Hearing in Schoolchildren After Neonatal Exposure to a High-Dose Gentamicin Regimen.

OBJECTIVE: To assess the association between gentamicin exposure in the neonatal period and hearing in school age. METHODS: This study included children exposed to a high-dose (6 mg/kg) gentamicin regimen as neonates (2004-2012), invited for follow-up at school age, and a healthy age-matched control group. We assessed hearing with pure tone audiometry including the extended high-frequency (EHF) range. Outcomes were average hearing thresholds in the midfrequencies (0.5-4 kHz) and the EHFs (9-16 kHz). The measures of gentamicin exposure were cumulative dose and highest trough plasma concentration. We used linear regression models to assess the impact of gentamicin exposure, and other peri- and postnatal morbidities, on hearing thresholds. RESULTS: A total of 219 gentamicin-exposed and 33 healthy-control children were included in the audiological analysis. In the gentamicin cohort, 39 (17%) had a birth weight <1500 g. Median cumulative doses and trough plasma concentrations were 30 (interquartile range 24-42) mg/kg and 1.0 (interquartile range 0.7-1.2) mg/L, respectively. Median hearing thresholds for the midfrequencies and the EHFs were 2.5 (0 to 6.3) dB hearing level and -1.7 (-5.0 to 5.0) dB hearing level, both of which were within the normal range. In an adjusted analysis, increasing hearing thresholds were associated with lower birth weight and postnatal middle-ear disease but not level of gentamicin exposure. After adjusting for birth weight, there was no difference in hearing threshold between the gentamicin-exposed cohort and healthy controls. CONCLUSIONS: Exposure to a high-dose gentamicin regimen in the neonatal period was not associated with an increase in hearing thresholds in schoolchildren being able to complete audiometry.

Antibiotic therapy in neonates and impact on gut microbiota and antibiotic resistance development: a systematic review.

Objectives: To systematically review the impact of antibiotic therapy in the neonatal period on changes in the gut microbiota and/or antibiotic resistance development. Methods: Data sources were PubMed, Embase, Medline and the Cochrane Database, supplemented by manual searches of reference lists. Randomized controlled trials (RCTs) and observational studies were included if they provided data on different categories of antibiotic treatment (yes versus no, long versus short duration and/or broad- versus narrow-spectrum regimens) and subsequent changes in the gut microbiota and/or antibiotic resistance development. We evaluated risk of bias using the Cochrane Handbook, adapted to include observational studies. When appropriate, we used the vote-counting method to perform semi-quantitative meta-analyses. We applied the Grades of Recommendation, Assessment, Development and Evaluation approach to rate the quality of evidence (QoE). Study protocol registration: PROSPERO CRD42015026743. Results: We included 48 studies, comprising 3 RCTs and 45 observational studies. Prolonged antibiotic treatment was associated with reduced gut microbial diversity in all three studies investigating this outcome (very low QoE). Antibiotic treatment was associated with reduced colonization rates of protective commensal anaerobic bacteria in four of five studies (very low QoE). However, all three categories of antibiotic treatment were associated with an increased risk of antibiotic resistance development, in particular MDR in Gram-negative bacteria, and we graded the QoE for these outcomes as moderate. Conclusions: We are moderately confident that antibiotic treatment leads to antibiotic resistance development in neonates and it may also induce potentially disease-promoting gut microbiota alterations. Our findings emphasize the need to reduce unnecessary antibiotic treatment in neonates.

Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis.

