Neutropenia is independently associated with sub-therapeutic serum concentration of vancomycin

Choi, Min Hyuk; Choe, Yeon Hwa; Lee, Sang-Guk; Jeong, Seok Hoon; Kim, Jeong-Ho

doi:10.1016/j.cca.2016.12.021

Cited by 14 publications

(20 citation statements)

References 27 publications

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“…This is of special importance in neutropenic patients with hematological disease, as these patients are often immunocompromised, and S. aureus infections are associated with high mortality rates of up to 40-50% [9,10]. Our findings confirm the earlier exploratory study by Haeseker et al who also revealed neutropenia as principal independent predictor of clearance as well as the study by Choi et al who showed the association between neutropenia and subtherapeutic levels of vancomycin [6,7]. Similarly, Fernandez de Gatta et al and Normand et al found an increased clearance in neutropenic patients [4,15].…”

Section: Discussionsupporting

confidence: 90%

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The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults

Bury

Heine

Garde

et al. 2019

Eur J Clin Pharmacol

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Aim There is accumulating evidence that neutropenic patients require higher dosages of vancomycin. To prevent sub-therapeutic drug exposure, it is of utmost importance to obtain adequate exposure from the first dose onwards. We aimed to quantify the effect of neutropenia on the pharmacokinetics of vancomycin. Methods Data were extracted from a matched patient cohort of patients known with (1) hematological disease, (2) solid malignancy, and (3) patients not known with cancer. Pharmacokinetic analysis was performed using non-linear mixed effects modeling with neutropenia investigated as a binary covariate on clearance and volume of distribution of vancomycin. Results A total of 116 patients were included (39 hematologic patients, 39 solid tumor patients, and 38 patients not known with cancer). In total, 742 paired time-concentration observations were available for the pharmacokinetic analysis. Presence of neutropenia showed to significantly (p = 0.00157) increase the clearance of vancomycin by 27.7% (95% CI 10.2-46.2%), whereas it did not impact the volume of distribution (p = 0.704). Conclusions This study shows that vancomycin clearance is increased in patients with neutropenia by 27.7%. Therefore, the vancomycin maintenance dose should be pragmatically increased by 25% in neutropenic patients at the start of treatment. Since the volume of distribution appeared unaffected, no adjustment in loading dose is required. These dose adjustments do not rule out the necessity of further dose individualization by means of therapeutic drug monitoring.

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Section: Discussionsupporting

confidence: 90%

“…This difference is likely due to an increased clearance of vancomycin in this specific patient population. Specifically, recent studies show that especially neutropenia is a risk factor associated with the increased clearance of vancomycin [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults

Bury

Heine

Garde

et al. 2019

Eur J Clin Pharmacol

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“…22 These findings are also in line with other studies, which noted a correlation between neutropenia and the decreased therapeutic activity of vancomycin. 4,23 Another study also noted that in chronically ill patients, vancomycin CL was higher. 24 Several explanations have been offered to explain these findings.…”

Section: Discussionmentioning

confidence: 95%

Optimization of Vancomycin Dosing Regimen in Cancer Patients using Pharmacokinetic/Pharmacodynamic Modeling

