Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy.

OBJECTIVE: To provide updates on the epidemiology and recommendations for management of candidemia in patients with critical illness. DATA SOURCES: A literature search using the PubMed database (inception to March 2023) was conducted using the search terms "invasive candidiasis," "candidemia," "critically ill," "azoles," "echinocandin," "antifungal agents," "rapid diagnostics," "antifungal susceptibility testing," "therapeutic drug monitoring," "antifungal dosing," "persistent candidemia," and "Candida biofilm." STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Ongoing trials were identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 109 articles were reviewed including 25 pharmacokinetic/pharmacodynamic studies and 30 studies including patient data, 13 of which were randomized controlled clinical trials. The remaining 54 articles included fungal surveillance data, in vitro studies, review articles, and survey data. The current 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Management of Candidiasis provides recommendations for selecting empiric and definitive antifungal therapies for candidemia, but data are limited regarding optimized dosing strategies in critically ill patients with dynamic pharmacokinetic changes or persistent candidemia complicated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Outcomes due to candidemia remain poor despite improved diagnostic platforms, antifungal susceptibility testing, and antifungal therapy selection for candidemia in critically ill patients. Earlier detection and identification of the species causing candidemia combined with recognition of patient-specific factors leading to dosing discrepancies are crucial to improving outcomes in critically ill patients with candidemia. CONCLUSIONS: Treatment of candidemia in critically ill patients must account for the incidence of non-albicans Candida species and trends in antifungal resistance as well as overcome the complex pathophysiologic changes to avoid suboptimal antifungal exposure.

Therapeutic Options for Adult Patients With Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Narrative Review.

OBJECTIVE: To compare the efficacy of antimicrobial therapies used in the management of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. DATA SOURCES: A literature search using the PubMed database (inception to December 2022) was conducted using the search terms "Staphylococcus aureus bacteremia," "methicillin-susceptible Staphylococcus aureus bacteremia," "persistent methicillin-susceptible Staphylococcus aureus bacteremia," and "refractory methicillin-susceptible Staphylococcus aureus bacteremia ." In addition, therapeutic agents which could be used as treatment for MSSA including "nafcillin," "oxacillin," "cefazolin," "ceftaroline," "gentamicin," "rifampin," and "daptomycin" were also combined with the aforementioned search terms to capture data using these agents. STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Articles and abstracts were considered for inclusion in addition to ongoing trials identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 78 articles were reviewed including 17 in vitro or animal model studies and 39 studies including patient data. The remaining 22 articles included guidelines, review articles, and editorials. Recent data evaluating use of dual ß-lactam regimens for persistent MSSA bacteremia were limited to 8 case reports or case series. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: At present, there is little guidance on how to best manage patients with persistent MSSA bacteremia. This narrative review collates the available data to assist clinicians in selecting the best possible antimicrobial regimen when facing this clinical conundrum. CONCLUSIONS: Modification of antimicrobial therapy, in conjunction with source control and infectious diseases consultation, may all be necessary to sterilize blood cultures in patients with persistent MSSA bacteremia.

The Oddity Detection in Diverse Scenes (ODDS) database: Validated real-world scenes for studying anomaly detection.

Many applied screening tasks (e.g., medical image or baggage screening) involve challenging searches for which standard laboratory search is rarely equivalent. For example, whereas laboratory search frequently requires observers to look for precisely defined targets among isolated, non-overlapping images randomly arrayed on clean backgrounds, medical images present unspecified targets in noisy, yet spatially regular scenes. Those unspecified targets are typically oddities, elements that do not belong. To develop a closer laboratory analogue to this, we created a database of scenes containing subtle, ill-specified "oddity" targets. These scenes have similar perceptual densities and spatial regularities to those found in expert search tasks, and each includes 16 variants of the unedited scene wherein an oddity (a subtle deformation of the scene) is hidden. In Experiment 1, eight volunteers searched thousands of scene variants for an oddity. Regardless of their search accuracy, they were then shown the highlighted anomaly and rated its subtlety. Subtlety ratings reliably predicted search performance (accuracy and response times) and did so better than image statistics. In Experiment 2, we conducted a conceptual replication in which a larger group of naïve searchers scanned subsets of the scene variants. Prior subtlety ratings reliably predicted search outcomes. Whereas medical image targets are difficult for naïve searchers to detect, our database contains thousands of interior and exterior scenes that vary in difficulty, but are nevertheless searchable by novices. In this way, the stimuli will be useful for studying visual search as it typically occurs in expert domains: Ill-specified search for anomalies in noisy displays.

