Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

The neonatal gut microbiome and global health.

The role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.

Neonatal sepsis with meningitis, ventriculitis and brain abscess caused by Edwardsiella tarda.

A case of neonatal sepsis caused by Edwardsiella tarda, an uncommon pathogen typically associated with aquatic lifeforms, is described. The infant presented in septic shock with seizures and respiratory failure and was found to have meningitis, ventriculitis and a brain abscess requiring drainage. Only a small number of case reports of neonatal E. tarda infection, several with sepsis with poor auditory or neurodevelopmental outcomes or meningitis, have been described in the literature. This case report suggests that E. tarda, while uncommon, can be a cause of serious central nervous system disease in the neonatal population and that an aggressive approach to pursuing and treating complications may lead to improved neurodevelopmental outcomes.

High prevalence of multidrug-resistant Enterobacterales carrying extended-spectrum beta-lactamase and AmpC genes isolated from neonatal sepsis in Ahvaz, Iran.

OBJECTIVES: In the recent years, multidrug resistant (MDR) neonatal septicemia-causing Enterobacterales has been dramatically increased due to the extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes. This study aimed to assess the antibiotic resistance pattern, prevalence of ESBLs/AmpC beta-lactamase genes, and Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) fingerprints in Enterobacterales isolated from neonatal sepsis. RESULTS: In total, 59 Enterobacterales isolates including 41 (69.5%) Enterobacter species, 15 (25.4%) Klebsiella pneumoniae and 3 (5.1%) Escherichia coli were isolated respectively. Resistance to ceftazidime and cefotaxime was seen in all of isolates. Furthermore, all of them were multidrug-resistant (resistant to three different antibiotic categories). The phenotypic tests showed that 100% of isolates were ESBL-positive. Moreover, AmpC production was observed in 84.7% (n = 50/59) of isolates. Among 59 ESBL-positive isolates, the highest percentage belonged to blaCTX-M-15 gene (66.1%) followed by blaCTX-M (45.8%), blaCTX-M-14 (30.5%), blaSHV (28.8%), and blaTEM (13.6%). The frequency of blaDHA, blaEBC, blaMOX and blaCIT genes were 24%, 24%, 4%, and 2% respectively. ERIC-PCR analysis revealed that Enterobacterales isolates were genetically diverse. The remarkable prevalence of MDR Enterobacterales isolates carrying ESBL and AmpC beta-lactamase genes emphasizes that efficient surveillance measures are essential to avoid the more expansion of drug resistance amongst isolates.

A decade of neonatal sepsis in Stockholm, Sweden: Gram-positive pathogens were four times as common as Gram-negatives.

PURPOSE: To assess Gram-positive bacterial (GPB) bloodstream infection (BSI) in neonates, covering incidence, morbidity, mortality, antimicrobial resistance patterns and biomarkers in Region Stockholm, Sweden between 2006 and 2016. METHODS: A population-based retrospective epidemiological study including infants with GPB-BSI, admitted to the neonatal units at Karolinska University Hospital (KUH). Data were collected from patient records, the Swedish Neonatal Quality Register, the microbiological laboratory at KUH and the Swedish Public Health Agency. RESULTS: We identified 357 infants with GPB-BSI, representing an incidence of 1.47/1000 live births (LB). Group B streptococcus (GBS) was the most common pathogen causing BSI in full-term infants and early-onset sepsis (EOS) (0.20/1000 LB), while coagulase-negative staphylococci (CoNS) were predominant in infants born very preterm and in late-onset sepsis (LOS) (0.79/1000 LB). There were no fatal GBS BSI cases, but 10.2% developed meningitis. The GPB case fatality rate was 9.5% and the sepsis fatality rate 2.8%. In GPB-BSI, 1/10 did not have an elevated C-reactive protein level. Staphylococcus aureus (S. aureus) BSI increased during the study period, but no methicillin or vancomycin resistant strains were found. The antimicrobial resistance (AMR) rate was highest in CoNS isolates. CONCLUSION: GPB-BSI was four times more common than Gram-negative BSI in neonates but resulted in lower mortality rate. GBS was the most common pathogen in full-term infants and in EOS. CoNS was the most common pathogen in LOS and infants born very preterm, and the AMR rate was high in these isolates. The increasing trend of S. aureus BSI indicates a need of further investigation.

