Low penetration of caspofungin into cerebrospinal fluid following intravenous administration of standard doses.

The kinetics of caspofungin (CAS) in cerebrospinal fluid (CSF) following intravenous (i.v.) administration has been studied exclusively in animal models. Human data are missing so far. In this study, 13 CSF samples were obtained at different time points following i.v. infusion of CAS in ten paediatric haemato-/oncological patients (age range 1.0-14.2 years, median 8.6 years) without signs of central nervous system (CNS) infection (n = 10 samples) or with infectious meningitis (n = 3 samples). Serum samples were obtained concurrently. Liquid chromatography-tandem mass spectrometry was used for CAS quantification. Whilst CAS serum levels were in the expected range, varying between 0.6 and 20.3 µg/mL (median 7.0 µg/mL), 11 of 13 CSF levels were below the limit of detection of 0.084 µg/mL at 3.0-48.0 h (median 23.3 h) following i.v. infusion. Only two (of three) levels in patients with bacterial meningitis were above the limit of detection (0.3 µg/mL and 0.09 µg/mL, respectively). These results indicate the low capacity of CAS to penetrate into the CNS even in inflamed meninges. Monotherapy with standard doses of CAS appears not to be suitable for treatment of fungal CNS infections.

Serum bile acids in term and preterm neonates: A case-control study determining reference values and the influence of early-onset sepsis.

Serum bile acids (BA) reference values are lacking for neonates. Therefore, this study aimed to determine serum BA reference values in term and preterm neonates. Furthermore, as serum BA concentrations are well-known to rise in septic adults, BA values were determined in early-onset neonatal sepsis (EOS), a common and serious disease in neonates.Using high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS), we profiled serum BA in 236 infants, including healthy term neonates (n = 84), premature infants (n = 101), and both term infants (n = 35) and preterm infants (n = 16) with EOS. We examined the impact of prematurity and EOS on BA concentrations.The median reference values of serum BA were 8.0 µmol/L, interquartile range (IQR): 4.6 to 12.9, in healthy term neonates and 10.1 µmol/L, IQR: 5.7 to 15.7, in preterm neonates. Neonates with EOS had significantly lower median BA values, term (4.7 µmol/L, IQR: 2.7-7.6; P < 0.01) as well as preterm (6.4 µmol/L, IQR: 3.5-8.4; P < 0.01). Furthermore, primary and conjugated BA were most abundant in all groups. Taurine-conjugated BA were predominant in all neonates; glycine-conjugated BA were significantly lower in term neonates with EOS than in controls (P < 0.05). Multivariate regression analysis results obtained for BA and inflammatory parameters revealed that BA are an independent factor associated with EOS.This is the first study to determine standard value ranges of serum BA in neonates using HPLC-HRMS. In contrast to adults with sepsis, neonates suffering from EOS exhibit significantly lower BA values than do controls of the same gestational age. These data suggest BA as a supplementary parameter within a panel of biomarkers for EOS in the future.

Inflammatory indices in meconium aspiration syndrome.

INTRODUCTION: Meconium aspiration syndrome (MAS) is linked to inflammation, but data on the patterns of hematological indices and C-reactive protein (CRP) in MAS are lacking. The aim of the study was to evaluate CRP, white blood cell count (WBC), absolute neutrophil count (ANC), and immature-to-total neutrophil ratio (IT-ratio) in MAS and to assess their association with disease severity. METHODS: Retrospective cross-sectional study including 239 consecutively admitted neonates with MAS to a level III NICU. Neonates with early onset sepsis were excluded. Results Neonates with severe MAS (invasive mechanical ventilation for <7 days) and very severe MAS (invasive mechanical ventilation for ≥7 days or high frequency ventilation or ECMO) had higher CRP and IT-ratio compared to neonates with non-severe MAS (no invasive mechanical ventilation) during the first 2 days of life (CRP: 13.0 and 40.9 vs. 9.5 mg/L, P = 0.039 and <0.001, respectively) and neonates with very severe MAS had lower WBC and ANC. All four inflammatory indices correlated significantly with duration of invasive mechanical ventilation, duration of respiratory support and with length of hospital stay, arterial hypotension, and persistent pulmonary hypertension. Neonates with all four inflammatory indices beyond the normal range had a more than 20-fold increase in risk for very severe MAS. CONCLUSION: High CRP and IT-ratio and low WBC and ANC values were closely linked to a more severe course of MAS during the early phases of the disease. These findings reflect the role of inflammation in the pathogenesis of MAS. Pediatr Pulmonol. 2016;51:601-606. 2015 Wiley Periodicals, Inc.

