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Poorly controlled diabetes leads to comorbidities and enhanced susceptibility to infections. While the immune components involved in wound healing in diabetes have been studied, the components involved in susceptibility to skin infections remain unclear. Here, we examined the effects of the inflammatory lipid mediator leukotriene B4 (LTB4) signaling through its receptor B leukotriene receptor 1 (BLT1) in the progression of methicillin-resistant Staphylococcus aureus (MRSA) skin infection in 2 models of diabetes. Diabetic mice produced higher levels of LTB4 in the skin, which correlated with larger nonhealing lesion areas and increased bacterial loads compared with nondiabetic mice. High LTB4 levels were also associated with dysregulated cytokine and chemokine production, excessive neutrophil migration but impaired abscess formation, and uncontrolled collagen deposition. Both genetic deletion and topical pharmacological BLT1 antagonism restored inflammatory response and abscess formation, followed by a reduction in the bacterial load and lesion area in the diabetic mice. Macrophage depletion in diabetic mice limited LTB4 production and improved abscess architecture and skin host defense. These data demonstrate that exaggerated LTB4/BLT1 responses mediate a derailed inflammatory milieu that underlies poor host defense in diabetes. Prevention of LTB4 production/actions could provide a new therapeutic strategy to restore host defense in diabetes.
The early events that shape the innate immune response to restrain pathogens during skin infections remain elusive. Methicillin-resistant Staphylococcus aureus (MRSA) infection engages phagocyte chemotaxis, abscess formation, and microbial clearance. Upon infection, neutrophils and monocytes find a gradient of chemoattractants that influence both phagocyte direction and microbial clearance. The bioactive lipid leukotriene B4 (LTB4) is quickly (seconds to minutes) produced by 5-lipoxygenase (5-LO) and signals through the G protein-coupled receptors LTB4R1 (BLT1) or BLT2 in phagocytes and structural cells. Although it is known that LTB4 enhances antimicrobial effector functions in vitro, whether prompt LTB4 production is required for bacterial clearance and development of an inflammatory milieu necessary for abscess formation to restrain pathogen dissemination is unknown. We found that LTB4 is produced in areas near the abscess and BLT1 deficient mice are unable to form an abscess, elicit neutrophil chemotaxis, generation of neutrophil and monocyte chemokines, as well as reactive oxygen species-dependent bacterial clearance. We also found that an ointment containing LTB4 synergizes with antibiotics to eliminate MRSA potently. Here, we uncovered a heretofore unknown role of macrophage-derived LTB4 in orchestrating the chemoattractant gradient required for abscess formation, while amplifying antimicrobial effector functions.
BACKGROUND - Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is one of the most common causes of skin and soft tissue infections in the United States, and a variety of genetic host factors are suspected to be risk factors for recurrent infection. Based on the CDC definition, we have developed and validated an electronic health record (EHR) based CA-MRSA phenotype algorithm utilizing both structured and unstructured data.
METHODS - The algorithm was validated at three eMERGE consortium sites, and positive predictive value, negative predictive value and sensitivity, were calculated. The algorithm was then run and data collected across seven total sites. The resulting data was used in GWAS analysis.
RESULTS - Across seven sites, the CA-MRSA phenotype algorithm identified a total of 349 cases and 7761 controls among the genotyped European and African American biobank populations. PPV ranged from 68 to 100% for cases and 96 to 100% for controls; sensitivity ranged from 94 to 100% for cases and 75 to 100% for controls. Frequency of cases in the populations varied widely by site. There were no plausible GWAS-significant (p < 5 E -8) findings.
CONCLUSIONS - Differences in EHR data representation and screening patterns across sites may have affected identification of cases and controls and accounted for varying frequencies across sites. Future work identifying these patterns is necessary.
BACKGROUND - Prevalence of Staphylococcus aureus community-acquired pneumonia (CAP) and its clinical features remain incompletely understood, complicating empirical selection of antibiotics.
METHODS - Using a multicenter, prospective surveillance study of adults hospitalized with CAP, we calculated the prevalence of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) among all CAP episodes. We compared the epidemiologic, radiographic, and clinical characteristics of S. aureus CAP (per respiratory or blood culture) with those of pneumococcal (per respiratory or blood culture or urine antigen) and all-cause non-S. aureus CAP using descriptive statistics.
