Linezolid pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model.

To describe the relationship between the ratio of the 24-h area under the concentration-time curve (AUC(24)) to minimum inhibitory concentration (MIC) as well as the effect of linezolid on Staphylococcus aureus, the killing kinetics of three S. aureus strains was studied by in vitro simulation of 5-day antibiotic dosing over a wide range of AUC(24)/MIC ratios. Similarly susceptible meticillin-resistant S.

Telavancin and vancomycin pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model.

Objectives: The aim of this study was to compare the pharmacodynamics of telavancin (TLV) and vancomycin (VAN) with Staphylococcus aureus. Their concentrations were simulated between the MIC and the mutant prevention concentration (MPC), and above the MPC.

Methods: Two strains of S.

Enrichment of fluoroquinolone-resistant Staphylococcus aureus: oscillating ciprofloxacin concentrations simulated at the upper and lower portions of the mutant selection window.

The time inside the mutant selection window (MSW), T(MSW), appears to be less predictive of the selection of fluoroquinolone-resistant Staphylococcus aureus than is the ratio of the area under the concentration-time curve (AUC) to the MIC. This observation might be attributed to the fact that T(MSW) does not consider the actual position of simulated antibiotic concentrations inside the MSW, which also might influence the amplification of resistant mutants. To test this hypothesis, the enrichment of ciprofloxacin-resistant S.

Selection of linezolid-resistant Enterococcus faecium in an in vitro dynamic model: protective effect of doxycycline.

Objectives: To relate the enrichment of linezolid-resistant Enterococcus faecium with linezolid pharmacokinetics, the pharmacodynamics of linezolid and its ability to prevent the selection of resistant mutants were studied in an in vitro model that simulates antibiotic concentrations in and out of the mutant selection window (MSW), i.e. the concentration range from the MIC to the mutant prevention concentration (MPC).

Concentration-response relationships as a basis for choice of the optimal endpoints of the antimicrobial effect: daptomycin and vancomycin pharmacodynamics with staphylococci in an in vitro dynamic model.

The abilities of different indices of bacterial killing to ensure reasonable concentration-response relationships have been compared only in studies in vitro with fluoroquinolones. To ascertain the relevance of conclusions drawn in these studies to other antibiotic classes, five widely used indices that reflect the rate of initial killing (time to reduce the initial inoculum 10- and 100-fold-T(90%) and T(99%), respectively), the extent of killing (minimal number of surviving organisms-N(min)), and the entire antimicrobial effect (number of surviving organisms (N(t)) at the time t close to the end of the observation period (48 h in most experiments), and area between the control growth curve and the time-kill curve from zero point to t-ABBC) were examined with daptomycin (DAP)- and vancomycin (VAN)-exposed Staphylococcus aureus. To compare the pharmacodynamics of DAP and VAN and examine different parameters, killing kinetics of differentially susceptible S.

Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model.

Objectives: To extend the mutant selection window (MSW) hypothesis to include antibiotics in addition to fluoroquinolones, the pharmacodynamics of daptomycin (DAP) and vancomycin (VAN) and their ability to prevent the selection of resistant Staphylococcus aureus were studied in an in vitro model that simulates antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC.

Methods: Two clinical isolates of S. aureus, S.

Comparative pharmacodynamics of telithromycin and clarithromycin with Streptococcus pneumoniae and Staphylococcus aureus in an in vitro dynamic model: focus on clinically achievable antibiotic concentrations.

To compare the pharmacodynamics of telithromycin and clarithromycin, killing kinetics of differentially susceptible Streptococcus pneumoniae and Staphylococcus aureus exposed to clinical doses of telithromycin and clarithromycin were studied in an in vitro dynamic model that simulates human pharmacokinetics. With S. pneumoniae, a bacterial strain-independent and antibiotic-independent relationship was delineated for the area between the control growth curve and the time-kill curve (ABBC) and the simulated ratio of the area under the curve (AUC) to minimum inhibitory concentration (MIC).

Antistaphylococcal effect related to the area under the curve/MIC ratio in an in vitro dynamic model: predicted breakpoints versus clinically achievable values for seven fluoroquinolones.

Prediction of the relative efficacies of different fluoroquinolones is often based on the ratios of the clinically achievable area under the concentration-time curve (AUC) to the MIC, usually with incorporation of the MIC50 or the MIC90 and with the assumption of antibiotic-independent patterns of the AUC/MIC-response relationships. To ascertain whether this assumption is correct, the pharmacodynamics of seven pharmacokinetically different quinolones against two clinical isolates of Staphylococcus aureus were studied by using an in vitro model. Two differentially susceptible clinical isolates of S.

Comparative pharmacodynamics of the new fluoroquinolone ABT492 and levofloxacin with Streptococcus pneumoniae in an in vitro dynamic model.