Early-Onset Neonatal Sepsis: Still Room for Improvement in Procalcitonin Diagnostic Accuracy Studies.

To perform a systematic review assessing accuracy and completeness of diagnostic studies of procalcitonin (PCT) for early-onset neonatal sepsis (EONS) using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative.EONS, diagnosed during the first 3 days of life, remains a common and serious problem. Increased PCT is a potentially useful diagnostic marker of EONS, but reports in the literature are contradictory. There are several possible explanations for the divergent results including the quality of studies reporting the clinical usefulness of PCT in ruling in or ruling out EONS.We systematically reviewed PubMed, Scopus, and the Cochrane Library databases up to October 1, 2014. Studies were eligible for inclusion in our review if they provided measures of PCT accuracy for diagnosing EONS. A data extraction form based on the STARD checklist and adapted for neonates with EONS was used to appraise the quality of the reporting of included studies.We found 18 articles (1998-2014) fulfilling our eligibility criteria which were included in the final analysis. Overall, the results of our analysis showed that the quality of studies reporting diagnostic accuracy of PCT for EONS was suboptimal leaving ample room for improvement. Information on key elements of design, analysis, and interpretation of test accuracy were frequently missing.Authors should be aware of the STARD criteria before starting a study in this field. We welcome stricter adherence to this guideline. Well-reported studies with appropriate designs will provide more reliable information to guide decisions on the use and interpretations of PCT test results in the management of neonates with EONS.

The whole spectrum of cystic periventricular leukomalacia of the preterm infant: results from a large consecutive case series.

PURPOSE: The purpose of this study is to describe features of cystic periventricular leukomalacia (PVL) in a large consecutive cohort study including long-term neurodevelopmental follow-up. METHODS: We performed a retrospective single-centre cohort study including all preterm infants ≤35 weeks of gestational age with PVL diagnosed by ultrasound scans (US) from a tertiary care university hospital between 1988 and 2012. RESULTS: The majority of 160 consecutively diagnosed cases had a gestational age between 28 and 32 weeks (60.6%), and male sex was predominant (60.6%). The most common associated clinical findings included respiratory distress syndrome, preterm premature rupture of the membranes, and chorioamnionitis (57.5, 49.4, and 39.4%, respectively). Infants presented with apnoeas in 66.3 and neonatal seizures in 23.1%. Any kind of respiratory support was present in 75.0%. Associated low-grade intraventricular haemorrhage was evident in 33.1, high-grade haemorrhage in 9.4%. Cysts were located on both hemispheres in 75% and PVL grades 3 and 4 were predominant (75.6%). Neurodevelopmental follow-up of 146 cases at a median age of 72 months revealed normal development in 11.0, mental retardation in 50.0, and cerebral palsy in 83.6%. Visual impairment was diagnosed in 21.9% and hearing impairment in one case. A quarter of cases (27.4%) developed seizure disorders. Outcome data were significantly better in unilateral compared to bilateral PVL. CONCLUSIONS: Long-term neurodevelopmental outcome of bilateral PVL always was adverse and different from unilateral PVL. The latter might be negatively influenced by associated intra- and periventricular haemorrhages.

Fetal and early neonatal interleukin-6 response.

In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.

Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B.

