Pharmacokinetic and Pharmacodynamic Issues in the Treatment of Bacterial Infectious Diseases
Total Page：16
File Type：pdf, Size：1020Kb
Eur J Clin Microbiol Infect Dis (2004) 23: 271–288 DOI 10.1007/s10096-004-1107-7 Complete Table of Contents CURRENT TOPIC: REVIEW Subscription Information for P. S. McKinnon . S. L. Davis Pharmacokinetic and Pharmacodynamic Issues in the Treatment of Bacterial Infectious Diseases Published online: 10 March 2004 # Springer-Verlag 2004 Abstract This review outlines some of the many factors a gies to optimize antibiotic selection and dosing remain at clinician must consider when selecting an antimicrobial the forefront of our clinical research today. dosing regimen for the treatment of infection. Integration The appropriate use of antimicrobial agents requires an of the principles of antimicrobial pharmacology and the understanding of the characteristics of the drug, the host pharmacokinetic parameters of an individual patient factors, and the pathogen, all of which impact selection of provides the most comprehensive assessment of the the antibiotic agent and dose. Figure 1 illustrates the interactions between pathogen, host, and antibiotic. For complexity of the multiple interactions between the each class of agent, appreciation of the different patient, the pathogen, and the antibiotic. Characteristics approaches to maximize microbial killing will allow for of the patient that must be considered include those that optimal clinical efficacy and reduction in risk of develop- affect the interaction between the patient and the infection, ment of resistance while avoiding excessive exposure and such as comorbid factors and underlying immune status, as minimizing risk of toxicity. Disease states with special well as patient-specific factors such as organ function and considerations for antimicrobial use are reviewed, as are weight, which will impact the pharmacokinetics of the situations in which pathophysiologic changes may alter antibiotic. Characteristics of the bacteria include its role as the pharmacokinetic handling of antimicrobial agents. a pathogen in causing infection at the site, the pattern of susceptibility to antibiotics, and possible consequences of resistant bacterial subpopulations. Lastly, considerations Introduction for selection of the antibiotic include antibacterial activity, clinical efficacy, safety, and potential for drug interactions. Since the introduction of penicillin and sulfonamides, Pharmacologic properties such as tissue penetration, clinicians have been challenged with the issue of how to protein binding, and metabolism and elimination char- achieve optimal outcomes in patients with bacterial acteristics will affect the resulting pharmacokinetic profile infections. While the discovery of these life-saving agents and must be evaluated as well. This article reviews revolutionized modern medical treatment, balancing their selected concepts to be considered when using antibacte- use with the loss of activity resulting from bacterial rial agents. Special emphasis is placed on the importance resistance has become a challenge. For as long as these of pharmacologic principles, the application of which may agents have been used clinically, there has been ongoing assist in optimizing efficacy while minimizing the risk of investigation into the best way to use antibiotics. As early drug-related toxicity. as the 1940s, the effect of dose and dosing interval on bactericidal activity has been investigated [1], and strate- Pharmacokinetics and Pharmacodynamics P. S. McKinnon (*) Detroit Receiving Hospital, Anti-Infective Research Laboratory As described above, the selection of an antimicrobial and Wayne State University, treatment regimen is based on many factors, including the 4201 St. Antoine Boulevard, 1B-UHC, Detroit, MI 48201, USA pharmacokinetic and pharmacodynamic properties of the e-mail: [email protected] antibacterial drugs. Antibiotic pharmacodynamics inte- Tel.: +1-313-9660464 grates the complex relationship between organism suscep- Fax: +1-313-7451117 tibility and patient pharmacokinetics. The most routine S. L. Davis method for determining pathogen susceptibility and the Wayne State University, 4201 St. Antoine Boulevard, 1B-UHC, one used clinically is minimum inhibitory concentration Detroit, MI 48201, USA (MIC) testing. Pharmacokinetics describes the fundamen- 272 Fig. 1 Schematic representation of the complexity of interactions between patient, pathogen and antibiotic Fig. 2 Concentration-versus-time curve with minimum inhibitory concentration superimposed and pharmacokinetic and pharmacody- namic markers tal processes of absorption, distribution, metabolism, and elimination and the resulting concentration-versus-time profile of an agent administered in vivo. Pharmacokinetic T>MIC is generally identified as the most