Tackling antimicrobial resistance in neonatal sepsis
Authors: Laura Folgori, Sally J Ellis, Julia A Bielicki, Paul T Heath, Mike Sharland, Manica Balasegaram
Journal: The Lancet Global Health (2017)

The reduction of maternal and child mortality, which has halved worldwide in the past two decades, is considered one of the greatest successes of the Millennium Development Goals programme.1Lawn JE Blencowe H Oza S et al.Every newborn: progress, priorities, and potential beyond survival.Lancet. 2014; 384: 189-205Summary Full Text Full Text PDF PubMed Scopus (1030) Google Scholar However, the number of neonatal deaths has remained unacceptably high, with an estimated 2·9 million deaths every year (44% of all deaths in children younger than 5 years, worldwide).2Liu L Oza S Hogan D et al.Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis.Lancet. 2015; 385: 430-440Summary Full Text Full Text PDF PubMed Scopus (1981) Google Scholar In 2012, the most common causes of neonatal death globally were preterm-birth complications, intrapartum-related conditions, and infections. Globally, infections cause nearly a quarter (23%) of all neonatal deaths, with neonatal sepsis accounting for 15% of these deaths.1Lawn JE Blencowe H Oza S et al.Every newborn: progress, priorities, and potential beyond survival.Lancet. 2014; 384: 189-205Summary Full Text Full Text PDF PubMed Scopus (1030) Google Scholar Severe bacterial infections in neonates account for about 3% of all disability-adjusted life-years.3Seale AC Blencowe H Manu AA et al.Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis.Lancet Infect Dis. 2014; 14: 731-741Summary Full Text Full Text PDF PubMed Scopus (183) Google Scholar Prompt diagnosis and appropriate treatment are crucially important in reducing mortality. However, the worldwide spread of antimicrobial resistance represents a major challenge, with nearly half of the pathogens that cause severe neonatal bacterial infections reported to be resistant to the first-line (ampicillin or penicillin, and gentamicin) and second-line (third-generation cephalosporins) WHO-recommended treatments.4Downie L Armiento R Subhi R Kelly J Clifford V Duke T Community-acquired neonatal and infant sepsis in developing countries: efficacy of WHO's currently recommended antibiotics—systematic review and meta-analysis.Arch Dis Child. 2013; 98: 146-154Crossref PubMed Scopus (115) Google Scholar In 2016, the first estimate of neonatal deaths attributable to antimicrobial resistance was published,5Laxminarayan R Matsoso P Pant S et al.Access to effective antimicrobials: a worldwide challenge.Lancet. 2016; 387: 168-175Summary Full Text Full Text PDF PubMed Scopus (653) Google Scholar with multidrug-resistant pathogens approximated to account for 30% of all global neonatal sepsis mortality.5Laxminarayan R Matsoso P Pant S et al.Access to effective antimicrobials: a worldwide challenge.Lancet. 2016; 387: 168-175Summary Full Text Full Text PDF PubMed Scopus (653) Google Scholar Multidrug-resistant pathogens are a challenge in high-income countries, but are even more so in low-income and middle-income countries because of insufficient access to antibiotics, higher burden of infectious diseases, weak health-care systems, and resources limitations. Nowadays, multidrug-resistance Gram-negative bacteria are of the greatest concern in neonates because few therapeutic options are available.6Folgori L Bielicki J Heath PT Sharland M Antimicrobial-resistant Gram-negative infections in neonates: burden of disease and challenges in treatment.Curr Opin Infect Dis. 2017; 30: 281-288Crossref PubMed Scopus (39) Google Scholar Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) are responsible for an increasing number of outbreaks of health-care-associated infection in neonatal intensive care units (NICUs), and are associated with substantial morbidity and mortality. The emergence and spread of ESBL and CRE among NICUs has inevitably led to the reintroduction of old antibiotics, such as colistin and fosfomycin, often with minimal information distributed on drug safety and optimal dosing. Few data are available to support an optimal treatment of multidrug-resistant infections, even in adults, with very few randomised trials and most data coming from retrospective observational studies. Data6Folgori L Bielicki J Heath PT Sharland M Antimicrobial-resistant Gram-negative infections in