OBJECTIVES: Although amphotericin B (AmB) and its lipid formulations are used for the treatment of fungal infections of the CNS, the kinetics of AmB in the CSF after intravenous administration of liposomal amphotericin B (LAmB) are not well characterized. PATIENTS AND METHODS: From 14 paediatric haemato-oncological patients (aged 0.4-19.5 years, median 7.6 years), we obtained 30 CSF samples by means of routine punctures (performed for intrathecal treatment of the underlying diseases) at different timepoints after the prophylactic intravenous infusion of LAmB (AmBisome, 3 mg/kg/day). Concurrent serum samples were obtained to calculate the transfer rates. An HPLC method was used for AmB detection. RESULTS: CSF levels of AmB 1-100 h after the intravenous infusion of LAmB were between 10 and 120 ng/mL, except in one case with a level of 529 ng/mL. Concurrent serum levels were about 1000-fold higher, ranging between 3 and 75 µg/mL. CSF levels did not show a clear time-dependent concentration profile, but remained at a steady-state for longer than 48 h after infusion. The transfer rate ranged from 0.02% to 0.92% (median 0.13%) and correlated significantly (r=0.801, P<0.001) with increasing time after infusion. CONCLUSIONS: After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

Cord blood procalcitonin and Interleukin-6 are highly sensitive and specific in the prediction of early-onset sepsis in preterm infants.

We studied the predictive value of cord blood procalcitonin (PCT) and interleukin-6 (IL-6) in the diagnosis of early-onset sepsis (EOS) in the preterm infant. Retrospectively, PCT and IL-6 were correlated with clinical and/or blood culture positive EOS and negative infectious status between February 2008 and March 2011. Receiver operating curves (ROC) were generated and the area under the curve (AUC) was calculated by use of Youden's Index to detect the best cut-off values for sensitivity and specificity. Thirty of 218 preterm infants (13.8%) were diagnosed as having EOS. The optimal cut-off value for PCT was 0.235 µg/L (sensitivity 78.6%, specificity 86.3%), and for IL-6 15.85 ng/L (sensitivity 73.7%, specificity 84.2%), the combination of PCT and IL-6 revealed sensitivity 77.1% and specificity 91.7%. The combined determination of PCT and IL-6 from cord blood was highly sensitive and specific in the prediction of EOS.

The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates.

OBJECTIVE: The aim of this study was to show and discuss an association between fetal inflammatory response syndrome (FIRS) and an adverse neonatal outcome defined as combined severe neonatal morbidity and mortality in preterm neonates hospitalized in our neonatal intensive care unit. STUDY DESIGN: This was an observational study including all preterm neonates hospitalized in our neonatal intensive care unit over a 21 month period. FIRS was defined as cord blood interleukin (IL)-6 greater than 11 pg/mL. Main outcome parameter was an adverse neonatal outcome defined as hospital mortality and/or the presence of any of 5 prespecified morbidities (bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, and early- or late-onset sepsis). RESULTS: Fifty-seven of 176 preterm infants hospitalized during the study period (32%) had an adverse neonatal outcome and 62 of these 176 infants (35%) had FIRS with median IL-6 values of 51.8 pg/mL (range, 11.2 to >1000 pg/mL). In a regression analysis, FIRS was significantly associated with adverse neonatal outcome (P < .001) and with the single outcome parameters, intraventricular hemorrhage and early-onset sepsis (P = .006 and P = .018, respectively). In the bivariate analysis, FIRS was associated with death and bronchopulmonary dysplasia (P = .004 and P < .001, respectively). IL-6 correlated with adverse neonatal outcome (r = 0.411, P < .001). When comparing the correlation in neonates less than 32 weeks' gestational age (r = 0.481, P < .001) with neonates 32 weeks or longer (r = 0.233, P = .019), the difference was nearly significant (P = .065). CONCLUSION: FIRS is a risk factor for adverse neonatal outcome in preterm infants. In particular, the combination of IL-6 greater than 11 pg/mL and low gestational age increased the risk for severe neonatal morbidity or death.

Age- and gender-related differences in teicoplanin levels in paediatric patients.

