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)
Neal Russell
(1)
,
Wolfgang Stöhr
(2)
,
Nishad Plakkal
(3)
,
Aislinn Cook
(1)
,
James A. Berkley
(4, 5)
,
Bethou Adhisivam
(3)
,
Ramesh Agarwal
(6)
,
Nawshad Uddin Ahmed
(7, 8)
,
Manica Balasegaram
(9, 10)
,
Daynia Ballot
(11)
,
Adrie Bekker
(12)
,
Eitan Naaman Berezin
(13)
,
Davide Bilardi
(14)
,
Suppawat Boonkasidecha
(15)
,
Cristina Carvalheiro
(16)
,
Neema Chami
(11)
,
Suman Chaurasia
(6)
,
Sara Chiurchiu
(17)
,
Viviane Rinaldi Favarin Colas
(13)
,
Simon Cousens
(18)
,
Tim Cressey
(19, 20)
,
Ana Carolina Dantas de Assis
(16)
,
Tran Minh Dien
(21)
,
Yijun Ding
(21)
,
Nguyen Trong Dung
(21)
,
Han Dong
(22)
,
Angela Dramowski
(12)
,
Madhusudhan Ds
(23, 24)
,
Ajay Dudeja
(25)
,
Jinxing Feng
(26)
,
Youri Glupczynski
(27)
,
Srishti Goel
(25)
,
Herman Goossens
(27)
,
Doan Thi Huong Hao
(21)
,
Mahmudul Islam Khan
(7, 8)
,
Tatiana Munera Huertas
(1)
,
Mohammad Shahidul Islam
(7, 8)
,
Daniel Jarovsky
(13)
,
Nathalie Khavessian
(10)
,
Meera Khorana
(15)
,
Angeliki Kontou
(28)
,
Tomislav Kostyanev
(27)
,
Premsak Laoyookhon
(15)
,
Sorasak Lochindarat
(15)
,
Mattias Larsson
(29)
,
Maia De Luca
(17)
,
Surbhi Malhotra-Kumar
(27)
,
Nivedita Mondal
(3)
,
Nitu Mundhra
(23, 24)
,
Philippa Musoke
(30, 31)
,
Marisa Mussi-Pinhata
(16)
,
Ruchi Nanavati
(23, 24)
,
Firdose Nakwa
(11)
,
Sushma Nangia
(25)
,
Jolly Nankunda
(30, 32)
,
Alessandra Nardone
(14)
,
Borna Nyaoke
(10)
,
Christina Obiero
(4, 33, 34, 35)
,
Maxensia Owor
(30, 32)
,
Wang Ping
(22)
,
Kanchana Preedisripipat
(36)
,
Shamim Qazi
(37)
,
Lifeng Qi
(26)
,
Tanusha Ramdin
(11)
,
Amy Riddell
(1)
,
Lorenza Romani
(17)
,
Praewpan Roysuwan
(19, 20)
,
Robin Saggers
,
Emmanuel Roilides
(28)
,
Samir Saha
(8, 7)
,
Kosmas Sarafidis
(28)
,
Valerie Tusubira
(30, 31)
,
Reenu Thomas
(11)
,
Sithembiso Velaphi
(11)
,
Tuba Vilken
(27)
,
Xiaojiao Wang
(22)
,
Yajuan Wang
(38)
,
Yonghong Yang
(26)
,
Liu Zunjie
(22)
,
Sally Ellis
(10)
,
Julia Bielicki
(1)
,
A. Sarah Walker
(2)
,
Paul Heath
(1)
,
Mike Sharland
(1)
1
St George's, University of London
2 UCL - University College of London [London]
3 Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)
4 KWTRP - KEMRI-Wellcome Trust Research Programme
5 Nuffield Department of Clinical Medicine [Oxford]
6 All India Institute of Medical Sciences [New Delhi]
7 Dhaka Shishu Hospital [Bangladesh]
8 CHRF - Child Health Research Foundation
9 Drugs for Neglected Diseases Initiative
10 GARDP - Global Antibiotic Research and Development Partnership [Geneva, Switzerland]
11 WITS - University of the Witwatersrand [Johannesburg]
12 Stellenbosch University
13 Faculdade de Ciências Médicas Santa Casa de São Paulo [Brazil]
14 Penta [Padova]
15 Queen Sirikit National Institute of Child Health [Bangkok]
16 Universidade de Ribeirão Preto
17 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
18 LSHTM - London School of Hygiene and Tropical Medicine
19 IRD_PHPT - Épidémiologie clinique, santé mère-enfant et VIH en Asie du Sud-Est
20 MIVEGEC - Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle
21 National Children Hospital [Hanoi , Vietnam]
22 CUMS - Capital University of Medical Sciences [Beijing]
23 Seth Gordhandas Sunderdas Medical College, India
24 King Edward Memorial Hospital [Mumbai]
25 LHMC - Lady Hardinge Medical College & Associated Smt. Sucheta Kriplani & Kalawati Saran Children Hospital
26 Shenzhen Children's Hospital = 深圳市儿童医院
27 UA - University of Antwerp
28 Hippokration General Hospital, Aristotle University Of Thessaloniki
29 Karolinska Institutet [Stockholm]
30 MAK - Makerere University [Kampala, Ouganda]
31 MUJHURC - MUJHU Research Collaboration [Kampala, Uganda]
32 JHU - Johns Hopkins University
33 Amsterdam UMC - Amsterdam University Medical Centers
34 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
35 Academic Medical Center - Emma Children's Hospital [Amsterdam, Netherlands]
36 Chiangrai Prachanukroh Hospital
37 OMS / WHO - Organisation Mondiale de la Santé / World Health Organization Office [Genève, Suisse]
38 Beijing Childrens Hospital
2 UCL - University College of London [London]
3 Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)
4 KWTRP - KEMRI-Wellcome Trust Research Programme
5 Nuffield Department of Clinical Medicine [Oxford]
6 All India Institute of Medical Sciences [New Delhi]
7 Dhaka Shishu Hospital [Bangladesh]
8 CHRF - Child Health Research Foundation
9 Drugs for Neglected Diseases Initiative
