Complicated Staphylococcus Aureus Bacteremia Research Articles

Does adjunctive clindamycin have a role in Staphylococcus aureus bacteremia? A protocol for the adjunctive treatment domain of the S. aureus Network Adaptive Platform (SNAP) randomized controlled trial.

The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and is recommended in many guidelines, but there is limited evidence underpinning this. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leucocidins (e.g., Panton-Valentine Leucocidin (PVL), toxic shock syndrome toxin 1 (TSST-1), exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multi-center adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either five days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard of care antibiotics. Most participants with SAB (within 72hr of index blood culture and not contraindicated) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and PVL-positive isolate.

The Utility of Risk Factors to Define Complicated Staphylococcus aureus Bacteremia in a Setting With Low Methicillin-Resistant S. aureus Prevalence.

Recommended duration of antibiotic treatment of Staphylococcus aureus bacteremia (SAB) is frequently based on distinguishing uncomplicated and complicated SAB, and several risk factors at the onset of infection have been proposed to define complicated SAB. Predictive values of risk factors for complicated SAB have not been validated, and consequences of their use on antibiotic prescriptions are unknown. In a prospective cohort, patients with SAB were categorized as complicated or uncomplicated through adjudication (reference definition). Associations and predictive values of 9 risk factors were determined, compared with the reference definition, as was accuracy of Infectious Diseases Society of America (IDSA) criteria that include 4 risk factors, and the projected consequences of applying IDSA criteria on antibiotic use. Among 490 patients, 296 (60%) had complicated SAB. In multivariable analysis, persistent bacteremia (odds ratio [OR], 6.8; 95% confidence interval [CI], 3.9-12.0), community acquisition of SAB (OR, 2.9; 95% CI, 1.9-4.7) and presence of prosthetic material (OR, 2.3; 95% CI, 1.5-3.6) were associated with complicated SAB. Presence of any of the 4 risk factors in the IDSA definition of complicated SAB had a positive predictive value of 70.9% (95% CI, 65.5-75.9) and a negative predictive value of 57.5% (95% CI, 49.1-64.8). Compared with the reference, IDSA criteria yielded 24 (5%) false-negative and 90 (18%) false-positive classifications of complicated SAB. Median duration of antibiotic treatment of these 90 patients was 16 days (interquartile range, 14-19), all with favorable clinical outcome. Risk factors have low to moderate predictive value to identify complicated SAB and their use may lead to unnecessary prolonged antibiotic use.

Update on Staphylococcus aureus bacteraemia.

To review recently published evidence relevant to Staphylococcus aureus bacteremia (SAB). Staphylococcus aureus is the most common pathogen causing co-infections and superinfections in patients with COVID-19. Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia ratios have sharply risen during the pandemic. SAB mortality is 18% at 1 month and 27% at 3 months but has gradually decreased over the last 30 years. Recurrences and reinfections are common (9%). Standardised items to define complicated SAB, and a new cut-off defining persisting bacteremia after 2 days with positive blood cultures have been proposed. Multiple antibiotic combinations have been trialled including vancomycin or daptomycin with β-lactams, fosfomycin, or clindamycin, without significant results. In the recently published guidelines, vancomycin remains the first line of treatment for MRSA bacteremia. For the management of methicillin-susceptible Staphylococcus aureus , cefazolin less frequently causes acute kidney injury than flucloxacillin, and when susceptibility is demonstrated, de-escalation to penicillin G is suggested. Our review confirms that Staphylococcus aureus represents a special aetiology among all causes of bloodstream infections. Pending results of platform and larger trials, its distinct epidemiology and determinants mandate careful integration of clinical variables and best available evidence to optimize patient outcomes.

Heterogeneity in Staphylococcus aureus Bacteraemia Clinical Trials Complicates Interpretation of Findings.

We systematically evaluated randomized-controlled trials (RCTs) for Staphylococcus aureus bacteremia (SAB). There was intertrial heterogeneity in cohort characteristics, including bacteremia source, complicated SAB, and comorbidities. Reporting of cohort characteristics was itself variable, including bacteremia source and illness severity. Selection bias was introduced by exclusion criteria relating to comorbidities, illness severity, infection types, and source control. Mortality was lower in RCT control arms compared with observational cohorts. Differences in outcome definitions impedes meta-analysis. These issues complicate the interpretation and application of SAB RCT results. The value of these trials should be maximized by a standardized approach to recruitment, definitions, and reporting.

