Arwen J. Sprij

Therapeutic Drug Monitoring of Aminoglycosides in Neonates

The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to extended-interval dosing. This evolution has also taken place in neonates. Neonates, however, display large interindividual differences in the pharmacokinetics of aminoglycosides due to developmental differences early in life. The volume of distribution of aminoglycosides shows a strong relationship with bodyweight, which tends to be larger (corrected for bodyweight) in more premature infants and those with sepsis. Renal clearance of aminoglycosides increases with gestational age and accelerates immediately after birth. Because of these developmental influences, there is great inter- and intraindividual variability in the volume of distribution and clearance of these drugs, and investigators have established aminoglycoside dosing regimens based on bodyweight and/or gestational age. Widely practised dosing regimens comprise 4–5 mg/kg bodyweight of gentamicin every 24–48 hours as a first dose, followed by dose adjustment based on therapeutic drug monitoring. Although formal toxicity studies are scarce, there is no evidence that aminoglycoside toxicity in neonates differs from that in adults. Monitoring of blood drug concentrations and intelligent reconstruction of individual pharmacokinetic behaviour using a population pharmacokinetic model, optimally chosen blood sampling times and appropriate pharmacokinetic software, help clinicians to quickly optimize aminoglycoside dosing regimens to maximize the clinical effect and minimize the toxicity of these drugs.

Association between colonization with Group B Streptococcus and preterm delivery: A systematic review

Up to 36% of pregnant women are colonized with Group B Streptococcus (GBS). Preterm delivery in colonized mothers is a risk factor for early onset neonatal GBS disease, but whether maternal GBS genital colonization is related to preterm delivery is unclear. The objective of this review was to determine the relationship between maternal colonization with GBS and preterm delivery. Pubmed searches and reference lists of all selected publications were used to find studies reporting on the relationship between maternal GBS colonization and preterm delivery. Study characteristics were abstracted, and validity scores were performed. To assess the relationship between GBS colonization and pregnancy outcome, four‐fold prognostic tables were constructed for each study. Out of more than 60 full‐text articles, 16 follow‐up studies and four case control studies were included in this review. Follow‐up studies were divided into ‘cohort studies,’ in which cultures were taken early in pregnancy and which reported on pregnancy outcome, and ‘cross‐sectional studies’, in which cultures were collected during delivery. Studies differed widely in methods, validity score, and GBS prevalence. The combined estimate from a random effect meta‐analysis of the 11 cohort studies was 1.06 (95% confidence intervals (CI) 0.95–1.19) and for the five cross‐sectional studies 1.75 (95% CI 1.43–2.14). For the case control studies, the pooled odds ratio was 1.59 (95% CI 1.03–2.44). This systematic review did not show an association between maternal GBS colonization during pregnancy and preterm delivery. However, in case of preterm delivery, there is an increased risk of subsequent maternal GBS colonization.

Recombinant Human Deoxyribonuclease in Infants With Respiratory Syncytial Virus Bronchiolitis

BACKGROUND Treatment of hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis is mainly supportive. Bronchodilators and systemic steroids are often used but do not reduce the length of hospital stay. Because hypoxia and airways obstruction develop secondary to viscous mucus in infants with RSV bronchiolitis, and because free DNA is present in RSV mucus, we tested the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase). METHODS In a multicenter, randomized, double-blind, controlled clinical trial, 225 oxygen-dependent infants admitted to the hospital for RSV bronchiolitis were randomly assigned to receive 2.5 mg bid of nebulized rhDNase or placebo until discharge. The primary end point was length of hospital stay. Secondary end points were duration of supplemental oxygen, improvement in symptom score, and number of intensive care admissions. RESULTS There were no significant differences between the groups with regard to the length of hospital stay (p = 0.19) or the duration of supplemental oxygen (p = 0.07). The ratio (rhDNase/placebo) of geometric means of length of stay was 1.12 (95% confidence interval, 0.96 to 1.33); for the duration of supplemental oxygen, the ratio was 1.28 (95% confidence interval, 0.97 to 1.68). There were no significant differences in the rate of improvement of the symptom score or in the number of intensive care admissions. CONCLUSIONS Administration of rhDNase did not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.

Timing of Group B Streptococcus Screening in Pregnancy: A Systematic Review

Background: Group B streptococcus (GBS) is an important cause of neonatal sepsis. Guidelines advise to collect cultures at 35–37 weeks’ gestation and to administer intrapartum antibiotic prophylaxis in case of GBS-positive cultures, as well as in all preterm deliveries. Improved effectiveness of antenatal cultures might help to further decrease GBS early-onset disease. Objective: To determine the best timing of antenatal cultures, which may help establish optimal prevention of perinatal GBS infection in both term and preterm neonates. Methods: PubMed and EMBASE databases were searched for relevant articles published from 1966 to February 2009. Nine articles were included. Information about study features and predictive values of antenatal cultures were abstracted. Results: Positive predictive values for antenatal GBS cultures ranged from 43 to 100% (mean 69%) and negative predictive values from 80 to 100% (mean 94%). GBS cultures collected in late pregnancy had high positive predictive values for colonization during delivery. The negative predictive value was high and relatively constant regardless of GA. Conclusions: This systematic review confirms recommendations to screen pregnant women for colonization of GBS at 35–37 weeks’ gestation, but one should be aware of the limitations of screening, with 6% of GBS carriers remaining undetected in antenatal cultures.