OBJECTIVES: Teicoplanin is a glycopeptide antibiotic active against Gram-positive bacteria, including methicillin-resistant staphylococci. While teicoplanin trough levels (TTLs) >10 mg/L are commonly considered appropriate, levels >20 mg/L are aimed for in the treatment of severe infections. Due to toxicity, it is recommended to avoid levels >60 mg/L. PATIENTS AND METHODS: In our institution, the initial dosing schedule of teicoplanin (10-15 mg/kg every 12 h for three loading doses and every 24 h thereafter) is adapted according to TTLs analysed by a fluorescence polarization immunoassay on treatment days 2 to 4. Teicoplanin peak levels (TPLs) are analysed in selected cases 30 min after the end of infusion. In a retrospective analysis we evaluated 1357 TTLs and 333 TPLs from 410 treatment episodes from 2005 to 2011. RESULTS: Initial TTLs were <10 mg/L in 14.1% and <20 mg/L in 72.6% of episodes. Toddlers had significantly lower TTLs, with a 2-fold and 2.5-fold increased risk of having levels <10 mg/L (24.6%) and <20 mg/L (82.6%), respectively. For the entire cohort, follow-up TTLs were less likely to be <10 mg/L and more likely to be >20 mg/L when compared with initial TTLs (P < 0.001, each). Adolescent girls had significantly higher initial TPLs (P = 0.001) and significantly higher follow-up TTLs (P = 0.016) than adolescent boys. In parallel, adolescent girls had initial TPLs >60 mg/L significantly more frequently (P = 0.012) and follow-up TTLs <10 mg/L significantly less frequently (P = 0.005). CONCLUSIONS: More tailored dosing regimens with higher loading doses, especially for toddlers, should be considered. While further pharmacokinetic data in paediatric patients are pending, therapeutic drug monitoring is mandatory.

Performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates.

AIMS: The aim of this study was to examine the applicability of the definitions of the systemic inflammatory response syndrome (SIRS) and sepsis to neonates during the first 3 days of life. METHODS: This is a retrospective study of all term neonates hospitalized within the first 24 h of life from 2004 to 2010 at our neonatal intensive care unit. RESULTS: Of 476 neonates, 30 (6 %) had a diagnosis of culture-proven early-onset sepsis (EOS) and 81 (17 %) had culture-negative clinical EOS or suspected EOS. SIRS and sepsis criteria were applied to 116 (24 %) and 61 (13 %) neonates, respectively. Of 30 neonates with culture proven, EOS 14 (53 %) fulfilled SIRS and sepsis criteria. The single diagnostic criterion of SIRS applied to 20 % (hypothermia or fever), 43 % (white blood cell count/immature-to-total neutrophil ratio), 87 % (respiratory symptoms), and 33 % (cardiocirculatory symptoms) of all neonates with culture-proven EOS. CONCLUSIONS: The definitions of SIRS and sepsis did not apply to about half of all cases of culture-proven EOS. An evidence-based approach to find the appropriate criteria for defining EOS in the neonate is needed.

An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks.

C-reactive protein (CRP) is one of the most studied and most used laboratory tests for neonatal sepsis. As part of the acute-phase reaction to infection, it plays a central role in the humoral response to bacterial invasion. The delayed synthesis during the inflammatory response accounts for its low sensitivity during the early phases of the disease. Diagnostic accuracy clearly improves by the performance of serial determinations and by the combination with earlier markers such as interleukins or procalcitonin. CRP is as well particularly useful for monitoring the response to treatment and guiding antibiotic therapy, though nothing replaces the clinical impression and the gold standard (i.e. culture results). In spite of the large amount of research done on CRP in neonates, some topics are still not fully understood, such as the influence of noninfectious factors on CRP levels in healthy as well as in symptomatic neonates and the role of gestational age and birthweight on CRP kinetics. In this review, we aim to give an update on the current evidence on the use of CRP in neonates.

Neonates presenting with temperature symptoms: role in the diagnosis of early onset sepsis.