Late Neonatal Sepsis in Very-low-birth-weight Premature Newborns Is Associated With Alterations in Neurodevelopment at Twenty-five Months of Age.

AIM: To evaluate the impact of late-onset sepsis (LOS) on the neurodevelopment of very-low-birth-weight (VLBW) premature infants. METHODS: This is a retrospective cohort study of VLBW premature infants. The Mental Development Index (MDI) was determined for a population of 546 VLBW infants, at 14 and 25 months of age, and evaluated using the Bayley test. A history of meningitis or early neonatal sepsis was considered an exclusion criterion. The study parameters analyzed included perinatal variables, the development of neonatal comorbidities and a history of LOS. Multivariate linear regression and multinomial logistic regression analyses were performed. RESULTS: LOS was observed in 115 newborns, among whom microbiological testing showed that 65.0% presented Gram-positive bacteria, with Staphylococcus epidermidis being responsible for 55.4%. There was a significant association between the 25-month MDI and a history of LOS. This represents a decrease of 7.9 points in the MDI evaluation of newborns with a history of LOS. The latter history is also associated with the following neurodevelopmental alternations: mild motor disorders [odds ratio (OR): 2.75; 95% confidence intervals (CI): 1.07-7.05], moderate cognitive delay (OR: 3.07; 95% CI: 1.17-8.00) and cerebral palsy (OR: 2.41; 95% CI: 1.09-5.35). CONCLUSIONS: In our study cohort, LOS was associated with alterations in neurodevelopment, including reduced MDI, together with motor and cognitive disorders and cerebral palsy. To improve neurodevelopmental outcomes in this group of newborns, neonatal intensive care unit personnel should focus attention on preventing hospital-acquired infections.

Differential Abundances of Bdellovibrio and Rheinheimera in the Oral Microbiota of Neonates With and Without Clinical Sepsis.

BACKGROUND: Neonatal sepsis is associated with high rates of morbidity and mortality, long hospital stays and high cost of care, thereby inflicting a burden on health care systems. Oral care with breast milk has been shown to modify the intestinal tract microbiota and immune system. Herein, we attempted to identify probiotics that may be beneficial to prevent or treat neonatal sepsis. METHODS: This was a secondary analysis comparing the microbiota during oropharyngeal care in very-low-birth-weight infants with and without clinical sepsis. Oral samples were collected before oral feeding was initiated. The primary outcome was oral microbiota composition including diversity, relative abundance and linear discriminant analysis effect size. RESULTS: Sixty-three neonates, including 39 and 24 with and without clinical sepsis, respectively, were enrolled. The medians gestational age and birth weight were 29 (27-30) weeks and 1010 (808-1263) g. Neonates with clinical sepsis had lower gestational age, birth weight (both P < 0.001) and lower rate of oral care with breast milk ( P = 0.03), but higher doses and days of antibiotic exposure (both P < 0.001) compared to neonates without clinical sepsis. No differences in alpha and beta diversities were found between groups and Streptococcus agalactiae was the most common bacteria in both groups. Linear discriminant analysis effect size analysis revealed that neonates without clinical sepsis had significantly higher abundances of order Bdellovibrionales, family Bdellovibrionaceae, genus Bdellovibrio and genus Rheinheimera . CONCLUSIONS: Neonates without clinical sepsis had a significantly greater abundance of the Bdellovibrio and Rheinheimera genera.

Ten- vs. 14-day antibiotic therapy for culture-positive neonatal sepsis.

BACKGROUND: Neonatal sepsis is a major determinant of neonatal mortality. There is a scarcity of evidence-based guidelines for the duration of antibiotics in culture-positive sepsis. OBJECTIVES: The aim of this study was to compare the efficacy of 10- and 14-day antibiotic therapies in the management of culture-positive neonatal sepsis. METHODS: This randomized controlled trial was conducted in the neonatal intensive care unit of a tertiary care center among the neonates suffering from culture-positive sepsis (with signs of clinical remission on day 9 of antibiotic) between January 2023 and May 2023. Newborns with major congenital anomaly, deep-seated infections, multi-organ dysfunction, associated fungal infections/infection by multiple organisms and severe birth asphyxia were excluded. Two hundred and thirty-four newborns were randomized into two groups-study (received 10 days of antibiotics) and control (received 14 days of antibiotics). Treatment failure, hospital stay and adverse effects were compared between the two groups. p < 0.05 was taken as the limit of statistical significance. RESULTS: Median [interquartile range (IQR)] birth weight and gestational age of the study population (53.8% boys) were 2.424 kg (IQR: 2.183-2.695) and 37.3 weeks (IQR: 35.5-38.1), respectively. Acinetobacter was the most commonly isolated species (56, 23.9%). The baseline characteristics of both groups were almost similar. Treatment failure was similar in the study and control groups (3.8% vs. 1.7%, p = 0.40), with a shorter hospital stay [median (IQR): 14 (13-16) vs. 18 (17-19) days, p < 0.001]. CONCLUSION: Ten-day antibiotic therapy was comparable with 14-day antibiotic therapy in efficacy, with a shorter duration of hospital stay and without any significant increase in adverse effects.

