Antimicrobial Pharmacodynamics Research Articles

Antimicrobial Pharmacodynamics in Theory and Clinical Practice

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Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd edition ‐ Edited by Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, and Takeo Murakawa

Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd edition ‐ Edited by Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, and Takeo Murakawa

Pharmacokinetics and Pharmacodynamics of Antimicrobials

Antibiotics are some of our most commonly used drugs. Until recently, little has been known about how to optimize administration of these agents. Unfortunately, the rate of discovery of new antibiotics has been declining, coincident with the explosion in the number of multidrug-resistant organisms in both the community and hospital environments. This development makes the identification of optimal regimens that will result in good clinical and microbiological outcomes important, but it also makes clear the necessity of identifying regimens that will suppress the emergence of resistant organisms. Given that new agents for multidrug-resistant pathogens will take nearly a decade to become available to physicians, keeping organisms susceptible to drugs that are already available is even more critical. Pharmacodynamics allows identification of the drug exposure measure that is closely associated with the ability to kill organisms and, also, to suppress the emergence of resistant subpopulations of organisms. Use of Monte Carlo simulation allows identification of drug doses in the clinical arena to accomplish these ends. Such approaches should be applied to all old and new antibacterial agents.

Employing pharmacokinetic and pharmacodynamic principles to optimize antimicrobial treatment in the face of emerging resistance

Antimicrobial efficacy in vivo is not exclusively defined by the activity of an antibiotic as determined in the in vitro susceptibility test. Knowledge of the pharmacokinetics and pharmacodynamics of antimicrobials and all phenomena occurring between antimicrobial agents and microorganisms is imperative. The pharmacodynamic (PD) parameters most often used in studies of antibiotic effect include the following relationships: the maximum free concentration (fCmax) to minimum inhibitory concentration (MIC) ratio, the free area under the curve (fAUC/MIC) ratio and the duration of time the free concentration exceeds the MIC (fT>MIC). Utilization of known pharmacokinetic/ pharmacodynamic surrogate relationships should help to optimize treatment outcome, especially in the face of emerging resistance among Gram-positive and Gram-negative bacteria. Clinical studies in the field of antibacterial PD are still relatively scarce, and much information is needed to enable relevant dosing strategies for all types of antibiotics against all common infections and microorganisms. In this review, the distinctive patterns of antimicrobial activitybased on PD parameters are discussed. Various antibioticsand bacterial pathogens can be used as models to demonstrate the utilityof PD parameters in predicting the in vivo efficacy of antimicrobialtherapy. And finally, the use of computer modeling with Monte Carlo populationsimulations can further enhance the predictability of antimicrobial efficacywhen using PD parameters.

Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: A report from the OPTAMA Program

Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: A report from the OPTAMA Program

Applying antimicrobial pharmacodynamics to resistant gram-negative pathogens

Guided antibiotic adjustment for the treatment of multidrug-resistant, gram-negative pathogens is explored. Multidrug-resistant pathogens are being isolated with increasing frequency, while the production of novel agents to circumvent resistance has slowed to a near halt. Hence, antimicrobial adjustment based on drug pharmacokinetic and pharmacodynamic properties has moved to the forefront of treatment. Pharmacodynamic principles for major classes of antimicrobials are reviewed, and the use of susceptibility reports to optimize pharmacodynamics to treat gram-negative infections is described. The need for the application of antimicrobial pharmacodynamics continues to grow as resistance to the agents becomes more common. Susceptibility reports, including antibiograms, and their limitations are briefly discussed. The resistance profiles of the beta-lactams (including carbapenems), aminoglycosides, fluoroquinolones, tetracyclines and glycylcyclines, and the polymyxins are reviewed, and the pharmacodynamic optimization of these profiles is explored. Various mechanisms account for resistance of bacteria to antibiotics. The appropriate use of pharmacokinetics and pharmacodynamics can guide antibiotic therapy and enhance the likelihood of success.

Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: A report from the OPTAMA Program

To compare the probability of achieving specific pharmacodynamic exposures of commonly used intravenous antibiotics for the empirical treatment of nosocomial pneumonia against those pathogens most commonly implicated in the disease. Ten thousand-subject Monte Carlo simulation. Research center. None. Pharmacodynamic analysis was conducted for the following antimicrobials at standard doses: meropenem, imipenem-cilastatin, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin. Prevalence of causative pathogens was based on the 2000 SENTRY Antimicrobial Surveillance Study, and minimum inhibitory concentration (MIC) values were obtained using the 2003 US MYSTIC database. The probabilities of each drug and dosing regimen in achieving pharmacodynamic targets were calculated. Bactericidal targets were defined as 40% T>MIC for the carbapenems, 50% T>MIC for other beta-lactams, and an area under the curve (AUC)/MIC ratio of 125 for ciprofloxacin. A sensitivity analysis was performed using two alternate models to determine the impact of varying pathogen prevalence on target attainment. Meropenem and imipenem provided high probabilities of achieving their bactericidal target of 40% T>MIC, with target attainments of 98% for all regimens. At the bactericidal end point of 50% T>MIC, cefepime 2 g every 8 hrs displayed the highest target attainment at 99.9%, followed by cefepime 2 g every 12 hrs, ceftazidime 2 g every 8 hrs, piperacillin/tazobactam 4.5 g every 6 hrs and 3.375 g every 6 hrs, cefepime 1 g every 12 hrs, and ceftazidime 1 g every 8 hrs with target attainments of 95.0%, 92.5%, 92.3%, 91.3%, 90.3%, and 67.9%, respectively. Ciprofloxacin presented the lowest probability of achieving its bactericidal target of an AUC/MIC ratio of 125, with target attainments of 54.7% and 12.0% when given as 400 mg every 8 hrs and 400 mg every 12 hrs, respectively. Meropenem, imipenem, cefepime, ceftazidime (2 g every 8 hrs), and piperacillin/tazobactam have high probabilities of achieving adequate pharmacodynamic exposures when given for the empirical treatment of nosocomial pneumonia in the absence of methicillin-resistant S. aureus. Ceftazidime 1g every 8 hrs and ciprofloxacin produce low target attainment rates and will not likely result in high clinical success rates when given as monotherapy.

Lack of development of new antimicrobial drugs: a potential serious threat to public health

Antimicrobial resistance is threatening the management of infections such as pneumonia, tuberculosis, malaria, and AIDS. In the past, resistance could be handled by development of new drugs active against resistant microbes. However, the pharmaceutical industry has reduced its research efforts in infections; genomics has not delivered the anticipated novel therapeutics; new regulatory requirements have increased costs; antibiotic use in common infections-eg, bronchitis and sinusitis-is questioned; and, compared with other drugs, return on investments is lower for antimicrobials. To avoid a serious threat to public health, academia, biotechnology and pharmaceutical industry, regulators, and healthcare providers must find solutions to this problem. Academia should concentrate on technologies to unlock new drug targets, and industry on drug candidates. In addition, regulators and pharmaceutical companies should agree on new clinical-trial designs so that information on therapeutic efficacy is generated in fewer patients-eg, by studying pharmacodynamics of antimicrobials in patients with defined infections.

Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'.

Antimicrobial pharmacodynamics is the discipline that integrates microbiology and pharmacology, with the aim of linking a measure of drug exposure, relative to a measure of drug potency for the pathogen in question, to the microbiological or clinical effect achieved. The delineation of such relationships allows the drug dose to be chosen in a rational manner, so that the desired effect (for example, the maximal bactericidal effect) can be achieved in a large proportion of the intended patient population. Ultimately, the goal of any anti-infective therapy is to administer a dose of drug that has an acceptably high probability of achieving the desired therapeutic effect balanced with an acceptably low probability of toxicity. Appropriate use of the latest pharmacodynamic modelling approaches can minimize the emergence of resistance and optimize the outcome for patients.

Pharmacodynamics of Vancomycin and Other Antimicrobials in Patients with Staphylococcus aureus Lower Respiratory Tract Infections

