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Model identifies ideal vancomycin concentrations for infants
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Researchers have developed a population-based pharmacokinetic model to identify target levels for vancomycin treatment so that infants infected with Staphylococcus aureus receive effective therapy.
Study researcher Amanda Gwee, DTMH, PhD, a general pediatrician, infectious disease physician and clinical pharmacologist from the Royal Children’s Hospital Melbourne, Australia, told Infectious Diseases in Children that the current approach to vancomycin treatment in infants is to measure the lowest level of the antibiotic in the blood, or the trough level.
However, “the effectiveness of vancomycin to treat S. aureus infections is not determined by the trough level but instead relates to the drug concentrations in blood over time, or area under the concentration-time curve (AUC),” she said.
Gwee and colleagues wrote that for adults with S. aureus infection, the pharmacodynamic target correlates with the ratio of the AUC over 24 hours (AUC24) to the minimum inhibitory concentration (MIC) of the bacteria above 400 — or AUC24/MIC>400.
To develop their model, Gwee and colleagues analyzed data from 104 infants who were enrolled in a randomized clinical trial of vancomycin. The trial occurred between Sept. 1, 2014, and Dec. 31, 2017.
The researchers found that the 48-hour trough concentrations that provided a 90% probability of target attainment were greater than 20 mg/L for a 6-hour dosage interval and greater than 15 mg/L for a 12-hour dosage interval. Importantly, the researchers developed a clinical tool that enables hospital staff to look up the vancomycin level required to achieve the target AUC for both premature and term infants.
“Our study helps clinicians understand the relationship between the trough level that we routinely measure and the drug exposure, which determines effectiveness of treatment,” Gwee said. “As a result, we have now identified new values for vancomycin trough levels that clinicians can target to ensure that all babies receive doses of vancomycin that will be effective to treat S. aureus infections.” – by Katherine Bortz
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Melanie A. Wellington, MD, MPH
In critically ill infants and children, vancomycin remains the mainstay of our therapy against MRSA and other gram-positive pathogens. Unfortunately, of all the antibiotics we use in children, vancomycin has one of the narrowest therapeutic indexes. In other words, there is a very narrow window between the level of vancomycin that is required to successfully treat MRSA and the level at which significant drug toxicity occurs.
Both efficacy and toxicity are a function of the overall vancomycin concentration over time, which is measured as the AUC. Because the AUC cannot be directly measured, it is the standard of care to monitor a patient’s trough vancomycin concentration and then extrapolate from the trough to the AUC level. There are good data to guide interpretation of vancomycin trough levels in adults. However, we have very little information about the relationship between the vancomycin trough and the AUC in children and almost no information in neonates.
The study by Gwee and colleagues is one of two recent investigations designed to evaluate the relationship between vancomycin AUC and trough concentration in neonates. Using pharmacokinetic modeling, the authors generated a series of probability curves that correlate trough concentration with the probability of achieving therapeutic AUC levels. The major advance of this study is that they performed this analysis over a wide spectrum of post-menstrual ages and dosing intervals, thus providing a resource for all of us who need to use vancomycin in the treatment of our neonatal patients.
The pharmacokinetic models generated in the current study indicate that vancomycin trough levels of at least 15 to 20 mg/L are required to achieve appropriate AUC levels for most neonates. This is in contrast to the results reported in Frymoyer and colleagues; their model indicates that much lower target vancomycin levels — 7 to 11 mg/L — are likely to produce effective AUC levels.
One main difference between these studies is that most patients in the Frymoyer study were treated with vancomycin every 12 or 24 hours, whereas the Gwee study had more patients who were treated every 6 or 8 hours. As the dosing interval has a significant impact on vancomycin levels, this difference may account for the difference in their models.
Importantly, both studies highlight the longstanding difficulty with vancomycin dosing: it is very difficult to treat neonates and children with vancomycin levels high enough to provide therapeutic efficacy without a substantial risk of toxicity.
Fortunately, there may be a solution to this problem: continuous vancomycin infusions.
With continuous infusion, therapeutic levels are achieved much faster than with intermittent dosing, dose adjustments are much simpler, and the overall daily vancomycin dose is lower. The data used in the current study was obtained as part of a multicenter randomized controlled trial of continuous vs. intermittent vancomycin dosing. More studies on continuous antibiotic infusions in pediatric patients are needed to determine if we can use this technique to more successfully clear our patient’s infections while simultaneously avoiding toxicity. Until then, the increased understanding of the relationship between vancomycin trough concentrations and expected treatment efficacy provided by Gwee and colleagues will help guide the treatment of neonates today.
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