Publication:
Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS)

Issued Date

2021-12-01

Resource Type

Article

ISSN

14744457
14733099

DOI

10.1016/S1473-3099(21)00050-5

Other identifier(s)

2-s2.0-85115984937

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

The Lancet Infectious Diseases. Vol.21, No.12 (2021), 1677-1688

Suggested Citation

Kathryn M. Thomson, Calie Dyer, Feiyan Liu, Kirsty Sands, Edward Portal, Maria J. Carvalho, Matthew Barrell, Ian Boostrom, Susanna Dunachie, Refath Farzana, Ana Ferreira, Francis Frayne, Brekhna Hassan, Ellis Jones, Lim Jones, Jordan Mathias, Rebecca Milton, Jessica Rees, Grace J. Chan, Delayehu Bekele, Abayneh Mahlet, Sulagna Basu, Ranjan K. Nandy, Bijan Saha, Kenneth Iregbu, Fatima Modibbo, Stella Uwaezuoke, Rabaab Zahra, Haider Shirazi, Najeeb U. Syed, Jean Baptiste Mazarati, Aniceth Rucogoza, Lucie Gaju, Shaheen Mehtar, Andre N.H. Bulabula, Andrew Whitelaw, Johan G.C. van Hasselt, Timothy R. Walsh, Samir Saha, Maksuda Islam, Zabed Bin-Ahmed, Wazir Ahmed, Taslima Begum, Mitu Chowdhury, Shaila Sharmin, Chumki Rani Dey, Uttam, Abdul Matin, Sowmitra Ranjan Chakraborty, Sadia Tasmin, Dipa Rema, Rashida Khatun, Liza Nath, Nigatu Balkachew, Katherine Schaughency, Semaria Solomon, Zenebe Gebreyohanes, Rozina Ambachew, Oludare Odumade, Misgana Haileselassie, Grace Chan, Abigail Russo, Redeat Workneh, Gesit Metaferia, Mahlet Abayneh, Yahya Zekaria Mohammed, Tefera Biteye, Alula Teklu, Wendimagegn Gezahegn, Partha Sarathi Chakravorty, Anuradha Mukherjee, Samarpan Roy, Anuradha Sinha, Sharmi Naha, Sukla Saha Malakar, Siddhartha Bose, Monaki Majhi, Subhasree Sahoo, Putul Mukherjee, Sumitra Kumari Routa, Chaitali Nandi, Pinaki Chattopadhyay, Fatima Zara Isa Modibbo, Dilichukwu Meduekwe, Khairiyya Muhammad, Queen Nsude, Ifeoma Ukeh, Mary Joe Okenu, Akpulu Chinenye, Samuel Yakubu, Vivian Asunugwo, Folake Aina, Isibong Issy, Dolapo Adekeye, Adiele Eunice, Abdulmlik Amina, R. Oyewole, I. Oloton, B. C. Nnaji Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS). The Lancet Infectious Diseases. Vol.21, No.12 (2021), 1677-1688. doi:10.1016/S1473-3099(21)00050-5 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/77519

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Title

Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS)

Author(s)

Kathryn M. Thomson
 Calie Dyer
 Feiyan Liu
 Kirsty Sands
 Edward Portal
 Maria J. Carvalho
 Matthew Barrell
 Ian Boostrom
 Susanna Dunachie
 Refath Farzana
 Ana Ferreira
 Francis Frayne
 Brekhna Hassan
 Ellis Jones
 Lim Jones
 Jordan Mathias
 Rebecca Milton
 Jessica Rees
 Grace J. Chan
 Delayehu Bekele
 Abayneh Mahlet
 Sulagna Basu
 Ranjan K. Nandy
 Bijan Saha
 Kenneth Iregbu
 Fatima Modibbo
 Stella Uwaezuoke
 Rabaab Zahra
 Haider Shirazi
 Najeeb U. Syed
 Jean Baptiste Mazarati
 Aniceth Rucogoza
 Lucie Gaju
 Shaheen Mehtar
 Andre N.H. Bulabula
 Andrew Whitelaw
 Johan G.C. van Hasselt
 Timothy R. Walsh
 Samir Saha
 Maksuda Islam
 Zabed Bin-Ahmed
 Wazir Ahmed
 Taslima Begum
 Mitu Chowdhury
 Shaila Sharmin
 Chumki Rani Dey
 Uttam
 Abdul Matin
 Sowmitra Ranjan Chakraborty
 Sadia Tasmin
 Dipa Rema
 Rashida Khatun
 Liza Nath
 Nigatu Balkachew
 Katherine Schaughency
 Semaria Solomon
 Zenebe Gebreyohanes
 Rozina Ambachew
 Oludare Odumade
 Misgana Haileselassie
 Grace Chan
 Abigail Russo
 Redeat Workneh
 Gesit Metaferia
 Mahlet Abayneh
 Yahya Zekaria Mohammed
 Tefera Biteye
 Alula Teklu
 Wendimagegn Gezahegn
 Partha Sarathi Chakravorty
 Anuradha Mukherjee
 Samarpan Roy
 Anuradha Sinha
 Sharmi Naha
 Sukla Saha Malakar
 Siddhartha Bose
 Monaki Majhi
 Subhasree Sahoo
 Putul Mukherjee
 Sumitra Kumari Routa
 Chaitali Nandi
 Pinaki Chattopadhyay
 Fatima Zara Isa Modibbo
 Dilichukwu Meduekwe
 Khairiyya Muhammad
 Queen Nsude
 Ifeoma Ukeh
 Mary Joe Okenu
 Akpulu Chinenye
 Samuel Yakubu
 Vivian Asunugwo
 Folake Aina
 Isibong Issy
 Dolapo Adekeye
 Adiele Eunice
 Abdulmlik Amina
 R. Oyewole
 I. Oloton
 B. C. Nnaji

