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)
Authors: Russell Neal J. , Stöhr Wolfgang , Plakkal Nishad , Cook Aislinn , Berkley James A. , Adhisivam Bethou , Agarwal Ramesh , Ahmed Nawshad Uddin , Balasegaram Manica , Ballot Daynia , Bekker Adrie , Berezin Eitan Naaman , Bilardi Davide , Boonkasidecha Suppawat , Carvalheiro Cristina G. , Chami Neema , Chaurasia Suman , Chiurchiu Sara , Colas Viviane Rinaldi Favarin , Cousens Simon , Cressey Tim R. , de Assis Ana Carolina Dantas , Dien Tran Minh , Ding Yijun , Dung Nguyen Trong , Dong Han , Dramowski Angela , DS Madhusudhan , Dudeja Ajay , Feng Jinxing , Glupczynski Youri , Goel Srishti , Goossens Herman , Hao Doan Thi Huong , Khan Mahmudul Islam , Huertas Tatiana Munera , Islam Mohammad Shahidul , Jarovsky Daniel , Khavessian Nathalie , Khorana Meera , Kontou Angeliki , Kostyanev Tomislav , Laoyookhon Premsak , Lochindarat Sorasak , Larsson Mattias , Luca Maia De , Malhotra-Kumar Surbhi , Mondal Nivedita , Mundhra Nitu , Musoke Philippa , Mussi-Pinhata Marisa M. , Nanavati Ruchi , Nakwa Firdose , Nangia Sushma , Nankunda Jolly , Nardone Alessandra , Nyaoke Borna , Obiero Christina W. , Owor Maxensia , Ping Wang , Preedisripipat Kanchana , Qazi Shamim , Qi Lifeng , Ramdin Tanusha , Riddell Amy , Romani Lorenza , Roysuwan Praewpan , Saggers Robin , Roilides Emmanuel , Saha Samir K. , Sarafidis Kosmas , Tusubira Valerie , Thomas Reenu , Velaphi Sithembiso , Vilken Tuba , Wang Xiaojiao , Wang Yajuan , Yang Yonghong , Zunjie Liu , Ellis Sally , Bielicki Julia A. , Walker A. Sarah , Heath Paul T. , Sharland Mike 
Published: June 2023

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).