Katherine Y. Le

Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections

BACKGROUND Cardiovascular implantable electronic device (CIED) infections are associated with increased mortality. However, detailed analyses of the impact of device removal on mortality have been limited. OBJECTIVE This study sought to evaluate the impact of timing device removal on mortality in patients with CIED infections. METHODS We retrospectively reviewed all cases of CIED infections seen at Mayo Clinic Rochester between 1991 and 2008. The impact of device removal on 30-day and 1-year mortality was evaluated using Cox proportional hazards models. RESULTS Of 416 patients with CIED infection, 23 (5.5%) died by 30 days and 61 (14.6%) died by 1 year. Forty-four (12.0%) developed complications related to device removal, and 3 (0.8%) died. Complete procedural success was achieved in 341 (81.9%) and clinical success in 391 (93.9%) cases. In multivariate analysis, antimicrobial therapy without device removal was associated with a 7-fold increase in 30-day mortality (hazard ratio [HR] 6.97, 95% confidence interval [CI] 1.36 to 35.60). Although device removal complications were associated with increased mortality at 30 days (HR 4.33, 95% CI 1.47 to 12.70) and at 1 year (HR 3.77, 95% CI 1.88 to 7.55), immediate device removal, when compared to delay in device removal in favor of initial conservative therapy with antimicrobials alone, and no device removal, was associated with a 3-fold decrease in 1-year mortality (HR 0.35, 95% CI 0.16 to 0.75). CONCLUSION Although device removal resulted in fatal complications in a few patients, the mortality associated with a delay in device removal was significantly higher. Therefore, early and complete device removal was associated with improved outcomes.

Clinical predictors of cardiovascular implantable electronic device-related infective endocarditis

Background: Cardiovascular implantable electronic device (CIED)‐related infective endocarditis (CIED‐IE) is a serious complication of cardiac device infection and is associated with increased mortality. At present, there exist no criteria to predict CIED‐IE in patients who present with CIED infection.

Quorum-sensing regulation in staphylococci—an overview

Staphylococci are frequent human commensals and some species can cause disease. Staphylococcus aureus in particular is a dangerous human pathogen. In staphylococci, the ability to sense the bacterial cell density, or quorum, and to respond with genetic adaptations is due to one main system, which is called accessory gene regulator (Agr). The extracellular signal of Agr is a post-translationally modified peptide containing a thiolactone structure. Under conditions of high cell density, Agr is responsible for the increased expression of many toxins and degradative exoenzymes, and decreased expression of several colonization factors. This regulation is important for the timing of virulence factor expression during infection and the development of acute disease, while low activity of Agr is associated with chronic staphylococcal infections, such as those involving biofilm formation. Accordingly, drugs inhibiting Agr are being evaluated for their capacity to control acute forms of S. aureus infection.

Molecular determinants of staphylococcal biofilm dispersal and structuring

Staphylococci are frequently implicated in human infections, and continue to pose a therapeutic dilemma due to their ability to form deeply seated microbial communities, known as biofilms, on the surfaces of implanted medical devices and host tissues. Biofilm development has been proposed to occur in three stages: (1) attachment, (2) proliferation/structuring, and (3) detachment/dispersal. Although research within the last several decades has implicated multiple molecules in the roles as effectors of staphylococcal biofilm proliferation/structuring and detachment/dispersal, to date, only phenol soluble modulins (PSMs) have been consistently demonstrated to serve in this role under both in vitro and in vivo settings. PSMs are regulated directly through a density-dependent manner by the accessory gene regulator (Agr) system. They disrupt the non-covalent forces holding the biofilm extracellular matrix together, which is necessary for the formation of channels, a process essential for the delivery of nutrients to deeper biofilm layers, and for dispersal/dissemination of clusters of biofilm to distal organs in acute infection. Given their relevance in both acute and chronic biofilm-associated infections, the Agr system and the psm genes hold promise as potential therapeutic targets.

Role of Phenol-Soluble Modulins in Formation of Staphylococcus aureus Biofilms in Synovial Fluid

ABSTRACT Staphylococcus aureus is a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (>1 mm). We found that while specific S. aureus surface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction of S. aureus surface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms of S. aureus infection, and have important implications for antistaphylococcal therapeutic strategies.

Clinical Features and Outcomes of Cardiovascular Implantable Electronic Device Infections Due to Staphylococcal Species

Staphylococci account for the bulk of cardiovascular implantable electronic device (CIED) infections. However, a detailed analysis of clinical features and outcomes of CIED infections due to staphylococcal species has not been published. We retrospectively reviewed all cases of CIED infection seen at the Mayo Clinic from 1991 through 2008. Differences in device and host factors, clinical features, and patient outcomes were compared between cases of early and late Staphylococcus aureus and coagulase-negative staphylococci (CoNS) CIED infections. Of 280 cases of staphylococcal CIED infections, 43.9% were due to S. aureus and 56.0% were due to CoNS. Staphylococcus aureus CIED infection cases more frequently involved initially implanted devices. Late S. aureus CIED infection cases compared to late CoNS cases were associated with corticosteroid therapy, hemodialysis, implanted catheters, prosthetic valves, and remote sources of bacteremia. Cases of S. aureus endovascular infections had longer duration of bacteremia (56.0% vs 20.3% ≥3 days), longer hospitalization (37.4% vs 15.2% >20 days), and increased mortality (25.2% vs 9.5%) compared to cases of CoNS endovascular infections (p <0.001 for all comparisons). Overall, CoNS CIED infections compared to S. aureus were associated with a history of multiple device revisions and a higher number of total and abandoned leads at presentation (p <0.001 for all comparisons). In conclusion, CIED infections due to S. aureus and CoNS have distinct clinical features and outcomes.

