Persistent Gram-negative Bloodstream Infection Increases the Risk of Recurrent Bloodstream Infection With the Same Species.

The association between persistent gram-negative bloodstream infection (GN-BSI), or ongoing positive cultures, and recurrent GN-BSI has not been investigated. Among 992 adults, persistent GN-BSI was associated with increased recurrent GN-BSI with the same bacterial species and strain (6% vs 2%; P = .04). Persistent GN-BSI may be a marker of complicated infection.

Female Sex and Mortality in Patients with Staphylococcus aureus Bacteremia: A Systematic Review and Meta-analysis.

Importance: Staphylococcus aureus is the leading cause of death due to bacterial bloodstream infection. Female sex has been identified as a risk factor for mortality in S aureus bacteremia (SAB) in some studies, but not in others. Objective: To determine whether female sex is associated with increased mortality risk in SAB. Data Sources: MEDLINE, Embase, and Web of Science were searched from inception to April 26, 2023. Study Selection: Included studies met the following criteria: (1) randomized or observational studies evaluating adults with SAB, (2) included 200 or more patients, (3) reported mortality at or before 90 days following SAB, and (4) reported mortality stratified by sex. Studies on specific subpopulations (eg, dialysis, intensive care units, cancer patients) and studies that included patients with bacteremia by various microorganisms that did not report SAB-specific data were excluded. Data Extraction and Synthesis: Data extraction and quality assessment were performed by 1 reviewer and verified by a second reviewer. Risk of bias and quality were assessed with the Newcastle-Ottawa Quality Assessment Scale. Mortality data were combined as odds ratios (ORs). Main Outcome and Measures: Mortality at or before 90-day following SAB, stratified by sex. Results: From 5339 studies retrieved, 89 were included (132 582 patients; 50 258 female [37.9%], 82 324 male [62.1%]). Unadjusted mortality data were available from 81 studies (109 828 patients) and showed increased mortality in female patients compared with male patients (pooled OR, 1.12; 95% CI, 1.06-1.18). Adjusted mortality data accounting for additional patient characteristics and treatment variables were available from 32 studies (95 469 patients) and revealed a similarly increased mortality risk in female relative to male patients (pooled adjusted OR, 1.18; 95% CI, 1.11-1.27). No evidence of publication bias was encountered. Conclusions and Relevance: In this systematic review and meta-analysis, female patients with SAB had higher mortality risk than males in both unadjusted and adjusted analyses. Further research is needed to study the potential underlying mechanisms.

Risk Factors and Outcomes of Hematogenous Vertebral Osteomyelitis in Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: Hematogenous vertebral osteomyelitis (HVOM) is an incompletely understood complication of Staphylococcus aureus bacteremia (SAB). METHODS: Eligible SAB patients with and without HVOM were prospectively enrolled from 1995 through 2019 at Duke University Health System. HVOM was diagnosed either radiographically or microbiologically. Multivariable logistic regression analysis was performed to identify clinical and microbial factors associated with HVOM risk. All bloodstream S. aureus isolates were genotyped using spa typing. RESULTS: Of 3165 cases of SAB, 127 (4.0%) developed HVOM. Patients who experienced HVOM were more likely to have community-acquired SAB (30.7% vs 16.7%, P < .001), have a longer time to diagnosis of SAB (median, 5 days; interquartile range [IQR], 2-10.5 vs median, 2 days; IQR, 0-4; P < .001), and to exhibit persistent bacteremia (48.8% vs 20.6%, P < .001). A significant number of HVOM patients developed infective endocarditis (26% vs 15.2%, P = .002). Overall, 26.2% (n = 33) of SAB patients with HVOM underwent surgical intervention. Methicillin resistance (46.6% vs 41.7%, P = .318) and bacterial genotype were not associated with the development of HVOM. At the 12-month follow-up, 22% of patients with HVOM had died. Of the surviving patients, 20.4% remained on antibiotic therapy, and 29.6% had recurrence of either HVOM or SAB. CONCLUSIONS: Among patients with SAB, HVOM risk was associated with clinical factors and not bacterial genotype. Despite being a rare complication of SAB, patients with HVOM had high all-cause mortality rates and healthcare resource requirements up to 1 year after their HVOM diagnosis. Close clinical monitoring is indicated in this vulnerable population.

