Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation: Selecting the Best Antimicrobial Dose to Treat an Infection

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When faced with a neonate, infant, or child with a suspected infection, the clinician must select a specific antimicrobial at a specific dose for a specific duration to treat that infection. Many issues require careful consideration, and include knowledge of the suspected pathogens and their susceptibility to the antimicrobials under consideration, the pharmacokinetic (PK) characteristics of the antimicrobials, and the clinician's assessment of the need to achieve a cure for that particular patient (Table 1). PK and pharmacodynamics (PD) principles together with Monte Carlo simulation can assist the clinician in selecting the appropriate antimicrobial and dosing regimen.1 Recent advances in our understanding of antimicrobial PK and PD have lead to important insights in the parameters associated with a successful outcome, and in ways to minimize both drug toxicity and the development of antimicrobial resistance.VARIABILITY IN PLASMA AND TISSUE CONCENTRATIONS ACROSS POPULATIONSGiven the availability of sensitive assays to measure antibiotic concentrations in plasma and various tissue sites using smaller quantities of blood or tissue fluids, our ability to assess antibiotic exposures at the tissue level, the actual site of infection, has increased. As regulatory agencies request more sophisticated antimicrobial exposure data for investigational drugs, these data are frequently collected in clinical trials and thus, are becoming more readily available for analysis. As a result, our knowledge of the PK of antimicrobials (ie, concentrations in plasma and in different tissue sites over time) and the variability inherent between patients receiving the same antimicrobial agent is better understood. Both the distribution of antimicrobials within tissue compartments and drug elimination differs by pediatric age group “populations,” from the neonate to the adolescent. Fortunately, antimicrobial PK and variability in each pediatric “population” can also be described.2 Children with organ dysfunction may not eliminate antimicrobials as effectively as those with normal organ function. For example, the PK of vancomycin in children with some degree of renal failure will be different than in children with normal renal function. Data from populations with organ failure are becoming more widely available, increasing our knowledge of the variability of drug elimination among those populations. The description of the statistical characteristics of the variability of antimicrobial concentrations across carefully defined populations is known as “population pharmacokinetics.”PHARMACODYNAMICSOur understanding of how antimicrobial agents eradicate bacteria has also increased. The relationship between the antimicrobial concentrations required at the infection site over the dosing interval to eradicate a pathogen and hence, achieve a cure, is known as pharmacodynamics.3 These defined exposures, indexed to the minimum inhibitory concentration (MIC) of the antimicrobial to that pathogen, have been used to evaluate the PK-PD measure that best describes antimicrobial activity for that particular antimicrobial/pathogen pair. The 3 most common PK-PD measures associated with efficacy are (1) the percent of the dosing interval that a drug concentration remains above the MIC (%T > MIC); (2) the ratio of the maximal drug concentration to the MIC (Cmax:MIC); and (3) the ratio of the area under the drug concentration-versus-time curve (AUC) to the MIC (AUC:MIC).For aminoglycosides (eg, gentamicin) and fluoroquinolones (eg, ciprofloxacin), the PK-PD measure that is most predictive of efficacy is one for which bactericidal activity is concentration-dependent (Cmax:MIC for gentamicin, and AUC:MIC for ciprofloxacin). In contrast, amoxicillin and other beta-lactam agents demonstrate a time-dependent pattern of bactericidal activity (%T > MIC).4 Therefore, when fluoroquinolone concentrations increase, the rate and extent of bacterial eradication will increase. For amoxicillin, maximal bacterial eradication occurs when infection site concentrations exceed the MIC for approximately 40% of the dosing interval.

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