RESULTS - Among 2259 adults hospitalized for CAP, 37 (1.6%) had S. aureus identified, including 15 (0.7%) with MRSA and 22 (1.0%) with MSSA; 115 (5.1%) had Streptococcus pneumoniae Vancomycin or linezolid was administered to 674 (29.8%) patients within the first 3 days of hospitalization. Chronic hemodialysis use was more common among patients with MRSA (20.0%) than pneumococcal (2.6%) and all-cause non-S. aureus (3.7%) CAP. Otherwise, clinical features at admission were similar, including concurrent influenza infection, hemoptysis, multilobar infiltrates, and prehospital antibiotics. Patients with MRSA CAP had more severe clinical outcomes than those with pneumococcal CAP, including intensive care unit admission (86.7% vs 34.8%) and in-patient mortality (13.3% vs 4.4%).
CONCLUSIONS - Despite very low prevalence of S. aureus and, specifically, MRSA, nearly one-third of adults hospitalized with CAP received anti-MRSA antibiotics. The clinical presentation of MRSA CAP overlapped substantially with pneumococcal CAP, highlighting the challenge of accurately targeting empirical anti-MRSA antibiotics with currently available clinical tools and the need for new diagnostic strategies.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail email@example.com.
BACKGROUND - Infectious complications of musculoskeletal trauma are an important factor contributing to patient morbidity. Biofilm-dispersive bone grafts augmented with D-amino acids (D-AAs) prevent biofilm formation in vitro and in vivo, but the effects of D-AAs on osteocompatibility and new bone formation have not been investigated.
QUESTIONS/PURPOSES - We asked: (1) Do D-AAs hinder osteoblast and osteoclast differentiation in vitro? (2) Does local delivery of D-AAs from low-viscosity bone grafts inhibit new bone formation in a large-animal model?
METHODS - Methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus clinical isolates, mouse bone marrow stromal cells, and osteoclast precursor cells were treated with an equal mass (1:1:1) mixture of D-Pro:D-Met:D-Phe. The effects of the D-AA dose on biofilm inhibition (n = 4), biofilm dispersion (n = 4), and bone marrow stromal cell proliferation (n = 3) were quantitatively measured by crystal violet staining. Osteoblast differentiation was quantitatively assessed by alkaline phosphatase staining, von Kossa staining, and quantitative reverse transcription for the osteogenic factors a1Col1 and Ocn (n = 3). Osteoclast differentiation was quantitatively measured by tartrate-resistant acid phosphatase staining (n = 3). Bone grafts augmented with 0 or 200 mmol/L D-AAs were injected in ovine femoral condyle defects in four sheep. New bone formation was evaluated by μCT and histology 4 months later. An a priori power analysis indicated that a sample size of four would detect a 7.5% difference of bone volume/total volume between groups assuming a mean and SD of 30% and 5%, respectively, with a power of 80% and an alpha level of 0.05 using a two-tailed t-test between the means of two independent samples.
RESULTS - Bone marrow stromal cell proliferation, osteoblast differentiation, and osteoclast differentiation were inhibited at D-AAs concentrations of 27 mmol/L or greater in a dose-responsive manner in vitro (p < 0.05). In methicillin-sensitive and methicillin-resistant S aureus clinical isolates, D-AAs inhibited biofilm formation at concentrations of 13.5 mmol/L or greater in vitro (p < 0.05). Local delivery of D-AAs from low-viscosity grafts did not inhibit new bone formation in a large-animal model pilot study (0 mmol/L D-AAs: bone volume/total volume = 26.9% ± 4.1%; 200 mmol/L D-AAs: bone volume/total volume = 28.3% ± 15.4%; mean difference with 95% CI = -1.4; p = 0.13).
CONCLUSIONS - D-AAs inhibit biofilm formation, bone marrow stromal cell proliferation, osteoblast differentiation, and osteoclast differentiation in vitro in a dose-responsive manner. Local delivery of D-AAs from bone grafts did not inhibit new bone formation in vivo at clinically relevant doses.
CLINICAL RELEVANCE - Local delivery of D-AAs is an effective antibiofilm strategy that does not appear to inhibit bone repair. Longitudinal studies investigating bacterial burden, bone formation, and bone remodeling in contaminated defects as a function of D-AA dose are required to further support the use of D-AAs in the clinical management of infected open fractures.
BACKGROUND - The use of cardiac implantable electronic devices (CIEDs) has expanded dramatically over the past decade, but net clinical benefit has been curtailed by increasing infectious complications. In particular, CIED-related infectious endocarditis (IE) is a serious condition with significant morbidity and mortality.
METHODS - We performed a single-center, retrospective study between July 2006 and February 2011 with CIED-related IE, defined by either lead vegetations detected on echocardiography or by fulfilling Duke criteria for definite endocarditis. Clinical parameters and outcomes were detailed by electronic medical record review and vital status was confirmed by the Social Security Death Index.
