William A. Craig

Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men

Investigations over the past 20 years have demonstrated that antibacterials can vary markedly in the time course of antimicrobial activity. These differences in pharmacodynamic activity have implications for optimal dosage regimens. The results of more recent studies suggest that the magnitude of the pharmacokinetic/pharmacodynamic parameters required for efficacy are relatively similar in animal infection models and in human infections. However, there is still much to learn. Additional studies are needed to further correlate pharmacokinetic/pharmacodynamic parameters for many antibacterials with therapeutic efficacy in a variety of animal infection models and in human infections. The potential value of using pharmacokinetic/pharmacodynamic parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms, for setting susceptibility breakpoints, and for reducing the cost of drug development should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.

Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for the Prevention of Antimicrobial Resistance in Hospitals

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.

Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins

The broad-spectrum cephalosporins exhibit time-dependent bactericidal activity and produce prolonged postantibiotic effects only with staphylococci. The duration of time that serum levels exceed the minimum inhibitory concentration (MIC) is the important pharmacodynamic parameter correlating with efficacy for these drugs. Maximal efficacy for cephalosporins in several animal infection models is approached when serum levels are above the MIC for 60%-70% of the dosing interval for Enterobacteriaceae and streptococci and for 40%-50% of the dosing interval for Staphylococcus aureus. Based on MIC90 values of 0.5 microgram/ml for enteric bacilli and 4 micrograms/ml for S. aureus, these time above MIC goals can be easily met in infected and/or elderly patients following 1-2 g of cefotaxime at 12-h intervals. Full knowledge of the interrelationships between pharmacokinetics and pharmacodynamics is important for determining effective dosage regimens for the broad-spectrum cephalosporins.

Pharmacokinetics and pharmacodynamics of antibiotics in otitis media

The pharmacology of antimicrobial chemotherapy can be divided into two components. Pharmacokinetics deals with the absorption, distribution and elimination of antimicrobials. These factors, combined with the dosing regimen, determine the time course of drug concentrations in serum and in body tissue

Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid

Time above MIC for free drug concentrations is the important PK-PD parameter correlating with the efficacy of beta-lactam antibiotics. The duration of time plasma concentrations needed to exceed the MIC is relatively similar for most organisms except staphylococci. Neutrophils contribute very little to the overall activity of beta-lactams. The appearance of increasing antimicrobial resistance can challenge the efficacy of these drugs when concentrations do not exceed the MIC for 40% to 50% of the dosing interval. Time above MIC with oral amoxicillin and amoxicillin-clavulanate can be enhanced with high-dose formulations. Time above MIC with parenteral preparations can be enhanced by longer intravenous infusions or even continuous infusion. The 24-hour AUC-MIC is probably the important PK-PD parameter correlating with the efficacy of vancomycin and teicoplanin. It clearly is the important parameter for the efficacy of linezolid. Usual doses of these drugs generally provide adequate plasma concentrations to treat effectively infections in which plasma concentrations are predictive of tissue concentrations. Penetration of these drugs into respiratory secretions, such as ELF, is enhanced for linezolid and reduced for vancomycin. This may give linezolid an advantage over vancomycin in certain respiratory infections.

Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance

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.

Animal model pharmacokinetics and pharmacodynamics: a critical review

Animals have been extensively used in the evaluation of antimicrobials. The value of animals in the pharmacokinetic and pharmacodynamic characterization of antimicrobials is critically reviewed. Animal studies have demonstrated that the pharmacokinetic/pharmacodynamic (PK/PD) target determining efficacy can vary for different classes of antimicrobials. However, the magnitude of the target required for bacteriological efficacy is relatively similar for various sites of infection, various pathogens and various drugs within the same class, provided free drug levels are used.

The Postantibiotic Effect

Excerpt Suppression of bacterial growth that persists after short exposure of organisms to antimicrobial agents has been seen since early investigations with penicillin. For example, Parker and Lus...

Kinetics of antimicrobial activity

Assessment of antimicrobial activity from standard in vitro minimum inhibitory and minimum bactericidal concentration determinations alone is incomplete. Rate of bacterial killing, effect of increasing concentration, sub-MIC effects, and degree of suppression of bacterial growth after limited exposure (post-antibiotic effect) more precisely describe the course of antimicrobial activity. Aminoglycoside antibiotics exhibit concentration-dependent bactericidal activity and a prolonged post-antibiotic effect. beta-Lactam antibiotics demonstrate more time-dependent killing and lack post-antibiotic effects, except with staphylococci. Most bacteriostatic antimicrobial agents also produce post-antibiotic suppression of growth. Studies in different animal infection models with a variety of organisms suggest that beta-lactams are more efficacious with continuous dosing, whereas the efficacy of aminoglycosides is relatively independent of dosing regimen, even when administered once daily. Knowledge of the kinetics of antimicrobial action is useful in predicting optimal dosage regimens.

In Vivo Pharmacodynamic Activity of Daptomycin

ABSTRACT Daptomycin is a lipopeptide antibiotic with activity against a wide range of gram-positive bacteria. We used the neutropenic murine thigh model to characterize the pharmacodynamics of daptomycin. ICR/Swiss mice were rendered neutropenic with cyclophosphamide; and the thigh muscles of the mice were infected with strains of Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Animals were treated by subcutaneous injection of daptomycin at doses of 0.20 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Daptomycin exhibited linear pharmacokinetics, with an area under the concentration-time curve (AUC) from time zero to infinity/dose of 9.4 and a half-life of 0.9 to 1.4 h. The level of protein binding was 90%. Free daptomycin exhibited concentration-dependent killing and produced in vivo postantibiotic effects (PAEs) of 4.8 to 10.8 h. Nonlinear regression analysis was used to determine which pharmacokinetic (PK) or pharmacodynamic (PD) parameter was important for efficacy by using free drug concentrations. The peak concentration/MIC (peak/MIC) ratio and 24-h AUC/MIC ratio were the PK and PD parameters that best correlated with in vivo efficacy (R2 = 83 to 87% for peak/MIC and R2 = 86% for the AUC/MIC ratio, whereas R2 = 47 to 50% for the time that the concentration was greater than the MIC) against standard strains of S. aureus and S. pneumoniae. The peak/MIC ratios required for a bacteriostatic effect ranged from 12 to 36 for S. pneumoniae, 59 to 94 for S. aureus, and 0.14 to 0.25 for E. faecium. The AUC/MIC ratios needed for a bacteriostatic effect ranged from 75 to 237 for S. pneumoniae, 388 to 537 for S. aureus, and 0.94 to 1.67 for E. faecium. The free daptomycin concentrations needed to average from one to two times the MIC over 24 h to produce a bacteriostatic effect and two to four times the MIC over 24 h to produce greater than 99% killing. The long PAE and potent bactericidal activity make daptomycin an attractive option for the treatment of infections caused by gram-positive bacteria.