Every bug counts : neonatal colonization and infection of Gram-negative bacilli - aspects on antibiotic resistance in Sweden and Ecuador

Neonatal infections caused by extended-spectrum beta-lactamase (ESBL)-producing Gramnegative bacilli are associated with high morbidity and mortality. In order to perform targeted preventive interventions against the impacts of antibiotic resistance in neonates, it is crucial to study colonization, infection and the spread of EPE-bacteria. Methods and results Study I. A prospective observational study where the proportion of intestinal colonization with EPE, their resistance pattern and risk factors of EPE-colonization were assessed in a neonatal intensive care unit in Ecuador. In total, 56% of the neonates were colonized with EPE. The strains found were ESBL-E. coli (ESBL-EC, 89%) and ESBL-K. pneumoniae (ESBL-KP, 11 %) and the main risk factor for colonization was length of hospital stay. Two of the isolated clones were epidemic and known to disseminate carbapenem-hydrolysing beta-lactamases. These results underline the necessity of implementing colonization surveillance and improved hygiene standards in this and similar neonatal care settings. Study II. A prospective cohort study where we analysed the ESBL-KP isolates in a neonatal outbreak of EPE and determined the duration of intestinal colonization of EPE in affected neonates (n= 14). The intestinal relative abundance of EPE was determined in each carrier. One fourth of the neonates were still carriers of EPE, two years after a NICU outbreak. The median length of colonization was 12.5 months. The low virulent but highly resistant ESBLKP strain ST101 persisted in 2/13 children. One patient was colonized with ESBL-EC at five years of age. No infant suffered from an EPE-infection during the 5-year follow-up. Study III. In this study, the findings in study 2 were extended by characterizing the resistance encoding plasmids using optical DNA mapping (ODM) combined with Cas9- assisted identification of resistance genes. The method detected two plasmids; one small (80 kb) and one large plasmid (220 kb) in all ESBL-KP isolates. We found that the blaCTX-M-15 gene was located on the small plasmid and that this plasmid was stable in the ESBL-KP clone for two years. There was an unrelated acquisition of an ESBL-EC strain, contradicting plasmid transfer between KP and EC in this outbreak. ODM is a promising and rapid tool for surveillance and infection control in clinical settings. Study IV. In a population-based retrospectively matched cohort study, we investigated the incidence, mortality and bacterial characteristics of neonatal sepsis caused by Gram-negative bacilli (GNB) sepsis in Stockholm County during a 11-year period. The primary outcome was death before discharge and secondary outcomes were death within 5 and 30 days after sepsis onset. The cumulative incidence of GNB-sepsis was 0.35 cases per 1,000 live born and for early onset sepsis (EOS) 0.11 and late onset sepsis (LOS) 0.24 respectively. Case fatality rate was 5/33 (15%) in GNB-EOS and 26/74 (35%) in GNB LOS. Neonates with GNB-LOS were 3.9 times more likely (adjusted OR, 95% CI: 1.6-9.4) to die before discharge compared to the uninfected matched control group. Overall, 6.5% (7/107) of the isolates were multidrug-resistant. The incidence of both GNB-EOS and GNB-LOS was lower than reported in previous studies from other high-income countries comparable settings. Mortality in GNB-LOS remains high. The occurrence of acquired antibiotic resistance was low and did not change substantially over time. Conclusions A high proportion (56%) of the neonates at a NICU in a tertiary hospital in Ecuador, became colonized by EPE. These EPE included two clones of ESBL-KP that are known to disseminate carbapenemases. Infants that were colonized during an EPE-outbreak at two NICUs in Stockholm carried the same ESBL-KP for 26 months. There was no plasmid transfer between bacteria during the outbreak. During a 11-year period in Stockholm, Gramnegative sepsis was rare but a major risk for neonatal mortality

Less is more: Antibiotics at the beginning of life.

Antibiotic exposure at the beginning of life can lead to increased antimicrobial resistance and perturbations of the developing microbiome. Early-life microbiome disruption increases the risks of developing chronic diseases later in life. Fear of missing evolving neonatal sepsis is the key driver for antibiotic overtreatment early in life. Bias (a systemic deviation towards overtreatment) and noise (a random scatter) affect the decision-making process. In this perspective, we advocate for a factual approach quantifying the burden of treatment in relation to the burden of disease balancing antimicrobial stewardship and effective sepsis management

Analysis of Antibiotic Exposure and Early-Onset Neonatal Sepsis in Europe, North America, and Australia.

