Variation in antibiotic consumption in very preterm infants-a 10 year population-based study.

OBJECTIVES: Wide variations in antibiotic use in very preterm infants have been reported across centres despite similar rates of infection. We describe 10 year trends in use of antibiotics and regional variations among very preterm infants in Norway. PATIENTS AND METHODS: All live-born very preterm infants (<32 weeks gestation) admitted to any neonatal unit in Norway during 2009-18 were included. Main outcomes were antibiotic consumption expressed as days of antibiotic therapy (DOT) per 1000 patient days (PD), regional variations in use across four health regions, rates of sepsis and sepsis-attributable mortality and trends of antibiotic use during the study period. RESULTS: We included 5296 infants: 3646 (69%) were born at 28-31 weeks and 1650 (31%) were born before 28 weeks gestation with similar background characteristics across the four health regions. Overall, 80% of the very preterm infants received antibiotic therapy. The most commonly prescribed antibiotics were the combination of narrow-spectrum ß-lactams and aminoglycosides, but between 2009 and 2018 we observed a marked reduction in their use from 100 to 40 DOT per 1000 PD (P < 0.001). In contrast, consumption of broad-spectrum ß-lactams remained unchanged (P = 0.308). There were large variations in consumption of vancomycin, broad-spectrum ß-lactams and first-generation cephalosporins, but no differences in sepsis-attributable mortality across regions. CONCLUSIONS: The overall antibiotic consumption was reduced during the study period. Marked regional variations remained in consumption of broad-spectrum ß-lactams and vancomycin, without association to sepsis-attributable mortality. Our results highlight the need for antibiotic stewardship strategies to reduce consumption of antibiotics that may enhance antibiotic resistance development.

Early Empirical Antibiotics and Adverse Clinical Outcomes in Infants Born Very Preterm: A Population-Based Cohort.

OBJECTIVE: The objective of this study was to evaluate the association between empirical antibiotic therapy in the first postnatal week in uninfected infants born very preterm and the risk of adverse outcomes until discharge. STUDY DESIGN: Population-based, nationwide registry study in Norway including all live-born infants with a gestational age <32 weeks surviving first postnatal week without sepsis, intestinal perforation, or necrotizing enterocolitis (NEC) between 2009 and 2018. Primary outcomes were severe NEC, death after the first postnatal week, and/or a composite outcome of severe morbidity (severe NEC, severe bronchopulmonary dysplasia [BPD], severe retinopathy of prematurity, late-onset sepsis, or cystic periventricular leukomalacia). The association between empirical antibiotics and adverse outcomes was assessed using multivariable logistic regression models, adjusting for known confounders. RESULTS: Of 5296 live-born infants born very preterm, 4932 (93%) were included. Antibiotics were started in first postnatal week in 3790 of 4932 (77%) infants and were associated with higher aOR of death (aOR 9.33; 95% CI: 1.10-79.5, P = .041), severe morbidity (aOR 1.88; 95% CI: 1.16-3.05, P = .01), and severe BPD (aOR 2.17; 95% CI: 1.18-3.98; P = .012), compared with those not exposed. Antibiotics ≥ 5 days were associated with higher odds of severe NEC (aOR 2.27; 95% CI: 1.02-5.06; P = .045). Each additional day of antibiotics was associated with 14% higher aOR of death or severe morbidity and severe BPD. CONCLUSIONS: Early and prolonged antibiotic exposure within the first postnatal week was associated with severe NEC, severe BPD, and death after the first postnatal week.

Late-onset sepsis in very preterm infants in Norway in 2009-2018: a population-based study.

OBJECTIVE: To evaluate epidemiology and outcomes among very preterm infants (<32 weeks' gestation) with culture-positive and culture-negative late-onset sepsis (LOS). DESIGN: Cohort study using a nationwide, population-based registry. SETTING: 21 neonatal units in Norway. PARTICIPANTS: All very preterm infants born 1 January 2009-31 December 2018 and admitted to a neonatal unit. MAIN OUTCOME MEASURES: Incidences, pathogen distribution, LOS-attributable mortality and associated morbidity at discharge. RESULTS: Among 5296 very preterm infants, we identified 582 culture-positive LOS episodes in 493 infants (incidence 9.3%) and 282 culture-negative LOS episodes in 282 infants (incidence 5.3%). Extremely preterm infants (<28 weeks' gestation) had highest incidences of culture-positive (21.6%) and culture-negative (11.1%) LOS. The major causative pathogens were coagulase-negative staphylococci (49%), Staphylococcus aureus (15%), group B streptococci (10%) and Escherichia coli (8%). We observed increased odds of severe bronchopulmonary dysplasia (BPD) associated with both culture-positive (adjusted OR (aOR) 1.7; 95% CI 1.3 to 2.2) and culture-negative (aOR 1.6; 95% CI 1.3 to 2.6) LOS. Only culture-positive LOS was associated with increased odds of cystic periventricular leukomalacia (cPVL) (aOR 2.2; 95% CI 1.4 to 3.4) and severe retinopathy of prematurity (ROP) (aOR 1.8; 95% CI 1.2 to 2.8). Culture-positive LOS-attributable mortality was 6.3%, higher in Gram-negative (15.8%) compared with Gram-positive (4.1%) LOS, p=0.009. Among extremely preterm infants, survival rates increased from 75.2% in 2009-2013 to 81.0% in 2014-2018, p=0.005. In the same period culture-positive LOS rates increased from 17.1% to 25.6%, p<0.001. CONCLUSIONS: LOS contributes to a significant burden of disease in very preterm infants and is associated with increased odds of severe BPD, cPVL and severe ROP.