10 GARDP - Global Antibiotic Research and Development Partnership [Geneva, Switzerland]
11 WITS - University of the Witwatersrand [Johannesburg]
12 Stellenbosch University
13 Faculdade de Ciências Médicas Santa Casa de São Paulo [Brazil]
14 Penta [Padova]
15 Queen Sirikit National Institute of Child Health [Bangkok]
16 Universidade de Ribeirão Preto
17 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
18 LSHTM - London School of Hygiene and Tropical Medicine
19 IRD_PHPT - Épidémiologie clinique, santé mère-enfant et VIH en Asie du Sud-Est
20 MIVEGEC - Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle
21 National Children Hospital [Hanoi , Vietnam]
22 CUMS - Capital University of Medical Sciences [Beijing]
23 Seth Gordhandas Sunderdas Medical College, India
24 King Edward Memorial Hospital [Mumbai]
25 LHMC - Lady Hardinge Medical College & Associated Smt. Sucheta Kriplani & Kalawati Saran Children Hospital
26 Shenzhen Children's Hospital = 深圳市儿童医院
27 UA - University of Antwerp
28 Hippokration General Hospital, Aristotle University Of Thessaloniki
29 Karolinska Institutet [Stockholm]
30 MAK - Makerere University [Kampala, Ouganda]
31 MUJHURC - MUJHU Research Collaboration [Kampala, Uganda]
32 JHU - Johns Hopkins University
33 Amsterdam UMC - Amsterdam University Medical Centers
34 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
35 Academic Medical Center - Emma Children's Hospital [Amsterdam, Netherlands]
36 Chiangrai Prachanukroh Hospital
37 OMS / WHO - Organisation Mondiale de la Santé / World Health Organization Office [Genève, Suisse]
38 Beijing Childrens Hospital
Neal Russell
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- PersonId : 1507410
- ORCID : 0000-0002-9538-7695
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Wolfgang Stöhr
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- ORCID : 0000-0002-6533-2888
Nishad Plakkal
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- ORCID : 0000-0003-2729-7310
Aislinn Cook
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- ORCID : 0000-0002-9189-7815
James A. Berkley
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Bethou Adhisivam
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Ramesh Agarwal
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Nawshad Uddin Ahmed
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Manica Balasegaram
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Daynia Ballot
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Adrie Bekker
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Eitan Naaman Berezin
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Cristina Carvalheiro
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Sara Chiurchiu
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Tim Cressey
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Angela Dramowski
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- ORCID : 0000-0002-0161-9791
Madhusudhan Ds
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- ORCID : 0000-0002-3336-886X
Tatiana Munera Huertas
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- ORCID : 0000-0003-0943-3489
Mohammad Shahidul Islam
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Daniel Jarovsky
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Meera Khorana
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Tomislav Kostyanev
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Nivedita Mondal
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Shamim Qazi
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Tanusha Ramdin
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Amy Riddell
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Lorenza Romani
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Robin Saggers
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Emmanuel Roilides
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Samir Saha
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Valerie Tusubira
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Sally Ellis
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Julia Bielicki
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A. Sarah Walker
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Mike Sharland
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- IdRef : 201853604
Résumé
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.
Domaines
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