Neonatal sepsis is a major cause of neonatal mortality in developing countries like India. Textbooks recommend 14-day antibiotic treatment for culture-positive neonatal sepsis. However, these guidelines are not strictly evidence based. Prolonged antibiotic treatment might be associated with drug resistance, secondary infections and organ damage. A shorter course of antibiotic, if found effective, would be beneficial especially in the resource-constrained settings like India. Hence, this study was undertaken to compare a shorter duration antibiotic treatment (10 days) with the conventional 14-day antibiotic therapy. Two hundred and thirty-four newborns with culture-positive sepsis were randomized into the study group (received 10 days of antibiotics) and the control group (received 14 days of antibiotics). Socio-demographic characters, clinical and laboratory features and bacteriological profile of both the groups were recorded. Both the groups were comparable in baseline features. Two-thirds of them were suffering from Gram-negative sepsis, Acinetobacter being the most commonly isolated organism. Incidence of treatment failure was similar in the study and control groups. Duration of hospital stay was significantly lower in the study group than in the control group. This observation was true irrespective of gestational age and type of organisms. There were no significant differences in adverse effects between the groups. However, there are certain limitations in the study, and hence, multi-centric research should be undertaken before making generalized recommendations of practising short duration of antibiotics.

Global, regional, and national estimates of the impact of a maternal Klebsiella pneumoniae vaccine: A Bayesian modeling analysis.

BACKGROUND: Despite significant global progress in reducing neonatal mortality, bacterial sepsis remains a major cause of neonatal deaths. Klebsiella pneumoniae (K. pneumoniae) is the leading pathogen globally underlying cases of neonatal sepsis and is frequently resistant to antibiotic treatment regimens recommended by the World Health Organization (WHO), including first-line therapy with ampicillin and gentamicin, second-line therapy with amikacin and ceftazidime, and meropenem. Maternal vaccination to prevent neonatal infection could reduce the burden of K. pneumoniae neonatal sepsis in low- and middle-income countries (LMICs), but the potential impact of vaccination remains poorly quantified. We estimated the potential impact of such vaccination on cases and deaths of K. pneumoniae neonatal sepsis and project the global effects of routine immunization of pregnant women with the K. pneumoniae vaccine as antimicrobial resistance (AMR) increases. METHODS AND FINDINGS: We developed a Bayesian mixture-modeling framework to estimate the effects of a hypothetical K. pneumoniae maternal vaccine with 70% efficacy administered with coverage equivalent to that of the maternal tetanus vaccine on neonatal sepsis infections and mortality. To parameterize our model, we used data from 3 global studies of neonatal sepsis and/or mortality-with 2,330 neonates who died with sepsis surveilled from 2016 to 2020 undertaken in 18 mainly LMICs across all WHO regions (Ethiopia, Kenya, Mali, Mozambique, Nigeria, Rwanda, Sierra Leone, South Africa, Uganda, Brazil, Italy, Greece, Pakistan, Bangladesh, India, Thailand, China, and Vietnam). Within these studies, 26.95% of fatal neonatal sepsis cases were culture-positive for K. pneumoniae. We analyzed 9,070 K. pneumoniae genomes from human isolates gathered globally from 2001 to 2020 to quantify the temporal rate of acquisition of AMR genes in K. pneumoniae isolates to predict the future number of drug-resistant cases and deaths that could be averted by vaccination. Resistance rates to carbapenems are increasing most rapidly and 22.43% [95th percentile Bayesian credible interval (CrI): 5.24 to 41.42] of neonatal sepsis deaths are caused by meropenem-resistant K. pneumoniae. Globally, we estimate that maternal vaccination could avert 80,258 [CrI: 18,084 to 189,040] neonatal deaths and 399,015 [CrI: 334,523 to 485,442] neonatal sepsis cases yearly worldwide, accounting for more than 3.40% [CrI: 0.75 to 8.01] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert over 6% of all neonatal deaths. Nevertheless, our modeling only considers country-level trends in K. pneumoniae neonatal sepsis deaths and is unable to consider within-country variability in bacterial prevalence that may impact the projected burden of sepsis. CONCLUSIONS: A K. pneumoniae maternal vaccine could have widespread, sustained global benefits as AMR in K. pneumoniae continues to increase.

