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)

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

Surface Properties of Polymer Resins Fabricated with Subtractive and Additive Manufacturing Techniques

This study aimed to compare the surface roughness, hardness, and flexure strength of interim indirect resin restorations fabricated with CAD-CAM (CC), 3D printing (3D), and conventional techniques (CV). Twenty disk (3 mm × Ø10 mm) and ten bar specimens (25 × 2 × 2 mm) were fabricated for the CC, 3D, and CV groups, to be used for surface roughness, micro-hardness, and flexural strength testing using standardized protocol. Three indentations for Vickers micro-hardness (VHN) were performed on each disk and an average was identified for each specimen. Surface micro-roughness (Ra) was calculated in micrometers (μm) using a 3D optical non-contact surface microscope. A three-point bending test with a universal testing machine was utilized for assessing flexural strength. The load was applied at a crosshead speed of 3 mm/min over a distance of 25 mm until fracture. Means and standard deviations were compared using ANOVA and post hoc Tukey–Kramer tests, and a p-value of ≤0.05 was considered statistically significant. Ra was significantly different among the study groups (p < 0.05). Surface roughness among the CC and CV groups was statistically comparable (p > 0.05). However, 3D showed significantly higher Ra compared to CC and CV samples (p < 0.05). Micro-hardness was significantly higher in 3D samples (p < 0.05) compared to CC and CV specimens. In addition, CC and CV showed comparable micro-hardness (p > 0.05). A significant difference in flexural strength was observed among the study groups (p < 0.05). CC and 3D showed comparable strength outcomes (p > 0.05), although CV specimens showed significantly lower (p < 0.05) strength compared to CC and 3D samples. The 3D-printed provisional restorative resins showed flexural strength and micro-hardness comparable to CAD-CAM fabricated specimens, and surface micro-roughness for printed specimens was considerably higher compared to CAD-CAM and conventional fabrication techniques