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).

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. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Antibiotics needed to treat multidrug-resistant infections in neonates.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Les infections demeurent l'une des principales causes de décès chez les nouveau-nés. Les rares projets de développement d'antibiotiques et les défis posés par la recherche néonatale ont entraîné une pénurie d'antibiotiques efficaces spécialement étudiés pour traiter les infections multirésistantes (MR) chez les nouveau-nés, en dépit d'une mortalité galopante due à une résistance accrue aux antimicrobiens. Sur 40 antibiotiques autorisés pour les adultes depuis 2000, quatre à peine sont munis d'un étiquetage indiquant la posologie adaptée aux nouveau-nés. Actuellement, 43 essais cliniques portant sur des antibiotiques recrutent des patients du côté des adultes, contre six seulement du côté des nouveau-nés. Dans le présent document, nous passons en revue la liste prioritaire d'agents pathogènes établie par l'Organisation mondiale de la Santé (OMS) pour soigner la septicémie néonatale et proposons de réunir, sous l'égide de l'OMS, des parties prenantes issues de plusieurs domaines d'expertise afin de promouvoir la création d'une liste prioritaire de développement d'antibiotiques destinés aux nouveau-nés. Objectif: parvenir à un consensus international et interdisciplinaire visant à accélérer le programme de mise au point d'antibiotiques à usage néonatal. Ce programme permettrait d'orienter les recherches vers des antibiotiques identifiés comme prioritaires pour les nouveau-nés, en vue de faire baisser les taux de morbidité et de mortalité excessifs qu'engendrent les infections MR au sein de cette population vulnérable.

Las infecciones siguen siendo una de las principales causas de muerte en los recién nacidos. Debido al escaso desarrollo de los antibióticos y a las dificultades para llevar a cabo la investigación neonatal, son pocos los antibióticos eficaces que se estudian de manera adecuada para tratar las infecciones multirresistentes (MR) en los recién nacidos, a pesar de la creciente carga de mortalidad mundial causada por la resistencia a los antimicrobianos. De los 40 antibióticos aprobados para su uso en adultos desde el 2000, solo cuatro han incluido información sobre la dosis para recién nacidos en su etiquetado. En la actualidad, 43 ensayos clínicos con antibióticos para adultos están reclutando pacientes, en comparación con solo seis ensayos que reclutan recién nacidos. Se revisa la lista de patógenos prioritarios de la Organización Mundial de la Salud (OMS) relevantes para la sepsis neonatal y se propone una reunión de la OMS con múltiples expertos para promover el desarrollo de una lista de antibióticos prioritarios para los recién nacidos. El objetivo es desarrollar un consenso internacional e interdisciplinario para establecer un programa acelerado de desarrollo de antibióticos neonatales. Este programa permitiría centrar la investigación en los antibióticos prioritarios identificados para los recién nacidos con el fin de reducir el exceso de morbilidad y mortalidad causado por las infecciones MR en esta población vulnerable.

A Nonprofit Drug Development Model Is Part of the Antimicrobial Resistance (AMR) Solution.

Antibiotics underpin modern medicine and are critical for pandemic preparedness. Push funding has revitalized the preclinical antimicrobial resistance (AMR) pipeline and government funding via CARB-X and BARDA, as well as private sector-led investment via the AMR Action Fund, will help several new antibiotics obtain regulatory approval. Nevertheless, revenues generated by new antibiotics are not considered sufficiently profitable by commercial developers to address unmet need. The question remains: Who could viably fund development and secure global equitable access for new antibiotics? Public health need should be the primary driver for antibiotic development. Improved prioritization and government oversight by funders who allocate public resources are a needed first step. In this framework, nonprofit research and development organizations, with support from public funders, and unconstrained by commercial profitability requirements are well positioned to work with public and private actors to viably provide new antibiotics to all in need.

Shortage of essential antimicrobials: a major challenge to global health security.

The lack of access to safe and effective antimicrobials for human populations is a threat to global health security and a contributor to the emergence and spread of antimicrobial resistance (AMR). The increasingly common shortages of antimicrobials are an additional threat to the emergence of AMR. While the threat of such drug shortages is most acutely experienced in low-income and middle-income settings, their consequences impact the quality and effectiveness of antimicrobials worldwide. Furthermore, there is a need for robustly conducted studies examining the impact of these increasingly prevalent shortages on patient outcomes and on the emergence and spread of AMR. In this review, we have mapped common drivers for antimicrobial shortages and propose strategies for rethinking the regulation, supply and pricing of antimicrobials to secure their sustainable access across diverse healthcare systems and to help minimise the unintended consequences of weak and ineffective supply chains. Greater government involvement in antimicrobial manufacture and supply is essential to ensure no one is left behind. Dedicated demand systems need to be developed for antimicrobials which take into consideration evolving AMR patterns, burden of diseases, pandemic events and supply and demand issues and facilitate implementation of strategies to address them. Interventions, ranging from advocacy and forecasting to public-private collaborations, new economic models and international consortia working across countries and supply chains, will help assure access to safe and effective antimicrobials to all populations around the globe and ensure that shortages no longer contribute to AMR.