Evaluation of Ceftazidime Use in the Neonatal Intensive Care Unit and Association With Cephalosporin-Resistant Gram-Negative Bacteria.

BACKGROUND: Cefotaxime shortage in 2015 led to increased ceftazidime use in the neonatal intensive care unit (NICU). OBJECTIVE: The purpose was to explore whether ceftazidime increases risk for development of resistant gram-negative organisms. METHODS: Retrospective evaluation of NICU patients with cultures positive for Escherichia coli, Pseudomonas aeruginosa, Klebsiella species, or Stenotrophomonas maltophilia between January1, 2015 and August 31, 2020. Isolates were excluded if obtained from same patient and source within 90 days or if patient ≤7 days of life or admitted from a referring hospital. Data collection included demographics and clinical parameters, and culture/susceptibility data. The primary objective was comparison of pathogens and clinical parameters in those with and without third-generation cephalosporin resistance. The secondary objectives included a comparison between those with and without ceftazidime exposure and identification of factors associated with resistance. Comparisons were made using χ2, Fisher exact tests, or Wilcoxon tests. A logistic regression was used to identify risk factors for resistance. RESULTS: Overall, 349 isolates, representing 215 patients, were included. The most common source was endotracheal (n = 192, 55.0%) and pathogens were E coli (31.8%) and P aeruginosa (29.2%). Overall, 12.3% (n = 43) were resistant and these were obtained after longer parenteral nutrition (PN), central line access, and antibiotic days versus susceptible isolates. Higher resistance was noted after ceftazidime exposure versus no exposure, 19.1% versus 6.6%. Each day of ceftazidime was associated with 13% greater odds of P aeruginosa resistance (adjusted odds ratio: 1.13 [95% confidence interval: 1.03-1.23]). CONCLUSION AND RELEVANCE: Ceftazidime duration was associated with increased risk for P aeruginosa resistance. Additional studies are needed to confirm these findings.

Social Network and Behavioral Synchrony Influences On Maternal and Infant Cortisol Response.

This study examined the contributions of mothers' social network stability and mother-infant behavioral synchrony on cortisol response in infants and their mothers during separation. The quality and stability of mothers' social network system and mother-infant bond have both been shown to affect infant neuroendocrine response. Yet, no studies have directly addressed how these two forms of social relationships might differentially affect infants' and mothers' neuroendocrine responses during separation. First-time mothers (N = 133) and their 3-month-old infants participated in the study. Maternal social network stability, mother-infant behavioral synchrony, and mother and infant cortisol response during an infant challenge task were assessed. Behavioral synchrony accounted for significant variance in infants' cortisol response, and after adjusting for synchrony, mothers' network stability measures did not explain variance in infant cortisol. Social network stability, but not synchrony, accounted for significant variance in mothers' cortisol response. These results demonstrate that, when mothers and infants experience brief separation, the quality of their bond is associated with a lower stress response for infants; but for mothers, it is the longevity of her social relationships outside of the mother-infant relationship context that is associated with her lower stress response.

Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain.

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain often with comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. We identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of gastrointestinal (GI) microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.

The spatial arrangement method of measuring similarity can capture high-dimensional semantic structures.

