Population pharmacokinetics of flucloxacillin as intermittent bolus infusion in patients with Staphylococcus aureus bloodstream infection.

BACKGROUND: Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients. OBJECTIVES: To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens. METHODS: Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling. RESULTS: Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin. CONCLUSIONS: By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial.

Whole genome-based antimicrobial resistance, virulence, and phylogenetic characteristics of Trueperella pyogenes clinical isolates from humans and animals.

Trueperella pyogenes is an opportunistic zoonotic bacterial pathogen, whose antimicrobial resistance, virulence, and genetic relatedness between strains from animals and humans are barely studied. These characteristics were therefore analyzed for clinical T. pyogenes strains from 31 animals of 11 different species and 8 humans determining their complete circular genome sequence and antimicrobial susceptibility. The MICs of 19 antimicrobials including 3 antiseptics correlated to the resistance genes identified in silico within the genomes revealing a predominance of resistance to streptomycin (aadA9), sulfamethoxazole (sul1), and tetracycline (tet(33), tet(W/N/W)) among strains from humans and cattle. Additional resistance genes (erm(X), erm(56), cmx, drfA1, aadA1, aph(3'')-Ib (strA), aph(6)-Id (strB), aac(3)-IVa, aph(4)-Ia) were found only sporadically. The resistance genes were localized on genetic elements integrated into the chromosome. A cgMLST-based phylogenetic analysis revealed two major clusters each containing genetically diverse strains. The human strains showed the closest relatedness to strains from cattle. Virulence genes coding for fimbriae (fimA, fimC), neuroamidase (nanP, nanH), pyolysin (plo), and collagen binding protein (cbpA) were identified in strains from different hosts, but no correlation was observed between virulence factors and strain origin. The existence of resistance genes typically found in Gram-negative bacteria within the Gram-positive T. pyogenes indicates a wider capacity to adapt to antimicrobial selective pressure. Moreover, the presence of similar antimicrobial resistance profiles found in cattle and human strains as well as their closest relatedness suggests common zoonotic features and cattle as the potential source for human infections.

How do I manage refractory invasive pulmonary aspergillosis.

BACKGROUND: Invasive aspergillosis is associated with significant morbidity and mortality in patients with haematologic malignancies and haematopoietic cell transplant recipients. The prognosis is worse among patients who have failed primary antifungal treatment. OBJECTIVES: We aim to provide guidance on the diagnosis and management of refractory invasive pulmonary aspergillosis. SOURCES: Using PubMed, we performed a review of original articles, meta-analyses, and systematic reviews. CONTENT: We discuss the diagnostic criteria for invasive pulmonary aspergillosis and the evidence on the treatment of primary infection. We outline our diagnostic approach to refractory disease. We propose a treatment algorithm for refractory disease and discuss the role of experimental antifungal agents. IMPLICATIONS: For patients with worsening disease while on antifungal therapy, a thorough diagnostic evaluation is required to confirm the diagnosis of aspergillosis and exclude another concomitant infection. Treatment should be individualized. Current options include switching to another triazole, transitioning to a lipid formulation of amphotericin B, or using combination antifungal therapy.

What is the agreement between principles and practice of antibiotic stewardship in the management of diabetic foot infection: an in-hospital quality control study.

Introduction: Standardization of diagnostic and treatment concepts in diabetes-related foot infection (DFI) is challenging. In 2019, specific recommendations regarding diagnostic principles and antibiotic therapy (ABT) for DFI, including the one for osteomyelitis (DFO), were introduced in our institution. In this study, we assessed the adherence to these in-house guidelines 2 years after their implementation. Methods: Adult patients with DFI with and without DFO who underwent surgical intervention between 2019 and 2021 were included. Patients' charts were retrospectively reviewed. Accordance to recommendations regarding biopsy sampling, labeling, requesting microbiological and histopathological examinations, and treatment duration were assessed. Results: A total of 80 patients with 117 hospital episodes and 163 surgical interventions were included; 84.6 % required an amputation. Patients with HbA1c levels of < 6.5  % more often required a revision during the same hospitalization than those with HbA1c levels of ≥ 6.5  % (29.4 % vs. 12.1 %, respectively, p = 0.023 ). Specimens were obtained in 71.8 % of operations and sent for histological examination in 63.2 %. The mean duration of ABT was 9 (interquartile range (IQR) 5-15) d in macroscopically surgically cured episodes and 40.5 (IQR 15-42) d in cases with resection margins in non-healthy bone ( p < 0.0001 ). Treatment duration results were similar when using histological results: 13 (IQR 8-42) d for healthy bone vs. 29 (IQR 13-42) d for resection margins consistent with osteomyelitis ( p = 0.026 ). Conclusion: The adherence to recommendations in terms of biopsy sampling was good, moderate for histopathological analysis and poor for labeling the anatomic location. Adherence to recommendations for ABT duration was good, but further shortening of treatment duration for surgically cured cases is necessary.

Optimal antibiotics duration following surgical management of septic olecranon bursitis: a 12-year retrospective analysis.

Introduction: The absence of a standardized postoperative antibiotic treatment approach for patients with surgically treated septic bursitis results in disparate practices. Methods: We retrospectively reviewed charts of adult patients with surgically treated septic olecranon bursitis at Mayo Clinic sites between 1 January 2000 and 20 August 2022, focusing on their clinical presentation, diagnostics, management, postoperative antibiotic use, and outcomes. Results: A total of 91 surgically treated patients were identified during the study period. Staphylococcus aureus was the most common pathogen (64 %). Following surgery, 92 % (84 of 91 patients) received systemic antibiotics. Excluding initial presentations of bacteremia or osteomyelitis (n=5), the median duration of postoperative antibiotics was 21 d (interquartile range, IQR: 14-29). Postoperative complications were observed in 23 % (21 of 91) of patients, while cure was achieved in 87 % (79 of 91). Active smokers had 4.53 times greater odds of clinical failure compared with nonsmokers (95 % confidence interval, 95 % CI: 1.04-20.50; p=0.026). The highest odds of clinical failure were noted in cases without postoperative antibiotic administration (odds ratio, OR: 7.4). Conversely, each additional day of antibiotic treatment, up to 21 d, was associated with a progressive decrease in the odds of clinical failure (OR: 1 at 21 d). Conclusion: The optimal duration of antibiotics postoperatively in this study was 21 d, which was associated with a 7.4-fold reduction in the odds clinical failure compared with cases without postoperative antibiotics. Further validation through a randomized controlled trial is needed.