Biomedical subjects

Sergey N Vostrov

Publications and source records attributed to Sergey N Vostrov.

12 recordsLinked to original sources

PubMed2006

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. aureus 866 (MIC(DAP) 0.35, MIC(VAN) 0.7, MPC(DAP) 1.1, MPC(VAN) 2.4 mg/L) and S. aureus 10 (MIC(DAP) 1.1, MIC(VAN) 1.3, MPC(DAP) 5.5, MPC(VAN) 11 mg/L), were exposed for five consecutive days to once-daily daptomycin (half-life 9 h) and twice-daily vancomycin (half-life 6 h) at the ratio of 24 h area under the concentration-time curve (AUC24) to MIC that varied over a 16- to 30-fold range. The cumulative antimicrobial effect was expressed by its intensity (I(E)). Changes in susceptibility and numbers of surviving organisms on agar plates containing 2x and 4x MIC of daptomycin or vancomycin were monitored daily. RESULTS: The I(E)-log AUC24/MIC plots were bacterial strain- and antibiotic-independent. This allowed combination of data obtained with both antibiotics and both organisms. Based on the sigmoid relationship between I(E) and the AUC24/MIC (r2 = 0.9), the antistaphylococcal effect of the therapeutic doses of daptomycin (4 and 6 mg/kg) against a hypothetical S. aureus with MIC equal to the MIC90 (AUC24/MIC90 380 and 570 h, respectively) was predicted to be similar to the effect of two 1 g doses of vancomycin given at a 12 h interval (AUC24/MIC90 200 h). AUC24/MIC relationships of the final-to-initial MIC ratio and logarithm of the ratio of maximal-to-initial numbers of organisms resistant to 2x and 4x MIC of daptomycin or vancomycin were bell-shaped and bacterial strain- and antibiotic-independent. Based on these relationships, an AUC24/MIC ratio that protects against the selection of resistant mutants was predicted at > or = 200 h. This protective value is less than the AUC24/MIC90s provided by the 4 mg/kg dose and considerably less than the 6 mg/kg dose of daptomycin, but it is close to the AUC24/MIC90 provided by two 1 g doses of vancomycin. CONCLUSIONS: These findings support the MSW hypothesis and suggest comparable antistaphylococcal effects of clinically achievable AUC24/MIC90s of daptomycin and vancomycin but slightly better prevention against the selection of resistant S. aureus by daptomycin.

Anti-Bacterial Agents↗

PubMed2005

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). Based on the ABBC-AUC/MIC relationship, a greater anti-pneumococcal effect of 800mg telithromycin compared with 2x500 mg clarithromycin was predicted for a hypothetical strain with MICs equal to the respective MIC50 values. Although telithromycin was less efficient against S. aureus, treatment for 3 days with telithromycin was not accompanied by a loss in susceptibility, whereas the enrichment of resistant staphylococci occurred with one of the two clarithromycin-treated strains.

Anti-Bacterial Agents↗

PubMed2005

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. aureus were exposed to two 12-h doses of ciprofloxacin (CIP) and one dose of gatifloxacin (GAT), gemifloxacin (GEM), grepafloxacin (GRX), levofloxacin (LVX), moxifloxacin (MXF), and trovafloxacin (TVA) over similar AUC/MIC ranges from 58 to 932 h. A specific bacterial strain-independent AUC/MIC relationship with the antimicrobial effect (I(E)) was associated with each quinolone. Based on the I(E)-log AUC/MIC relationships, breakpoints (BPs) that are equivalent to a CIP AUC/MIC ratio of 125 h were predicted for GRX, MXF, and TVA (75 to 78 h), GAT and GEM (95 to 103 h) and LVX (115 h). With GRX and LVX, the predicted BPs were close to those established in clinical settings (no clinical data on other quinolones are available in the literature). To determine if the predicted AUC/MIC BPs are achievable at clinical doses, i.e., at the therapeutic AUCs (AUC(ther)s), the AUC(ther)/MIC50 ratios were studied. These ratios exceeded the BPs for GAT, GEM, GRX, MXF, TVA, and LVX (750 mg) but not for CIP and LVX (500 mg). AUC/MIC ratios above the BPs can be considered of therapeutic potential for the quinolones. The highest ratios of AUC(ther)/MIC50 to BP were achieved with TVA, MXF, and GEM (2.5 to 3.0); intermediate ratios (1.5 to 1.6) were achieved with GAT and GRX; and minimal ratios (0.3 to 1.2) were achieved with CIP and LVX.

