RESUMEN
Chemokines are best recognized for their role within the innate immune system as chemotactic cytokines, signaling and recruiting host immune cells to sites of infection. Certain chemokines, such as CXCL10, have been found to play an additional role in innate immunity, mediating CXCR3-independent killing of a diverse array of pathogenic microorganisms. While this is still not clearly understood, elucidating the mechanisms underlying chemokine-mediated antimicrobial activity may facilitate the development of novel therapeutic strategies effective against antibiotic-resistant Gram-negative pathogens. Here, we show that CXCL10 exerts antibacterial effects on clinical and laboratory strains of Escherichia coli and report that disruption of pyruvate dehydrogenase complex (PDHc), which converts pyruvate to acetyl coenzyme A, enables E. coli to resist these antimicrobial effects. Through generation and screening of a transposon mutant library, we identified two mutants with increased resistance to CXCL10, both with unique disruptions of the gene encoding the E1 subunit of PDHc, aceE. Resistance to CXCL10 also occurred following deletion of either aceF or lpdA, genes that encode the remaining two subunits of PDHc. Although PDHc resides within the bacterial cytosol, electron microscopy revealed localization of immunogold-labeled CXCL10 to the bacterial cell surface in both the E. coli parent and aceE deletion mutant strains. Taken together, our findings suggest that while CXCL10 interacts with an as-yet-unidentified component on the cell surface, PDHc is an important mediator of killing by CXCL10. To our knowledge, this is the first description of PDHc as a key bacterial component involved in the antibacterial effect of a chemokine.
Asunto(s)
Antibacterianos/metabolismo , Proteínas de la Membrana Bacteriana Externa/metabolismo , Quimiocina CXCL10/metabolismo , Inmunidad Innata/inmunología , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Sitios de Unión , Dihidrolipoamida Deshidrogenasa/genética , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/genética , Farmacorresistencia Bacteriana Múltiple/genética , Escherichia coli , Técnicas de Inactivación de Genes , Humanos , Unión Proteica , Piruvato Deshidrogenasa (Lipoamida)/genéticaRESUMEN
Diagnostic stewardship seeks to improve ordering, collection, performance, and reporting of tests. Test results play an important role in reportable HAIs. The inclusion of HAIs in public reporting and pay for performance programs has highlighted the value of diagnostic stewardship as part of infection prevention initiatives. Inappropriate testing should be discouraged, and approaches that seek to alter testing solely to impact a reportable metric should be avoided. HAI definitions should be further adapted to new testing technologies, with focus on actionable and clinically relevant test results that will improve patient care.
Asunto(s)
Infección Hospitalaria , Reembolso de Incentivo , Humanos , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/prevención & control , Encuestas y Cuestionarios , Benchmarking , Atención a la SaludRESUMEN
BACKGROUND: The American Heart Association (AHA) guidelines for infective endocarditis (IE) management recommend end-of-therapy (EOT) echocardiography (ETE) to "establish a new baseline" and based on "expert opinion." METHODS: Medical records of IE patients treated between January 2005 and December 2011 were reviewed. Utilization of ETE and cumulative incidence of re-treatment with antimicrobials or cardiovascular surgery (re-Rx/CVS) within 1 year after EOT were evaluated. RESULTS: A total of 243 patients completed clinical follow-up at EOT and 170 at 1 year after EOT. One hundred seventy-seven of 243 (72.8%) underwent ETE, the majority (51.4%) transthoracic echocardiography. One hundred thirty-three of 177 (75.1%) were without new/worsened signs or symptoms (new/w-SSx). One hundred forty-one of 177 (79.7%) overall and 117/133 (87.9%) patients without new/w-SSx had no new ETE findings as compared with initial echocardiography. Among 36/177 (20.3%) with new ETE findings, 20/36 (55.6%) had new/w-SSx; ETE findings were more likely in patients with new/w-SSx (39.2% vs 8.3%; Pâ <â 0.001) at EOT. Patients were at increased risk of re-Rx/CVS with either new ETE findings (hazard ratio [HR], 25.86; 95% confidence interval [CI], 7.64-87.56; Pâ <â .001) or new/w-SSx (HR, 5.35; 95% CI, 2.87-9.95; Pâ <â .001). The highest risk of re-Rx/CVS was in patients with both new/w-SSx and new ETE findings (HR, 45.94; 95% CI, 19.07-110.71). Conversely, only 7/187 (3.4%) patients without new/w-SSx who had an ETE required re-Rx/CVS. CONCLUSIONS: The majority of patients without new/w-SSx at EOT will not have new ETE findings or need re-Rx/CVS within 1 year after EOT. EOT new/w-SSx is associated with new ETE findings and predicts the need for re-Rx/CVS. Further study is needed to determine whether patients without new/w-SSx need ETE.