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).

Autor: Russell NJ; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom., Stöhr W; Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom., Plakkal N; Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India., Cook A; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom., Berkley JA; Clinical Research Department, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.; Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya., Adhisivam B; Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India., Agarwal R; Newborn Division and WHO-CC, All India Institute of Medical Sciences, New Delhi, India., Ahmed NU; Child Health Research Foundation (CHRF), Dhaka Shishu Hospital, Dhaka, Bangladesh., Balasegaram M; Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland., Ballot D; Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Bekker A; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa., Berezin EN; Pediatric Infectious Diseases Unit, Santa Casa de São Paulo, São Paulo, Brazil., Bilardi D; Penta Foundation, Padova, Italy., Boonkasidecha S; Queen Sirikit National Institute of Child Health, Bangkok, Thailand., Carvalheiro CG; Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil., Chami N; Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Chaurasia S; All India Institute of Medical Sciences, Department of Paediatrics, New Delhi, India., Chiurchiu S; Academic Hospital Paediatric Department, Bambino Gesù Children's Hospital, Rome, Italy., Colas VRF; Pediatric Infectious Diseases Unit, Santa Casa de São Paulo, São Paulo, Brazil., Cousens S; Faculty of Epidemiology and Population Health, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom., Cressey TR; PHPT/IRD-MIVEGEC, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand., de Assis ACD; Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil., Dien TM; Vietnam National Children's Hospital, Hanoi, Vietnam and Surgical Intensive Care Unit, Vietnam National Children's Hospital, Hanoi, Vietnam., Ding Y; Vietnam National Children's Hospital, Hanoi, Vietnam and Surgical Intensive Care Unit, Vietnam National Children's Hospital, Hanoi, Vietnam., Dung NT; Vietnam National Children's Hospital, Hanoi, Vietnam and Surgical Intensive Care Unit, Vietnam National Children's Hospital, Hanoi, Vietnam., Dong H; Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China., Dramowski A; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa., Ds M; Neonatology Department, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, India., Dudeja A; Department of Neonatology, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India., Feng J; Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China., Glupczynski Y; Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium., Goel S; Department of Neonatology, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India., Goossens H; Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium., Hao DTH; Vietnam National Children's Hospital, Hanoi, Vietnam and Surgical Intensive Care Unit, Vietnam National Children's Hospital, Hanoi, Vietnam., Khan MI; Child Health Research Foundation (CHRF), Dhaka Shishu Hospital, Dhaka, Bangladesh., Huertas TM; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom., Islam MS; Child Health Research Foundation (CHRF), Dhaka Shishu Hospital, Dhaka, Bangladesh., Jarovsky D; Pediatric Infectious Diseases Unit, Santa Casa de São Paulo, São Paulo, Brazil., Khavessian N; Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland., Khorana M; Neonatal Unit, Department of Pediatrics, Queen Sirikit National Institute of Child Health, College of Medicine, Rangsit University, Bangkok, Thailand., Kontou A; Neonatology Dept, School of Medicine, Faculty of Health Sciences, Aristotle University and Hippokration General Hospital, Thessaloniki, Greece., Kostyanev T; Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium., Laoyookhon P; Queen Sirikit National Institute of Child Health, Bangkok, Thailand., Lochindarat S; Queen Sirikit National Institute of Child Health, Bangkok, Thailand., Larsson M; Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden., Luca M; Academic Hospital Paediatric Department, Bambino Gesù Children's Hospital, Rome, Italy., Malhotra-Kumar S; Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium., Mondal N; Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India., Mundhra N; Neonatology Department, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, India., Musoke P; Department of Paediatrics and Child Health, College of Health Sciences, Makerere University and MUJHU Care, Kampala, Uganda., Mussi-Pinhata MM; Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil., Nanavati R; Neonatology Department, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, India., Nakwa F; Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Nangia S; Department of Neonatology, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India., Nankunda J; Makerere University - Johns Hopkins University Research Collaboration, Kampala, Uganda., Nardone A; Penta Foundation, Padova, Italy., Nyaoke B; Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland., Obiero CW; Clinical Research Department, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.; Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Department of Global Health, Amsterdam, the Netherlands., Owor M; Makerere University - Johns Hopkins University Research Collaboration, Kampala, Uganda., Ping W; Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China., Preedisripipat K; Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand., Qazi S; World Health Organization, Maternal, Newborn, Child and Adolescent Health Department, Geneva, Switzerland., Qi L; Department of Infectious Diseases, Shenzhen Children's Hospital, Shenzhen, China., Ramdin T; Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Department of Paediatrics and Child Health, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa., Riddell A; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom., Romani L; Academic Hospital Paediatric Department, Bambino Gesù Children's Hospital, Rome, Italy., Roysuwan P; PHPT/IRD-MIVEGEC, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand., Saggers R; Department of Paediatrics and Child Health, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa., Roilides E; Infectious Diseases Unit, 3rd Dept Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University and Hippokration General Hospital, Thessaloniki, Greece., Saha SK; Child Health Research Foundation (CHRF), Dhaka Shishu Hospital, Dhaka, Bangladesh., Sarafidis K; Neonatology Dept, School of Medicine, Faculty of Health Sciences, Aristotle University and Hippokration General Hospital, Thessaloniki, Greece., Tusubira V; Department of Paediatrics and Child Health, College of Health Sciences, Makerere University and MUJHU Care, Kampala, Uganda., Thomas R; Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Velaphi S; Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Vilken T; Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium., Wang X; Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Beijing, China., Wang Y; Department of Neonatology, Children's Hospital, Capital Institute of Pediatrics, Yabao Road, Chaoyang District, Beijing, China., Yang Y; Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China., Zunjie L; Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China., Ellis S; Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland., Bielicki JA; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom., Walker AS; Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom., Heath PT; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom., Sharland M; Center for Neonatal and Paediatric Infection (CNPI), Institute of Infection & Immunity, St George's University of London, London, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS medicine [PLoS Med] 2023 Jun 08; Vol. 20 (6), pp. e1004179. Date of Electronic Publication: 2023 Jun 08 (Print Publication: 2023).
DOI: 10.1371/journal.pmed.1004179
Abstrakt: 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).
Competing Interests: 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.
(Copyright: © 2023 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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