Acute kidney injury in Staphylococcus aureus bacteremia.

Acute kidney injury (AKI) is a frequent complication in patients with Staphylococcus aureus bacteremia (SAB), with a significant impact on patient management and outcome. This study aimed to provide insight in the proportion of patients with SAB that develop AKI, the risk factors for developing AKI in this population, and its reversibility. In this retrospective, multicenter cohort study, adult patients with SAB were eligible for inclusion. Patient characteristics, clinical variables, and laboratory results were retrieved from the electronic patient files. Primary outcome was development of AKI, defined as 1.5 times baseline creatinine. Secondary outcomes were reversibility of AKI and risk factors for AKI. A total of 315 patients with SAB were included, of whom 115/315 (37%) developed acute kidney injury. In 68/115 (59%), the AKI was reversible. If kidney function recovered, this occurred within 7days in 56/68 (82%) of patients. In multivariable logistic regression analyses, independent risk factors for AKI were as follows: complicated SAB, use of diuretics, and hemodynamic instability. Development of AKI was associated with 30-day mortality (OR 3.9; CI 2.2-6.9; p < 0.01). Acute kidney injury is a frequent complication in patients with Staphylococcus aureus bacteremia. Considering the irreversibility in a relevant proportion of patients, future research into the underlying pathophysiology and potential interventions is warranted.

167. A Phase 1b, Randomized, Double-blind, Placebo-controlled, Multiple-ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S in Patients with staphylococcus Aureus Bacteremia Receiving Standard-of-care Antibiotics

BackgroundNew treatment approaches for complicated Staphylococcus aureus bacteremia (SAB) are needed. DSTA4637S is a THIOMABTM antibody-antibiotic conjugate consisting of an engineered human IgG1 monoclonal antibody that binds to wall teichoic acid at the surface of S. aureus, a protease-cleavable linker, and a novel rifamycin class antibiotic, dmDNA31. This Phase 1b study assessed the safety, tolerability, and pharmacokinetics of DSTA4637S in patients with complicated SAB.MethodsMulticenter, double-blind, placebo controlled, multiple-ascending dose clinical trial. Patients 18–79 years old with complicated SAB requiring at least 4 weeks of IV anti-staphylococcal standard-of-care (SOC) antibiotics were randomized to receive 4–6 doses of 15, 45, and 100 mg/kg IV DSTA4637S or placebo (6 active:2 placebo) every 7 days in combination with SOC antibiotics. Patients needed ≥ 1 blood culture positive for S. aureus collected within 120 hours prior to randomization. Patients were followed for 120 days after the end of treatment.ResultsTwenty-five patients with complicated SAB (bone & joint, n=14; endocarditis, n=5; other endovascular, n=5; pneumonia, n=1) were randomized and received 1–6 doses of study drug (19 active:6 placebo). Nine patients (36%) had MRSA. Ten patients completed ≥4 doses of DSTA4637S. The most common treatment-related adverse events were infusion-related reactions (IRRs) (5/19), and abnormal serum color (5/19)/skin discoloration (3/19 (due to dmDNA31). IRRs were not dose-dependent and were reversible with supportive care. Ten of 19 patients (40%) discontinued study drug (9 DSTA4637S,1 placebo); 4/19 (21%) due to IRR. DSTA4637S recipients showed no dose-related changes in laboratory values or vital signs vs. placebo. Observed exposures (Cmax and AUC) were lower in patients immediately after dosing compared to a prior study in healthy volunteers; minimal accumulation occurred. No obvious trends in exploratory bacterial and inflammatory biomarkers were observed between treatment groups.ConclusionDSTA4637S in patients with complicated SAB demonstrated increased IRRs and decreased exposure compared to healthy volunteers, highlighting the importance of Phase I studies of novel treatments in infected SAB patients and not simply healthy controls.DisclosuresJeremy Lim, PharmD, Roche (Employee, Shareholder) Nicholas Lewin-Koh, PhD, Genentech (Employee) Tom Chu, MD, PhD, Genentech (Employee) Sharon M. Rymut, PhD, Genentech (Employee, Shareholder) Aklile Berhanu, PhD, Genentech, Inc. (Employee, Equity interest (Stock/Stock Options)) Montserrat Carrasco-Triguero, PhD, Genentech (Employee) Carrie C. Rosenberger, PhD, Genentech (Employee, Shareholder) Wouter L. Hazenbos, PhD, Genentech (Employee) Loren G. Miller, MD, MPH, genentech (Grant/Research Support) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) Jose M Miro, MD PhD, GENENTECH (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member) Jessica A. Couch, PhD, Genentech (Employee, Shareholder) Melicent C. Peck, MD, PhD, Genentech (Employee)