RESULTS - Eighty patients (median age 67, interquartile range 56-75, 58 M/22 F) were diagnosed with CIED-related IE. Overall mortality was 36% with a median time to death of 95 days from presentation. Over half (52%) of the deaths were infection related with a median time to death of 29 days. Multivariate analysis showed methicillin-resistant Staphylococcus aureus (MRSA) infection (odds ratio [OR] 0.158; 95% confidence interval [CI], 0.047-0.534; P = .003) and concomitant valve endocarditis (OR 0.141, CI 0.041-0.491, P = .002) independently predicted mortality.
CONCLUSION - In this contemporary series, all-cause mortality in patients with CIED-related IE was high with a short time to death from onset of infection. MRSA and concomitant valve infection were the most powerful independent predictors of mortality.
©2014 Wiley Periodicals, Inc.
In "A Genetic resource for Rapid and Comprehensive Phenotype Screening of Nonessential Staphylococcus aureus Genes" (mBio 4(2):e00537-12, doi: 10.1128/mBio.00537-12, 2013), Fey et al. describe the creation and application of a defined transposon mutant library of methicillin-resistant S. aureus. This library is well organized and made accessible to the research community through an easily navigable central repository. The mutant library promises to be a significant resource for researchers seeking a greater understanding of this pathogen.
Staphylococcus bacteremia is a common and life-threatening medical emergency, but it is treatable with appropriate antibiotic therapy. To identify opportunities that may reduce morbidity and mortality associated with S. aureus, we analyzed data from 293,094 chronic hemodialysis outpatients to characterize practices of antibiotic selection. In the study population, the overall rate of bacteremia was 15.4 per 100 outpatient-years; the incidence rate for methicillin-sensitive (MSSA) was 2.1 per 100 outpatient-years, and the incidence rate for methicillin-resistant (MRSA) S. aureus was 1.9 per 100 outpatient-years. One week after the collection of the index blood culture, 56.1% of outpatients with MSSA bacteremia were receiving vancomycin, and 16.7% of outpatients with MSSA were receiving cefazolin. Among MSSA-bacteremic patients who did not die or get hospitalized 1 week after blood culture collection, use of cefazolin was associated with a 38% lower risk for hospitalization or death compared with vancomycin (adjusted HR=0.62, 95% CI=0.46-0.84). In conclusion, vancomycin is commonly used to treat MSSA bacteremia in outpatients receiving chronic dialysis, but there may be more risk of treatment failure than observed among those individuals who receive a β-lactam antibiotic such as cefazolin.
BACKGROUND - Patients with AIDS incur higher rates of infection than the general population. However, little evidence exists to guide family physicians in selecting antibiotics for initial empiric therapy for suspected septicemia.
METHODS - We recorded the causative organisms of septicemia (defined here as bacteremia, fungemia, or both) in 83 patients with AIDS admitted to the teaching hospitals of the University of Louisville from 1996 to 2006. All patients fulfilled the requirements for a diagnosis of AIDS on the basis of the 1993 Centers for Disease Control criteria. In addition to the causative organism, demographic information, immunologic data, portal of entry, and mortality were collected.
RESULTS - Only 53% of the patients presented with fever and the median leukocyte count was 4400 cells/mm(3). The most common organisms causing septicemia were, in decreasing order, methicillin-sensitive Staphylococcus aureus (MRSA; n = 21; 21.4%), Mycobacterium avium complex (n = 10; 10.2%), coagulase-negative staphylococci (n = 9; 9.2%) and Streptococcus pneumoniae (n = 9; 9.2%). Other pathogens included Escherichia coli, Pseudomonas aeruginosa, and MRSA. Polymicrobial septicemia was identified in 12 cases (14.5% of the episodes). The portals of entry of the organism were (in decreasing order) primary, lung, intravascular line, and skin. The types of organisms found in patients with primary septicemia patterned those found overall. The mortality rate was 12.1%.
CONCLUSIONS - AIDS patients with septicemia may not present with the signs that would a non-AIDS patient with septicemia. On the basis of the range of organisms identified in this study, antibiotic coverage of AIDS patients with suspected septicemia, both in primary septicemia and septicemia overall, should take into consideration bacteremia with a wide range of organisms: Gram-positive organisms including MRSA and M. avium complex and Gram-negative organisms including Pseudomonas species. In addition, physicians should be aware that polymicrobial septicemia may be present.