Objectives: To systematically review and meta-analyse the relationship between antibiotic exposure in neonates and the following early adverse outcomes: necrotizing enterocolitis (NEC), invasive fungal infections (IFIs) and/or death. Methods: Data sources were PubMed, Embase, Medline and the Cochrane Database (to December 2016), supplemented by manual searches of reference lists. Randomized controlled trials (RCTs) and observational studies were included if they provided data on different categories of antibiotic exposures (yes versus no, long versus short duration, and/or broad- versus narrow-spectrum regimens) and the risk of developing NEC, IFI and/or death in the neonatal period. Two reviewers extracted data and evaluated the risk of bias using the Cochrane Handbook, adapted to include observational studies. When appropriate, meta-analyses were conducted using the random-effect model. Results: We identified 9 RCTs and 38 observational studies. The quality of the majority of studies was poor to moderate. There was a significant association between prolonged antibiotic exposure and an increased risk of NEC in five observational studies (5003 participants) and/or risk of death in five observational studies (13 534 participants). Eleven of 15 studies with data on broad- versus narrow-spectrum regimens reported an increased risk of IFI after broad-spectrum antibiotic exposure, in particular with third-generation cephalosporins and carbapenems. Meta-analysis was limited by few and old RCTs, insufficient sample sizes and diversity of antibiotic exposure and outcomes reported. Conclusions: Prolonged antibiotic exposure in uninfected preterm infants is associated with an increased risk of NEC and/or death, and broad-spectrum antibiotic exposure is associated with an increased risk of IFI.

Management of early-onset neonatal sepsis differs in the north and south of Scandinavia.

AIM: This study compared the management and outcomes of early-onset neonatal sepsis (EONS) in two tertiary neonatal units in Denmark and Norway. METHODS: We retrospectively studied all infants diagnosed with EONS between April 2010 and March 2013 and managed at Odense University Hospital, Denmark, and the University Hospital of North Norway, Norway. Clinical and laboratory data were collected from patient records. RESULTS: We identified 137 EONS cases in Denmark and 101 in Norway. There were 35 culture-confirmed EONS cases: 16% of the Danish cases and 13% of the Norwegian cases. Staphylococcus aureus was the most frequently detected pathogen in 11 cases (31%), followed by Group B streptococci in nine (26%) and Escherichia coli in six (17%). In 85% of the 238 cases, the empiric therapy comprised gentamicin and a beta-lactam, namely ampicillin in Denmark and benzylpenicillin in Norway. Patients with positive blood cultures had higher C-reactive protein levels than patients with negative blood cultures and higher sepsis-attributable mortality. Lumbar punctures were performed more frequently in Denmark. CONCLUSION: There were marginal differences in the management of EONS between units in Denmark and Norway, mainly in their choice of antibiotics and the use of lumbar punctures. Staphylococcus aureus was the most common pathogen.

High-dose gentamicin in newborn infants: is it safe?

Dosing regimens often recommend lower gentamicin doses in neonates (3-5 mg/kg) than in older children (7 mg/kg or more) despite the higher volume of distribution in neonates. We studied an extended-interval high-dose (6 mg/kg) gentamicin regimen in a single tertiary neonatal unit from 2004-2012. During the first week of life, dosing interval was 24 h for term infants, 36 h for preterm infants with gestational age (GA) 29-36 weeks and 48 h for preterm infants with GA <29 weeks. After the first week of life, dosing interval was 24 h if corrected age (GA + postnatal age) ≥29 weeks and 36 h if corrected age <29 weeks. Outcome measures were trough plasma concentration (TPC), ototoxicity and prescription errors. In 546 treatment episodes, TPC was measured prior to the third gentamicin dose. There were 37 episodes (6.7 %) of prescription errors, mainly a too long dosing interval. We included 509 treatment episodes (440 infants) in the final analysis. Mean (standard deviation) gentamicin TPC during the first week of life was 1.1 (0.5) mg/L and after the first week of life 0.8 (0.6) mg/L. In 31 (6 %) episodes, TPC was ≥2.0 mg/L, predominantly among term infants with renal impairment. Thirty-eight patients failed the neonatal hearing screening, but only four of these 38 had permanent hearing loss. All four had a TPC <2.0 mg/L. Conclusions: This extended-interval high-dose gentamicin regimen was associated with low numbers of elevated TPCs, low numbers of prescription errors and no evidence for ototoxicity.