Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?

Abstract

BackgroundDespite differences in types of infection and causative organisms, pharmacokinetic-pharmacodynamic (PKPD) targets of vancomycin therapy derived from adult studies are suggested for neonates. We aimed to identify doses needed for the attainment of AUC/MIC > 400 and AUC/MIC > 300 in neonates with sepsis and correlate these targets with recommended doses and treatment outcome.MethodsNeonates who had Vancomycin therapeutic drug monitoring (TDM) performed between January 1, 2010 and December 31, 2012 were studied. Clinical characteristics, episodes of Gram-positive sepsis with outcomes and all neonatal blood culture isolates in hospital were collected from medical records. To estimate probability of target attainment of AUC/MIC >400 and AUC/MIC >300 a 1000-subject Monte Carlo simulation was performed by calculating AUC using Anderson’s (Anderson et al. 2006) and TDM trough concentrations (Ctrough) based population PK models.ResultsFinal dataset included 76 patients; 57 with confirmed Gram-positive sepsis. TDM was taken after the 1st to 44th dose. 84.1% of Ctrough were within the range 5–15 mg/L. Currently recommended doses achieved probability of the targets (PTA) of AUC/MIC >400 and AUC/MIC >300 in less than 25% and 40% of cases, respectively. Doses required for 80% PTA of AUC/MIC > 400 for MIC ≥2 mg/L resulted in Ctrough values ≥14 mg/L. Mean AUC/MIC values were similar in treatment failure and success groups.ConclusionWith currently recommended vancomycin dosing the therapeutic target of AUC/MIC > 400 is achieved only by 25% of neonates. Appropriate PKPD targets and respective dosing regimens need to be defined in prospective clinical studies in this population.

Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data

“…Pauwels et al 13 suggest AUC24h,SS/MIC ≥400, and some, e.g. Padari et al 42 suggest a lower target might already be effective perhaps due to lower protein binding 11 and therefore higher unbound (i.e. active) vancomycin concentrations in neonates, compared to adults.…”

Vancomycin therapeutic drug monitoring and population pharmacokinetic models in special patient subpopulations

“…Finally, because of differences in matrix composition (eg, protein, bilirubin), assay‐related inaccuracies may differ in neonates . With currently recommended vancomycin dosing, the therapeutic target of AUC/MIC > 400 is achieved only by 25% of neonates . Most of Ctrough in neonates achieved using two published dosing regimens did not reach the 10 mg/L .…”

“…55 With currently recommended vancomycin dosing, the therapeutic target of AUC/MIC > 400 is achieved only by 25% of neonates. 56 Most of Ctrough in neonates achieved using two published dosing regimens did not reach the 10 mg/L. 57 There is no consensus on vancomycin dosing in newborns and young infants.…”

Optimizing Vancomycin Use Through 2‐Point AUC‐Based Therapeutic Drug Monitoring in Pediatric Patients

“…An AUC 24 /MIC of ≥400 has been shown to predict better clinical and bacteriological outcomes in adult pediatric patients with lower respiratory tract MRSA infections . A recent study of novel rabbit models of neonatal coagulase‐negative Staphlococcus central‐line associated bloodstream infections demonstrated that an AUC 24 /MIC >400 was associated with maximal bacterial killing and suppression of the emergence of vancomycin resistance . However, determination of AUC involves multiple blood samples and a linear‐trapezoidal formula or pharmacokinetic software that needs further pharmacokinetic modeling, understanding, and personnel training .…”

“…4,5 A recent study of novel rabbit models of neonatal coagulase-negative Staphlococcus central-line associated bloodstream infections demonstrated that an AUC 24 /MIC >400 was associated with maximal bacterial killing and suppression of the emergence of vancomycin resistance. 6,7 However, determination of AUC involves multiple blood samples and a linear-trapezoidal formula or pharmacokinetic software that needs further pharmacokinetic modeling, understanding, and personnel training. 8 These may contribute to limited use of AUC-based vancomycin monitoring in routine clinical practice.…”