Anti-Infective Agents↗

PubMed2004

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. aureus, 201 and 480--and a ciprofloxacin-resistant S. aureus 866, were exposed to clinically achievable ratios of area under the curve (AUC) to MIC in a dynamic model that simulated human pharmacokinetics of ABT492 (400 mg) and levofloxacin (500 mg) as a single dose. In addition, S. aureus 201 was exposed to single and multiple doses of ABT492 and levofloxacin (both once daily for 3 days) over wide ranges of 24 h AUC/MIC (AUC24/MIC) including clinically achievable AUC24/MIC ratios. RESULTS: With each isolate, ABT492 at clinically achievable AUC/MICs produced greater anti-staphylococcal effects than levofloxacin. Areas between the control growth and the time--kill curves (ABBC in single dose simulations and the sum of ABBCs determined after the first, second and third dosing in multiple dose simulations--ABBC(1+2+3)) were higher with ABT492 than levofloxacin. Moreover, at comparable AUC/MICs and AUC24/MICs, the maximal reductions in the starting inoculum of ABT492-exposed S. aureus were more pronounced than with levofloxacin. Loss in susceptibility of S. aureus 201 exposed to ABT492 or levofloxacin depended on the simulated AUC24/MIC. Although the maximal increase in MIC (MICfinal) related to its initial value (MICinitial) was seen at a higher AUC24/MIC ratio of ABT492 (120 h) than levofloxacin (50 h), similar AUC24/MICs (240 and 200 h, respectively) were protective against the selection of resistant S. aureus. These threshold values are readily achievable with 400 mg ABT492 (AUC24/MIC 870 h) but not with 500 mg levofloxacin (AUC24/MIC 70 h). CONCLUSION: Overall, these findings predict greater efficacy of clinically achievable AUC/MIC (or AUC24/MIC) of ABT492 both in terms of the anti-staphylococcal effect and prevention of the selection of resistant mutants.

Algorithms↗

PubMed2004

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. The simulated AUC(24)/MICs were designed to provide peak concentrations (C(max)s) close to the MIC, between the MIC and the mutant prevention concentration (MPC), i.e., within the mutant selection window (MSW), and above the MPC. With both NEK and IEK simulations, significant increases in MIC were observed at those AUC(24)/MICs that correspond to gatifloxacin concentrations within the MSW over most of the dosing interval (>25%). No such increases were observed at the smallest AUC(24)/MIC (10h with NEK and 20 h with IEK) when the simulated C(max)s were close to the MIC, with minimal if any bacterial killing, and at the highest AUC(24)/MICs (310 and 160 h, respectively) when gatifloxacin concentrations exceeded the MPC over most of the dosing interval, with maximal antimicrobial effect. These 'protective' AUC(24)/MIC ratios correspond to 135% of the usual gatifloxacin clinical dose (400 mg NEK) and 60% of the loading and maintenance doses (400 mg, then 200 mg IEK). This study predicts different protective potentials of gatifloxacin in IEK and NEK against staphylococcal resistance and supports the MSW concept.

Fluoroquinolones↗

PubMed2004

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. aureus susceptibility were examined in a dynamic model that simulates 5-day treatment with moxifloxacin and doxycycline, alone and in combination at sub-optimal AUC(24)/MICs of each agent. Significant increases in MIC were observed with monotherapy where moxifloxacin or doxycycline concentrations fell into the mutant selection window (MSW) for more than 80% of the dosing interval (AUC(24)/MIC 60 h). Less pronounced changes in MIC occurred when the summed concentrations of moxifloxacin (AUC(24)/MIC 30 and 60 h) and doxycycline (AUC(24)/MIC 30 and 60 h) were inside the MSWs for the individual drugs for 30-50% of the dosing interval. No loss in susceptibility was found at moxifloxacin or doxycycline AUC(24)/MIC 170 h combined with the smaller AUC(24)/MIC (60 h) of the second compound. These data suggest that the total AUC(24)/MIC of 230 h might protect against S. aureus resistance. As this value is very close to that predicted in monotherapy with moxifloxacin (220 h), an additive protective effect of quinolone+doxycycline on the selection of resistant S. aureus is proposed. The use of drug combinations may be useful for restricting the enrichment of resistant mutants with agents whose clinically achievable AUC(24)/MICs do not provide concentrations above the MPC.