Vancomycin is commonly used to treat staphylococcal infections, but there has not been a definitive analysis of the pharmacokinetics of this antibacterial in relation to minimum inhibitory concentration (MIC) that could be used to determine a target pharmacodynamic index for treatment optimisation. To clarify relationships between vancomycin dosage, serum concentration, MIC and antimicrobial activity by using data gathered from a therapeutic monitoring environment that observes failures in some cases. We investigated all patients with a Staphylococcus aureus lower respiratory tract infection at a 300-bed teaching hospital in the US during a 1-year period. Clinical and pharmacokinetic information was used to determine the following: (i) whether steady-state 24-hour area under the concentration-time curve (AUC24) divided by the MIC (AUC24/MIC) values for vancomycin could be precisely calculated with a software program; (ii) whether the percentage of time vancomycin serum concentrations were above the MIC (%Time>MIC) was an important determinant of vancomycin response; (iii) whether the time to bacterial eradication differed as the AUC24/MIC value increased; (iv) whether the time to bacterial eradication for vancomycin differed compared with other antibacterials at the same AUC24/MIC value; and (v) whether a relationship existed between time to bacterial eradication and time to significant clinical improvement of pneumonia symptoms. The median age of the 108 patients studied was 74 (range 32-93) years. Measured vancomycin AUC24/MIC values were precisely predicted with the A.U.I.C. calculator in a subset of our patients (r2 = 0.935). Clinical and bacteriological response to vancomycin therapy was superior in patients with higher (> or = 400) AUC24/MIC values (p = 0.0046), but no relationship was identified between vancomycin %Time>MIC and infection response. Bacterial eradication of S. aureus (both methicillin-susceptible and methicillin-resistant) occurred more rapidly (p = 0.0402) with vancomycin when a threshold AUC24/MIC value was reached. S. aureus killing rates were slower with vancomycin than with other antistaphylococcal antibacterials (p = 0.002). There was a significant relationship (p < 0.0001) between time to bacterial eradication and the time to substantial improvement in pneumonia score. Vancomycin AUC24/MIC values predict time-related clinical and bacteriological outcomes for patients with lower respiratory tract infections caused by methicillin-resistant S. aureus.

In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis.

The field of antimicrobial pharmacodynamics examines the relationship between drug pharmacokinetics and antimicrobial activity or host toxicity (9). These investigations have been valuable for defining optimal antimicrobial dosing regimens and validating in vitro susceptibility breakpoints (4, 14, 25). The concepts encompassing this discipline were defined initially with antibacterial compounds (9, 34, 35). With the advent of standardized and reproducible antifungal susceptibility testing, similar pharmacodynamic analyses have been undertaken (24). Both in vitro and in vivo models have been able to demonstrate a correlation between drug dose, the MIC for an organism, and outcome (15, 17, 18, 36, 37). These investigations have been important for describing the relative potencies of antifungal drugs against a number of important pathogens. More recent in vivo pharmacodynamic investigations have examined the relationship among drug dose, dosing interval, MIC, and treatment outcome to define the specific pharmacodynamic parameter and parameter magnitude predictive of antifungal drug activity. This minireview summarizes these in vivo antifungal pharmacodynamic investigations.

Nasopharyngeal carriage of Streptococcus pneumoniae: a review of the potential role of pharmacokinetics and pharmacodynamics

Much antibiotic prescribing is based upon irrational practice rather than scientific principles. The advent and the better understanding of the pharmacokinetics and pharmacodynamics of antimicrobials are slowly leading to a change whereby antibiotics are prescribed with a better rationale. The fundamental understanding of the pharmacokinetics of the antimicrobial, for example how well it is absorbed, metabolized, distributed and eliminated from the body, should lead to an appreciation of the correct dosing interval. Pharmacodynamic factors, in particular, appreciation of the MIC of an antimicrobial for an infecting pathogen and whether time-independent or -dependent killing occurs, will also have a profound influence upon how an antimicrobial is used. This review attempts to consider these features as they apply to nasopharyngeal carriage of Streptococcus pneumoniae. The reason for the dosing and dosing frequency of a number of agents is discussed and an attempt is made to point the way to more judicious antibiotic prescribing so as to maximize clinical efficacy yet minimize the possibility of resistance emerging during therapy.

Antimicrobial Pharmacodynamics in Theory and Clinical Practice

Antimicrobial Pharmacodynamics in Theory and Clinical Practice

Antimicrobial Pharmacodynamics in Theory and in Clinical Practice:Antimicrobial Pharmacodynamics in Theory and in Clinical Practice

Antimicrobial Pharmacodynamics in Theory and in Clinical Practice:Antimicrobial Pharmacodynamics in Theory and in Clinical Practice

Anthrax Prophylaxis and the Crisis of Resistant Pathogens

Journal of Gynecologic SurgeryVol. 18, No. 1 Antibiotics in GynecologyAnthrax Prophylaxis and the Crisis of Resistant PathogensNewton G. OsborneNewton G. OsborneSearch for more papers by this authorPublished Online:6 Jul 2004https://doi.org/10.1089/104240602753595494AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Anthrax Prophylaxis and the Crisis of Resistant Pathogens." , 18(1), pp. 37–38FiguresReferencesRelatedDetails Volume 18Issue 1Mar 2002 To cite this article:Newton G. Osborne.Anthrax Prophylaxis and the Crisis of Resistant Pathogens.Journal of Gynecologic Surgery.Mar 2002.37-38.http://doi.org/10.1089/104240602753595494Published in Volume: 18 Issue 1: July 6, 2004PDF download

Pharmacokinetic and pharmacodynamic properties of antimicrobials in the therapy of respiratory tract infections.