851. Compliance with Guidelines for Management of Staphylococcus aureus Bacteremia and its Effect on Mortality

BackgroundIn the US, Staphylococcus aureus Bacteremia (SAB) occurs in about 19.7 /100,000 people. A recent increase in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia infections rate and mortality has led to more infectious diseases (ID) consultations. We assessed if an infectious diseases consultation within 7 days of initial blood culture results was associated to greater compliance with Infectious Diseases Society of America (IDSA) guidelines for managing Staphylococcus aureus bacteremia and a decrease in all-cause mortality and relapse within 90 days.MethodsA retrospective cohort of patients admitted to two community hospitals from January 2014 to June 2016 with a positive blood culture for methicillin-susceptible S. aureus (MSSA), MRSA, or coagulase-negative Staphylococcus were included in the study. I. Patients were excluded if they were immunocompromised, had a polymicrobial blood stream infection, died within first 48 hours of admission, left against medical advice during treatment or participated in another study requiring an alternative treatment strategy.ResultsA total of 331 patients were included in the analysis. A significantly higher proportion of patients with complicated SAB had an ID consult (61% vs. 17.5%, p< .0001) and for uncomplicated SAB the reverse was true (39% vs 79%, P< .0001). An ID consult was associated with increased compliance with IDSA guidelines (75% vs. 5%, p< .0001). Patients with an ID consult had a significantly higher duration of antibiotic treatment [30(14-42) vs. 5(1.5-12), p< .0001], an earlier start of treatment in number of days [0(0-7) vs. 0(0-12), p=0.036] and a lower mortality within 90 days of blood culture (61% vs. 17.5%, p< .0001). Logistic regression model showed than an ID consult reduced 90-day mortality by 69%, OR 0.313[CI 95 %(0.313-0.154), p=0.001] and transesophageal echography by 78%, OR 0.228[CI 95 %(0.228-0.052), p=0.05].Population characteristics and outcomes ConclusionID consultation in the setting of SAB has been shown to increase compliance with IDSA guidelines and reduce 90-day mortality.Disclosures All Authors: No reported disclosures

Clinical Characteristics and Outcomes of S. Aureus Bacteremia in Patients Receiving Total Parenteral Nutrition.

Background: Patients on total parenteral nutrition (TPN) are at risk of developing central line-associated infections. Specifically, Staphylococcus aureus bacteremia (SAB) is feared for its high complication rates. This prospective cohort study compares characteristics, clinical course and outcome of SAB in patients with and without TPN support. Methods: Clinical and microbiological data from all patients with positive blood cultures for S. aureus from two facilities, including our referral center for TPN support, were retrieved (period 2013–2020). Primary outcome was overall mortality, and included survival analysis using a multivariate Cox regression model. Secondary outcomes comprised a comparison of clinical characteristics and outcomes between both patient groups and analysis of factors associated with complicated outcome (e.g., endocarditis, deep-seated foci, relapse and death) in patients on TPN specifically. Results: A total of 620 SAB cases were analyzed, of which 53 cases received TPN at the moment the blood culture was taken. Patients in the TPN group were more frequently female, younger and had less comorbidity (p < 0.001). In-hospital death and overall mortality were significantly lower in TPN patients (4% vs. 18%, p = 0.004 and 10% vs. 34%, p < 0.001, respectively). Positive follow-up blood cultures, delayed onset of therapy and previous catheter problems were associated with a higher incidence of complicated SAB outcome in patients on TPN. Conclusion: Our data show that patients on TPN have a milder course of SAB with lower mortality rates compared to non-TPN SAB patients.

Intermittent Negative Blood Cultures in Staphylococcus aureus Bacteremia; a Retrospective Study of 1071 Episodes.

