Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA.

The immunologic consequences of using bactericidal versus bacteriostatic antibiotic treatments are unclear. We observed a bacteriostatic (growth halting) treatment was more protective than a bactericidal (bacteria killing) treatment in a murine peritonitis model. To understand this unexpected difference, we compared macrophage responses to bactericidal treated bacteria or bacteriostatic treated bacteria.

Adjunctive linezolid versus clindamycin for toxin inhibition in β-lactam-treated patients with invasive group A streptococcal infections in 195 US hospitals from 2016 to 2021: a retrospective cohort study with target trial emulation.

Background: Adjunctive clindamycin use is associated with survival in invasive group A streptococcus (GAS) infections but increasing clindamycin resistance in GAS has called into question its durability for this indication. Linezolid also inhibits GAS toxin and virulence factor production, but clinical efficacy data remain sparse.

Methods: We retrospectively emulated a target multicentre, non-blinded, non-inferiority trial to assess the efficacy of adjunctive linezolid compared with clindamycin in adult inpatients with invasive GAS infection treated with a β-lactam using the PINC AI database between 2016 and 2021.

Efflux pump-mediated resistance to new beta lactam antibiotics in multidrug-resistant gram-negative bacteria.

The emergence and spread of bacteria resistant to commonly used antibiotics poses a critical threat to modern medical practice. Multiple classes of bacterial efflux pump systems play various roles in antibiotic resistance, and members of the resistance-nodulation-division (RND) transporter superfamily are among the most important determinants of efflux-mediated resistance in gram-negative bacteria. RND pumps demonstrate broad substrate specificities, facilitating extrusion of multiple chemical classes of antibiotics from the bacterial cell.

Bacterial Genomics for National Antimicrobial Resistance Surveillance in Cambodia.

Background: Antimicrobial resistance (AMR) surveillance in low- and middle-income countries (LMICs) often relies on poorly resourced laboratory processes. Centralized sequencing was combined with cloud-based, open-source bioinformatics solutions for national AMR surveillance in Cambodia.

Methods: Blood cultures growing gram-negative bacteria were collected at six Cambodian hospitals (January 2021 - October 2022).

Regional centromere configuration in the fungal pathogens of the genus.

Centromeres are constricted chromosomal regions that are essential for cell division. In eukaryotes, centromeres display a remarkable architectural and genetic diversity. The basis of centromere-accelerated evolution remains elusive.

Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection.

Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity.

The Host Adapted Fungal Pathogens of Genus Utilize Genic Regional Centromeres.

Centromeres are genomic regions that coordinate accurate chromosomal segregation during mitosis and meiosis. Yet, despite their essential function, centromeres evolve rapidly across eukaryotes. Centromeres are often the sites of chromosomal breaks which contribute to genome shuffling and promote speciation by inhibiting gene flow.

Association between minimum inhibitory concentration values and mortality risk in patients with infections: a retrospective cohort study of electronic health records from 148 US hospitals.

Background: Clinical data informing antimicrobial susceptibility breakpoints for infections are lacking. We sought to leverage real-world data to identify MIC values within the currently defined susceptible range that could discriminate mortality risk for patients with infections and guide future breakpoint revisions.

Methods: Inpatients with infection who received single-agent targeted therapy with levofloxacin or trimethoprim/sulfamethoxazole were identified in the Cerner HealthFacts electronic health record database.

Association between piperacillin/tazobactam MIC and survival among hospitalized patients with Enterobacterales infections: retrospective cohort analysis of electronic health records from 161 US hospitals.

Introduction: A recent randomized trial has suggested an increased risk of mortality for ceftriaxone-non-susceptible Enterobacterales infections treated with piperacillin/tazobactam compared with meropenem despite MICs within the susceptible range.

Methods: We conducted a retrospective cohort study of clinical encounters within the Cerner Health Facts database to identify all encounters between 2001 and 2017 in which Enterobacterales infections were treated empirically with piperacillin/tazobactam and for which MICs to the drug were available. Multivariate regression analysis was performed to enable partitioning of MICs into discrete strata based on statistically significant difference in mortality risk.

Comparative Evaluation of Current Biochemical-, Sequencing-, and Proteomic-Based Identification Methods for the Streptococcus bovis Group.

The Streptococcus bovis group (previously group D streptococci) consists of seven distinct species and subspecies. Definitive identification within the group is important, as certain organisms have been associated with gastrointestinal carcinoma, bacteremia, infective endocarditis, meningitis, biliary tract disease, and carcinoma, among others. Definitive identification, however, remains elusive due to limitations and inconsistencies across commonly used identification platforms in the United States.

Hypermutator strains of Pseudomonas aeruginosa reveal novel pathways of resistance to combinations of cephalosporin antibiotics and beta-lactamase inhibitors.