Antimicrobial pharmacodynamics examines the relationship between the pharmacokinetics of a drug over time and its treatment effect. Pharmacokinetic/pharmacodynamic parameters have been shown to be predictors of the antimicrobial activity of a variety of drugs. The pharmacodynamic parameter linked to efficacy has been demonstrated to vary for different antimicrobial classes. Within an antimicrobial class, the magnitude of the pharmacodynamic parameter predictive of efficacy has been shown to be similar, as long as free-drug levels in serum are considered. Treatment outcome predictions based upon parameter magnitudes have correlated well and have been useful for assessing the future course of both susceptible and resistant pathogens of the respiratory tract. This has been useful for the development of susceptibility breakpoints and antimicrobial treatment guidelines. Recent studies have begun to investigate the relationship between antimicrobial pharmacodynamics and the prevention of drug resistance.

PHARMACODYNAMICS OF ANTIBACTERIAL DRUGS

Pharmacodynamics of antibacterial agents relates the time course of drug concentration to its antimicrobial effects at the infection site. Antibacterial agents can be divided into three groups based on pharmacodynamic characteristics: agents that exhibit concentration-dependent bactericidal activity over a range of drug concentrations (e.g., aminoglycosides and fluoroquinolones); agents that exhibit time-dependent bactericidal activity that has little relationship to the magnitude of concentration, provided the concentrations are above a minimally effective level (e.g., beta-lactam antibiotics and vancomycin); and agents that exhibit a predominantly bacteriostatic effect. Knowledge of antimicrobial pharmacodynamics provides a rational basis for determining optimal regimens of dosage amounts and length of dosage intervals.

Clinical efficacy and antimicrobial pharmacodynamics.

Changes in the susceptibility of bacterial pathogens and the availability of new antimicrobial drugs mean that physicians need to understand the underlying pharmacodynamics of each antimicrobial therapy. Antimicrobial pharmacodynamics determine clinical efficacy and should therefore be carefully considered when selecting appropriate antibiotic agents in the therapeutic setting.

Achieving an optimal outcome in the treatment of infections. The role of clinical pharmacokinetics and pharmacodynamics of antimicrobials.

Over the past few decades, the importance of applying pharmacokinetic principles to the design of drug regimens has been increasingly recognised by clinicians. From the perspective of antimicrobial chemotherapy, an improvement in clinical outcome and/or a reduction in toxicity are of primary interest. Before application of these pharmacokinetic theories can be effective, the interrelationships between antimicrobial, pathogen and host factors must be clearly defined. Information regarding the pharmacokinetics of the antimicrobial and the quantification of pathogen susceptibility is required. Even though susceptibility end-points such as minimum inhibitory concentration (MIC) and minimum bactericidal concentration are widely employed, they do not provide any information on dynamic changes of bacterial densities. In this regard, time-kill studies can provide more basic knowledge of the complex bacterial responses to the antimicrobial. Better prediction of these responses can be afforded by the use of mathematical models. More recently, various surrogate end-points employing a combination of suitable pharmacokinetic parameters and susceptibility data, for example the ratio of peak concentration to MIC, the area under the concentration-time curve above the MIC (AUC > MIC), the time above the MIC, or the area under the inhibitory curve (AUIC), have been suggested for better prediction of the activity of different classes of antimicrobials. To allow more extensive investigations of the contribution of pharmacokinetics to the pharmacodynamics of antimicrobials, various in vitro kinetic models have been developed. However, certain limitations exist, and it is necessary to avoid over-interpretation of the data generated by these models. Two important microbial dynamic responses, postantibiotic effect and resistance selection, must be further explored before the full impact of pharmacokinetics on antimicrobial chemotherapy can be depicted. The present paper aims at discussing all the relevant factors and provides some pertinent information on the use of pharmacokinetic-pharmacodynamic principles in antimicrobial therapy.

A New In Vitro Model for the Assessment of Antimicrobial Pharmacodynamics

A New In Vitro Model for the Assessment of Antimicrobial Pharmacodynamics