BackgroundRecommended management of Staphylococcus aureus bacteremia (SAB) includes follow-up blood culture sets (BCs) to determine the duration of bacteremia. Duration of bacteremia is an important prognostic factor in SAB, and follow-up BCs have a critical role in differentiation of uncomplicated and complicated SAB. However, intermittent negative BCs occur in SAB. Clinical guidelines for SAB management do not specify an approach to follow-up BCs’ collection or define the number of negative BCs required to demonstrate resolution of bacteremia. This study assessed the frequency of intermittent negative BCs in SAB and used these findings to formulate a recommendation for collection of follow-up BCs.MethodsThis retrospective study reviewed 1071 episodes of SAB. Clinical and microbiological data including the duration of bacteremia and the occurrence of intermittent negative BCs (those preceded and followed by positive cultures) were considered.ResultsIntermittent bacteremia occurred in 13% (140/1071) of episodes. A single negative BC on days 1–3 had a predictive value of 87%–93% for resolution of bacteremia, although this was improved if all BCs collected within the same day were considered.ConclusionsIntermittent negative BCs are common in SAB. Given this, we would not recommend accepting a single negative BC as demonstrating resolution of the bacteremia. This is particularly important if a patient is to be classified as having uncomplicated SAB.

1040. Effects of An Antimicrobial Stewardship Team-led Staphylococcus aureus Bacteremia Management Bundle: A Quasi-Experimental Study

BackgroundMortality associated with Staphylococcus aureus bacteremia (SAB) has prompted the development of “bundle”-based approaches to improve outcomes. Components of bundled strategies include appropriate antibiotic selection, early source control, documenting negative cultures, echocardiogram, and adequate treatment duration. In 7/2016, the UNC Antimicrobial Stewardship Program (ASP) began prospective monitoring of SAB patients. Here we describe the impact of these ASP efforts.MethodsQuasi-experimental study of patients ≥16 years with SAB 9/2015-3/2016 (pre-intervention) and 9/201/2017 (post-intervention). Patients were excluded if the bloodstream infection was polymicrobial, therapy began at an outside hospital, or the patient was discharged or died within 72 hours of positive blood culture. Minimum adequate treatment duration was defined as 14 days for uncomplicated SAB; 28 days for complicated SAB; 42 days if endovascular disease or osteomyelitis present. Categorical variables were compared using the chi-squared test, significance level of P < 0.05. The study was approved by the UNC IRB.Results217 treatment courses were included; 114 pre- and 103 post-intervention. Rates of adequate empirical antibiotics were consistently high throughout the study (Table 1). Pre-intervention, individual bundle components occurred frequently: negative culture documented (95%), echocardiogram (80%), and adequate duration of an appropriate antibiotic (71%; Table 2). After ASP intervention, echocardiography and adequate treatment duration rates increased to 92% (P < 0.05, both outcomes), as did ID consultation rates (59% to 67%; P = 0.04). Overall bundle achievement increased from 54% to 82%. ASP interventions were documented for 11 (10%) and 32 (31%) of patients during the periods. Mortality and readmission within 6 months of discharge were unchanged (12% and 11%; 41% and 42%, respectively).ConclusionASP intervention was associated with increased rates of bundle achievement but did not impact mortality or 6-month readmission. Despite adequate empiric therapy and relatively high rates of adherence to best-evidenced practices, SAB continues to be associated with significant mortality and high rates of 6-month readmission. Disclosures All authors: No reported disclosures.

Staphylococcus aureus Bacteraemia - an Interdisciplinary Challenge

Staphylococcus aureus is the second-most-common pathogen among bloodstream infections. Due to a high hospital mortality rate (15 - 40%), frequent complications and recurrences the clinical management of Staphylococcus aureus bacteremia (SAB) is distinct from bacteremia from other pathogens. A literature search was performed using PubMed. Guidelines and best practice expert recommendations were included. The detection of S. aureus in blood culture should always be considered clinically relevant. The drug of choice for treatment of a bloodstream infection with methicillin-sensitive S. aureus is flucloxacillin (8 - 12 g i. v./d). In a bloodstream infection with methicillin-resistant S. aureus (MRSA) vancomycin or daptomycin (the latter not in pneumonic focus) are recommended. Follow-up blood cultures, source identification, including transoesophageal echocardiography in patients with risk profile, and rapid source control are important measures. The duration of therapy is at least 14 days with uncomplicated SAB, whereby the entire therapy should be carried out intravenously. In case of complicated SAB, a total therapy duration of at least 4 - 6 weeks is recommended. Adherence to this set of measures can reduce mortality by up to 50%. SAB is associated with high morbidity and mortality. Clinical management is complex. By adhering to diagnostic and therapeutic measures, the prognosis can be improved.

