Determining sample size in a personalized randomized controlled (PRACTical) trial.

In clinical settings with no commonly accepted standard-of-care, multiple treatment regimens are potentially useful, but some treatments may not be appropriate for some patients. A personalized randomized controlled trial (PRACTical) design has been proposed for this setting. For a network of treatments, each patient is randomized only among treatments which are appropriate for them.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs.

Estimating the impact of test-trace-isolate-quarantine systems on SARS-CoV-2 transmission in Australia.

Background: Australian states and territories used test-trace-isolate-quarantine (TTIQ) systems extensively in their response to the COVID-19 pandemic in 2020-2021. We report on an analysis of Australian case data to estimate the impact of test-trace-isolate-quarantine systems on SARS-CoV-2 transmission.

Methods: Our analysis uses a novel mathematical modelling framework and detailed surveillance data on COVID-19 cases including dates of infection and dates of isolation.

Safety and efficacy of whole-body chlorhexidine gluconate cleansing with or without emollient in hospitalised neonates (NeoCHG): a multicentre, randomised, open-label, factorial pilot trial.

Background: Healthcare-associated infections account for substantial neonatal in-hospital mortality. Chlorhexidine gluconate (CHG) whole body skin application could reduce sepsis by lowering bacterial colonisation density, although safety and optimal application regimen is unclear. Emollients, including sunflower oil, may independently improve skin condition, thereby reducing sepsis.

Practices and challenges related to antibiotic use in paediatric treatment in hospitals and health centres in Niger and Uganda: a mixed methods study.

Background: Antibiotic resistance is a significant public health problem and is responsible for high mortality in children and new-borns. Strengthening the rational use of antibiotics and improving the quality and access to existing antibiotics are important factors in the fight against antibiotic resistance. This study aims to provide knowledge on the use of antibiotics in children in resource-limited countries in order to identify problems and possible avenues for improvement of antibiotics use.

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).

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis.

Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs).

Emergent Omicron BR.2.1 sublineage of SARS-CoV-2 in New South Wales, Australia: a subvariant with high fitness but without increased disease severity.

Objectives: To describe the epidemiology and impact of Omicron BR.2.1, an emergent SARS-CoV-2 Omicron BA.

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.

Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings.

Background: Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum β-lactam (e.g.

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

Background: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin.

Objectives: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings.

Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis.

Objectives: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.

Methods: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards.

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload.

Objective: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.

Design: A single-centre open-label randomised controlled trial.

Setting: Kilifi County Hospital, Kenya.

Potential Antibiotics for the Treatment of Neonatal Sepsis Caused by Multidrug-Resistant Bacteria.

Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low- and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gentamicin. The Global Antibiotic Research and Development Partnership is aiming to develop alternative empiric antibiotic regimens that fulfil several criteria: (1) affordable in LMIC settings; (2) activity against neonatal bacterial pathogens, including extended-spectrum β-lactamase producers, gentamicin-resistant Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (MRSA); (3) a licence for neonatal use or extensive experience of use in neonates; and (4) minimal toxicities.

The role of combination therapy in the treatment of severe infections caused by carbapenem resistant gram-negatives: a systematic review of clinical studies.

Background: Effective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking.

Global antibiotic dosing strategies in hospitalised children: Characterising variation and implications for harmonisation of international guidelines.

Background: Paediatric global antibiotic guidelines are inconsistent, most likely due to the limited pharmacokinetic and efficacy data in this population. We investigated factors underlying variation in antibiotic dosing using data from five global point prevalence surveys.

Methods & Findings: Data from 3,367 doses of the 16 most frequent intravenous antibiotics administered to children 1 month-12 years across 23 countries were analysed.

Clinical management of severe infections caused by carbapenem-resistant gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations.

Objectives: Optimal treatment of carbapenem-resistant Gram-negative bacteria (CR-GNB) infections is uncertain because of the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide.

Methods: A 36-item questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum β-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e.

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no.

IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis.

Background: Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.

Objectives: To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data.

Global sales of oral antibiotics formulated for children.

Objective: To investigate international consumption patterns of child-appropriate oral formulations of antibiotics by formulation type, with a focus on dispersible tablets, using data from a global sales database.

Method: Antibiotic sales data for 2015 covering 74 countries and regional country groups were obtained from the MIDAS pharmaceutical sales database, which includes samples of pharmacy wholesalers and retailers. The focus was on sales of child-appropriate oral formulations of Access antibiotics in the 2017 World Health Organization's .

In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol.

Objective: There is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR , and Enterobacteriaceae and provide an unbiased overview of existing knowledge.

A comparison of five paediatric dosing guidelines for antibiotics.

Objective: To compare dosing guidance in the paediatric formularies of high- and middle-income countries for 32 commonly prescribed antibiotics on the World Health Organization's (WHO's) 2017

Methods: We identified paediatric antibiotic guidelines that were either widely used internationally or originated from countries in which antibiotic use has increased markedly in recent years (i.e. Brazil, China, India, the Russian Federation and South Africa).