Variability in Clinical Features of Early Versus Late Cardiovascular Implantable Electronic Device Pocket Infections

Cardiovascular implantable electronic device (CIED) pocket infections are often related to recent CIED placement or manipulation, but these infections are not well characterized. The clinical presentation of CIED pocket infection, based on temporal onset related to last CIED procedure, deserves further study.

Influence of vegetation size on the clinical presentation and outcome of lead-associated endocarditis: Results from the MEDIC registry

OBJECTIVES The purpose of this study was to determine whether the clinical presentation of lead-associated endocarditis (LAE) is related to the size of lead vegetations and how size is related to bacteriology and clinical outcomes. BACKGROUND Cardiac implantable electronic device (CIED) infection may present as either local pocket infection or bloodstream infection with or without LAE. LAE is associated with significant morbidity and mortality. METHODS The clinical presentation and course of LAE were evaluated by the MEDIC (Multicenter Electrophysiologic Device Cohort) registry, an international registry enrolling patients with CIED infection. Consecutive LAE patients enrolled in the MEDIC registry between January 1, 2009 and December 31, 2012 were analyzed. The clinical features and outcomes of 2 groups of patients were compared based on the size of the lead vegetation detected by echocardiography (> or <1 cm in diameter). RESULTS There were 129 patients with LAE enrolled into the MEDIC registry. Of these, 61 patients had a vegetation <1 cm in diameter (Group I) whereas 68 patients had a vegetation ≥1 cm in diameter (Group II). Patients in Group I more often presented with signs of local pocket infection, whereas Group II patients presented with clinical evidence of systemic infection. Staphylococcus aureus was the organism most often responsible for LAE, whereas infection with coagulase-negative staphylococci was associated with larger vegetations. Outcomes were improved among those who underwent complete device removal. However, major complications were associated with an open surgical approach for device removal. CONCLUSIONS The clinical presentation of LAE is influenced by the size of the lead vegetation. Prompt recognition and management of LAE depends on obtaining blood cultures and echocardiography, including transesophageal echocardiography, in CIED patients who present with either signs of local pocket or systemic infection.

Impact of prior aspirin therapy on clinical manifestations of cardiovascular implantable electronic device infections

AIMS Cardiovascular implantable electronic device (CIED) infection may present as pocket infection or as infective endocarditis (CIED-IE) with vegetation on device leads or heart valves. As aspirin has both anti-inflammatory properties and interferes with platelet aggregation, we hypothesized that ongoing anti-platelet therapy with aspirin may impact clinical and echocardiographic manifestations of CIED infection. METHODS AND RESULTS We retrospectively reviewed 415 cases of CIED infection admitted to Mayo Clinic Rochester from 1991 to 2008. Information regarding aspirin use was available in 392 (94.5%) cases and 178 (45%) had received aspirin therapy prior to clinical onset of CIED infection. Although there were no significant differences in pathogen distribution between patients who had received prior aspirin therapy as compared with those who did not, patients on aspirin therapy were less likely to report chills (25% vs. 35%, P = 0.04), sweats (9% vs.18%, P = 0.01), or have peripheral leukocytosis on admission (33% vs. 46%, P = 0.005). Overall, 82 (21%) of 392 patients met the clinical criteria for CIED-IE. Patients on prior aspirin therapy were significantly less likely to have vegetations on CIED leads or heart valves than those who had not received it (15% vs. 26%, P = 0.01). However, despite the lower frequency of CIED-IE in the aspirin group, there was no significant difference (P = 0.97) in the overall survival between the two groups. CONCLUSION Aspirin therapy prior to onset of CIED infection was associated with a lower likelihood of vegetation formation on CIED leads or heart valves and associated systemic manifestations of infection.

Do amyloid structures formed by Staphylococcus aureus phenol-soluble modulins have a biological function?

Phenol-soluble modulins (PSMs) are alpha-helical, amphipathic peptides that have multiple functions in staphylococcal physiology and virulence. Recent research has suggested that PSMs form amyloid fibrils and amyloids are involved in PSM-mediated phenotypes such as cytolysis and biofilm stability. While we observed PSM amyloid formation using electron microscopy and dye assays, there were no apparent differences in the production of extracellular fibrous material between a PSM-deficient strain and the isogenic wild-type strain. Furthermore, we detected no correlation between cytolytic or pro-inflammatory activities with the propensity of PSM derivatives to form amyloids. In addition, we propose a model based on our finding of non-specific attachment of PSMs to DNA, which we here report results in resistance to DNase digestion, explaining previous findings on PSM-mediated biofilm stability without the necessity to assume amyloid involvement. Collectively, our results indicate that PSM amyloid formation may not be of major relevance for known key biological functions of PSMs. Intriguingly, however, we found that amyloid-forming capacity of PSMalpha3 allows almost no amino acid exchanges, suggesting importance of amyloid formation in possibly yet unknown functions of PSMs.