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)
<p><strong>Background</strong><br> 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2023
|
| Subjects: |
| _version_ | 1826310699183243264 |
|---|---|
| author | Russell, NJ Stöhr, W Plakkal, N Cook, A Berkley, JA Adhisivam, B Agarwal, R Ahmed, NU Balasegaram, M Ballot, D Bekker, A Berezin, EN Bilardi, D Boonkasidecha, S Carvalheiro, CG Chami, N Chaurasia, S Chiurchiu, S Colas, VRF Cousens, S Cressey, TR de Assis, ACD Dien, TM Ding, Y Dung, NT Dong, H Dramowski, A Ds, M Dudeja, A Feng, J Glupczynski, Y Goel, S Goossens, H Hao, DTH Khan, MI Huertas, TM Islam, MS Jarovsky, D Khavessian, N Khorana, M Kontou, A Kostyanev, T Laoyookhon, P Lochindarat, S Larsson, M Luca, MD Malhotra-Kumar, S Mondal, N Mundhra, N Musoke, P Walker, AS |
| author_facet | Russell, NJ Stöhr, W Plakkal, N Cook, A Berkley, JA Adhisivam, B Agarwal, R Ahmed, NU Balasegaram, M Ballot, D Bekker, A Berezin, EN Bilardi, D Boonkasidecha, S Carvalheiro, CG Chami, N Chaurasia, S Chiurchiu, S Colas, VRF Cousens, S Cressey, TR de Assis, ACD Dien, TM Ding, Y Dung, NT Dong, H Dramowski, A Ds, M Dudeja, A Feng, J Glupczynski, Y Goel, S Goossens, H Hao, DTH Khan, MI Huertas, TM Islam, MS Jarovsky, D Khavessian, N Khorana, M Kontou, A Kostyanev, T Laoyookhon, P Lochindarat, S Larsson, M Luca, MD Malhotra-Kumar, S Mondal, N Mundhra, N Musoke, P Walker, AS |
| author_sort | Russell, NJ |
| collection | OXFORD |
| description | <p><strong>Background</strong><br>
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.</p><br>
<p><strong>Methods and findings</strong><br>
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.<br>
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% (<i>n</i> = 814) of infants started WHO first line regimens (Group 1—Access) and 13.8% (<i>n</i> = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2—“Low” Watch). The largest group (34.0%, <i>n</i> = 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% (<i>n</i> = 566) started a carbapenem (Group 4—“High” Watch), and 1.8% (<i>n</i> = 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 (<i>n</i> = 480; 65.9%).<br>
A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (<i>n</i> = 355) had a gram-negative organism, predominantly <i>Klebsiella pneumoniae</i> (<i>n</i> = 132) or <i>Acinetobacter</i> spp. (<i>n</i> = 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 <i>Staphylococcus aureus</i> isolates.<br>
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%, <i>n</i> = 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.</p><br>
<p><strong>Conclusion</strong><br>
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.</p><br>
<p><strong>Trial registration</strong><br>
ClinicalTrials.gov, (NCT03721302).</p> |
| first_indexed | 2024-03-07T07:57:20Z |
| format | Journal article |
| id | oxford-uuid:4d2126d1-e240-4a7a-a2de-bab1c51e2612 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:57:20Z |
| publishDate | 2023 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:4d2126d1-e240-4a7a-a2de-bab1c51e26122023-08-25T18:13:53ZPatterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: a global neonatal sepsis observational cohort study (NeoOBS)Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4d2126d1-e240-4a7a-a2de-bab1c51e2612SepsisLow and middle income countriesBirth weightAntibioticsNeonatal sepsisBacterial pathogensBloodMedical risk factorsEnglishSymplectic ElementsPublic Library of Science2023Russell, NJStöhr, WPlakkal, NCook, ABerkley, JAAdhisivam, BAgarwal, RAhmed, NUBalasegaram, MBallot, DBekker, ABerezin, ENBilardi, DBoonkasidecha, SCarvalheiro, CGChami, NChaurasia, SChiurchiu, SColas, VRFCousens, SCressey, TRde Assis, ACDDien, TMDing, YDung, NTDong, HDramowski, ADs, MDudeja, AFeng, JGlupczynski, YGoel, SGoossens, HHao, DTHKhan, MIHuertas, TMIslam, MSJarovsky, DKhavessian, NKhorana, MKontou, AKostyanev, TLaoyookhon, PLochindarat, SLarsson, MLuca, MDMalhotra-Kumar, SMondal, NMundhra, NMusoke, PWalker, AS<p><strong>Background</strong><br> 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.</p><br> <p><strong>Methods and findings</strong><br> 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.<br> 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% (<i>n</i> = 814) of infants started WHO first line regimens (Group 1—Access) and 13.8% (<i>n</i> = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2—“Low” Watch). The largest group (34.0%, <i>n</i> = 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% (<i>n</i> = 566) started a carbapenem (Group 4—“High” Watch), and 1.8% (<i>n</i> = 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 (<i>n</i> = 480; 65.9%).<br> A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (<i>n</i> = 355) had a gram-negative organism, predominantly <i>Klebsiella pneumoniae</i> (<i>n</i> = 132) or <i>Acinetobacter</i> spp. (<i>n</i> = 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 <i>Staphylococcus aureus</i> isolates.<br> 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%, <i>n</i> = 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.</p><br> <p><strong>Conclusion</strong><br> 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.</p><br> <p><strong>Trial registration</strong><br> ClinicalTrials.gov, (NCT03721302).</p> |