Vaginal carriage of Haemophilus influenzae in a non-pregnant reproductive-age population.

BACKGROUND: Haemophilus influenzae (Hi) is an emerging cause of early onset neonatal sepsis, but mechanisms of transmission are not well understood. We aimed to determine the prevalence of vaginal carriage of Hi in reproductive age women and to examine behavioral and demographic characteristics associated with its carriage. METHODS: We performed a secondary analysis of stored vaginal lavage specimens from a prospective cohort study of nonpregnant reproductive-age women. After extraction of bacterial genomic DNA, samples were tested for the presence of the gene encoding Haemophilus protein d (hpd) by quantitative real-time polymerase chain reaction (PCR) using validated primers and probe. PCR for the V3-V4 region of the 16 S rRNA gene (positive control) assessed sample quality. Samples with cycle threshold (CT) value < 35 were defined as positive. Sanger sequencing confirmed the presence of hpd. Behavioral and demographic characteristics associated with vaginal carriage of Hi were examined. RESULTS: 415 samples were available. 315 (75.9%) had sufficient bacterial DNA and were included. 14 (4.4%) were positive for hpd. There were no demographic or behavioral differences between the women with Hi vaginal carriage and those without. There was no difference in history of bacterial vaginosis, vaginal microbiome community state type, or presence of Group B Streptococcus in women with and without vaginal carriage of Hi. CONCLUSION: Hi was present in vaginal lavage specimens of 4.4% of this cohort. Hi presence was unrelated to clinical or demographic characteristics, though the relatively small number of positive samples may have limited power to detect such differences.

Perinatal bacterial colonization and neonatal early-onset sepsis: A case-control study.

BACKGROUND: The utility of determining maternal-neonatal surface colonization as detected by standard microbiological cultures around the time of birth is unclear. The aim of this study is to evaluate the association between maternal and neonatal surface colonization at birth and neonatal early onset sepsis (EOS). OBJECTIVE: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. METHODS: We conducted a case-control study of newborns admitted to the neonatal department of a referral women's and children's hospital from 2009 to 2017. Cases were infants with blood-culture-confirmed EOS (<3 days of life), and controls were infants without EOS randomly chosen based on the cases' date of birth. Maternal genitourinary and neonatal ear swab cultures were used to determine bacterial surface colonization status. RESULTS: Fifty-one infants were diagnosed with EOS during the study period, where Escherichia coli (45%), and Group B Streptococcus (23%) accounted for 68% of infecting organisms. Compared to infants without EOS, those infected were more likely to have surface colonization of the mothers (60% vs 40%, p = 0.048) and infants (90% vs 11%, p < 0.001). In univariate analysis, chorioamnionitis [7.1 (95% CI 2.9, 16.8)], small-for-gestational-age [OR 0.08 (95% CI 0.02, 0.4)], exposure to antibiotics around time of birth [2.3 (95% CI 1.0, 5.1)], maternal surface colonization [2.2 (95% CI 1.0, 4.9)] and neonatal surface colonization [23.5 (95% CI 7.3, 76.1)] were significantly associated with EOS. Adjusting for potential confounders, neonatal colonization remained significantly associated with neonatal EOS [AOR 15.0 (95% CI 3.5, 64.2), p < 0.001]. CONCLUSION: In our setting with predominant Gram-negative EOS, neonatal colonization but not maternal colonization was significantly associated with EOS in the newborn.

Early warning for healthcare acquired infections in neonatal care units in a low-resource setting using routinely collected hospital data: The experience from Haiti, 2014-2018.

