Background: Brain abscess is an uncommon condition, but carries high mortality. Current treatment guidelines are based on limited data. Surveillance of clinical, radiological and microbiology data is important to inform patient stratification, interventions, and antimicrobial stewardship. Methods: We undertook a retrospective, observational study of patients with brain abscess, based on hospital coding, in a UK tertiary referral teaching hospital. We reviewed imaging data, laboratory microbiology, and antibiotic prescriptions. Results: Over a 47 month period, we identified 47 adults with bacterial brain abscess (77% male, median age 47 years). Most of the abscesses were solitary frontal or parietal lesions. A microbiological diagnosis was secured in 39/47 (83%) of cases, among which the majority were of the Streptococcus milleri group (27/39; 69%), with a predominance of Streptococcus intermedius (19/27; 70%). Patients received a median of 6 weeks of intravenous antibiotics (most commonly ceftriaxone), with variable oral follow-on regimens. Ten patients (21%) died, up to 146 days after diagnosis. Mortality was significantly associated with increasing age, multiple abscesses, immunosuppression and the presence of an underlying cardiac anomaly. Conclusion: Our data suggest that there has been a shift away from staphylococcal brain abscesses, towards S. intermedius as a dominant pathogen. In our setting, empiric current first line therapy with ceftriaxone remains appropriate on microbiological grounds and narrower spectrum therapy may sometimes be justified. Mortality of this condition remains high among patients with comorbidity. Prospective studies are required to inform optimum dose, route and duration of antimicrobial therapy.

Antimicrobial resistance (particularly by extended spectrum β-lactamase and aminoglycoside modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, causing significant mortality. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis; ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16 arm dose ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented emergence of resistance compared to monotherapy of either antibiotic. Modelling of the experimental quantitative outputs and data from checkerboard assays, indicated synergy. We further assessed the combination regimen at clinically relevant doses in HFIM with nine Enterobacterales strains with high fosfomycin/amikacin MICs and demonstrated successful kill to sterilisation in 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales - MIC F * MIC A < 256 (where MIC F and MIC A are MICs for fosfomycin and amikacin). Monte Carlo simulations predict that a standard fosfomycin/amikacin neonatal regimen will achieve a >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empiric treatment of neonatal sepsis and is suitable for further clinical assessment in a randomised controlled trial.

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 extendedspectrum 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. In this review, we identify five antibiotics that fulfil these criteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime. We describe the available characteristics of each in terms of mechanism of action, resistance mechanisms, clinical pharmacokinetics, pharmacodynamics, and toxicity profile. We also identify some knowledge gaps: (1) the neonatal pharmacokinetics of cefepime is reliant on relatively small and limited datasets, and the pharmacokinetics of flomoxef are also reliant on data from a limited demographic range and (2) for all reviewed agents, the pharmacodynamic index and target has not been definitively established for both bactericidal effect and emergence of resistance, with many assumed to have an identical index/ target to similar class molecules. These five agents have the potential to be used in novel combination empiric regimens for neonatal sepsis. However, the data gaps need addressing by pharmacokinetic trials and pharmacodynamic characterisation. Key PointsAmikacin, tobramycin, fosfomycin, flomoxef, and cefepime are five safe and off-patent antibiotics with experience of use in neonates that can be potentially used as empiric treatment of neonatal sepsis in low-and middle-income settings where antimicrobial resistance complicates current standard-of-care regimens.The neonatal pharmacokinetics are well characterised for most, with cefepime and flomoxef needing some additional data.