The pharmacology of antimicrobial therapy can be divided increasing antimicrobial concentrations. Similarly, the MIC does not provide any information on persistent effects of antibacterial into two distinct components (figure 1). The first of these components is pharmacokinetics, or the absorption, distribution, agents-inhibitory effects that persist after exposure to an antimicrobial. These persistent effects include the postantibiotic efand elimination of drugs. These factors, combined with the dosage regimen, determine the time course of drug concentrafect (PAE), the postantibiotic sub-MIC effect (PAE-SME), and the postantibiotic leukocyte enhancement (PALE) [5][6][7]. The tions in serum, which in turn determine the time course of drug concentrations in tissues and body fluids. With respect to effect of increasing concentrations on the bactericidal activity of antimicrobials and the magnitude of persistent effects give a antimicrobials, the time course of drug concentrations at the site of infection is of special interest. Pharmacodynamics is the much better description of the time course of antimicrobial activity than is provided by the MIC and MBC. relationship between serum concentration and the pharmacological and toxicological effects of drugs. With respect to antimicrobials, the primary interest is in the relationship between Bactericidal Activity concentration and the antimicrobial effect. The time course of antimicrobial activity is a reflection of the interrelationship Shah et al. [8] were the first investigators to propose that between pharmacokinetics and pharmacodynamics. antibacterials could be divided into different groups on the basis Studies over the past 20 years have demonstrated marked of their patterns of bactericidal activity. The first pattern is chardifferences in the time course of antimicrobial activity among acterized by concentration-dependent killing over a wide range antibacterials [1][2][3]. Furthermore, the pattern of antimicrobial of concentrations. The higher the drug concentration, the greater activity over time is an important determinant of effective dosage the rate and extent of bactericidal activity. This pattern is obregimens [4]. This review will focus on the interrelationship served with the aminoglycosides and fluoroquinolones and with between pharmacokinetics and pharmacodynamics in determinexposure of anaerobic bacteria to metronidazole [2,3, 8]. In ing dosing regimens for different classes of antibacterials. The contrast, the second pattern is characterized by minimal concenability of specific pharmacokinetic/pharmacodynamic parametration-dependent killing. Saturation of the killing rate occurs at ters to predict the efficacy of antibacterial activity in animal low multiples of the MIC-usually around four to five times models of infection and in human infections will be emphasized. the MIC. Concentrations above these values do not kill the organisms any faster or more extensively. Thus, the extent of Pharmacodynamics: Parameters of Antimicrobial killing in this pa...

The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.

Current antimicrobial dosing regimens are designed to maintain active drug levels for most of the dosing interval and are based on 40-y-old observations. With use of numerous multiple-dosing regimens in an animal model, this study is the first to successfully minimize the interdependence between pharmacokinetic parameters and thereby determine, by stepwise multivariate regression analysis, that the time that serum levels exceeded the minimum inhibitory concentration (MIC) was the most significant parameter determining efficacy for beta-lactams and erythromycin against various pathogens, whereas the log area under the curve was the major parameter for aminoglycosides. Optimal dosing intervals were no greater than the time that serum levels exceeded the MIC plus the duration of the postantibiotic effect. Careful application of these concepts should allow other investigators to use more optimally dosed regimens than those previously used in preclinical trials and to design studies to improve on current dosing regimens for humans.

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Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. Prevention of the emergence of resistance and the dissemination of resistant microorganisms will reduce these adverse effects and their attendant costs. Appropriate antimicrobial stewardship that includes optimal selection, dose, and duration of treatment, as well as control of antibiotic use, will prevent or slow the emergence of resistance among microorganisms. A comprehensively applied infection control program will interdict the dissemination of resistant strains.

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Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects of pharmacokinetic profiles. We compared the relative efficacy and potency of three beta-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals. For beta-lactams, Emaxs were similar, whereas P50s increased 10- to 50-fold with longer intervals in both models. Aminoglycosides were significantly more bactericidal in the lung than in the thigh, and dosing interval had little impact on P50s in either model. Recognizing the variable impact of dosing interval on efficacy for different classes of antibiotics is mandatory for the proper design and interpretation of comparative trials.