Early-Onset Sepsis in Neonates - A Population-Based Study in South-West Norway From 1996 to 2018.

Background: The epidemiology of early-onset sepsis (EOS) may change over time. Longitudinal surveillance of causative pathogens, antibiotic susceptibility patterns and antibiotic therapy is important for optimal therapy strategies. Objectives: To describe the incidence of culture-confirmed EOS, causative pathogens, antibiotic susceptibility patterns and antibiotic therapy over a 23-year period. Methods: Retrospective population-based study from a single-center neonatal intensive care unit at Stavanger University Hospital, Norway, covering a population in South-West Norway, during the 23-year period 1996-2018. Results: Of 104,377 live born infants, 101 infants (0.97/1,000) had culture-confirmed EOS; 89 with Gram positive and 12 with Gram-negative bacteria. The EOS-attributable mortality was 6/101 (5.8%). For the three most prevalent pathogens the incidences were; Group B streptococcus (GBS) 0.57/1,000, Escherichia coli 0.11/1,000 and viridans group streptococci (VGS) 0.10/1,000. GBS was the most common pathogen (59/93; 63%) in infants with gestational age (GA) ≥ 28 weeks. In contrast, among extremely preterm infants (GA <28 weeks) the incidence of E. coli infection was higher than for GBS infection. The second most common bacterial pathogens causing EOS among term infants were VGS. There was no change in the incidence of EOS for the entire study period, but from 2000 to 2018 there was a mean decline in EOS by 6% per year (95% CI 1%-10%) (p = 0.019). The incidences of GBS and E. coli did not change during the study period. The initial empirical antibiotic regimen for EOS was in all cases a combination of benzylpenicillin or ampicillin and an aminoglycoside, but in 21/101 (21%) of cases a broad-spectrum antibiotic was either added or substituted this regimen. In 2/101 (2%) EOS cases, the pathogens were nonsusceptible to the empirical antibiotic regimen. All E. coli isolates were susceptible to aminoglycosides. Conclusion: GBS was the most common causative pathogens in EOS, but E. coli dominated in infants with GA <28 weeks. There was no change in the incidence of EOS during the entire study period. The current empiric regimen with benzylpenicillin and gentamicin provides a very high coverage for EOS in our setting.

Reduced Antibiotic Exposure by Serial Physical Examinations in Term Neonates at Risk of Early-onset Sepsis.

BACKGROUND: Suspected early-onset sepsis (EOS) results in antibiotic treatment of a substantial number of neonates who are uninfected. We evaluated if an approach using serial physical examinations (SPEs) can reduce antibiotic exposure for suspected EOS in term neonates during the first 3 days of life, without affecting safety. METHODS: Within a quality-improvement framework, SPEs for 24-48 hours for neonates with suspected EOS was implemented in the neonatal intensive care unit, Stavanger, Norway. The proportion of neonates ≥37 weeks gestation exposed to antibiotics, antibiotic therapy-days and the safety outcome time from birth to start antibiotics were compared between a baseline period (April 2014-February 2016), when a risk factor based approach was used, and a post-SPE-implementation period (January 2017-November 2018). RESULTS: We included all term live born neonates (n = 17,242) in the 2 periods. There was a 57% relative reduction in neonates exposed to antibiotics; 2.9% in the baseline and 1.3% in the post-implementation period, P < 0.001. There was a 60% relative reduction in mean antibiotic therapy-days/1000 patient-days; from 320 to 129, P < 0.001, and a 50% relative reduction in time to initiate antibiotics in suspected EOS-cases, from median (interquartile range) 14 (5-28) to 7 (3-17) hours, P = 0.003. The incidence of culture-positive EOS remained unchanged. There were no infection-attributable deaths. CONCLUSIONS: Implementing SPE to guide empiric antibiotic therapy in term neonates with suspected EOS more than halved the burden of antibiotic exposure, without delay of antibiotic treatment of infected neonates or increased sepsis-related mortality.