Black and White Patients With Staphylococcus aureus Bacteremia Have Similar Outcomes but Different Risk Factors.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) disproportionately affects Black patients. The reasons for this disparity are unclear. METHODS: We evaluated a prospectively ascertained cohort of patients with SAB from 1995 to 2020. Clinical characteristics, bacterial genotypes, and outcome were compared among Black and White patients with SAB. Multivariable logistic regression models were used to determine factors independently associated with the outcomes. RESULTS: Among 3068 patients with SAB, 1107 (36%) were Black. Black patients were younger (median, 56 years vs 63 years; P < .001) and had higher rates of diabetes (47.5% vs 34.5%, P < .001), hemodialysis dependence (40.0% vs 7.3%, P < .001), and human immunodeficiency virus (6.4% vs 0.6%, P < .001). Black patients had higher rates of methicillin-resistant S. aureus (49.3% vs 44.9%, P = .020), including the USA300 hypervirulent clone (11.5% vs 8.4%, P = .007). White patients had higher rates of corticosteroid use (22.4% vs 15.8%, P < .0001) and surgery in the preceding 30 days (28.1% vs 18.7%, P < .001). Although the median Acute Physiology Score (APS) at the time of initial SAB diagnosis was significantly higher in Black patients (median APS, 9; interquartile range [IQR], 5-14 vs median APS, 7; IQR, 4-12; P < .001), race was not associated with 90-day mortality (risk ratio, 1.02; 95% confidence interval, .93-1.12), and rates of metastatic infection were lower among Black patients (37.2% vs 41.3% White, P = .029). CONCLUSIONS: Despite differences in Black patients' higher APS on presentation and more risk factors, including a 5 times higher risk of hemodialysis dependence, 90-day mortality among Black and White patients with SAB was similar.

Association of Follow-up Blood Cultures With Mortality in Patients With Gram-Negative Bloodstream Infections: A Systematic Review and Meta-analysis.

Importance: Obtaining follow-up blood cultures (FUBCs) in patients with Staphylococcus aureus bloodstream infection (BSI) is standard practice, although its utility in patients with gram-negative bacterial BSI (GN-BSI) is unclear. Objective: To examine whether obtaining FUBCs is associated with decreased mortality (key question [KQ] 1) and whether positive vs negative FUBCs are associated with increased mortality (KQ2). Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and gray literature were searched from inception to March 11, 2022. Study Selection: Two investigators used predefined eligibility criteria to independently screen titles, abstracts, and relevant full texts. Randomized clinical trials or observational studies that matched or statistically adjusted for differences in, at minimum, level of acute illness between patients in the intervention (eg, FUBCs obtained) and control (eg, FUBCs not obtained) groups were included in primary analyses. Articles published in languages other than English were excluded. Data Extraction and Synthesis: Data abstraction and quality assessments were performed by one investigator and verified by a second investigator. Risk of bias was assessed with the Newcastle-Ottawa Scale. Effect sizes were pooled using random-effects models. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcomes and Measures: Mortality before hospital discharge or up to 30 days from the index blood culture. Results: From 3495 studies, 15 were included (all nonrandomized). In the 5 studies (n = 4378 patients) that met criteria for the KQ1 primary analysis, obtaining FUBCs was associated with decreased mortality (hazard ratio, 0.56; 95% CI, 0.45-0.71). For KQ2, 2 studies met criteria for the primary analysis (ie, matched or statistically adjusted for differences in patients with positive vs negative FUBCs), so an exploratory meta-analysis of all 9 studies that investigated KQ2 (n = 3243 patients) was performed. Positive FUBCs were associated with increased mortality relative to negative blood cultures (odds ratio, 2.27; 95% CI, 1.54-3.34). Limitations of the literature included a lack of randomized studies and few patient subgroup analyses. Conclusions and Relevance: In this systematic review and meta-analysis, obtaining FUBCs in patients with GN-BSI was associated with decreased mortality. The benefit of FUBCs may stem from identification of patients with positive FUBCs, which was a poor prognostic marker.

Neutrophil functional heterogeneity is a fixed phenotype and is associated with distinct gene expression profiles.