| spellingShingle | Sepsis Low and middle income countries Birth weight Antibiotics Neonatal sepsis Bacterial pathogens Blood Medical risk factors Russell, NJ Stöhr, W Plakkal, N Cook, A Berkley, JA Adhisivam, B Agarwal, R Ahmed, NU Balasegaram, M Ballot, D Bekker, A Berezin, EN Bilardi, D Boonkasidecha, S Carvalheiro, CG Chami, N Chaurasia, S Chiurchiu, S Colas, VRF Cousens, S Cressey, TR de Assis, ACD Dien, TM Ding, Y Dung, NT Dong, H Dramowski, A Ds, M Dudeja, A Feng, J Glupczynski, Y Goel, S Goossens, H Hao, DTH Khan, MI Huertas, TM Islam, MS Jarovsky, D Khavessian, N Khorana, M Kontou, A Kostyanev, T Laoyookhon, P Lochindarat, S Larsson, M Luca, MD Malhotra-Kumar, S Mondal, N Mundhra, N Musoke, P Walker, AS 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) |
| title | 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) |
| title_full | 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) |
| title_fullStr | 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) |
| title_full_unstemmed | 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) |
| title_short | 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) |
| title_sort | 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 |
| topic | Sepsis Low and middle income countries Birth weight Antibiotics Neonatal sepsis Bacterial pathogens Blood Medical risk factors |
| work_keys_str_mv | AT russellnj patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT stohrw patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT plakkaln patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT cooka patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT berkleyja patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT adhisivamb patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT agarwalr patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT ahmednu patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT balasegaramm patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT ballotd patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT bekkera patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT berezinen patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT bilardid patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT boonkasidechas patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT carvalheirocg patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT chamin patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT chaurasias patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT chiurchius patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT colasvrf patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT cousenss patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT cresseytr patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT deassisacd patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dientm patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dingy patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dungnt patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dongh patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dramowskia patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dsm patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT dudejaa patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT fengj patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT glupczynskiy patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT goels patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT goossensh patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT haodth patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT khanmi patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT huertastm patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT islamms patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT jarovskyd patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT khavessiann patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT khoranam patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT kontoua patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT kostyanevt patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT laoyookhonp patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT lochindarats patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT larssonm patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT lucamd patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT malhotrakumars patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT mondaln patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT mundhran patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT musokep patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs AT walkeras patternsofantibioticusepathogensandpredictionofmortalityinhospitalizedneonatesandyounginfantswithsepsisaglobalneonatalsepsisobservationalcohortstudyneoobs |