Anti-Bacterial Agents↗

PubMed2004

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. aeruginosa 4226 were exposed to ABT492 (single dose) and ciprofloxacin (two 12 h doses) at the ratios of area under the curve (AUC) to MIC varying from 60 to 480 h and at clinically achievable AUC/MIC ratios of ABT492 (1,740 and 140 h, respectively) and ciprofloxacin (2,200 and 120 h, respectively) that correspond to a 400 mg dose of ABT492 and two 500 mg doses of ciprofloxacin. In addition, a double dose of ABT492 (800 mg; AUC/MIC 280 h) and two 12 h doses of ABT492 (2 x 400 mg) were used with P. aeruginosa. Maximal reductions in the starting inoculum of E. coli and P. aeruginosa were greater with ABT492 than with ciprofloxacin at a given AUC/MIC ratio (60-480 h), whereas the times to regrowth were shorter with ABT492. A specific AUC/MIC relationship of the antimicrobial effect was inherent in each quinolone-pathogen pair. With both E. coli and P. aeruginosa, AUC/MIC plots of the area between the control growth and the time-kill curves (I(E)) were steeper for ciprofloxacin than ABT492 and they were species-independent. The effect of ABT492 on E. coli at the clinically achievable AUC/MIC ratio (1740h) was more pronounced than the respective AUC/MIC of ciprofloxacin (2,200 h). With P. aeruginosa, a 140 h AUC/MIC of ABT492 (400 mg as a single dose) provided 1.8-fold less effect than a 120 h AUC/MIC of ciprofloxacin (2 x 500 mg). However, two 12 h doses of ABT492 (AUC/MIC 2 x 140 h) but not a double single dose (800 mg) were more efficient than ciprofloxacin. These findings predict comparable efficacies of clinically achievable AUC/MICs of ABT492 and ciprofloxacin against E. coli (q.d. versus b.i.d. quinolone dosing) and P. aeruginosa at b.i.d. but not at q.d. ABT492.

Anti-Infective Agents↗

PubMed2003

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.e., within or "inside" the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC(24)) to the MIC varied from 13 to 244 h, and the starting inoculum was 10(8) CFU/ml (6 x 10(9) CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC(24)/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC(24)/MIC values (15 to 16 h) of GAT and CIP, whose C(max) exceeded the MICs. No such increases were observed with the smallest AUC(24)/MIC values (13 to 17 h) of MOX and LEV, whose C(max) were close to the MICs. Also, less pronounced but significant increases in MIC occurred at AUC(24)/MIC values (107 to 123 h) that correspond to quinolone concentrations partly overlapping the MIC-to-MPC range. With all four drugs, no change in MIC was seen at the highest AUC(24)/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These "protective" AUC(24)/MIC ratios correspond to 66% of the usual clinical dose of MOX (400 mg), 190% of a 400-mg dose of GAT, 220% of a 500-mg dose of LEV, and 420% of two 500-mg doses of CIP. Thus, MOX may protect against resistance development at subtherapeutic doses, whereas GAT, LEV, and CIP provide similar effects only at doses that exceed their usual clinical doses. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the MSW and suggest that in vitro dynamic models can be used to predict the relative abilities of quinolones to prevent mutant selection.

Anti-Infective Agents↗

PubMed2002

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. The intensity of the AME (I(E)) correlated well with log AUC/MIC for both ciprofloxacin and trovafloxacin (r(2) = 0.99 and 0.97, respectively) in a strain-independent fashion. At a given AUC/MIC ratio, AMEs of trovafloxacin were greater than ciprofloxacin. However, based on the respective I(E)-logD curves, 200 mg trovafloxacin produced a slightly greater AME than 2 x 500 mg ciprofloxacin only with the most susceptible P. aeruginosa. With the less susceptible P. aeruginosa ciprofloxacin was more efficient than trovafloxacin. This study suggests that both bacterial strain-independent AUC/MIC- and the respective strain-specific dose-response relationships of the AME are important for comprehensive pharmacodynamic evaluation of antimicrobial agents.