Differences in the ability of neutrophils to perform relevant effector functions has been identified in a variety of disease states. Although neutrophil functional heterogeneity is increasingly recognized during disease, few studies have examined neutrophil functional heterogeneity during periods of health. In this study, we systematically characterize neutrophil functional heterogeneity in a cohort of healthy human subjects using a range of biologically relevant agonists including immune complexes, bacterial ligands, and pathogens. With repeated testing over several years, we show that neutrophil functional capability represents a fixed phenotype for each individual. This neutrophil phenotype is preserved across a range of agonists and extends to a variety of effector functions including degranulation, neutrophil extracellular trap release, reactive oxygen species generation, phagocytosis, and bacterial killing. Using well-phenotyped healthy human subjects, we demonstrate that neutrophil functional heterogeneity is characterized by differences in neutrophil gene expression patterns. Altogether, our findings demonstrate that while neutrophil function is highly heterogeneous among healthy subjects, each individual's functional capability represents a fixed phenotype defined by a distinct neutrophil gene expression profile. These findings may be relevant during disease states where the ability to perform relevant neutrophil effector functions may impact disease course and/or clinical outcome.

Staphylococcus aureus Bacteremia Among Patients Receiving Maintenance Hemodialysis: Trends in Clinical Characteristics and Outcomes.

RATIONALE & OBJECTIVE: Staphylococcus aureus (Saureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes with SAB in this population over a 21-year period. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 453 hospitalized, non-neutropenic adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015. EXPOSURE: Clinical characteristics and bacterial genotype. OUTCOME: All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic complications. ANALYTICAL APPROACH: Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression. RESULTS: Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% [95% CI, 0.36%-0.46%] per year), persistent bacteremia (0.86% [95% CI, 0.14%-1.55%] per year), metastatic complications (0.84% [95% CI, 0.11%-1.56%] per year), and infection with the virulent Saureus clone USA300 (1.47% [95% CI, 0.33%-2.52%] per year). Over time, the suspected source of SAB was less likely to be a central venous catheter (-1.32% [95% CI, -2.05 to-0.56%] per year) or arteriovenous graft (-1.08% [95% CI, -1.54 to-0.56] per year), and more likely to be a nonvascular access source (1.89% [95% CI, 1.29%-2.43%] per year). Patients with a nonvascular access suspected source of infection were more likely to die as a result of their S aureus infection (OR, 3.20 [95% CI, 1.36-7.55]). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR, 2.96 [95% CI, 1.12-7.83]) but did not explain the observed increases in SAB-attributable mortality (OR, 0.83 [95% CI, 0.19-3.61]) or metastatic complications (OR, 1.34 [95% CI, 0.53-3.41]). LIMITATIONS: Single-center, inpatient cohort. CONCLUSIONS: The clinical and molecular epidemiology of SAB in patients receiving maintenance HD has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections.

Bacterial genotype and clinical outcomes in solid organ transplant recipients with Staphylococcus aureus bacteremia.

INTRODUCTION: Outcomes from Staphylococcus aureus bacteremia (SAB) in solid organ transplant (SOT) recipients are poorly understood. METHODS: This is a prospective cohort study comparing the bacterial genotype and clinical outcomes of SAB among SOT and non-transplant (non-SOT) recipients from 2005 to 2019. Each subject's initial S. aureus bloodstream isolate was genotyped using spa typing and assigned to a clonal complex. RESULTS: A total of 103 SOT and 1783 non-SOT recipients with SAB were included. Bacterial genotype did not differ significantly between SOT and non-SOT recipients (p = .4673), including the proportion of SAB caused by USA300 (13.2% vs. 16.0%, p = .2680). Transplant status was not significantly associated with 90-day mortality (18.4% vs. 29.5%; adjusted odds ratio [aOR] 0.74; 95% confidence interval [CI]: 0.44, 1.25), but was associated with increased risk for septic shock (50.0% vs. 21.8%; aOR 2.31; 95% CI: 1.48, 3.61) and acute respiratory distress syndrome (21.4% vs. 13.7%; aOR 2.03; 95% CI: 1.22, 3.37), and a significantly lower risk of metastatic complications (33.0% vs. 45.5%; aOR 0.49; 95% CI: 0.32, 0.76). No association was found between bacterial genotype and 90-day mortality (p = .6222) or septic shock (p = .5080) in SOT recipients with SAB. CONCLUSIONS: SOT recipients with SAB do not experience greater mortality than non-SOT recipients. The genotype of S. aureus bloodstream isolates in SOT recipients is similar to that of non-SOT recipients, and does not appear to be an important determinant of outcome in SOT recipients with SAB.