The kinetics of killing of Streptococcus pneumoniae exposed to ABT492 or levofloxacin were compared. S. pneumoniae ATCC 49619 and four ciprofloxacin-resistant clinical isolates, S.

Comparative pharmacodynamics of the new fluoroquinolone ABT492 and ciprofloxacin with Escherichia coli and Pseudomonas aeruginosa in an in vitro dynamic model.

The killing kinetics of Escherichia coli and Pseudomonas aeruginosa were compared when exposed to ABT492 and ciprofloxacin. E. coli ATCC 25922 and a clinical isolate of P.

ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model.

Objective: To compare the kinetics of killing/regrowth of differentially susceptible clinical isolates of Staphylococcus aureus exposed to ABT492 and levofloxacin and to explore their relative abilities to prevent the selection of resistant mutants.

Methods: Three clinical isolates of S. aureus--including two ciprofloxacin-susceptible S.

Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination.

Twenty-four hour ratios of area under the curve (AUC(24)) to MIC of 200-240 h providing quinolone concentrations above the mutant prevention concentration (MPC) protected from enrichment of resistant Staphylococcus aureus in our recent study that simulated the pharmacokinetics of moxifloxacin, gatifloxacin, levofloxacin and ciprofloxacin. These protective AUC(24)/MICs might also be achieved by using antibiotic combinations, assuming additive effects of two anti-staphylococcal agents. To test this hypothesis, changes in S.

Concentration-dependent changes in the susceptibility and killing of Staphylococcus aureus in an in vitro dynamic model that simulates normal and impaired gatifloxacin elimination.

To demonstrate the impact of normal (NEK) and impaired elimination kinetics (IEK) of gatifloxacin on its ability to protect from losses in the susceptibility of Staphylococcus aureus, a clinical isolate of methicillin-resistant S. aureus at a starting inoculum of 10(8)cfu/ml was exposed to 3 days of quinolone dosing. A series of monoexponential pharmacokinetic profiles with half-lives of 7 h (NEK) and 31 h (IEK) were simulated over 32- and 8-fold ranges of the 24 h area under the concentration-time curve (AUC(24))-to-MIC ratio, respectively.

Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing.

Objectives: According to the mutant selection window (MSW) hypothesis, resistant mutants are selected or enriched at antibiotic concentrations above the MIC but below the mutant prevention concentration (MPC). To test this hypothesis, Streptococcus pneumoniae ATCC 49619 (MIC 0.1 mg/L; MPC 0.

In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus.

To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Staphylococcus aureus exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (C(max)) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.

Species-independent pharmacodynamics of gemifloxacin and ciprofloxacin with Haemophilus influenzae and Moraxella catarrhalis in an in vitro dynamic model.

To demonstrate the antimicrobial effects of the different pharmacokinetics of gemifloxacin and ciprofloxacin, the pharmacodynamics of gemifloxacin and ciprofloxacin were studied using two clinical isolates each of Haemophilus influenzae and Moraxella catarrhalis. Monoexponentially decreasing concentrations of gemifloxacin (single dose, half-life 7.4 h) and ciprofloxacin (two 12-h doses, half-life 4 h) were simulated in an in vitro dynamic model over 8-fold ranges of the area under the curve (AUC)-to-MIC ratio: from 56 to 466 and 112-932 h, respectively.

AUC/MIC relationships to different endpoints of the antimicrobial effect: multiple-dose in vitro simulations with moxifloxacin and levofloxacin.

Most integral endpoints of antimicrobial effect, including area between the control growth and time-kill curves (ABBC), area above the curve (AAC) and area under the time-kill curve (AUBC) are determined over a dosing interval (tau), regardless of the actual effect duration. Unlike these tau-related endpoints, the intensity of antimicrobial effect (I(E)) considers the area between the control growth and time-kill curves from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of antibiotic, even if this time is greater than tau. Recently, important differences between ABBC-, AAC-, AUBC- and I(E)-AUC/MIC relationships were reported in single-dose simulations.

Bacterial strain-independent AUC/MIC and strain-specific dose-response relationships reflecting comparative fluoroquinolone anti-pseudomonal pharmacodynamics in an in vitro dynamic model.

To compare the antimicrobial effects (AMEs) of two quinolones in terms of the AUC/MIC- and dose (D)-response relationships, five differentially susceptible clinical isolates of Pseudomonas aeruginosa were exposed to decreasing concentrations of ciprofloxacin (two 12-h doses with T(1/2) = 4 h) and trovafloxacin (a single dose with T(1/2) = 9.2 h). The simulated AUC/MICs of ciprofloxacin ranged from 58 to 932 and those of trovafloxacin, from 54 to 466 h.