The glutathione import system satisfies the Staphylococcus aureus nutrient sulfur requirement and promotes interspecies competition.

Sulfur is an indispensable element for bacterial proliferation. Prior studies demonstrated that the human pathogen Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a five-gene locus comprising a putative ABC-transporter and predicted γ-glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter operon the glutathione import system (gisABCD). Ggt is encoded within the gisBCD operon, and we show that the enzyme is capable of liberating glutamate using either GSH or GSSG as substrates, demonstrating it is a bona fide γ-glutamyl transpeptidase. We also determine that Ggt is expressed in the cytoplasm, representing only the second example of cytoplasmic Ggt localization, the other being Neisseria meningitidis. Bioinformatic analyses revealed that Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologs. However, homologous systems were not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH- and GSSG-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSSG in addition to GSH and promotes competition against other staphylococci commonly associated with the human microbiota.

The Hypothetical Impact of Accelerate Pheno on Time to Effective Therapy and Time to Definitive Therapy for Bloodstream Infections Due to Drug-Resistant Gram-Negative Bacilli.

Strategies are needed to improve time to optimal therapy in patients with bloodstream infections (BSI) due to resistant Gram-negative (GN) pathogens. Accelerate Pheno (ACC) can provide antimicrobial susceptibility results within 7 h of a positive culture and may more rapidly optimize therapy. The primary objective of this study was to evaluate the hypothetical impact of ACC on time to effective therapy (TTET) and time to definitive therapy (TTDT) among patients with BSI due to resistant GN pathogens. ACC was performed on resistant GN BSI isolates, and results were not available to clinicians in real time. A potential benefit of having ACC on TTET or TTDT was determined if modifications to antimicrobial regimens could have been made sooner with ACC. Comparisons on the impact of ACC in the presence or absence of testing by the Verigene Gram-negative blood culture test (Verigene GN-BC) were performed. Sixty-one patients with resistant GN BSI were evaluated. The median actual TTET and TTDT in the cohort were 25.9 h (interquartile range [IQR], 18.5, 42.1) and 47.6 h (IQR, 24.9, 79.6), respectively. Almost half of the patients had potential improvement in TTET and/or TTDT with ACC. In patients who would have had a benefit the median potential decreases in TTET and TTDT were 16.6 h (IQR, 5.5 to 30.6) and 29.8 h (IQR, 13.6 to 43), respectively. The largest potential improvements were seen in patients for whom Verigene results were not available. In conclusion, among patients with resistant GN BSI in a setting where other rapid diagnostic technologies are utilized, ACC results could have further improved TTET and TTDT.

The hypothetical impact of Accelerate Pheno™ system on time to effective therapy and time to definitive therapy in an institution with an established antimicrobial stewardship programme currently utilizing rapid genotypic organism/resistance marker identification.

Background: Rapid organism identification and antimicrobial susceptibility testing (AST) can optimize antimicrobial therapy in patients with bacteraemia. The Accelerate Pheno™ system (ACC) can provide identification and AST results within 7 h of a positive culture. Objectives: To assess the hypothetical impact of ACC on time to effective therapy (TTET), time to definitive therapy (TTDT) and antimicrobial usage at the Detroit Medical Center (DMC). Methods: Patients with positive blood cultures from 29 March to 24 June 2016 were included. ACC was performed in parallel with normal laboratory procedures, but results were not made available to the clinicians. The potential benefit of having ACC results was determined if clinicians modified therapy based on actual AST results. Potential changes in TTET, TTDT and antibiotic usage were calculated. Results: One hundred and sixty-seven patients were included. The median TTET was 2.4 h (IQR 0.5, 15.1). Had ACC results been available, TTET could have been improved in four patients (2.4%), by a median decrease of 18.9 h (IQR 11.3, 20.4). The median TTDT was 41.4 h (IQR 21.7, 73.3) and ACC results could have improved TTDT among 51 patients (30.5%), by a median decrease of 25.4 h (IQR 18.7, 37.5). ACC implementation could have led to decreases in usage of cefepime (16% reduction), aminoglycosides (23%), piperacillin/tazobactam (8%) and vancomycin (4%). Conclusions: ACC results could potentially improve time to de-escalation and reduce use of antimicrobials. The impact of ACC on TTET was small, likely related to the availability of other rapid diagnostic tests at DMC.

Long-Acting Lipoglycopeptides for the Treatment of Bone and Joint Infections.

Background: The long-acting lipoglycopeptides dalbavancin and oritavancin possess excellent microbiologic activity against gram-positive bacteria and provide prolonged tissue exposure at sites of infection. Moreover, these antibiotics are well tolerated and do not require therapeutic drug monitoring. Methods: Pharmacokinetic/pharmacodynamic experiments ascertained that one to two doses of these long-acting agents can provide an extended period (≥6 weeks) of antimicrobial therapy. Results: Clinical studies subsequently found that microbiologic and clinical response rates with these agents were comparable to standard antibiotic agents used in the treatment of bone and joint infections. In addition, pharmacoeconomic analyses have discovered cost savings with the use of these antimicrobial agents in the treatment of serious deep-seated bacterial infections. Conclusions: Thus, these long-acting lipoglycopeptides offer potential for cost-effective outpatient parenteral antibiotic therapy of difficult to treat infections, such as osteomyelitis.

Exercise and Cardioprotection: A Natural Defense Against Lethal Myocardial Ischemia-Reperfusion Injury and Potential Guide to Cardiovascular Prophylaxis.

Similar to ischemic preconditioning, high-intensity exercise has been shown to decrease infarct size following myocardial infarction. In this article, we review the literature on beneficial effects of exercise, exercise requirements for cardioprotection, common methods utilized in laboratories to study this phenomenon, and discuss possible mechanisms for exercise-mediated cardioprotection.

Prevention of Infection Due to Clostridium difficile.

Clostridium difficile is one of the foremost nosocomial pathogens. Preventing infection is particularly challenging. Effective prevention efforts typically require a multifaceted bundled approach. A variety of infection control procedures may be advantageous, including strict hand decontamination with soap and water, contact precautions, and using chlorine-containing decontamination agents. Additionally, risk factor reduction can help reduce the burden of disease. The risk factor modification is principally accomplished though antibiotic stewardship programs. Unfortunately, most of the current evidence for prevention is in acute care settings. This review focuses on preventative approaches to reduce the incidence of Clostridium difficile infection in healthcare settings.