Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Procalcitonin for Detecting Culture-Positive Sepsis in Neonates: A Prospective, Multicenter Study.

INTRODUCTION: It is unclear if serum procalcitonin (PCT) estimated at sepsis suspicion can help detect culture-positive sepsis in neonates. We evaluated the diagnostic performance of PCT in culture-positive sepsis in neonates. METHODS: This was a prospective study (February 2016 to September 2020) conducted in four level-3 units in India. We enrolled neonates suspected of sepsis in the first 28 days of life. Neonates with birth weight <750 g, asphyxia, shock, and major malformations were excluded. Blood for PCT assay was drawn along with the blood culture at the time of suspicion of sepsis and before antibiotic initiation. The investigators labeled the neonates as having culture-positive sepsis or "no sepsis" based on the culture reports and clinical course. PCT assay was performed by electrochemiluminescence immunoassay, and the clinicians were masked to the PCT levels while assigning the label of sepsis. Primary outcomes were the sensitivity, specificity, and likelihood ratios to identify culture-positive sepsis. RESULTS: The mean birth weight (SD) and median gestation (IQR) were 2,113 (727) g and 36 (32-38) weeks, respectively. Of the 1,204 neonates with eligible cultures, 155 (12.9%) had culture-positive sepsis. Most (79.4%) were culture-positive within 72 h of birth. The sensitivity, specificity, and positive and negative likelihood ratios at 2 ng/mL PCT threshold were 52.3% (95% confidence interval: 44.1-60.3), 64.5% (60.7-68.1), 1.47 (1.23-1.76), and 0.74 (0.62-0.88), respectively. Adding PCT to assessing neonates with 12.9% pretest probability of sepsis generated posttest probabilities of 18% and 10% for positive and negative test results, respectively. CONCLUSION: Serum PCT did not reliably identify culture-positive sepsis in neonates.

Less invasive surfactant administration via infant feeding tube versus InSurE method in preterm infants: a randomized control trial.

There is growing evidence that less invasive surfactant administration (LISA) is a better alternative to the standard Intubate-surfactant-extubate (InSurE) procedure in spontaneously breathing preterm infants with RDS. The infant feeding tube is easily available and cost-effective in comparison to special catheters used for surfactant administration in various studies on LISA and cost-effective health care is the need of the hour for countries like ours which are Low and middle-income countries(LMICs).The present study was planned to compare the total duration of respiratory support in preterm babies between 26 to 34 weeks of gestation with RDS requiring surfactant therapy administered by LISA technique using an infant feeding tube or InSurE method. In this unblinded randomised controlled trial, 150 infants were allocated to LISA (n = 74) or InSurE group (n = 76). An 8F feeding tube was used for surfactant delivery in the LISA group. The primary outcome was the total duration of respiratory support required and secondary outcomes included the proportion of babies developing BPD, IVH, PDA, NEC, ROP, air leaks, CPAP failure, and those requiring a repeat dose of surfactant along with the duration of hospitalization, time to regain birth weight and Death. The baseline variables including birth weight and gestation age were similar in the two groups. Nearly 27% of the mothers did not receive any dose of antenatal steroids (ANS) while around 37% of the mothers received complete course of ANS. A high proportion of babies (57%) were delivered by cesarean section. Intrapharyngeal reflux was significantly more in babies who received surfactant with the LISA method in comparison to InSurE technique (32% v/s 3%, p < 0.001). There was no statistically significant difference in the primary outcome of the total duration of respiratory support in both groups with a median duration of 120 h, 95% CI (69-235), and p = 0.618. The need for invasive mechanical ventilation was significantly lower in the LISA group (p = 0.017) with RR (95% CI) 0.498 (0.259-0.958). The rate of CPAP failure was significantly lower in the LISA group (p = 0.005) with RR (95% CI) 0.55 (0.34-0.89). In this study, the total duration of hospital stay was reduced in the LISA group (19 days) compared to InSurE group (26 days), although the same was not statistically significant. LISA with an 8F feeding tube is feasible and an effective strategy for surfactant administration which resulted in a significant reduction in CPAP failure and the need for invasive mechanical ventilation.Trial registration: www.ctri.nic.in id CTRI/2020/05/025360. Trial was registered at CTRI on 26/05/2020. First case of trial was enrolled on 28/05/2020.

Comparison of oral ibuprofen with oral indomethacin for PDA closure in Indian preterm neonates: a randomized controlled trial.

Oral ibuprofen is being used as an alternative to indomethacin in medical management of patent ductus arteriosus (PDA), but limited data exist on oral efficacy of these drugs for PDA closure in India. To assess and compare the efficacy of oral ibuprofen and oral indomethacin for PDA closure in preterm Indian neonates, we designed a randomized controlled study on clinically diagnosed and echocardiographically confirmed hemodynamically significant PDA in preterm neonates. Patients were assigned to receive either oral ibuprofen at a dosage of 10, 5, 5 mg/kg every 24 h or three doses of oral indomethacin (0.20-0.25 mg/kg every 24 h) starting on the third day of life or when diagnosed. A second course of ibuprofen/indomethacin was given, if PDA failed to close within 48 h after the first course. Patients were monitored for complications like oliguria, bleeding, necrotizing enterocolitis, intraventricular hemorrhage, oxygen dependency, and gastrointestinal side effects. The baseline characteristics were comparable in both groups. Of the 83 children enrolled, 57.8 % received oral ibuprofen and 42.1 % received oral indomethacin. The overall closure rate of PDA was 60 and 65.7 % in the ibuprofen and indomethacin groups, respectively. Closure rate was significantly higher when the drugs were administered at an early postnatal age (<8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) in neonates >28 weeks (ibuprofen group 66.7 % [p = 0.02]; indomethacin group 65.5 % [p = 0.04]) and in babies with birth weight >1,000 g (ibuprofen group 62.2 %; indomethacin group 70 % [p = 0.04 in both groups]). Complications were similar in both groups. The efficacy of both drugs was similar. Poor closure in our study could be because of genetic differences in pharmacokinetics of drug metabolism in the Indian population. Regimens with higher doses or increased duration of treatment may increase the frequency of closure. Studies with larger numbers of subjects with evaluation of pharmacokinetic parameters are therefore required.

Congenital rickets presenting as refractory respiratory distress at birth.

Congenital rickets is a very rare entity in the spectrum of metabolic bone disease in children. The authors report an as yet unreported case of congenital rickets presenting with respiratory distress at birth. The radiographs of long bones and wrist showed generalized osteopenia with cupping and fraying of epiphyseal ends in the second week of life. The patient was managed with very high doses of vitamin D which led to clinico-radiological and biochemical improvement. More than being interesting for its extreme rarity, this report assumes importance as it brings forth the possibility of congenital rickets being a differential diagnosis for a newborn with respiratory distress.