Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

Abstract

Traditionally, the in vitro activity of antibacterial agents is characterized by their minimal inhibitory concentrations. However, these endpoints are, by nature, discrete and do not provide information on time-dependent killing of the bacteria during the incubation period. Nevertheless, the pharmacodynamic characteristics of antibacterial agents are almost always defined by correlating a static endpoint describing the antibacterial activity of an agent with the pharmacokinetics, describing the time-dependent fluctuation of drug concentrations. This approach is basically a contradiction in itself. Therefore, it would be more logical to correlate pharmacokinetics to in vitro parameters describing the time- and concentration-dependent antibacterial action of an agent. Thus, experimental methods and mathematical models quantifying the decrease in growth rate of a bacterial population due to the action of an antibacterial agent as a function of time and drug concentration have been applied to quantitate their pharmacodynamics. The effect of nine antibacterial agents representing drug classes of penicillins, cephalosporins, penems, macrolides, and fluoroquinolones were mathematically analyzed by using three different but related models. The kill rate, maximal kill, the 50%-effective concentration (EC50), the Hill coefficient, and concentrations and times needed to obtain a 1,000-fold decrease of the initial number of viable counts were calculated. Both the phenotypic description of the time-kill curves and these five parameters mirror the bacteriostatic or bactericidal activity of all nine agents studied as a function of time and concentration. Therefore, it would be more logical to correlate a parameter quantifying the kinetics of antibacterial in vitro activity with the pharmacokinetics of the drug, thus, replacing static endpoints like minimal inhibitory concentrations.

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

“…This disconnect between MICs and kill rates is very well in agreement with previously published data [8,20,[40][41][42][43][44][45][46][47]. Wouldn't it be more conclusive to derive PD measures not from static but from dynamic endpoints like kill-rates [65]? In summary, it can be concluded that diverse methods affect discrete static or dynamic endpoints differently.…”

Evaluation of Pharmacokinetic/Pharmacodynamic Relationships of PD-0162819, a Biotin Carboxylase Inhibitor Representing a New Class of Antibacterial Compounds, Using In Vitro Infection Models

“…1 is the most parsimonious model that was fitted to the observed data. It is similar to previously published models (2,10,13,16,18,20,22), but the basic structure of the model is most similar to the net effect model (2). Comparisons of the different mathematical models showed that potency estimates produced by the various mathematical models were similar (analysis not shown).…”

Dichotomous selection of high-level oxacillin resistance in Staphylococcus aureus by fluoroquinolones

“…The low MRSA-selective potential of moxifloxacin in contrast to the high selective potential of ciprofloxacin and levofloxacin is likely due to the high and pronounced bactericidal activity of moxifloxacin against MSSA and MRSA, whereas ciprofloxacin and levofloxacin reduce viable counts of S. aureus much more slowly as described in this study and as published previously [17,[38][39][40].…”