Assessment of effects of protein binding on daptomycin and vancomycin killing of Staphylococcus aureus by using an in vitro pharmacodynamic model

The pharmacodynamic properties of levofloxacin (an optically active isomer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combination with rifampin, were evaluated over 24 to 48 h against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) energy-dependent efilux process mediated by the norA gene appeared to be responsible for the resistance observed. Our data suggest that with levofloxacin there is a more rapid onset of bactericidal activity than with ofloxacin or ciprofloxacin against MSSA 1199 and that the activity of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even when the pharmacokinetics of the drug were set to equal those of ciprofloxacin, suggesting that ofloxacin differs from ciprofloxacin irrespective of time of exposure. The resistance to ciprofloxacin that developed in our in vitro model may be mediated by the cfxc-ofr locus, which has been shown to be associated with low-level fluoroquinolone resistance. Overall, levofloxacin demonstrated potent bactericidal activity against S. aureus, without the emergence of resistance in our infection model. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not synergistic but prevented the emergence of ciprofloxacin resistance.

Section: Materuils and Methodsmentioning

confidence: 99%

Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model

Kang

Rybak

McGrath

et al. 1994

“…In vitro pharmacokinetic and pharmacodynamic models have increasingly been used to study therapeutic issues in infectious disease pharmacotherapy (21,34,35). We described an in vitro model adapted to incorporate simulated endocardial vegetations.…”

Section: In Vitro Model Of Endocarditis a One-compartment In Vitromentioning

confidence: 99%

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis

McGrath

Kang

Kaatz

et al. 1994

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%o)

“…Experiments with this strain of S. aureus showed a 41% greater kill down when using a fixed concentration of vancomycin of 80 versus 20 jig/ml (12). Only one study has addressed the effects of exponentially declining concentrations of vancomycin (9). This was undertaken using a dynamic two compartment in vitro model.…”

mentioning

confidence: 99%

Efficacies of different vancomycin dosing regimens against Staphylococcus aureus determined with a dynamic in vitro model

Duffull

Begg

Chambers

et al. 1994

A dynamic in vitro model was used to assess four different vancomycin dosing regimens against Staphylococcus aureus. These regimens achieved peak drug concentrations of 48 ,ug/mI (single dose) and 30 ,ug/ml (dosed every 12 h) and constant concentrations of 16 and 8 ,ig/ml. Analysis of the area under the bacterial concentration-time curve, area under the first moment of the bacterial concentration-time curve, and bacterial elimination rate constant showed no difference in the rate or extent of bacterial killing. The optimal dosing method may be that which achieves the lowest area under the curve while concentrations are maintained above the MBC. (14)(15)(16)(17)20). Similarly, most in vitro experiments using fixed concentrations of vancomycin have not demonstrated concentrationdependent killing of various microorganisms (1,18,19). These studies suggest that the best dosing strategy would be to maintain the total area under the concentration-time curve (AUC) as small as possible to reduce dose-related toxicity while still maintaining adequate efficacy.In this study we assessed the efficacy of vancomycin against Staphylococcus aureus over a 24-h period in a dynamic in vitro model using a variety of dosing regimens, including some that are common in clinical practice. These experiments were designed to compare the efficacies of three different dosing schedules with the same AUC and a schedule with a smaller AUC.The dynamic in vitro model used in this experiment has been described previously (3)(4)(5) 37°C. At time zero a bolus of vancomycin (Sigma Laboratories; lot 20H0377) was added to each central chamber to achieve the desired initial concentration. A personal computer controlled two series of pumps with a purpose-developed computer program. The first series of pumps were syringe pumps which infused broth to dilute the contents of each central chamber at a predetermined rate, resulting in a desired exponential decline of vancomycin concentrations (with a half-life of 6 h). The second series were peristaltic pumps which returned the volume of the central chamber to its original level by removing the excess volume each hour. This excess provided a sample which was used to count the number of viable CFU per milliliter. The MIC was estimated prior to the study and following exposure to vancomycin and was 0.75 ,ug/ml by the standard dilution tube technique, with an inoculum size of 2.3 x 105 CFU/ml. The test strain used for the experiments was incubated in MHB overnight and diluted 2.5 h before the experiment to produce an inoculum of _107 CFU/ml in log-phase growth.The study assessed the following vancomycin regimens: (i) a peak concentration of 48 ,ug/ml and a trough of 3 ,ug/ml at 24 h (AUC from 0 to 24 h [AUCO24] = 389 ,ug -h -ml-'); (ii) a peak concentration of 30 ,ug/ml and a trough of 7.5 ,ug/ml at 12 h, dose repeated at 12 h (AUCO24 = 389 ,ug* h * ml-1); (iii) a constant concentration of 16.2 ,ug/ml, representing a 24-h infusion (AUCO024 = 389 ,ug h ml-1); and (iv) a constant concentration of 8 ,ug/ml, repres...