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 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 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.

scholarly journals Influence of the Protein Kinase C Activator Phorbol Myristate Acetate on the Intracellular Activity of Antibiotics against Hemin- and Menadione-Auxotrophic Small-Colony Variant Mutants of Staphylococcus aureus and Their Wild-Type Parental Strain in Human THP-1 Cells

2012 ◽  
Vol 56 (12) ◽  
pp. 6166-6174 ◽  
Author(s):  
Laetitia G. Garcia ◽  
Sandrine Lemaire ◽  
Barbara C. Kahl ◽  
Karsten Becker ◽  
Richard A. Proctor ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Parental Strain ◽  
Wild Type ◽  
Content Type ◽  
Small Colony Variant ◽  
Intracellular Activity ◽  
Kinase C ◽  
Pharmacodynamic Profile ◽  
Small Colony ◽  
Intracellular Fate

ABSTRACTIn a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700–3711, 2012), we evaluated the intracellular fate ofmenDandhemBmutants (corresponding to menadione- and hemin-dependent small-colony variants, respectively) of the parental COL methicillin-resistantStaphylococcus aureusstrain and the pharmacodynamic profile of the intracellular activity of a series of antibiotics in human THP-1 monocytes. We have now examined the phagocytosis and intracellular persistence of the same strains in THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and measured the intracellular activity of gentamicin, moxifloxacin, and oritavancin in these cells. Postphagocytosis intracellular counts and intracellular survival were lower in PMA-activated cells, probably due to their higher killing capacities. Gentamicin and moxifloxacin showed a 5- to 7-fold higher potency (lower static concentrations) against the parental strain, itshemBmutant, and the genetically complemented strain in PMA-activated cells and against themenDstrain in both activated and nonactivated cells. This effect was inhibited when cells were incubated withN-acetylcysteine (a scavenger of oxidant species). In parallel, we observed that the MICs of these drugs were markedly reduced if bacteria had been preexposed to H2O2. In contrast, the intracellular potency of oritavancin was not different in activated and nonactivated cells and was not decreased by the addition ofN-acetylcysteine, regardless of the phenotype of the strains. The oritavancin MIC was also unaffected by preincubation of the bacteria with H2O2. Thus, activation of THP-1 cells by PMA may increase the intracellular potency of certain antibiotics (probably due to synergy with reactive oxygen species), but this effect cannot be generalized to all antibiotics.

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 Discrepancy between Uptake and Intracellular Activity of Moxifloxacin in a Staphylococcus aureus-Human THP-1 Monocytic Cell Model

2002 ◽  
Vol 46 (2) ◽  
pp. 288-293 ◽  
Author(s):  
Delphine Paillard ◽  
Jean Grellet ◽  
Véronique Dubois ◽  
Marie-Claude Saux ◽  
Claudine Quentin
Keyword(s):  
Staphylococcus Aureus ◽  
High Performance ◽  
Cell Model ◽  
Extracellular Fluid ◽  
Maximum Effect ◽  
Minimal Bactericidal Concentration ◽  
Monocytic Cell ◽  
Intracellular Activity ◽  
Mueller Hinton

ABSTRACT The correlation between uptake of moxifloxacin by THP-1, a continuous line of monocytic cells devoid of intrinsic bactericidal properties, and its activity against Staphylococcus aureus ATCC 25923, a susceptible reference strain (MIC and minimal bactericidal concentration of moxifloxacin, 0.1 mg/liter), was studied in a 5-h assay. The uptake of the drug, added to the culture medium at 0.2 to 32 mg/liter, was evaluated by high-performance liquid chromatography. The ratio of the cellular to extracellular concentration of moxifloxacin reached, at equilibrium, 4.36 ± 0.39 in uninfected cells and 6.25 ± 0.41 in infected cells. The intracellular activity of moxifloxacin, introduced into the extracellular fluid at 0.06 to 8 mg/liter, was determined by the enumeration of viable bacteria. At concentrations ≤0.2 mg/liter, the drug inhibited only the intracellular bacterial growth, while at concentrations ≥0.5 mg/liter, it decreased the bacterial inoculum by less than 1 log10 unit, with a maximum effect at 3 to 4 h, followed by regrowth of surviving bacteria to 80 to 120% of the original level at 5 h. In contrast, when killing curves were determined by using Mueller-Hinton broth with a similar inoculum (107 CFU/ml), moxifloxacin at concentrations ≥0.2 mg/liter reduced the inoculum by at least 3 log10 units at 3 to 4 h, leaving ≤0.1% survival at 24 h. Persisters exhibited a fluoroquinolone susceptibility identical to that of S. aureus ATCC 25923. Our data indicate that moxifloxacin at therapeutic extracellular concentrations accumulates approximately sixfold in infected THP-1 cells and remains active intracellularly, but significantly less active than under in vitro conditions.

