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)

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 tri...

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Published in:	PLoS medicine Vol. 20; no. 6; p. e1004179
Main 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
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 08-06-2023 Public Library of Science (PLoS)
Subjects:	Analysis Anti-Bacterial Agents - therapeutic use Antibiotics Antimicrobial agents Antimicrobial resistance Beta lactamases Biology and Life Sciences Birth weight Blood Blood culture Carbapenems Carbapenems - therapeutic use Care and treatment Cefotaxime Ceftazidime Ceftriaxone Cephalosporins Clinical trials Cohort analysis Cohort Studies Colistin Diagnosis Dosage and administration Drug resistance Earth Sciences Fatalities Hospital patients Hospitalization Hospitals Humans Infant Infant, Newborn Infants Infants (Newborn) Infection Laboratories Medical examination Medical research Medicin och hälsovetenskap Medicine and Health Sciences Medicine, Experimental Microbiology Mortality Neonatal Sepsis - diagnosis Neonatal Sepsis - drug therapy Neonates Observational studies Pathogenic microorganisms Pathogens Patient outcomes Piperacillin Piperacillin-tazobactam Prediction models Prospective Studies Regression analysis Risk groups Sepsis Sepsis - diagnosis Sepsis - drug therapy Sepsis - microbiology Social Sciences South Asia Sub-Saharan Africa Tazobactam Vital signs β Lactamase China Sub-Saharan Africa South Asia
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Summary:	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. 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. 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. ClinicalTrials.gov, (NCT03721302).
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 These authors share first authorship on this work. I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (MB, NK, SE) participated as authors on the study, reviewed the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist.
ISSN:	1549-1676 1549-1277 1549-1676
DOI:	10.1371/journal.pmed.1004179