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)

Abstract

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).

Fig 1. Antibiotic treatment.

(A) Initial empiric baseline therapy overall and by site. (B) First change of initial regimen, by baseline regimen. (C) Cumulative incidence of stopping all IV antibiotics (death on IV antibiotics as competing risk). Group 1 = First-line WHO-recommended penicillin-based regimen (e.g., ampicillin and gentamicin) (Access). Group 2 = third-generation cephalosporin (e.g., cefotaxime/ceftriaxone)-based WHO regimens (“Low” Watch). Group 3 = regimens with partial anti-ESBL or pseudomonal activity (e.g., piperacillin-tazobactam/ceftazidime/fluoroquinolone-based) (“Medium” Watch). Group 4 = Carbapenems (“High” Watch). Group 5 = Reserve antibiotics targeting carbapenem-resistant organisms (e.g., colistin). ESBL, extended-spectrum beta-lactamase; IV, intravenous.

Fig 2. Pathogens isolated in baseline blood culture, overall and by infants’ day of life.

Fig 3. Antibiotic resistance among leading pathogens in baseline blood culture.

(A) K. pneumoniae (n = 132). (B) Acinetobacter spp. (n = 72). (C) E. coli (n = 47). pip-taz = piperacillin/tazobactam.

Fig 4. Mortality.

(A) Overall mortality and mortality by site. (B) Mortality by pathogen in baseline blood culture. Figures present unadjusted Kaplan–Meier estimates.

Fig 5. NeoSep Severity Score at baseline.

(A) Distribution of the Severity Score at baseline (bottom), and the proportion (95% CI) of infants who eventually died within 28 days per score point (top) in the derivation (dark gray) and in the validation dataset (light gray). (B) Mortality (95% CI) in risk groups based on the Severity Score and selected sepsis subgroups. (C) Mortality (95% CI) in risk groups based on the Severity Score and region.

Fig 6. Distribution of the NeoSep Recovery Score.

Distribution of the Recovery Score, based on clinical signs in the last 24 h, in the derivation (A) and validation (B) data. Numbers in parentheses: number of infants per group. s = survived, d = died the next day. Infants who died on same day are excluded for the relevant time points. The violin plots show the distribution of the Recovery Score as density plots plus median, interquartile range, and upper- and lower-adjacent values in infants with a score > 0.

Fig 7. NeoSep Recovery Score: Time-updated area under the ROC curve.

Time-updated area under the ROC curve (AUROCC) plus 95% CI in the derivation (A) and validation (B) data. Lines represent the trend in predictive value over time of the recovery score on a particular day for death in subsequent days. AUC (+ 95% CI) = area under the curve (+ 95% confidence interval), ROC = receiver operating characteristic.