Infective endocarditis and solid organ transplantation: Only worse outcomes during initial transplantation hospitalization.

BACKGROUND: The epidemiology, and outcome of infective endocarditis (IE) among solid organ transplant (SOT) recipients is unknown. METHODS: We used data from the 2013-2018 Nationwide Readmissions Database (NRD). IE- and SOT-associated hospitalizations were identified using diagnosis and procedure codes. Outcomes included inpatient mortality, length of stay, and inpatient costs. Adjusted analyses were performed using weighted regression models. RESULTS: A total of 99,052 IE-associated hospitalizations, corresponding to a weighted national estimate of 193,164, were included for analysis. Of these, 794 (weighted n = 1,574) were associated with transplant history (SOT-IE). Mortality was not significantly different between SOT-IE and non-SOT-IE (17.2% vs. 15.8%, adjusted relative risk [aRR]: 0.86, 95% confidence interval [CI] [0.71, 1.03]), and fewer SOT-IE patients underwent valve repair or replacement than non-SOT-IE (12.5% vs. 16.2%, aRR 0.82, 95% CI [0.71, 0.95]). We then compared outcomes of patients diagnosed with IE during their index transplant hospitalization (index-SOT-IE) to patients without IE during their transplant hospitalization (index-SOT). Index-SOT-IE occurred most frequently among heart transplant recipients (45.1%), and was associated with greater mortality (27.1% vs. 2.3%, aRR 6.07, 95% CI [3.32, 11.11]). CONCLUSION: Dual diagnosis of SOT and IE was associated with worse outcomes among SOT recipients during index hospitalization, but not overall among patients with IE.

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study.

We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1ß (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).

Surgical infection prophylaxis prior to left ventricular assist device implantation: A survey of clinical practice.

BACKGROUND: Short duration, antimicrobial prophylaxis that includes antistaphylococcal activity is recommended at the time of left ventricular assist device (LVAD) implantation to reduce infection-related complications. There continues to be wide variability in surgical infection prophylaxis (SIP) regimens among implantation centers. The aim of this study is to characterize current SIP regimens at different LVAD centers. METHODS: A survey study was conducted from 26 September 2017 to 25 October 2017. Surveys were distributed electronically to LVAD coordinators and infectious diseases specialists at 75 US medical centers identified as having an LVAD program. Data collection included information about antimicrobial selection, duration, Staphylococcus aureus screening, and decolonization procedures. RESULTS: We received 29 survey responses. The majority of surveys were completed by infectious diseases physicians (72.4% [21 out of 29]). Most responding centers reported LVAD programs established for greater than 10 years (20 out of 29 [69%]). Cardiac transplantation was performed in 28 out of 29 (96%) centers. Of centers reporting a defined SIP regimen for non-penicillin allergic patients (96% [28 out of 29]), 17.9% (5 out of 28) reported a four-drug regimen, 35.7% (10 out of 28) reported a three-drug regimen, and 46.4% (13 out of 28) reported a two-drug regimen, while no centers reported a single-drug regimen. Empiric fluconazole was common (50% [14 out of 28]) and 96.4% (27 out of 28) of regimens included vancomycin. Duration of antimicrobial prophylaxis (24 hours to 5 days), S. aureus screening, decolonization procedures, and alterations due to drug allergies varied across participating centers. CONCLUSIONS: Our survey results indicate wide variation in SIP regimens among participating LVAD centers. These results highlight the need for studies evaluating the implications of SIP regimens, and whether clinical factors that prolong antimicrobial duration impact postoperative infection rates.

Risk stratification biomarkers for Staphylococcus aureus bacteraemia.