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated Staphylococcus aureus Bacteremia.

Background Staphylococcus aureus (SA) bacteremia often requires a long treatment duration with antibiotics to prevent relapse due to the ability of SA to establish reservoirs of infection in sites such as heart and bone. These metastatic sites of infection cannot be serially sampled to monitor the clearance of SA infection. This study aimed to establish a link between persistence of circulating SA deoxyribonucleic acid (SA-DNA) and tissue reservoirs in patients with SA bacteremia.MethodsA highly sensitive quantitative polymerase chain reaction was used to measure whole blood SA-DNA and plasma-derived SA cell-free DNA (SA-cfDNA) in a set of longitudinal samples from 73 patients with confirmed SA bacteremia and correlated with clinical features.ResultsBlood SA-DNA was detected for longer than the duration of positive blood cultures. Longer duration of circulating bacterial DNA was observed in complicated SA bacteremia infections, such as endocarditis and osteoarticular infections, compared with uncomplicated bloodstream infections. In contrast, traditional blood cultures demonstrated similar time to clearance regardless of foci of infection. Plasma-derived SA-cfDNA showed concordance with blood SA-DNA levels. Baseline levels of SA-DNA were higher in patients presenting with greater clinical severity and complicated bacteremia.ConclusionsProlonged levels of circulating SA-DNA in patients with complicated tissue reservoirs after clearance of blood cultures observed in this single-center study should be validated in additional cohorts to assess the potential utility for monitoring clearance of infection in patients with SA bacteremia.

Early Oral Switch to Linezolid for Low-risk Patients With Staphylococcus aureus Bloodstream Infections: A Propensity-matched Cohort Study.

Oral switch to linezolid is a promising alternative to standard parenteral therapy (SPT) in Staphylococcus aureus bacteremia (SAB). We conducted a prospective cohort study of all adult cases of SAB between 2013 and 2017 in a Spanish university hospital. We compared the efficacy, safety, and length of hospital stay of patients receiving SPT and those where SPT was switched to oral linezolid between days 3 and 9 of treatment until completion. We excluded complicated SAB and osteoarticular infections. A k-nearest neighbor algorithm was used for propensity score matching with a 2:1 ratio. After propensity score matching, we included 45 patients from the linezolid group and 90 patients from the SPT group. Leading SAB sources were catheter related (49.6%), unknown origin (20.0%), and skin and soft tissue (17.0%). We observed no difference in 90-day relapse between the linezolid group and the SPT group (2.2% vs 4.4% respectively; P = .87). No statistically significant difference was observed in 30-day all-cause mortality between the linezolid group and the SPT group (2.2% vs 13.3%; P = .08). The median length of hospital stay after onset was 8 days in the linezolid group and 19 days in the SPT group (P < .01). No drug-related events leading to discontinuation were noted in the linezolid group. Treatment of SAB in selected low-risk patients with an oral switch to linezolid between days 3 and 9 of treatment until completion yielded similar clinical outcomes as SPT, allowing earlier discharge from the hospital.

Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia.

The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10−3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10−4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10−4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10−3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-β transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in leukocyte activation.

Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteremia.

To improve management of Staphylococcus aureus bacteremia (SAB), better understanding of host-pathogen interactions is needed. In vitro studies have shown that S. aureus bacteria induce dose-dependent immunosuppression that is evidenced by reduced expression of major histocompatibility complex (MHC) class II on antigen presenting cells. Thus, the aim of this study was to determine whether expression of the MHC class II-related genes HLA-DRA and CD74 is more greatly reduced in complicated SAB, with its probable higher loads of S. aureus, than in uncomplicated SAB. Adult patients with SAB were prospectively included and blood samples taken on the day of confirmation of SAB (Day 1) and on Days 2, 3, 5 and 7. HLA-DRA and CD74 mRNA expression was determined by quantitative reverse transcription PCR. Sepsis was defined according to the Sepsis-3 classification and SAB was categorized as complicated in patients with deep-seated infection and/or hematogenous seeding. Twenty patients with SAB were enrolled and samples obtained on all assessment days. HLA-DRA and CD74 expression did not differ significantly between patients with SAB and sepsis (n = 13) and those without sepsis (n = 7) on any assessment day. However, patients with complicated SAB (n = 14) had significantly weaker HLA-DRA expression on all five assessment days than patients with uncomplicated SAB (n = 6). Additionally, they tended to have weaker CD74 expressions. Neutrophil, monocyte and leukocyte counts did not differ significantly between complicated and uncomplicated SAB. In conclusion, patients with complicated SAB show weaker HLA-DRA expression than those with uncomplicated SAB during the first week of bacteremia.