significant studies describe parameters such as Cmax or peak concen- pharmacodynamic surrogate. Since glycopeptide antibio- tration, the serum half-life (t1/2), and cumulative exposure tics display relatively slow but concentration-independent to an agent (area-under-the-concentration-time curve killing and are cell-wall-active agents similar to β-lactams, [AUC]) for a 24-h period (Fig. 2). Because agents vary it has been presumed that T>MIC is important for efficacy; in degree of protein binding, it is recommended by some however, recent studies have shown that the AUC/MIC investigators that free drug concentrations be used for ratio is an important predictor of successful outcome with dynamic comparisons. To ensure a successful outcome, a vancomycin. To recommend the most effective dosing of specific pharmacodynamic interaction between the anti- the various antimicrobial classes, it is necessary to microbial agent and its bacterial target must be achieved. understand the target surrogate pharmacodynamic end- These specific relationships provide a surrogate target for point necessary for the different classes of antibiotics. This predicting outcomes such as bacterial eradication and/or review will emphasize the aminoglycosides, the fluor- clinical cure. These surrogates relate various pharmacoki- oquinolones, the β-lactam agents, and the glycopeptides. netic parameters such as Cmax or AUC to a measure of the Data to explain the pharmacodynamics of antimicrobial pharmacodynamic interaction (the MIC). Another surro- agents has been derived from numerous sources. Assess- gate relationship is the time that the serum concentration ment of the in vitro killing demonstrated by antimicrobial of a given agent exceeds the MIC, or percent time above agents is the most basic step necessary for understanding MIC, (T>MIC). These relationships are illustrated in the antibacterial activity of an agent. In vitro pharmaco- Fig. 2. When evaluating the concentration-versus-time dynamic models and animal models of infection have also curve for an antimicrobial agent, the introduction of the been used to create a more dynamic environment in which MIC onto the graph provides an illustration of the to examine the activity of an antibiotic. These models relationship between the concentration and the MIC. An provide a better understanding of how changes in increase in dose will provide a significant increase in Cmax, antibiotic exposure over time may influence activity, yet while a shorter dosing interval will predominantly increase they remain limited in their ability to accurately reflect the the time that concentrations remain above the MIC of the human infection and host environment. Most do not infecting pathogen. It should be noted that an increase in incorporate a means to evaluate the role of the host dose will increase both Cmax and AUC, frequently immune system in bacterial killing. While pharmacody- resulting in covariance of these pharmacodynamic targets. namic outcome studies in humans are frequently difficult Different dosing strategies may be used to optimize dosing to conduct, their influence on our understanding of for the various classes of antibiotics, as noted in Fig. 2. antimicrobial activity in vivo is invaluable for evaluating Studies using in vitro investigations, animal models, the application of dosing principles. Where data exists, and human clinical trials have established which of these human trials will be emphasized and an approach to surrogate markers provide the best description of the application of pharmacodynamics to clinical decision- activity of each antimicrobial class. An overview of key making will be outlined. studies for each antibiotic class and the pharmacodynamic target identified is provided in Table 1. In short, the fluoroquinolone and aminoglycoside agents exhibit con- Aminoglycoside Antibiotics centration-dependent killing. Studies have demonstrated that the Cmax/MIC and AUC/MIC ratios are important When considering pharmacodynamic effects of antibiotics, predictors of outcome for these antimicrobial agents. For aminoglycoside antibiotics are among the most readily cell-wall-active agents such as the β-lactam antibiotics, understood because serum concentration data is frequently Table 1 Pharmacodynamic surrogate markers predictive of outcome Drug class Author [ref.] Drug Organism(s) Setting Parameter Value Fluoroquinolones Blaser et al. [14] enoxacin P. aeruginosa, K. pneumoniae, in vitro peak:MIC 8:1 E. coli, S. aureus Hyatt et al. [15] ciprofloxacin S. pneumoniae, S. aureus, P. aeruginosa in vitro AUC/MIC 350–450 Lister [20] gatifloxacin S. pneumoniae in vitro AUC/MIC >30 Drusano et al. [134] lomefloxacin P. aeruginosa neutropenic rat peak:MIC >10:1 Forrest et al. [12] ciprofloxacin various gram-negative organisms human AUC/MIC ≥250 Ambrose et al. [19]