OBJECTIVES: To identify risk stratification biomarkers to enrich for the subset of Staphylococcus aureus bacteraemia patients who develop deep-seated tissue infections with high morbidity and mortality to guide clinical trial enrolment and clinical management. METHODS: We evaluated the prognostic value of eight biomarkers for persistent bacteraemia, mortality and endovascular infection foci in a validation cohort of 160 patients with S. aureus bacteraemia enrolled consecutively over 3 years. RESULTS: High levels of IL-17A, IL-10 or soluble E-selectin at bacteraemia diagnosis correlated with the duration of positive blood cultures. When thresholds defined in an independent cohort were applied, these biomarkers were robust predictors of persistent bacteraemia or endovascular infection. High serum levels of IL-17A and IL-10 often preceded the radiographic diagnosis of infective endocarditis, suggesting potential utility for prioritising diagnostic radiographic imaging. High IL-8 was prognostic for all-cause mortality, while IL-17A and IL-10 were superior to clinical metrics in discriminating between attributable mortality and non-attributable mortality. High IL-17A and IL-10 identified more patients who developed microbiological failure or mortality than were identified by infective endocarditis diagnosis. CONCLUSION: These biomarkers offer potential utility to identify patients at risk of persistent bacteraemia to guide diagnostic imaging and clinical management. Low biomarker levels could be used to rule out the need for more invasive TEE imaging in patients at lower risk of infective endocarditis. These biomarkers could enable clinical trials by enriching for patients with the greatest need for novel therapies.

Prognostic Power of Pathogen Cell-Free DNA in Staphylococcus aureus Bacteremia.

BACKGROUND: Staphylococcus aureus is a leading global cause of bacteremia that can cause invasive tissue infections with high morbidity and mortality despite appropriate antibiotic therapy. Clinicians lack sufficient tools to rapidly identify patients with a poor prognosis to guide diagnostic workup and treatment decisions. Host cell-free DNA provides prognostic value across a spectrum of critical illnesses, including S. aureus bacteremia and sepsis. Metrics of high bacterial load are associated with disease severity in S. aureus bacteremia, and the objective of this study was to evaluate whether incorporating quantitation of cell-free bacterial DNA would provide additive prognostic value when combined with biomarkers of the inflammatory response. METHODS: S. aureus cell-free DNA was measured by quantitative polymerase chain reaction (PCR) in baseline serum samples from an observational cohort of 111 patients with complicated S. aureus bacteremia and correlated with host inflammatory markers and clinical outcomes. RESULTS: High levels of S. aureus cell-free DNA at the time of positive index blood culture were prognostic for all-cause and attributable mortality and persistent bacteremia and were associated with infective endocarditis. However, they did not provide additive value to biomarkers of the host response to infection in multivariate analysis. CONCLUSIONS: Measurements of bacterial load by PCR are a clinically feasible candidate biomarker for stratifying patients at higher risk for complications and poor outcomes. Their diagnostic and prognostic value for identifying foci of infection and influencing treatment remain to be evaluated in additional cohorts.

Changing Characteristics of Staphylococcus aureus Bacteremia: Results From a 21-Year, Prospective, Longitudinal Study.

BACKGROUND: We conducted a longitudinal study to evaluate changes in the clinical presentation and epidemiology of Staphylococcus aureus bacteremia (SAB) in an academic, US medical center. METHODS: Consecutive patients with monomicrobial SAB were enrolled from January 1995 to December 2015. Each person's initial bloodstream S. aureus isolate was genotyped using spa typing. Clonal complexes (CCs) were assigned using Ridom StaphType software. Changes over time in both the patient and bacterial characteristics were estimated with linear regression. Associations between genotypes or clinical characteristics and complications were estimated using multivariable regression models. RESULTS: Among the 2348 eligible participants, 54.2% had an implantable, foreign body of some type. This proportion increased significantly during the 21-year study period, by 0.96% annually (P = .002), as did comorbid conditions and acquisition outside of the hospital. Rates of any metastatic complication also significantly increased, by 0.94% annually (P = .019). Among the corresponding bloodstream S. aureus isolates, spa-CC012 (multi-locus sequence type [MLST] CC30), -CC004 (MLST CC45), -CC189 (MLST CC1), and -CC084 (MLST CC15) all significantly declined during the study period, while spa-CC008 (MLST CC8) significantly increased. Patients with SAB due to spa-CC008 were significantly more likely to develop metastatic complications in general, and abscesses, septic emboli, and persistent bacteremia in particular. After adjusting for demographic, racial, and clinical variables, the USA300 variant of spa-CC008 was independently associated with metastatic complications (odds ratio 1.42; 95% confidence interval 1.02-1.99). CONCLUSIONS: Systematic approaches for monitoring complications of SAB and genotyping the corresponding bloodstream isolates will help identify the emergence of hypervirulent clones and likely improve clinical management of this syndrome.

Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most successful modern pathogens. The same organism that lives as a commensal and is transmitted in both health-care and community settings is also a leading cause of bacteraemia, endocarditis, skin and soft tissue infections, bone and joint infections and hospital-acquired infections. Genetically diverse, the epidemiology of MRSA is primarily characterized by the serial emergence of epidemic strains. Although its incidence has recently declined in some regions, MRSA still poses a formidable clinical threat, with persistently high morbidity and mortality. Successful treatment remains challenging and requires the evaluation of both novel antimicrobials and adjunctive aspects of care, such as infectious disease consultation, echocardiography and source control. In this Review, we provide an overview of basic and clinical MRSA research and summarize the expansive body of literature on the epidemiology, transmission, genetic diversity, evolution, surveillance and treatment of MRSA.

A Prognostic Model of Persistent Bacteremia and Mortality in Complicated Staphylococcus aureus Bloodstream Infection.

BACKGROUND: Staphylococcus aureus is a leading cause of bacteremia, yet there remains a significant knowledge gap in the identification of relevant biomarkers that predict clinical outcomes. Heterogeneity in the host response to invasive S. aureus infection suggests that specific biomarker signatures could be utilized to differentiate patients prone to severe disease, thereby facilitating earlier implementation of more aggressive therapies. METHODS: To further elucidate the inflammatory correlates of poor clinical outcomes in patients with S. aureus bacteremia, we evaluated the association between a panel of blood proteins at initial presentation of bacteremia and disease severity outcomes using 2 cohorts of patients with S. aureus bacteremia (n = 32 and n = 124). RESULTS: We identified 13 candidate proteins that were correlated with mortality and persistent bacteremia. Prognostic modeling identified interleukin (IL)-8 and CCL2 as the strongest individual predictors of mortality, with the combination of these biomarkers classifying fatal outcome with 89% sensitivity and 77% specificity (P < .0001). Baseline IL-17A levels were elevated in patients with persistent bacteremia (P < .0001), endovascular (P = .026) and metastatic tissue infections (P = .012). CONCLUSIONS: These results demonstrate the potential utility of selected biomarkers to distinguish patients with the highest risk for treatment failure and bacteremia-related complications, providing a valuable tool for clinicians in the management of S. aureus bacteremia. Additionally, these biomarkers could identify patients with the greatest potential to benefit from novel therapies in clinical trials.

On-demand release of Candida albicans biofilms from urinary catheters by mechanical surface deformation.

Candida albicans is a leading cause of catheter-associated urinary tract infections and elimination of these biofilm-based infections without antifungal agents would constitute a significant medical advance. A novel urinary catheter prototype that utilizes on-demand surface deformation is effective at eliminating bacterial biofilms and here the broader applicability of this prototype to remove fungal biofilms has been demonstrated. C. albicans biofilms were debonded from prototypes by selectively inflating four additional intralumens surrounding the main lumen of the catheters to provide the necessary surface strain to remove the adhered biofilm. Deformable catheters eliminated significantly more biofilm than the controls (>90% eliminated vs 10% control; p < 0.001). Mechanical testing revealed that fungal biofilms have an elastic modulus of 45 ± 6.7 kPa with a fracture energy of 0.4-2 J m-2. This study underscores the potential of mechanical disruption as a materials design strategy to combat fungal device-associated infections.

The Risk of Cardiac Device-Related Infection in Bacteremic Patients Is Species Specific: Results of a 12-Year Prospective Cohort.