Anti-Infective Agents↗

PubMed2002

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. With each quinolone, log-linear relationships were established between the intensity of the antimicrobial effect (I(E)) and AUC/MIC. The I(E)-log AUC/MIC plots were bacterial strain- and species-independent and the gemifloxacin and ciprofloxacin plots were not superimposable. To generalize the findings obtained with the studied organisms, the effects of gemifloxacin and ciprofloxacin on hypothetical strains of H. influenzae and M. catarrhalis with MICs equal to the respective MIC(90)s were predicted. Based on these predictions, the AUC/MIC(90)s of 320 mg gemifloxacin (800 h with H. influenzae and 400 h with M. catarrhalis) may be 31-34% more efficient than those of 2 x 500 mg ciprofloxacin (730 and 365 h, respectively). These data suggest greater efficacy of gemifloxacin against H. influenzae and M. catarrhalis relative to ciprofloxacin at clinically achievable AUC/MIC ratios.

Anti-Infective Agents↗

PubMed2002

Comparative pharmacodynamics of azithromycin and roxithromycin with S. pyogenes and S. pneumoniae in a model that simulates in vitro pharmacokinetics in human tonsils.

Most macrolides penetrate and persist in peripheral tissues, irrespective of plasma concentrations. For this reason, comparative pharmacodynamics of macrolides might be better based on tissue rather than plasma pharmacokinetics. The present study compares the antimicrobial effects of azithromycin and roxithromycin on Streptococcus pyogenes and Streptococcus pneumoniae using in vitro simulations of steady-state pharmacokinetics in human tonsils expected after a third 500 mg dose of azithromycin administered once a day and after a sixth 150 mg dose of roxithromycin administered twice a day. Clinical isolates of S. pyogenes and S. pneumoniae (MICs 0.12 and 0.47 mg/L of azithromycin, and 0.15 and 0.60 mg/L of roxithromycin, respectively) were used. More pronounced antistreptococcal effects were observed with azithromycin than with roxithromycin. Despite similar rates of initial killing of S. pyogenes and S. pneumoniae, the respective 12 h areas between the control growth curve and the time-kill curve of antibiotic-exposed bacteria (ABBCs) were 22% and 36% greater with azithromycin than roxithromycin. Moreover, with azithromycin, viable bacterial counts reached the theoretically achievable limit of detection (10 cfu/mL) 8-10 h after drug administration, with no regrowth within 48 h. In contrast to azithromycin, S. pyogenes and S. pneumoniae exposed to roxithromycin regrew 26 and 6 h, respectively, after initial reduction of the starting inoculum. Further in vitro simulations of tissue pharmacokinetics might be useful for pharmacodynamic comparisons among other macrolides.

Anti-Bacterial Agents↗

PubMed2002

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. The present study was designed to examine these relationships in multiple-dose simulations. A clinical isolate of Staphylococcus aureus was exposed to simulated pharmacokinetics of moxifloxacin (MIC = 0.37 mg/L) and levofloxacin (MIC = 0.6 mg/L), simulating three consecutive 24 h doses, which varied over a 32-fold range in the 24 h AUC/MIC ratio (AUC(tau)/MIC: 14-444 h and 15-484 h, respectively). The cumulative effect of each treatment was expressed by I(E), determined from time zero to the time after the third dose when the effect could no longer be detected, and by ABBC, AAC and AUBC calculated over a 72 h period (i.e. over three dosing intervals). With all four endpoints, systematic AUCtau/MIC increase-induced changes in effect-an increase in I(E), ABBC and AAC, or a decrease in AUBC-were observed and the log AUC(tau)/MIC-response curves were fitted by an E(max) model. Using I(E), the effects of moxifloxacin and levofloxacin could be distinguished over a wider range of AUC(tau)/MIC ratios than with ABBC and AUBC, whereas no differences between the fluoroquinolones could be seen based on the AAC-AUC(tau)/MIC curves. Although ABBC and AUBC were more descriptive than AAC, these two endpoints distinguished the fluoroquinolone effects only over a relatively narrow AUC(tau)/MIC range ( approximately 40-100 h), which includes therapeutically achievable values for levofloxacin but not for moxifloxacin. Similar limitations of the tau-related endpoints might be critical in comparative studies with other new fluoroquinolones where therapeutic AUCtau/MIC ratios are >100 h.

Anti-Infective Agents↗