In low-resource settings, detection of healthcare-acquired outbreaks in neonatal units relies on astute clinical staff to observe unusual morbidity or mortality from sepsis as microbiological diagnostics are often absent. We aimed to generate reliable (and automated) early warnings for potential clusters of neonatal late onset sepsis using retrospective data that could signal the start of an outbreak in an NCU in Port au Prince, Haiti, using routinely collected data on neonatal admissions. We constructed smoothed time series for late onset sepsis cases, late onset sepsis rates, neonatal care unit (NCU) mortality, maternal admissions, neonatal admissions and neonatal antibiotic consumption. An outbreak was defined as a statistical increase in any of these time series indicators. We created three outbreak alarm classes: 1) thresholds: weeks in which the late onset sepsis cases exceeded four, the late onset sepsis rates exceeded 10% of total NCU admissions and the NCU mortality exceeded 15%; 2) differential: late onset sepsis rates and NCU mortality were double the previous week; and 3) aberration: using the improved Farrington model for late onset sepsis rates and NCU mortality. We validated pairs of alarms by calculating the sensitivity and specificity of the weeks in which each alarm was launched and comparing each alarm to the weeks in which a single GNB positive blood culture was reported from a neonate. The threshold and aberration alarms were the strongest predictors for current and future NCU mortality and current LOS rates (p<0.0002). The aberration alarms were also those with the highest sensitivity, specificity, negative predictive value, and positive predictive value. Without microbiological diagnostics in NCUs in low-resource settings, applying these simple algorithms to routinely collected data show great potential to facilitate early warning for possible healthcare-acquired outbreaks of LOS in neonates. The methods used in this study require validation across other low-resource settings.

Nucleotide receptors mediate protection against neonatal sepsis and meningitis caused by alpha-hemolysin expressing Escherichia coli K1.

Neonatal meningitis-associated Escherichia coli (NMEC) is among the leading causes of bacterial meningitis and sepsis in newborn infants. Several virulence factors have been identified as common among NMEC, and have been shown to play an important role in the development of bacteremia and/or meningitis. However, there is significant variability in virulence factor expression between NMEC isolates, and relatively little research has been done to assess the impact of variable virulence factor expression on immune cell activation and the outcome of infection. Here, we investigated the role of NMEC strain-dependent P2X receptor (P2XR) signaling on the outcome of infection in neonatal mice. We found that alpha-hemolysin (HlyA)-expressing NMEC (HlyA+ ) induced robust P2XR-dependent macrophage cell death in vitro, while HlyA- NMEC did not. P2XR-dependent cell death was inflammasome independent, suggesting an uncoupling of P2XR and inflammasome activation in the context of NMEC infection. In vivo inhibition of P2XRs was associated with increased mortality in neonatal mice infected with HlyA+ NMEC, but had no effect on the survival of neonatal mice infected with HlyA- NMEC. Furthermore, we found that P2XR-dependent protection against HlyA+ NMEC in vivo required macrophages, but not neutrophils or NLRP3. Taken together, these data suggest that HlyA+ NMEC activates P2XRs which in turn confers macrophage-dependent protection against infection in neonates. In addition, our findings indicate that strain-dependent virulence factor expression should be taken into account when studying the immune response to NMEC.

The Multi-Component Causes of Late Neonatal Sepsis-Can We Regulate Them?

Elucidating the mechanisms of bacterial translocation is crucial for the prevention and treatment of neonatal sepsis. In the present study, we aimed to evaluate the potential of lactoferrin to inhibit the development of late-onset blood infection in neonates. Our investigation evaluates the role of key stress factors leading to the translocation of intestinal bacteria into the bloodstream and, consequently, the development of life-threatening sepsis. Three stress factors, namely weaning, intraperitoneal administration of Gram-positive cocci and oral intake of Gram-negative rods, were found to act synergistically. We developed a novel model of rat pups sepsis induced by bacterial translocation and observed the inhibition of this process by supplementation of various forms of lactoferrin: iron-depleted (apolactoferrin), iron-saturated (hololactoferrin) and manganese-saturated lactoferrin. Additionally, lactoferrin saturated with manganese significantly increases the Lactobacillus bacterial population, which contributes to the fortification of the intestinal barrier and inhibits the translocation phenomenon. The acquired knowledge can be used to limit the development of sepsis in newborns in hospital neonatal intensive care units.

Look Who's Talking: Host and Pathogen Drivers of Staphylococcus epidermidis Virulence in Neonatal Sepsis.

