Choice Of Treatment

ABSTRACTAlthoughStaphylococcus aureuspersistence in osteoblasts, partly as small-colony variants (SCVs), can contribute to bone and joint infection (BJI) relapses, the intracellular activity of antimicrobials is not currently considered in the choice of treatment strategies for BJI. Here, antistaphylococcal antimicrobials were evaluated for their intraosteoblastic activity and their impact on the intracellular emergence of SCVs in anex vivoosteoblast infection model. Osteoblastic MG63 cells were infected for 2 h with HG001S. aureus. After killing the remaining extracellular bacteria with lysostaphin, infected cells were incubated for 24 h with antimicrobials at the intraosseous concentrations reached with standard therapeutic doses. Intracellular bacteria and SCVs were then quantified by plating cell lysates. A bactericidal effect was observed with fosfomycin, linezolid, tigecycline, oxacillin, rifampin, ofloxacin, and clindamycin, with reductions in the intracellular inocula of −2.5, −3.1, −3.9, −4.2, −4.9, −4.9, and −5.2 log10CFU/100,000 cells, respectively (P< 10−4). Conversely, a bacteriostatic effect was observed with ceftaroline and teicoplanin, whereas vancomycin and daptomycin had no significant impact on intracellular bacterial growth. Ofloxacin, daptomycin, and vancomycin significantly limited intracellular SCV emergence. Overall, ofloxacin was the only molecule to combine an excellent intracellular activity while limiting the emergence of SCVs. These data provide a basis for refining the choice of antibiotics to prioritise in the management of BJI, justifying the combination of a fluoroquinolone for its intracellular activity with an anti-biofilm molecule, such as rifampin.

scholarly journals Increased intracellular activity of MP1102 and NZ2114 against Staphylococcus aureus in vitro and in vivo

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Xiao Wang ◽  
Xiumin Wang ◽  
Da Teng ◽  
Ruoyu Mao ◽  
Ya Hao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Intracellular Activity

scholarly journals Intracellular activity of trovafloxacin against Staphylococcus aureus

1999 ◽  
Vol 44 (2) ◽  
pp. 193-199 ◽  
Author(s):  
P. J. van den Broek ◽  
T. G. A. Koot ◽  
E. van Strijen ◽  
H. Mattie
Keyword(s):  
Staphylococcus Aureus ◽  
Intracellular Activity

scholarly journals Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in Human THP-1 Macrophages

2009 ◽  
Vol 53 (9) ◽  
pp. 3734-3743 ◽  
Author(s):  
Sandrine Lemaire ◽  
Françoise Van Bambeke ◽  
Paul M. Tulkens
Keyword(s):  
Staphylococcus Aureus ◽  
Listeria Monocytogenes ◽  
Legionella Pneumophila ◽  
Critical Role ◽  
Intracellular Accumulation ◽  
Cellular Accumulation ◽  
Intracellular Activity ◽  
P Glycoprotein

ABSTRACT CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages and Staphylococcus aureus (ATCC 25923 [methicillin (meticillin) sensitive]), Listeria monocytogenes (strain EGD), and Legionella pneumophila (ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of ≤6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (E max; approximately 1-log10-CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus than telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC50] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila, respectively. These differences in EC50s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here.

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