Complicated Staphylococcus aureus Bacteremia (SAB) Is Associated with Genetic Variation in GLS2

BackgroundSAB is a serious, common infection. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery set of patients, and then evaluated the nominally significant genes in a replication set of patients using custom-capture sequencing.MethodsThe discovery set comprised 84 complicated SAB cases (endocarditis or bone/joint infection) frequency-matched by age (in deciles), sex, and bacterial clonal complex (CC5/30, CC8) to 84 uncomplicated SAB controls. All were white inpatients at Duke University. WES utilized Agilent SureSelect 72Mb capture kits, followed by sequencing on an Illumina HiSeq2000, alignment and base calling with a standard pipeline. The SKAT-O and EPACTS packages were used for gene-based association tests and logistic regression models with Firth bias correction, respectively. Both controlled for age, sex, and clonal complex as covariates. The replication set of 122 complicated SAB cases and 118 uncomplicated SAB controls was frequency matched by age, sex, and clonal complex. All were white Europeans collected by the Statens Serum Institute. An Agilent SureSelect 2Mb capture array captured genic sequence for 342 genes nominally associated with complicated SAB in discovery (SKAT-O P < 0.035). Sequencing and data analysis proceeded as for WES. A Bonferroni-corrected gene-based test P-value of 1.5×10–4 determined significance in the replication set.ResultsOne gene, GLS2, was significantly associated with complicated SAB in the replication set (P = 1.2 x 10–4). The strongest single-variant association in all 342 genes was rs2657878 in GLS2 (p = 5×10−4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4x10-3) in which the minor allele (associated here with complicated SAB) has previously been shown to reduce circulating glutamine levels.ConclusionComprehensive examination of the coding sequence for association with complicated SAB in a two-stage discovery/replication design identified a novel candidate gene. GLS2 is an interesting candidate for complicated SAB due to its role in regulating glutamine production, a key factor in activation of T-cell production.Disclosures V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, Basilea, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Research grant; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: author on several chapters, Royalties

Staphylococcus aureus bacteremia in patients with rheumatoid arthritis – Data from the prospective INSTINCT cohort

Patients with rheumatoid arthritis (RA) are considered to be at increased risk of severe infections. We here describe the clinical characteristics, course and outcome of RA patients with Staphylococcus aureus bacteremia (SAB). We conducted a post hoc analysis of data from a German bi-center prospective SAB cohort study (period 2006-2014). Patients were followed-up for one year. Primary and secondary outcomes were survival time and osteoarticular infection (OAI). A total of 1069 patients with SAB were analyzed, with 31 patients suffering from RA. RA patients showed significantly more often OAI (15/31 patients, 48% vs. 152/1038, 15%), disseminated infection (12/31, 39% vs. 164/1038, 16%) and severe sepsis/septic shock (12/31, 39% vs. 235/1038, 23%). Day-30 mortality in RA patients was 36% (vs. 19% in non-RA patients, p=0.034), and day 90 mortality was 58% (vs. 32%, p=0.003). Multivariate analyses confirmed RA to be an independent risk factor for death (HR 2.3, 95% CI 1.4-3.7) and OAI (OR 4.2, 95% CI 1.8-9.8). Patients with RA exhibit a complicated SAB course and a high mortality, their management is challenging. Adequate antibiotic treatment, prompt invasive diagnostic and therapeutic procedures like joint lavage or surgery are of pivotal importance. Joint damage due to RA may confer a higher risk of acquiring OAI than immunosuppression.