Hypermutation due to DNA mismatch repair (MMR) deficiencies can accelerate the development of antibiotic resistance in Pseudomonas aeruginosa. Whether hypermutators generate resistance through predominantly similar molecular mechanisms to wild-type (WT) strains is not fully understood. Here, we show that MMR-deficient P.

Disseminated Infection in Patients With Phosphoinositide-3-Kinase Regulatory Subunit 1 Mutations.

is a rare cause of invasive infection in immunodeficient hosts. Phosphatidylinositol 3-kinase, regulatory subunit 1 () mutations predispose patients to sinopulmonary infections, alongside bronchiectasis autoimmunity and lymphoproliferation. We report 2 cases of deficiency with invasive and effective treatment options.

Trimethoprim-Sulfamethoxazole Versus Levofloxacin for Infections: A Retrospective Comparative Effectiveness Study of Electronic Health Records from 154 US Hospitals.

Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is considered first-line therapy for infections based on observational data from small studies. Levofloxacin has emerged as a popular alternative due to tolerability concerns related to TMP-SMX. Data comparing levofloxacin to TMP-SMX as targeted therapy are lacking.

In vivo evolution of an emerging zoonotic bacterial pathogen in an immunocompromised human host.

Zoonotic transfer of animal pathogens to human hosts can generate novel agents, but the genetic events following such host jumps are not well studied. Here we characterize the mechanisms driving adaptive evolution of the emerging zoonotic pathogen Bordetella hinzii in a patient with interleukin-12 receptor β1 deficiency. Genomic sequencing of 24 B.

Association Between Caseload Surge and COVID-19 Survival in 558 U.S. Hospitals, March to August 2020.

Background: Several U.S. hospitals had surges in COVID-19 caseload, but their effect on COVID-19 survival rates remains unclear, especially independent of temporal changes in survival.

Manual Reading of Sensititre Broth Microdilution System Panels Improves Accuracy of Susceptibility Reporting for Polymyxin Antibiotics.

Accurate and reproducible antimicrobial susceptibility testing (AST) of polymyxin antibiotics is critical, as these drugs are last-line therapeutic options for the treatment of multidrug-resistant Gram-negative bacterial infections. However, polymyxin AST in the routine laboratory remains challenging. In this study, we evaluated the performance of an automated broth microdilution (BMD) system (Sensititre, ThermoFisher) compared to that of agar dilution (AD) for colistin and polymyxin B AST of 129 , Pseudomonas aeruginosa, and Acinetobacter baumannii complex clinical isolates.

Disseminated Mycobacterium marinum in Human Immunodeficiency Virus Unmasked by Immune Reconstitution Inflammatory Syndrome.

Distinguishing disseminated Mycobacterium marinum from multifocal cutaneous disease in persons with human immunodeficiency virus/AIDS can present a diagnostic challenge, especially in the context of immune reconstitution inflammatory syndrome (IRIS). In this work, we demonstrate the utility of flow cytometry and whole genome sequencing (WGS) to diagnose disseminated M. marinum unmasked by IRIS following initiation of antiretroviral therapy.

Effectiveness of adjunctive clindamycin in β-lactam antibiotic-treated patients with invasive β-haemolytic streptococcal infections in US hospitals: a retrospective multicentre cohort study.

Background: Clindamycin is strongly recommended as an adjunctive treatment to β-lactam antibiotics in patients with severe invasive group A β-haemolytic streptococcal (iGAS) infections. However, there is little evidence of a benefit in the use of clindamycin in humans, and its role, if any, in treating patients with invasive non-group A/B β-haemolytic streptococcal (iNABS) infections is unclear.

Methods: For this retrospective multicentre cohort study, we used a dataset from patients in the Cerner Health Facts database, which contains electronic health-based data from 233 US hospitals.

Inappropriate empirical antibiotic therapy for bloodstream infections based on discordant in-vitro susceptibilities: a retrospective cohort analysis of prevalence, predictors, and mortality risk in US hospitals.

Background: The prevalence and effects of inappropriate empirical antibiotic therapy for bloodstream infections are unclear. We aimed to establish the population-level burden, predictors, and mortality risk of in-vitro susceptibility-discordant empirical antibiotic therapy among patients with bloodstream infections.

Methods: Our retrospective cohort analysis of electronic health record data from 131 hospitals in the USA included patients with suspected-and subsequently confirmed-bloodstream infections who were treated empirically with systemic antibiotics between Jan 1, 2005, and Dec 31, 2014.

ACKR1 Alleles at 5.6 kb in a Well-Characterized Renewable US Food and Drug Administration (FDA) Reference Panel for Standardization of Blood Group Genotyping.

The glycoprotein encoded by the ACKR1 gene expresses the Duffy blood group antigens and is a receptor for malaria parasites. We recently described 18 long-range ACKR1 alleles in an autochthonous population of a malaria endemic region. Extending this work, we sequenced the gene in a 53-sample repository established by the US Food and Drug Administration (FDA) as reference reagents for blood group genotyping.