neonates: burden of disease and challenges in treatment.Curr Opin Infect Dis. 2017; 30: 281-288Crossref PubMed Scopus (39) Google Scholar, 7Folgori L Bielicki J Ruiz B et al.Harmonisation in study design and outcomes in paediatric antibiotic clinical trials: a systematic review.Lancet Infect Dis. 2016; 16: e178-e189Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar on the number of robust clinical studies assessing old or new antibiotics involving neonates indicate that a very small number of trials are being conducted—ie, globally less than ten antibiotic trials involving preterm infants have been conducted. To address this need for additional data, the Global Antibiotic Research and Development Partnership (GARDP), a joint initiative of WHO and the Drugs for Neglected Diseases initiative (DNDi) in support of the Global Action Plan for Antimicrobial Resistance, established a new priority-setting framework, with the mission to develop new antibiotic regimens to address drug-resistant infections, promote their responsible use, and make them accessible for all populations in need.8Drugs for Neglected Diseases initiativeGlobal antibiotic research & development partnership (GARDP).https://www.dndi.org/diseases-projects/gardp/Date: 2016Google Scholar As part of this initiative, the GARDP has launched a neonatal sepsis programme, which will include the NeoAMR Project (to be launched on Nov 8, 2017). This project will aim to develop new, globally applicable, empirical antibiotic regimens and strategies for the treatment of neonatal sepsis that can be adapted to settings with varying prevalence of multidrug-resistant pathogens. The specific aim of the NeoAMR Project is to develop two treatments targeting two specific areas of need. First, an empirical regimen that serves as an alternative to amoxicillin and gentamicin in areas where a high prevalence of ESBL Gram-negative bacteria pathogens are suspected, and second, a treatment regimen to be used in situations when carbapenem-resistant Gram-negative bacteria have been shown. The panel summarises the main characteristics expected of these treatments.PanelTreatments expected to be developed as part of the NeoAMR ProjectRegimen 1IndicationEmpirical treatment of neonatal sepsis, including meningitis, in premature and term infants, early and late onset infectionPatient populationNeonates with possible severe bacterial infections in settings with a high prevalence of resistance to first-line WHO recommended treatmentRoute of administrationIntravenous, 30 min infusionsDosing scheduleOnce or twice dailyEfficacyComparable to amoxicillin-gentamicin or ceftriaxone-gentamicin in claimed indication, with activity against pathogens that are resistant to amoxicillin-gentamicin or ceftriaxone-gentamicinTreatment duration5–10 daysSafety and tolerabilityLow propensity for resistance development, large therapeutic window, minimal hepatotoxicity, nephrotoxicity, and central nervous system toxicity, no prolongation of the QT intervalDrug interactionsSimilar to the first-line WHO empirical treatmentsKey countriesSouth America, Asia, and AfricaPharmacoeconomicsReduction of intensive care unit and length of hospital stay (modelling)Current standard of careAmoxicillin-gentamicin or ceftriaxone-gentamicin, as per WHO recommendationsRegimen 2IndicationNeonatal sepsis and meningitis, when multidrug-resistance—specifically carbapenem-resistant, Gram-negative pathogens—has been shown, including Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter sppPatient populationNeonates admitted to hospital with severe infections, failure on optimal current treatment, and positive microbiological cultureRoute of administrationIntravenous, 30 min infusionDosing scheduleOnce or twice dailyEfficacySimilar to existing options in claimed indication and activity in pathogens resistant to carbapenemsTreatment duration5–10 daysSafety and tolerabilityLow propensity for resistance development, large therapeutic window, minimal hepatotoxicity, nephrotoxicity, and central nervous system toxicity, no prolongation of the QT intervalDrug interactionsSimilar to standard of careKey countriesSouth America, Asia, and AfricaPharmacoeconomicsReduction of intensive care unit and length of hospital stay (modelling)Current standard of careColistin monotherapy Regimen 1 Indication Empirical treatment of neonatal sepsis, including meningitis, in