BACKGROUND: In this study, we aimed to evaluate the role of fever, hypothermia, and temperature instability in term and preterm newborns during the first 3 days of life and to identify risk factors for early onset sepsis (EOS) among newborns presenting with these temperature symptoms. METHODS: In this retrospective cohort study set in our level III neonatal intensive care unit, we included all newborns hospitalized within the first 24 h of life from 2004 to 2007. RESULTS: Of 851 newborns, 127 presented with temperature symptoms during the first 3 days of life (15%): 69 had fever, 69 had hypothermia, and 55 had temperature instability (8%, 8%, and 6%, respectively). Of 127 newborns presenting with temperature symptoms, 14 had culture-proven EOS/pneumonia (33% of all 42 newborns with culture-proven EOS/pneumonia), 67 had clinical EOS (30% of all 209 newborns with clinical EOS) and 46 were EOS-negative (8% of all 600 EOS-negatives). Factors associated with culture-proven EOS/pneumonia in newborns presenting with temperature symptoms were maternal fever (P = 0.009), chorioamnionitis (P < 0.001), antibiotic therapy of the mother (P = 0.04), poor skin color (P = 0.001) and syndrome of persistent fetal circulation (P = 0.01). CONCLUSIONS: Every seventh newborn hospitalized at our neonatal intensive care unit developed fever, hypothermia and/or temperature instability during the first 3 days of life. Two-thirds of them had culture-proven or clinical sepsis. Temperature symptoms were rarely observed in EOS-negative newborns (8%) but despite low sensitivity, were highly specific for bacterial infection in preterm and term newborns.

Definitions of SIRS and sepsis in correlation with early and late onset neonatal sepsis.

Objective: To examine the applicability of the 2002 International Pediatric Sepsis Consensus Conference definitions of the systemic inflammatory response syndrome (SIRS) and sepsis to term and preterm newborns in the diagnosis of early (EOS) and late onset sepsis (LOS). Methods: Retrospective cohort study including 1) all newborns with hospitalization within the first 72 hours of life and 2) infants with episodes of suspected LOS at a tertiary care neonatal intensive care unit between 2004 and 2008, and correlating the definitions of SIRS and sepsis with culture proven and clinical EOS and LOS. Results: Association with EOS: Among term newborns SIRS and sepsis definitions applied to 62 and 39/245 newborns (25% and 16%, respectively) and to 5/13 cases of culture proven EOS (38%) and 34/66 cases of clinical EOS (52%), respectively. Among preterm newborns SIRS and sepsis definitions applied to 202 and 124/505 newborns (40% and 25%, respectively) and to 17/24 cases of culture proven EOS (71%) and 107/160 cases of clinical EOS (67%), respectively. Sensitivity of SIRS and sepsis definitions was higher in preterm compared to term newborns in case of culture proven and clinical EOS (p=.047 and p=0.03, respectively). Association with LOS: SIRS and sepsis definitions applied to 5/5 episodes of culture proven LOS (100%) and to 4/9 episodes of clinical LOS (44%) in newborns who were term at onset of sepsis (corrected gestational age) and to 14/19 episodes of culture proven LOS (74%) and 24/28 episodes of clinical LOS (86%) in preterm newborns. Conclusion: The definitions of SIRS and sepsis correlated well with LOS but poorly with EOS, where nearly two thirds of term and one quarter of preterm newborns would have been missed. Postnatal age rather than gestational age had a positive influence on the correlation.

Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life.

BACKGROUND: Our aim was to analyze C-reactive protein (CRP) values in term and preterm infants and correlate non-infection-associated increases with various neonatal disorders. METHODS: Retrospective cohort study that included all newborns hospitalized at a tertiary care center between 2004 and 2007 with documented CRP values in the first 3 days of life. Analysis of differences in CRP values between term and preterm newborns and cases with CRP increases in sepsis negative newborns. RESULTS: For diagnosis of blood culture proven sepsis (19 and 14 cases, respectively) in 353 preterm and 179 term newborns, CRP at a cut-off of 8 mg/L had sensitivities of 53% and 86% and specificities of 91% and 88%, respectively. The area under the receiver operating characteristics curves were 0.799 and 0.890, respectively. Preterm newborns had lower median values compared to term newborns in sepsis positive (9 vs. 18.5 mg/L, p < 0.001) and negative newborns (0.5 vs. 2 mg/L, p < 0.001). Increases in individuals without infection were correlated significantly with meconium aspiration syndrome and surfactant application in term newborns (p = 0.009 and 0.025, respectively) and with surfactant application and higher birth weight in preterm newborns (p < 0.001 and 0.031, respectively). CONCLUSIONS: CRP values were significantly lower in preterm compared to term newborns, and its application in the diagnosis of sepsis in preterm newborns was not as reliable as in term newborns. Meconium aspiration syndrome, surfactant application, and high birth weight were associated significantly with increased CRP values.