1. 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)
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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, null 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, Ranjan Kumar Nandy, 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, BC Nnaji, M Umejiego, PN Anoke, S Adebayo, GO Abegunrin, OB Omotosho, R Ibrahim, B Igwe, M Abroko, K Balami, L Bayem, C Anyanwu, H Haruna, J Okike, K Goroh, M Boi-Sunday, Augusta Ugafor, Maryam Makama, Kaniba Ndukwe, Anastesia Odama, Hadiza Yusuf, Patience Wachukwu, Kachalla Yahaya, Titus Kalade Colsons, Mercy Kura, Damilola Orebiyi, Kenneth C. Iregbu, Chukwuemeka Mmadueke, Lamidi Audu, Nura Idris, Safiya Gambo, Jamila Ibrahim, Edwin Precious, Ashiru Hassan, Shamsudden Gwadabe, Adeola Adeleye Falola, Muhammad Aliyu, Amina Ibrahim, Aisha Sani Mukaddas, Rashida Yakubu Khalid, Fatima Ibrahim Alkali, Maryam Yahaya Muhammad, Fatima Mohammad Tukur, Surayya Mustapha Muhammad, Adeola Shittu, Murjanatu Bello, Muhammad Abubakar Hassan, Fatima Habib Sa ad, Aishatu Kassim, Adil Muhammad, Syed Najeeb Ullah, Muhammad Hilal Jan, Rubina Kamran, null Sajana, Jazba Saeed, Noreen Maqsood, Maria Zafar, Saraeen Sadiq, Sumble Ahsan, Madiha Tariq, Sidra Sajid, Hasma Mustafa, Anees-ur Rehman, Atif Muhammad, Gahssan Mehmood, Mahnoor Nisar, Shermeen Akif, Tahira Yasmeen, Sabir Nawaz, Anam Shanal Atta, Mian Laiq-ur-Rehman, Robina Kousar, Kalsoom Bibi, Kosar Waheed, Zainab Majeed, Ayesha Jalil, Espoir Kajibwami, Innocent Nzabahimana, Mazarati Jean-Baptiste, Kankundiye Riziki, Brigette Uwamahoro, Rachel Uwera, Eugenie Nyiratuza, Kumwami Muzungu, Violette Uwitonze, Marie C Horanimpundu, Francine Nzeyimana, Prince Mitima, Angela Dramowski, Lauren Paterson, Mary Frans, Marvina Johnson, Eveline Swanepoel, Zoleka Bojana, Mieme du Preez, Andre Bulabula, Johan GC van Hasselt, Timothy Walsh, Maria Carvalho, Kathryn Thomson, Robert Andrews, John Watkins, David Gillespie, Kerry Hood, Katie Taiyai, Nigel Kirby, Maria Nieto, Thomas Hender, Patrick Hogan, Habiba Saif, Brad Spiller, Julian Parkhill, Apollo - University of Cambridge Repository, and Group, BARNARDS
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medicine.medical_specialty ,Staphylococcus aureus ,medicine.drug_class ,Antibiotics ,Sepsis ,Cohort Studies ,Antibiotic resistance ,Enterobacteriaceae ,Internal medicine ,medicine ,Humans ,Developing Countries ,Poverty ,Neonatal sepsis ,Virulence ,business.industry ,Enterobacteriaceae Infections ,Infant, Newborn ,Drug Resistance, Microbial ,Articles ,Amoxicillin ,Staphylococcal Infections ,medicine.disease ,Anti-Bacterial Agents ,Infectious Diseases ,Amikacin ,Colistin ,Gentamicin ,Drug Therapy, Combination ,Neonatal Sepsis ,business ,medicine.drug - 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.
- Published
- 2020