Other Contributor(s)

St. Paul‘s Hospital Millennium Medical College
 Rwanda Biomedical Center
 Cardiff University School of Medicine
 Centre Hospitalier Universitaire de Kigali
 Leiden Academic Centre for Drug Research
 Quaid-i-Azam University
 Pakistan Institute of Medical Sciences
 Institute of Post Graduate Medical Education and Research Kolkatta
 Harvard T.H. Chan School of Public Health
 Children's Hospital Boston
 University of Oxford
 Universidade de Aveiro
 Cardiff University
 Mahidol University
 Tygerberg Hospital
 Nuffield Department of Medicine
 National Hospital, Abuja
 National Institute of Cholera and Enteric Diseases India
 Stellenbosch University
 University Hospital of Wales
 54gene
 Federal Medical Centre Jabi

Abstract

Background: Sepsis is a major contributor to neonatal mortality, particularly in low-income and middle-income countries (LMICs). WHO advocates ampicillin–gentamicin as first-line therapy for the management of neonatal sepsis. In the BARNARDS observational cohort study of neonatal sepsis and antimicrobial resistance in LMICs, common sepsis pathogens were characterised via whole genome sequencing (WGS) and antimicrobial resistance profiles. In this substudy of BARNARDS, we aimed to assess the use and efficacy of empirical antibiotic therapies commonly used in LMICs for neonatal sepsis. Methods: In BARNARDS, consenting mother–neonates aged 0–60 days dyads were enrolled on delivery or neonatal presentation with suspected sepsis at 12 BARNARDS clinical sites in Bangladesh, Ethiopia, India, Pakistan, Nigeria, Rwanda, and South Africa. Stillborn babies were excluded from the study. Blood samples were collected from neonates presenting with clinical signs of sepsis, and WGS and minimum inhibitory concentrations for antibiotic treatment were determined for bacterial isolates from culture-confirmed sepsis. Neonatal outcome data were collected following enrolment until 60 days of life. Antibiotic usage and neonatal outcome data were assessed. Survival analyses were adjusted to take into account potential clinical confounding variables related to the birth and pathogen. Additionally, resistance profiles, pharmacokinetic–pharmacodynamic probability of target attainment, and frequency of resistance (ie, resistance defined by in-vitro growth of isolates when challenged by antibiotics) were assessed. Questionnaires on health structures and antibiotic costs evaluated accessibility and affordability. Findings: Between Nov 12, 2015, and Feb 1, 2018, 36 285 neonates were enrolled into the main BARNARDS study, of whom 9874 had clinically diagnosed sepsis and 5749 had available antibiotic data. The four most commonly prescribed antibiotic combinations given to 4451 neonates (77·42%) of 5749 were ampicillin–gentamicin, ceftazidime–amikacin, piperacillin–tazobactam–amikacin, and amoxicillin clavulanate–amikacin. This dataset assessed 476 prescriptions for 442 neonates treated with one of these antibiotic combinations with WGS data (all BARNARDS countries were represented in this subset except India). Multiple pathogens were isolated, totalling 457 isolates. Reported mortality was lower for neonates treated with ceftazidime–amikacin than for neonates treated with ampicillin–gentamicin (hazard ratio [adjusted for clinical variables considered potential confounders to outcomes] 0·32, 95% CI 0·14–0·72; p=0·0060). Of 390 Gram-negative isolates, 379 (97·2%) were resistant to ampicillin and 274 (70·3%) were resistant to gentamicin. Susceptibility of Gram-negative isolates to at least one antibiotic in a treatment combination was noted in 111 (28·5%) to ampicillin–gentamicin; 286 (73·3%) to amoxicillin clavulanate–amikacin; 301 (77·2%) to ceftazidime–amikacin; and 312 (80·0%) to piperacillin–tazobactam–amikacin. A probability of target attainment of 80% or more was noted in 26 neonates (33·7% [SD 0·59]) of 78 with ampicillin–gentamicin; 15 (68·0% [3·84]) of 27 with amoxicillin clavulanate–amikacin; 93 (92·7% [0·24]) of 109 with ceftazidime–amikacin; and 70 (85·3% [0·47]) of 76 with piperacillin–tazobactam–amikacin. However, antibiotic and country effects could not be distinguished. Frequency of resistance was recorded most frequently with fosfomycin (in 78 isolates [68·4%] of 114), followed by colistin (55 isolates [57·3%] of 96), and gentamicin (62 isolates [53·0%] of 117). Sites in six of the seven countries (excluding South Africa) stated that the cost of antibiotics would influence treatment of neonatal sepsis. Interpretation: Our data raise questions about the empirical use of combined ampicillin–gentamicin for neonatal sepsis in LMICs because of its high resistance and high rates of frequency of resistance and low probability of target attainment. Accessibility and affordability need to be considered when advocating antibiotic treatments with variance in economic health structures across LMICs. Funding: The Bill & Melinda Gates Foundation.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/77519

Collections

Scopus 2021