BACKGROUND: The species-specific risk of cardiac device-related infection (CDRI) among bacteremic patients is incompletely understood. METHODS: We conducted a prospective cohort study of hospitalized patients from October 2002 to December 2014 with a cardiac device (CD) and either Staphylococcus aureus bacteremia (SAB) or Gram-negative bacteremia (GNB). Cardiac devices were defined as either prosthetic heart valves (PHVs), including valvular support rings, permanent pacemakers (PPMs)/automatic implantable cardioverter defibrillators (AICDs), or left ventricular assist devices (LVADs). RESULTS: During the study period, a total of 284 patients with ≥1 CD developed either SAB (n = 152 patients) or GNB (n = 132 patients). Among the 284 patients, 150 (52.8%) had PPMs/AICDs, 72 (25.4%) had PHVs, 4 (1.4%) had LVADs, and 58 (20.4%) had >1 device present. Overall, 54.6% of patients with SAB and 16.7% of patients with GNB met criteria for definite CDRI (P < .0001). Multivariable logistic regression analysis revealed that 3 bacterial species were associated with an increased risk for CDRI: Staphylococcus aureus (odds ratio [OR] = 5.57; 95% confidence interval [CI], 2.16-14.36), Pseudomonas aeruginosa (OR = 50.28; 95% CI, 4.16-606.93), and Serratia marcescens (OR = 7.75; 95% CI, 1.48-40.48). CONCLUSIONS: Risk of CDRI among patients with bacteremia varies by species. Cardiac device-related infection risk is highest in patients with bacteremia due to S aureus, P aeruginosa, or S marcescens. By contrast, it is lower in patients with bacteremia due to other species of Gram-negative bacilli. Patients with a CD who develop bacteremia due to either P aeruginosa or S marcescens should be considered for diagnostic imaging to evaluate for the presence of CDRI.

Structural and In Vivo Studies on Trehalose-6-Phosphate Synthase from Pathogenic Fungi Provide Insights into Its Catalytic Mechanism, Biological Necessity, and Potential for Novel Antifungal Drug Design.

The disaccharide trehalose is critical to the survival of pathogenic fungi in their human host. Trehalose-6-phosphate synthase (Tps1) catalyzes the first step of trehalose biosynthesis in fungi. Here, we report the first structures of eukaryotic Tps1s in complex with substrates or substrate analogues. The overall structures of Tps1 from Candida albicans and Aspergillus fumigatus are essentially identical and reveal N- and C-terminal Rossmann fold domains that form the glucose-6-phosphate and UDP-glucose substrate binding sites, respectively. These Tps1 structures with substrates or substrate analogues reveal key residues involved in recognition and catalysis. Disruption of these key residues severely impaired Tps1 enzymatic activity. Subsequent cellular analyses also highlight the enzymatic function of Tps1 in thermotolerance, yeast-hypha transition, and biofilm development. These results suggest that Tps1 enzymatic functionality is essential for the fungal stress response and virulence. Furthermore, structures of Tps1 in complex with the nonhydrolyzable inhibitor, validoxylamine A, visualize the transition state and support an internal return-like catalytic mechanism that is generalizable to other GT-B-fold retaining glycosyltransferases. Collectively, our results depict key Tps1-substrate interactions, unveil the enzymatic mechanism of these fungal proteins, and pave the way for high-throughput inhibitor screening buttressed and guided by the current structures and those of high-affinity ligand-Tps1 complexes.IMPORTANCE Invasive fungal diseases have emerged as major threats, resulting in more than 1.5 million deaths annually worldwide. This epidemic has been further complicated by increasing resistance to all major classes of antifungal drugs in the clinic. Trehalose biosynthesis is essential for the fungal stress response and virulence. Critically, this biosynthetic pathway is absent in mammals, and thus, the two enzymes that carry out trehalose biosynthesis, namely, trehalose-6-phosphate synthase (Tps1) and trehalose-6-phosphate phosphatase (Tps2), are prominent targets for antifungal intervention. Here, we report the first eukaryotic Tps1 structures from the pathogenic fungi Candida albicans and Aspergillus fumigatus in complex with substrates, substrate analogues, and inhibitors. These structures reveal key protein-substrate interactions, providing atomic-level scaffolds for structure-guided drug design of novel antifungals that target Tps1.