Impact of an Unsolicited, Simple Standardized Form Based Antimicrobial Stewardship Intervention to Improve Guideline Adherence in the Management of Staphylococcus aureus Bacteremia

Background Staphylococcus aureusbacteremia (SAB) is associated with poor outcomes. The objective was to assess the impact of a pharmacist driven antimicrobial stewardship intervention on SAB management.MethodsA multicenter, pre-post quasi-experimental design was used to compare pre-intervention (Oct 2014 – Sep 2015) and intervention (Oct 2015 – Sep 2016) periods in hospitalized SAB patients. The antimicrobial stewardship program (ASP) developed an evidence based SAB management bundle that included: Infectious Diseases (ID) consult, blood culture clearance, appropriate empiric and definitive antibiotics, echocardiography, adequate treatment duration, and infectious source removal if applicable. ASP pharmacists performed prospective audit and feedback (PAF) using a standardized form after review with the ASP medical director. The primary outcome was bundle component adherence. Secondary outcomes were length of stay, 30 day readmission, in-hospital mortality, and 30 day mortality.Results127 patients were included (pre-intervention = 62, intervention = 65). The two groups had similar patient demographics. The intervention group had a higher rate of complicated SAB at diagnosis.Bundle implementation with PAF resulted in significant improvements in ID consultation (56.5% vs. 92.3%, P < 0.001), appropriate definitive antibiotic dosing (83.9% vs. 100%, P = 0.001), ordering echocardiography (72.6% vs. 93.8%, P = 0.001), and adequate treatment duration (87% vs. 100%, P = 0.009). Overall bundle adherence increased by 43.3% (P < 0.001). Readmission and 30 day mortality decreased but did not reach statistical significance.During the intervention, ASP pharmacists made 81 recommendations (93.8% accepted).A post hoc analysis was conducted due to the 35.8% increase in ID consults with the intervention. A significant decrease of 18.5% in in-hospital mortality (P = 0.041) and 21.7% in 30 day mortality (P = 0.009) with ID involvement was seen.ConclusionSAB management bundle development with PAF by ASP pharmacists significantly improved adherence rates to evidence based recommendations in SAB inpatients. This simple yet effective ASP intervention can ensure consistent management of a highly morbid infection.Disclosures C. Cervera, Sunovion: Scientific Advisor, Consulting fee

Concomitant Staphylococcus aureus bacteriuria is associated with complicated S. aureus bacteremia

To identify factors associated with complicated Staphylococcus aureus bacteremia (SAB) in adults. Prospective observational multicenter study during 2 years in Nice University Hospital and during 6 months in the Hôpital Européen Georges Pompidou, Paris, including all adult inpatients with SAB assessed by an Infectious Diseases (ID) specialist. We included 104 SAB (79 in Nice and 25 in Paris), of which 45 were complicated, including 18 endocarditis and 23 bone and joint infections. A concomitant urine sample was performed in 65% of the cases, showing S. aureus bacteriuria 23/68 (34%) times. Blood cultures were drawn 48-96h after an appropriate antibiotic therapy had been started in 70 of the 104 cases (67%) and were positive in 28 cases (40%). The 3 following factors were found to be associated with complicated SAB in univariate analysis: community acquisition (56% vs 26%, P=0.002), concomitant bacteriuria (47% vs 19%, P=0.016) and persistent bacteremia (55% vs 26%, P=0.016). This last factor was associated with endocarditis, but not with other complications such as bone and joint infections.

Clinical identifiers of complicated Staphylococcus aureus bacteremia.

Complications of Staphylococcus aureus bacteremia (SAB) are often difficult to identify. The ability to accurately predict the likelihood of these complications would impact patient management. This investigation sought to define readily available clinical characteristics that could help identify patients at risk for complicated SAB. A prospective, observational cohort study was conducted from September 1994 through December 1999. Patients were followed up for 12 weeks after the initial positive blood culture result. The primary end point was complicated SAB (attributable mortality, complicated infection, embolic stroke, or recurrent S aureus infection during the 12-week follow-up period). The predictive model was validated using bootstrap resampling. Complicated SAB was present in 43% of 724 consecutive adult hospitalized patients identified during the study period. The full predictive model had a high discriminative ability (bootstrap-corrected c index, 0.78). The strongest predictor of complicated SAB was a positive follow-up blood culture result at 48 to 96 hours. A scoring system based on the presence or absence of 4 risk factors (community acquisition, skin examination findings suggesting acute systemic infection, persistent fever at 72 hours, and positive follow-up blood culture results at 48-96 hours) accurately identified complicated SAB (bootstrap-corrected c index, 0.76). Readily available clinical variables can help identify patients at risk for complicated SAB.