Optimising antimicrobial use in humans - review of current evidence and an interdisciplinary consensus on key priorities for research.

Addressing the silent pandemic of antimicrobial resistance (AMR) is a focus of the 2021 G7 meeting. A major driver of AMR and poor clinical outcomes is suboptimal antimicrobial use. Current research in AMR is inequitably focused on new drug development. To achieve antimicrobial security we need to balance AMR research efforts between development of new agents and strategies to preserve the efficacy and maximise effectiveness of existing agents. Combining a review of current evidence and multistage engagement with diverse international stakeholders (including those in healthcare, public health, research, patient advocacy and policy) we identified research priorities for optimising antimicrobial use in humans across four broad themes: policy and strategic planning; medicines management and prescribing systems; technology to optimise prescribing; and context, culture and behaviours. Sustainable progress depends on: developing economic and contextually appropriate interventions; facilitating better use of data and prescribing systems across healthcare settings; supporting appropriate and scalable technological innovation. Implementing this strategy for AMR research on the optimisation of antimicrobial use in humans could contribute to equitable global health security.

Learning from COVID-19 to Tackle Antibiotic Resistance.

COVID-19 has brought into sharp focus the failure of not preventing and preparing for pandemics. As the world reels from the tragedy and economic fallout of COVID-19, there are vital lessons to learn and apply in the fight against drug resistance. The unchecked growth of drug-resistant infections is a silent pandemic with long-term implications for global public health and the global economy. Now more than ever, governments have the opportunity to make robust and comprehensive investments into the way they prepare and respond to antibiotic resistance. This could cascade into lasting and long-term benefits for people and countries.

The Global Antibiotic Research and Development Partnership (GARDP) Not-for-Profit Model of Antibiotic Development.

The Global Antibiotic Research and Development Partnership (GARDP) brings together public and private partners to accelerate the development and global availability of new antibiotics to treat the most challenging drug-resistant bacterial infections. Established in 2016, GARDP's recently launched strategy sets out its ambitious aim to deliver five new treatments by 2025, focusing on sexually transmitted infections, sepsis in newborns, and infections in hospitalized adults and children.

Antimicrobial resistance - moving forward?

BACKGROUND: When microorganisms (such as bacteria or viruses) are highly exposed to antimicrobial drugs, they can develop the capacity to defeat the drugs designed to eradicate them. Long-term accumulation of adaptations to survive drug exposure can lead to the development of antimicrobial resistance (AMR). The success of antibiotics has led to their widespread overuse and misuse in humans, animals and plants. MAIN TEXT: AMR is a global concern and solutions are not vertical actions in a single buy business model. Even if a transectoral approach is key, there is a lack of multi-disciplinary partnerships that allow for strategic cooperation between different sectors such as the pharmaceutical industry, agro-alimentary complex, patient care and education, NGOs and research and development. Global public health voices should lead this integration to align the progress of existing AMR successes. Maintaining the public's trust in preventive medicine, health systems and food production safety, together with public health driven, non-profit drug development, is a key factor. In its "Call for integrated action on AMR", signed by about 70 national and international organizations the World Federation of Public Health Associations (WFPHA) called "on all governments, the private sector, non-governmental organizations, health professionals, public and private research organizations, and all stakeholders to ensure that public health remains at the centre of all policy and scientific endeavours in the field of antimicrobial resistance". CONCLUSIONS: The "Global Charter for the Public's Health", developed by the WFPHA in association with WHO, is proposed in this article as a tool for implementation of complex public health actions such as AMR.

Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India.

BACKGROUND: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions. METHODS: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891. RESULTS: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related. CONCLUSION: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India. TRIAL REGISTRATION: Clinical trial is registered at Clinical trial registry of India (CTRI/2012/08/002891, Registered on 16/08/2012, Trial Registered Prospectively).

Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study.

BACKGROUND: Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. OBJECTIVES: To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. METHODS: Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. RESULTS: A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (-74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy). CONCLUSIONS: Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.