Preterm infants are at increased risk for invasive neonatal bacterial infections. S. epidermidis, a ubiquitous skin commensal, is a major cause of late-onset neonatal sepsis, particularly in high-resource settings. The vulnerability of preterm infants to serious bacterial infections is commonly attributed to their distinct and developing immune system. While developmentally immature immune defences play a large role in facilitating bacterial invasion, this fails to explain why only a subset of infants develop infections with low-virulence organisms when exposed to similar risk factors in the neonatal ICU. Experimental research has explored potential virulence mechanisms contributing to the pathogenic shift of commensal S. epidermidis strains. Furthermore, comparative genomics studies have yielded insights into the emergence and spread of nosocomial S. epidermidis strains, and their genetic and functional characteristics implicated in invasive disease in neonates. These studies have highlighted the multifactorial nature of S. epidermidis traits relating to pathogenicity and commensalism. In this review, we discuss the known host and pathogen drivers of S. epidermidis virulence in neonatal sepsis and provide future perspectives to close the gap in our understanding of S. epidermidis as a cause of neonatal morbidity and mortality.

Epidemiology, microbiological profile, and outcome of culture positive sepsis among outborn neonates at a tertiary hospital in Northern India.

AIMS AND OBJECTIVES: To study the epidemiology, microbiological profile, and outcome of culture positive sepsis among outborn neonates at a tertiary care teaching hospital in Northern India. MATERIALS AND METHODS: Neonates (n = 406) with blood culture positive sepsis were enrolled prospectively over a period of 1 year (February 2018-January 2019). Demographic details, clinical features, microbiological profile, antibiotic sensitivity pattern, treatment, and outcome were recorded. RESULTS: The mean (±SD) age at presentation was 2.4 (±0.6) days and 2/3rd were males. The mean (±SD) gestation was 35.5 (±3.4) weeks, birth weight was 2215 (±219) g, and 42.4% were preterm. The proportion of neonates with early and late onset sepsis were 69% and 31%, respectively. Predominant isolates were Gram-negative (46.5%), Gram-positive (27.6%) organisms, and yeast (25.9%). Klebsiella pneumoniae (46.5%), Acinetobacter baumannii (17.5%), and Escherichia coli (8%) were common Gram-negative; and coagulase negative Staphylococcus (CONS) (70%), Staphylococcus aureus (13.4%), and Enterococcus (12.5%) were common Gram-positive organisms. Among Gram-negative organisms, the antibiotic sensitivity pattern was ciprofloxacin 45%, cephalosporins 15-40%, aminoglycosides 20-42%, piperacillin-tazobactam 49%, carbapenems 34-51%, tetracyclines 55-70%, doxycycline 55%, chloramphenicol 42%, and colistin 98%; and among Gram-positive organisms were methicillin 30%, clindamycin 52%, vancomycin 100%, teicoplanin 98%, and linezolid 99%. The survival rate was 60.3%. The neonates with Gram-negative sepsis had higher requirement of oxygen, mechanical ventilation, and vasoactive drugs; had more complications; and lower survival (50.3% vs. 72.3%, p= .003) when compared to Gram-positive sepsis. CONCLUSIONS: Gram-negative organisms were commonest cause of neonatal sepsis, had low sensitivity to commonly used antibiotics, and associated with poor outcome.

Sepsis treatment options identified by 10-year study of microbial isolates and antibiotic susceptibility in a level-four neonatal intensive care unit.

AIM: This observational study investigated the microbiology of blood culture-positive sepsis episodes and susceptibility to empiric antibiotics in early-onset sepsis (EOS) and late-onset sepsis (LOS) in a level-four neonatal intensive care unit (NICU) from 2010 to 2019. METHODS: It was based on patient records and data that Oslo University Hospital, Norway, routinely submitted to the Norwegian Neonatal Network database. Clinical data were merged with blood culture results, including antibiotic susceptibility. RESULTS: We studied 5249 infants admitted to the NICU 6321 times and identified 324 positive blood cultures from 287 infants, with 30 EOS and 305 LOS episodes. Frequent causative agents for EOS were group B streptococci (33.3%), Escherichia coli (20.0%) and Staphylococcus aureus (16.7%). All were susceptible to empiric ampicillin and gentamicin. LOS was most frequently caused by coagulase-negative staphylococci (CONS) (73.8%), Staphylococcus aureus (15.7%) and Enterococci (6.9%). CONS, Staphylococcus aureus, Enterococci, Escherichia coli, Klebsiella and Enterobacter represented 91.9% of LOS episodes and were susceptible to vancomycin and cefotaxime (96.1%), vancomycin and gentamicin (97.0%) and cloxacillin and gentamicin (38.1%). CONCLUSION: Empiric treatment with ampicillin and gentamicin was adequate for EOS. Combining vancomycin and gentamicin may be a safer alternative to cefotaxime for LOS, as this reduces exposure to broad-spectrum antibiotics.