IMPORTANCE Appropriate use of antibiotics is life-saving in neonatal early-onset sepsis (EOS), but overuse of antibiotics is associated with antimicrobial resistance and long-term adverse outcomes. Large international studies quantifying early-life antibiotic exposure along with EOS incidence are needed to provide a basis for future interventions aimed at safely reducing neonatal antibiotic exposure. OBJECTIVE To compare early postnatal exposure to antibiotics, incidence of EOS, and mortality among different networks in high-income countries. DESIGN, SETTING, AND PARTICIPANTS This is a retrospective, cross-sectional study of late-preterm and full-term neonates born between January 1, 2014, and December 31, 2018, in 13 hospital-based or population-based networks from 11 countries in Europe and North America and Australia. The study included all infants born alive at a gestational age greater than or equal to 34 weeks in the participating networks. Data were analyzed from October 2021 to March 2022. EXPOSURES Exposure to antibiotics started in the first postnatal week. MAIN OUTCOMES AND MEASURES The main outcomes were the proportion of late-preterm and full-term neonates receiving intravenous antibiotics, the duration of antibiotic treatment, the incidence of culture-proven EOS, and all-cause and EOS-associated mortality. RESULTS A total of 757 979 late-preterm and full-term neonates were born in the participating networks during the study period; 21 703 neonates (2.86%; 95% CI, 2.83%-2.90%), including 12 886 boys (59.4%) with a median (IQR) gestational age of 39 (36-40) weeks and median (IQR) birth weight of 3250 (2750-3750) g, received intravenous antibiotics during the first postnatal week. The proportion of neonates started on antibiotics ranged from 1.18% to 12.45% among networks. The median (IQR) duration of treatment was 9 (7-14) days for neonates with EOS and 4 (3-6) days for those without EOS. This led to an antibiotic exposure of 135 days per 1000 live births (range across networks, 54-491 days per 1000 live births). The incidence of EOS was 0.49 cases per 1000 live births (range, 0.18-1.45 cases per 1000 live births). EOS-associated mortality was 3.20% (12 of 375 neonates; range, 0.00%-12.00%). For each case of EOS, 58 neonates were started on antibiotics and 273 antibiotic days were administered. CONCLUSIONS AND RELEVANCE The findings of this study suggest that antibiotic exposure during the first postnatal week is disproportionate compared with the burden of EOS and that there are wide (up to 9-fold) variations internationally. This study defined a set of indicators reporting on both dimensions to facilitate benchmarking and future interventions aimed at safely reducing antibiotic exposure in early life

PLoS ONE

Background and Aims Neonatal infections caused by Extended-spectrum beta-lactamase (ESBL)-producing bacteria are associated with increased morbidity and mortality. No data are available on neonatal colonization with ESBL-producing bacteria in Ecuador. The aim of this study was to determine the proportion of intestinal colonization with ESBL-producing Enterobacteriaceae, their resistance pattern and risk factors of colonization in a neonatal intensive care unit in Ecuador. Methods During a three month period, stool specimens were collected every two weeks from hospitalized neonates. Species identification and susceptibility testing were performed with Vitek2, epidemiologic typing with automated repetitive PCR. Associations between groups were analyzed using the Pearson X2 test and Fisher exact test. A forward step logistic regression model identified significant predictors for colonization. Results Fifty-six percent of the neonates were colonized with ESBL-producing Enterobacteriaceae. Length of stay longer than 20 days and enteral feeding with a combination of breastfeeding and formula feeding were significantly associated with ESBL-colonization. The strains found were E. coli (EC, 89%) and K. pneumoniae (KP, 11%) and epidemiological typing divided these isolates in two major clusters. All EC and KP had blaCTX-M group 1 except for a unique EC isolate that had blaCTX-M group 9. Multi-locus sequence typing performed on the K. pneumoniae strains showed that the strains belonged to ST855 and ST897. The two detected STs belong to two different epidemic clonal complexes (CC), CC11 and CC14, which previously have been associated with dissemination of carbapenemases. None of the E. coli strains belonged to the epidemic ST 131 clone. Conclusions More than half of the neonates were colonized with ESBL-producing Enterobacteriaceae where the main risk factor for colonization was length of hospital stay. Two of the isolated clones were epidemic and known to disseminate carbapenemases. The results underline the necessity for improved surveillance and infection control in this context.Cuencavolumen 8; número 1

Characteristics of ESBL-producing clones.

<p>CTX- cefotaxime, CAZ- ceftazidime, GEN- gentamicin, CIP- ciprofloxacin, TRI- trimethoprim, AKN- amikacin.</p>*<p>NT-MSLT not tested. <i>E.coli</i> compared to the clone ST131 and clearly divergent.</p

Characteristics of the neonates and risk factors for colonization with ESBL-producing Gram negative bacteria during NICU care.

*<p>Univariate analysis.</p>**<p>Forward step logistic regression.</p>#<p>In univariate analysis, when more than two categories were represented within a factor, each category was compared to all other categories.</p>***<p>Associated with less colonization. NS = not significant.</p

Different strain types of <i>E. coli</i> and <i>K. pneumoniae</i> isolated from various sampling occasions.

<p>E.C = <i>E.Coli</i>, K.P = <i>K. Pneumoniae</i>, ND = Verified ESBL, DL-typing not done.</p