The validity of biochemical markers in metabolic bone disease in preterm infants: a systematic review

To establish the validity of biochemical markers of metabolic bone disease (MBD) in preterm infants.

A virtual asthma clinic for children: Fewer routine outpatient visits, same asthma control

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits. In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6–16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids. We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42–2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09–2.25; p=0.03). No differences were found for other outcome measures. Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth. A virtual asthma clinic as an individualised online monitoring strategy can partly replace routine outpatient visits http://ow.ly/f9Vd30dqWvJ

Online asthma management for children is cost-effective

eHealth interventions have been proposed as an appealing method to improve health outcomes and reduce healthcare costs [1–3]. However, the development of an eHealth intervention is associated with high costs and this investment needs to be balanced by increased clinical effectiveness and related cost savings. Unfortunately, solid evidence for the effectiveness of eHealth with regard to health improvement is still limited [2–5], as is evidence regarding cost-effectiveness. This causes uncertainty about the effectiveness of eHealth and constitutes a barrier towards successful implementation in daily practice [6, 7]. Thus, it is necessary to assess both effectiveness and cost-effectiveness to convince colleagues and policymakers of its added value. Online asthma management in children can (partly) substitute routine outpatient visits and is cost-effective http://ow.ly/oabk30f7Sre

Extended-Interval Dosing of Gentamicin Aiming for a Drug-Free Period in Neonates : A Prospective Cohort Study

Background: Current gentamicin dosing algorithms in adult populations target a high peak concentration (Cmax) assuring efficacy and a drug-free period (concentration <0.5 mg/L) preventing toxicity. In contrast, gentamicin-based regimens in neonatal sepsis often aim for lower peak levels and trough concentrations of 0.5–2.0 mg·L−1. The latter concentrations are associated with an increased risk of aminoglycoside-related toxicity. Therefore, the primary aim of this study was to assess the target attainment of a simple and practical dosing regimen designed to attain drug-free periods in newborns. Methods: The study was of prospective observational design. Neonates admitted to a level II neonatal nursery diagnosed with (suspected) early-onset sepsis and commencing intravenous gentamicin therapy of 5 mg·kg−1 every 36 hours were eligible for inclusion. Gentamicin dosing was guided by drug concentration monitoring targeting Cmax values >8 mg·L−1 and estimated trough concentrations <0.5 mg·L−1. Relationships between body weight (BW), gestational age (GA), postnatal age, and pharmacokinetic parameters were analyzed using the Pearson correlation test, and univariate and multivariate logistic regression analyses were performed to identify covariates predictive of target attainment failure. Results: A total of 184 patients were included. 90.4% of patients (n = 166) achieved a Cmax value >8 mg·L−1 with a Cmin value <0.5 mg·L−1. Subsequently, significant correlations were found between GA and Cmax (r = 0.58, P < 0.001) between GA and Cmin (r = 0.44, P < 0.001), between BW and Cmax (r = 0.50, P < 0.001), and between BW and Cmin (r = 0.42, P < 0.001). Correlations between area under the curve (AUC) and GA (r = 0.064, P = 0.4), and between AUC and BW (r = 0.028, P = 0.7) were not significant. During multivariate analysis, only GA (P < 0.001) was retained as an independent predictor of underexposure. Conclusions: Extended interval dosing of gentamicin resulted in high target attainment rates in neonates admitted to a level II unit. In line with previous reports, low GA and BW were predictive of subtherapeutic peak and toxic trough levels. The AUC, however, was unaffected by the interpatient variation in GA and BW. Since AUC-guided dosing is gaining interest worldwide, the latter finding deserves further exploration in other neonatal cohorts.

Clinical availability of neonatal blood culture results at 48 hours

Background/aim: To minimize the use of antibiotics in the neonatal unit, it is crucial to know the time needed for a blood culture to become positive. With the development of newer automated blood culture systems, the time needed to detect a positive culture is said to be reduced to 48 hours. The aim of this study was to determine the time at which neonatal blood culture results become clinically available to the attending neonatologist. Design and methods: In an eighteen-months-period prospective study we collected 361 blood cultures from neonates admitted to our neonatal unit. Time to positivity (TTP) (the time between culture sampling and the moment the neonatologist received the results) was determined. Incubation time (time actually spent in the Bactec machine) was automatically registered. Results: 72 out of 361 blood cultures were positive (20%). 93% (67/72) of the positive cultures had a TTP of less than 48 hours. One sample had a TTP of 50 and one of 53 hours. Three samples had an incubation time of more than 94 hours. A total of 99% (68/69) of the remaining cultures were positive within 30 hours of incubation. Conclusion: This study demonstrated that 93% of blood cultures results are determined by 48 hours. Incubation time in the Bactec is consistent with reliable detection of pathogen microbes by 30 hours. If effort is made to improve logistics TTP can further be reduced to 30 hours resulting in further reduction of antibiotic usage in neonatal intensive care units.