scholarly journals Plectasin Shows Intracellular Activity against Staphylococcus aureus in Human THP-1 Monocytes and in a Mouse Peritonitis Model

2009 ◽  
Vol 53 (11) ◽  
pp. 4801-4808 ◽  
Author(s):  
Karoline Sidelmann Brinch ◽  
Anne Sandberg ◽  
Pierre Baudoux ◽  
Françoise Van Bambeke ◽  
Paul M. Tulkens ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Animal Studies ◽  
Kinetic Studies ◽  
Response To Therapy ◽  
In Vitro Studies ◽  
In Vivo Model ◽  
Intracellular Activity ◽  
Peritonitis Model

ABSTRACT Antimicrobial therapy of infections with Staphylococcus aureus can pose a challenge due to slow response to therapy and recurrence of infection. These treatment difficulties can partly be explained by intracellular survival of staphylococci, which is why the intracellular activity of antistaphylococcal compounds has received increased attention within recent years. The intracellular activity of plectasin, an antimicrobial peptide, against S. aureus was determined both in vitro and in vivo. In vitro studies using THP-1 monocytes showed that some intracellular antibacterial activity of plectasin was maintained (maximal relative efficacy [E max], 1.0- to 1.3-log reduction in CFU) even though efficacy was inferior to that of extracellular killing (E max, >4.5-log CFU reduction). Animal studies included a novel use of the mouse peritonitis model, exploiting extra- and intracellular differentiation assays, and assessment of the correlations between activity and pharmacokinetic (PK) parameters. The intracellular activity of plectasin was in accordance with the in vitro studies, with an E max of a 1.1-log CFU reduction. The parameter most important for activity was fC peak/MIC, where fC peak is the free peak concentration. These findings stress the importance of performing studies of extra- and intracellular activity since these features cannot be predicted from traditional MIC and killing kinetic studies. Application of both the THP-1 and the mouse peritonitis models showed that the in vitro results were similar to findings in the in vivo model with respect to demonstration of intracellular activity. Therefore the in vitro model was a good screening model for intracellular activity. However, animal models should be applied if further information on activity, PK/pharmacodynamic parameters, and optimal dosing regimens is required.

scholarly journals Quantitative Analysis of Gentamicin, Azithromycin, Telithromycin, Ciprofloxacin, Moxifloxacin, and Oritavancin (LY333328) Activities against Intracellular Staphylococcus aureus in Mouse J774 Macrophages

2003 ◽  
Vol 47 (7) ◽  
pp. 2283-2292 ◽  
Author(s):  
Cristina Seral ◽  
Françoise Van Bambeke ◽  
Paul M. Tulkens
Keyword(s):  
Electron Microscopy ◽  
Staphylococcus Aureus ◽  
Quantitative Analysis ◽  
Strain Atcc ◽  
Cellular Accumulation ◽  
Intracellular Activity ◽  
Infected Cells ◽  
Intracellular Activities ◽  
Extracellular Activity ◽  
Confocal And Electron Microscopy

ABSTRACT Using J774 macrophages, the intracellular activities of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) against Staphylococcus aureus (strain ATCC 25923) have been quantitatively assessed in a 24-h model. S. aureus was positively localized in phagolysosomes by confocal and electron microscopy, and extracellular growth was prevented with 0.5 mg of gentamicin/liter (1× MIC) in controls. When tested at extracellular concentrations equivalent to their maximum concentrations in human serum, all antibiotics except azithromycin caused a significant reduction of the postphagocytosis inoculum within 24 h, albeit to markedly different extents (telithromycin [2 mg/liter], 0.60 log; ciprofloxacin [4.3 mg/liter], 0.81 log; gentamicin [18 mg/liter], 1.21 log; moxifloxacin [4 mg/liter], 1.51 log; oritavancin [25 mg/liter], 3.49 log). Intracellular activities were not systematically related to drug accumulation (apparent cellular-to-extracellular concentration ratios in infected cells: ciprofloxacin, 3.2; gentamicin, 6.8; telithromycin, 8.7; moxifloxacin, 13.4; azithromycin, 50; oritavancin, 348). Intracellular activity was not directly correlated to extracellular activity as measured in broth. Conditions of pH 5 (i.e., mimicking that of phagolysosomes) markedly reduced the activity of gentamicin, azithromycin, and telithromycin (≥32×) and fairly extensively reduced that of ciprofloxacin and moxifloxacin (≥4×) but did not affect oritavancin activity. We conclude that the cellular accumulation of antibiotics is not the only parameter to take into account for intracellular activity but that local environmental conditions (such as pH) and other factors can also prove critical.

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