Duration of Antibiotic Therapy in Neonatal Gram-negative Bacterial Sepsis-10 Days Versus 14 Days: A Randomized Controlled Trial.

BACKGROUND: Optimal duration of antibiotic therapy in Gram-negative bacterial (GNB) sepsis in non-VLBW infants has not been specifically evaluated in previous studies. METHODS: This was an open labeled noninferiority randomized controlled trial. Non-VLBW infants with GNB sepsis without meningitis whose blood culture were sterile after day 7 of treatment and who were in clinical remission on day 9 of appropriate antibiotic were randomized to short duration (SDR) group and long duration (LDR) group. Infants in SDR group and LDR group received antibiotic therapy for 10 days and 14 days respectively. Primary objective was to compare treatment failure. Secondary objectives were to compare duration of hospitalization, complications of intravenous (IV) therapy and its duration, episodes of new-onset sepsis and all-cause mortality. RESULTS: Of 222 infants with GNB sepsis, 58 eligible infants were randomized in each group and 113 of these were analyzed. There was no difference in proportion of infants with multidrug-resistant (MDR) organism in SDR versus LDR group [33(60%) versus 32(55.1%) (P = 0.84)]. There were no treatment failures in either group. Median (IQR) duration of hospital stay was higher in LDR group as compared with SDR group: 20(18, 23) versus 16(13, 20) days (P < 0.001). Infants in LDR group required IV therapy for a longer duration as compared with SDR group mean (SD): 15.2(1.2) versus 10.9(0.8) days (P < 0.001). Median (IQR) episodes of extravasation were higher in LDR group: 5(4.7) versus 3(2.3) (P < 0.001). There was no difference in episodes of phlebitis and hematoma. No infants had died on follow up. CONCLUSION: In suitably selected non-VLBW infants with Gram-negative sepsis, 10 days therapy is noninferior to 14 days therapy.

Antimicrobial Susceptibility Profiles Among Neonatal Early-onset Sepsis Pathogens.

BACKGROUND: Empiric administration of ampicillin and gentamicin is recommended for newborns at risk of early-onset sepsis (EOS). There are limited data on antimicrobial susceptibility of all EOS pathogens. METHODS: Retrospective review of antimicrobial susceptibility data from a prospective EOS surveillance study of infants born ≥22 weeks' gestation and cared for in Neonatal Research Network centers April 2015-March 2017. Nonsusceptible was defined as intermediate or resistant on final result. RESULTS: We identified 239 pathogens (235 bacteria, 4 fungi) in 235 EOS cases among 217,480 live-born infants. Antimicrobial susceptibility data were available for 189/239 (79.1%) isolates. Among 81 Gram-positive isolates with ampicillin and gentamicin susceptibility data, all were susceptible in vitro to either ampicillin or gentamicin. Among Gram-negative isolates with ampicillin and gentamicin susceptibility data, 72/94 (76.6%) isolates were nonsusceptible to ampicillin, 8/94 (8.5%) were nonsusceptible to gentamicin, and 7/96 (7.3%) isolates were nonsusceptible to both. Five percent or less of tested Gram-negative isolates were nonsusceptible to each of third or fourth generation cephalosporins, piperacillin-tazobactam, and carbapenems. Overall, we estimated that 8% of EOS cases were caused by isolates nonsusceptible to both ampicillin and gentamicin; these were most likely to occur among preterm, very-low birth weight infants. CONCLUSIONS: The vast majority of contemporary EOS pathogens are susceptible to the combination of ampicillin and gentamicin. Clinicians may consider the addition of broader-spectrum therapy among newborns at highest risk of EOS, but we caution that neither the substitution nor the addition of 1 single antimicrobial agent is likely to provide adequate empiric therapy in all cases.