Correlation between free and total vancomycin serum concentrations in patients treated for Gram-positive infections

Berthoin, Karine; Ampe, Els; Tulkens, Paul M.; Carryn, Stéphane

doi:10.1016/j.ijantimicag.2009.08.005

Cited by 55 publications

(70 citation statements)

References 34 publications

(37 reference statements)

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“…The current study used data from only a single center, and the specific characteristics of our center may have influenced the population PK model developed. For example, the vancomycin concentration measured can vary depending on the analytical method used (34). Similarly, the measured serum creatinine levels in neonates vary by assay type, and the Jaffe method may result in higher serum creatinine than that obtained using enzymatic methods (35).…”

Section: Discussionmentioning

confidence: 99%

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

Frymoyer

Hersh

Elkomy

et al. 2014

Antimicrob Agents Chemother

117

122

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Section: Discussionmentioning

confidence: 99%

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

Frymoyer

Hersh

Elkomy

et al. 2014

Antimicrob Agents Chemother

117

122

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“…2. Second, one could question whether free drug monitoring for voriconazole should be implemented in daily practice in a manner comparable to what has recently been discussed for vancomycin (50). However, the most important issue for voriconazole administration is to avoid subtherapeutic VTCs and therapeutic failure, especially in a Caucasian population most often presenting with wild-type CYP2C9/CYP2C19 metabolism, rather than to avoid toxicity associated with supratherapeutic VTCs (51).…”

Section: Discussionmentioning

confidence: 99%

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Vanstraelen

Wauters

Vercammen

et al. 2014

Antimicrob Agents Chemother

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f Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P ‫؍‬ 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

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“…First, we measured the total fraction of vancomycin, which is not predictive of the free concentrations that eventually penetrate tissues and are effective in treating the infectious process (32). However, measurement of free concentrations is not available in daily clinical practice, and PK/PD targets have been defined only on the basis of total concentrations.…”

Section: Fig 3 Vancomycin Concentrations At Different Time Points In mentioning

confidence: 99%

New Regimen for Continuous Infusion of Vancomycin in Critically Ill Patients

Cristallini

Hites

Kabtouri

et al. 2016

Antimicrob Agents Chemother

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Vancomycin remains a primary treatment for infections caused by Gram-positive bacteria resistant to ␤-lactam antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and ampicillin-resistant enterococci (1). Despite extensive clinical use of vancomycin over recent years, the optimal dosing strategy for rapid achievement of therapeutic concentrations still remains a challenge for physicians. This is of particular interest for patients with septic shock, who require adequate antibiotic therapy, especially in terms of drug concentrations, from the early phase of treatment (2, 3). To rapidly achieve optimal vancomycin concentrations in such patients, a loading dose followed by a continuous drug infusion (CI) has been proposed (4).Although CI of vancomycin is increasingly used, especially in the intensive care unit (ICU), there is still a controversy as to whether this mode of administration provides better results than standard intermittent drug administration (II). Several studies have shown no differences in clinical efficacy or mortality between the two therapeutic strategies in infections with Gram-positive bacteria (4-6). However, Wysocki et al. (5) demonstrated that CI allowed faster achievement of target concentrations, presented less variability in drug concentrations, and resulted in reduced costs of therapy. Furthermore, a recent meta-analysis showed that CI was associated with a significantly lower risk of drug-related nephrotoxicity than II, despite the use of similar daily doses (6).Nevertheless, because of significant changes in vancomycin pharmacokinetics (PK) during critical illness, such as increased volume of distribution (V) and augmented clearance, the standard CI regimen (e.g., a loading dose of 15 mg/kg of body weight, followed by 30 mg/kg over 24 h for patients with normal renal function) (5) has been associated with inadequate drug concentrations in a high proportion of septic patients in the first 2 days of therapy (7). As such, Roberts et al. (8), using a population PK analysis, suggested that a vancomycin loading dose of 35 mg/kg, followed by daily doses adjusted to creatinine clearance (CrCL, ranging from 7 to 45 mg/kg/day), would rapidly achieve adequate drug concentrations in critically ill patients. Nevertheless, this approach has not been prospectively validated yet.Another important issue concerning vancomycin is that clinical efficacy is best predicted when the ratio between the area under the curve of drug concentrations over 24 h (AUC 0 -24 ) and the MIC for the pathogen isolated (AUC 0 -24 /MIC) exceeds 400 (9-12). To ensure optimal AUC 0 -24 /MIC ratios, several studies have proposed target serum drug concentrations between 15 and 30 mg/liter during CI of vancomycin (5, 13-15). Nevertheless, no study has evaluated the correlation between vancomycin concentrations and the achievement of an AUC 0 -24 /MIC ratio of Ն400 in critically ill patients, in particular during the first day of therapy.The aim of thi...

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Correlation between free and total vancomycin serum concentrations in patients treated for Gram-positive infections

Cited by 55 publications

References 34 publications

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

New Regimen for Continuous Infusion of Vancomycin in Critically Ill Patients

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