Psychologists collect similarity data to study a variety of phenomena including categorization, generalization and discrimination, and representation itself. However, collecting similarity judgments between all pairs of items in a set is expensive, spurring development of techniques like the Spatial Arrangement Method (SpAM; Goldstone, Behavior Research Methods, Instruments, & Computers, 26, 381-386, 1994), wherein participants place items on a two-dimensional plane such that proximity reflects perceived similarity. While SpAM greatly hastens similarity measurement, and has been successfully used for lower-dimensional, perceptual stimuli, its suitability for higher-dimensional, conceptual stimuli is less understood. In study 1, we evaluated the ability of SpAM to capture the semantic structure of eight different categories composed of 20-30 words each. First, SpAM distances correlated strongly (r = .71) with pairwise similarity judgments, although below SpAM and pairwise judgment split-half reliabilities (r's > .9). Second, a cross-validation exercise with multidimensional scaling fits at increasing latent dimensionalities suggested that aggregated SpAM data favored higher (> 2) dimensional solutions for seven of the eight categories explored here. Third, split-half reliability of SpAM dissimilarities was high (Pearson r = .90), while the average correlation between pairs of participants was low (r = .15), suggesting that when different participants focus on different pairs of stimulus dimensions, reliable high-dimensional aggregate similarity data is recoverable. In study 2, we show that SpAM can recover the Big Five factor space of personality trait adjectives, and that cross-validation favors a four- or five-dimension solution on this dataset. We conclude that SpAM is an accurate and reliable method of measuring similarity for high-dimensional items like words. We publicly release our data for researchers.

Review of Ceftazidime-Avibactam, Meropenem-Vaborbactam, and Imipenem/Cilastatin-Relebactam to Target Klebsiella pneumoniae Carbapenemase-Producing Enterobacterales.

Objective: To provide a review of 3 novel antimicrobial agents-ceftazidime-avibactam, meropenem-vaborbactam, and imipenem/cilastatin-relebactam-regarding treatment of Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC). Data Sources: A literature search of PubMed and OVID (MEDLINE) was performed up to March 2020 using the following search terms: Vabomere, meropenem-vaborbactam, vaborbactam, RPX7009, Klebsiella pneumoniae carbapenemase, KPC, carbapenem-resistant Enterobacteriaceae, CRE, relebactam, imipenem-relebactam, MK-7655, ceftazidime-avibactam. Abstracts from conferences, article bibliographies, and product information were also reviewed. Study Selection and Data Extraction: Articles were first screened by English language, then title, then abstract, and finally by review of the full article. Fifty-five clinical and preclinical studies were included. Data Synthesis: These 3 novel ß-lactam/ß-lactamase inhibitor combinations have shown considerable improvement in safety and efficacy as compared with traditional polymyxin-based combination therapy for the treatment of KPC infections. While meropenem-vaborbactam has not shown improved activity against Pseudomonas aeruginosa, it has shown decreased rates of resistance to KPC versus ceftazidime-avibactam. Conclusions: With increasing incidence of KPC infections on a global scale, pharmacists should be aware of the notable similarities and differences between these 3 agents, and the current data supporting their use. Pharmacists may want to consider meropenem-vaborbactam over ceftazidime-avibactam for KPC infections due to decreased likelihood of resistance.

Biomass utilization by gut microbiomes.

Mammals rely entirely on symbiotic microorganisms within their digestive tract to gain energy from plant biomass that is resistant to mammalian digestive enzymes. Especially in herbivorous animals, specialized organs (the rumen, cecum, and colon) have evolved that allow highly efficient fermentation of ingested plant biomass by complex anaerobic microbial communities. We consider here the two most intensively studied, representative gut microbial communities involved in degradation of plant fiber: those of the rumen and the human large intestine. These communities are dominated by bacteria belonging to the Firmicutes and Bacteroidetes phyla. In Firmicutes, degradative capacity is largely restricted to the cell surface and involves elaborate cellulosome complexes in specialized cellulolytic species. By contrast, in the Bacteroidetes, utilization of soluble polysaccharides, encoded by gene clusters (PULs), entails outer membrane binding proteins, and degradation is largely periplasmic or intracellular. Biomass degradation involves complex interplay between these distinct groups of bacteria as well as (in the rumen) eukaryotic microorganisms.