premature and term infants, early and late onset infection Patient population Neonates with possible severe bacterial infections in settings with a high prevalence of resistance to first-line WHO recommended treatment Route of administration Intravenous, 30 min infusions Dosing schedule Once or twice daily Efficacy Comparable to amoxicillin-gentamicin or ceftriaxone-gentamicin in claimed indication, with activity against pathogens that are resistant to amoxicillin-gentamicin or ceftriaxone-gentamicin Treatment duration 5–10 days Safety and tolerability Low propensity for resistance development, large therapeutic window, minimal hepatotoxicity, nephrotoxicity, and central nervous system toxicity, no prolongation of the QT interval Drug interactions Similar to the first-line WHO empirical treatments Key countries South America, Asia, and Africa Pharmacoeconomics Reduction of intensive care unit and length of hospital stay (modelling) Current standard of care Amoxicillin-gentamicin or ceftriaxone-gentamicin, as per WHO recommendationsRegimen 2 Indication Neonatal sepsis and meningitis, when multidrug-resistance—specifically carbapenem-resistant, Gram-negative pathogens—has been shown, including Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter spp Patient population Neonates admitted to hospital with severe infections, failure on optimal current treatment, and positive microbiological culture Route of administration Intravenous, 30 min infusion Dosing schedule Once or twice daily Efficacy Similar to existing options in claimed indication and activity in pathogens resistant to carbapenems Treatment duration 5–10 days Safety and tolerability Low propensity for resistance development, large therapeutic window, minimal hepatotoxicity, nephrotoxicity, and central nervous system toxicity, no prolongation of the QT interval Drug interactions Similar to standard of care Key countries South America, Asia, and Africa Pharmacoeconomics Reduction of intensive care unit and length of hospital stay (modelling) Current standard of care Colistin monotherapy The lead candidate for the first regimen consists of a combination of fosfomycin and amikacin since this combination would ensure adequate central nervous system penetration (which is essential considering the high incidence of meningitis in neonates with sepsis), low resistance development, good safety profile, and broad spectrum of activity. For the second regimen, a hollow fibre infection model has been developed9Ramos-Martín V Johnson A Livermore J et al.Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates.J Antimicrob Chemother. 2016; 71: 992-1002Crossref PubMed Scopus (34) Google Scholar to identify suitable candidate combinations. These regimens could consist of an optimally dosed polymyxin-based combination, or other antibiotics that are in development or recently registered for use in adults that could prevent the emergence of drug resistance while resulting in maximal antibacterial activity, or a combination of these drugs. The global shortage of antibiotics that are available for use in neonates is of increasing concern, particularly given the increase of antimicrobial resistance and the marked paucity of research in this vulnerable population. Neonates should be more highly prioritised in research and development globally, including in the development of enhanced diagnostics that are practical for use in low-income and middle-income countries, combined with the provision of novel evidence-based treatment options that can be available worldwide. The NeoAMR Project will provide the general framework for the design and implementation of large-scale neonatal sepsis trials across different geographical settings. It will also become the platform for future initiatives in this area, including monitoring the ongoing effect of these initiatives, and will seek to ensure that its outcomes are translated into appropriate policies and guidelines at both national and global levels. MS reports grants from GlaxoSmithKline, Pfizer, Cubist, and Drugs for Neglected Diseases Initiative (DNDi), outside the submitted work. SJE is a paid employee of DNDi and the Global Antibiotic Research and Development Partnership. JAB reports that her husband is senior corporate counsel at Novartis International AG, Switzerland, and holds Novartis stock and stock options. All other authors declare no competing interests.