et al. 2020

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BACKGROUND Gram-positive bacterial infections are considered one of the major causes of mortality and morbidity in patients with cancer. Hence, the challenge lies in regulating the pervasive use of vancomycin in the management of infections facing such patients due to the anomalous vancomycin pharmacokinetics (PKs) and pharmacodynamics (PDs). Inappropriate vancomycin exposure is associated with toxicity, pathogen resistance, and therapeutic failure. OBJECTIVE The aim of this study was to estimate vancomycin PK in patients with cancer and without cancer. The standard dosage regimens of vancomycin were then evaluated using data from PK modeling. METHODS In this observational PK study, the data were extracted from a matched patient cohort of those with cancer and those without cancer. Pharmacokinetic analysis was performed using Monolix version 4.4, and the PK parameters were compared in both groups (cancer vs noncancer). The standard and suggested vancomycin dosing regimens were evaluated using PK/PD modeling and Monte Carlo Simulations. RESULTS In total, 448 blood samples were analyzed from 147 patients enrolled in this study, of which 73 patients had cancer and 74 patients were noncancer patients. In general, no significant differences were observed between the two groups (cancer vs noncancer) in all characteristics except for the vancomycin levels, which were significantly lower in patients with cancer (p = 0.00104). This analysis showed that patients with cancer showed a significantly higher vancomycin clearance than noncancer patients (p = 0.002), whereas the volume of distribution (V) was found to be similar in both groups (p = 0.83).This resulted in most of the patients failing to achieve the target area under the curve from zero to 24 hours (AUC 0-2) to the minimum inhibitory concentration. These data showed that a higher maintenance dose of vancomycin is required to achieve the PD target. CONCLUSIONS The findings of this study showed that the patients with cancer have lower levels of vancomycin due to higher clearance than noncancer patients. Thus, higher doses than the standard vancomycin doses may be needed to treat invasive Methicillin-resistant Staphylococcus aureus infections in patients with cancer.

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“…Recently, febrile neutropenia was considered as an adverse factor of vancomycin target concentration achievement by causing low vancomycin levels in the adult via enhancing CL probably attributed to elevated renal CL. [32][33][34] Neutropenia induced a 27.7% to 34% increase in CL, or a 33% decrease in vancomycin trough concentration in adults. [32][33][34] In our present study, 50% were patients with febrile neutropenia, so neutrophil count was adopted as a candidate covariate to evaluate the influence of neutropenia on vancomycin PKs in the children.…”

Section: Discussionmentioning

confidence: 99%

“…[32][33][34] Neutropenia induced a 27.7% to 34% increase in CL, or a 33% decrease in vancomycin trough concentration in adults. [32][33][34] In our present study, 50% were patients with febrile neutropenia, so neutrophil count was adopted as a candidate covariate to evaluate the influence of neutropenia on vancomycin PKs in the children. Whether as a continuous or a categorical variable, neutrophil count failed to affect vancomycin PK, so it was not included in the final model.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Study of Vancomycin in Chinese Pediatric Patients with Hematological Malignancies

et al. 2020

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STUDY OBJECTIVES Vancomycin is a primary antibiotic for the treatment of severe infections in children with malignant hematological disease. However, precise dosing of vancomycin is difficult in children because of high interindividual variability and limited data of pharmacokinetic profiles. The present study aims to develop a population pharmacokinetic (PPK) model for vancomycin in Chinese pediatric patients with hematological malignancies. DESIGN This was a retrospective pharmacokinetic study. SETTING The setting for this study was a tertiary-care children's hospital. PATIENTS This study included 92 pediatric patients with hematological malignancies who received vancomycin and experienced therapeutic drug monitoring from February 2017 to December 2018. MEASUREMENTS AND MAIN RESULTS A PPK model was generated with a nonlinear mixed effects model. In addition, required doses to achieve target therapeutic concentrations were simulated based on the final model. A one-compartment model with first-order elimination fit the concentration data best. Actual body weight (BW) and glomerular filtration rate (GFR) were the significant influential factors on the clearance (CL) of vancomycin. The final PPK model for CL was CL (L/h) = 4.18 Â GFR=145 ð Þ 0:741 Â BW=25 ð Þ K , K = BW À0:856 ð Þ = BW À0:856 þ 6:53 À0:856 ð Þ , and the volume of distribution was 22.3 L. The model proved to be robust and reliable. Reference dosing regimens were proposed based on the final model. CONCLUSIONS A PPK model of vancomycin was established for Chinese pediatric patients with hematological malignancies using a nonlinear mixed effects model, which provided a reference for the clinical application of vancomycin. KEY WORDS vancomycin, pediatrics, hematological malignancies, population pharmacokinetics.

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Neutropenia is independently associated with sub-therapeutic serum concentration of vancomycin

Cited by 14 publications

References 27 publications

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults

Optimization of Vancomycin Dosing Regimen in Cancer Patients using Pharmacokinetic/Pharmacodynamic Modeling

Population Pharmacokinetic Study of Vancomycin in Chinese Pediatric Patients with Hematological Malignancies

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