Dysfunctional accessory gene regulator (agr) as a prognostic factor in invasive Staphylococcus aureus infection: a systematic review and meta-analysis

AbstractThe accessory gene regulator (agr) locus of Staphylococcus aureus is a quorum-sensing virulence regulator. Although there are many studies concerning the effect of dysfunctional agr on the outcomes of S. aureus infection, there is no systematic review to date. We systematically searched for clinical studies reporting outcomes of invasive S. aureus infections and the proportion of dysfunctional agr among their causative strains, and we performed a meta-analysis to obtain estimates of the odds of outcomes of invasive S. aureus infection with dysfunctional versus functional agr. Of 289 articles identified by our research strategy, 20 studies were meta-analysed for crude analysis of the impact of dysfunctional agr on outcomes of invasive S. aureus infection. Dysfunctional agr was generally associated with unfavourable outcomes (OR 1.32, 95% CI 1.05–1.66), and the impact of dysfunctional agr on outcome was more prominent in invasive methicillin-resistant S. aureus (MRSA) infections (OR 1.54, CI 1.20–1.97). Nine studies were meta-analysed for the impact of dysfunctional agr on the 30-day mortality of invasive S. aureus infection. Invasive MRSA infection with dysfunctional agr exhibited higher 30-day mortality (OR 1.40, CI 1.03–1.90) than that with functional agr. On the other hand, invasive MSSA infection with dysfunctional agr exhibited lower 30-day mortality (OR 0.51, CI 0.27–0.95). In the post hoc subgroup analysis by the site of MRSA infection, dysfunctional agr was associated with higher 30-day mortality in MRSA pneumonia (OR 2.48, CI 1.17–5.25). The effect of dysfunctional agr on the outcome of invasive S. aureus infection may vary depending on various conditions, such as oxacillin susceptibility and the site of infection. Dysfunctional agr was generally associated with unfavourable clinical outcomes and its effect was prominent in MRSA and pneumonia. Dysfunctional agr may be applicable for outcome prediction in cases of invasive MRSA infection with hardly eradicable foci such as pneumonia.

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Contribution of Lactococcus lactis Reducing Properties to the Downregulation of a Major Virulence Regulator in Staphylococcus aureus, theagrSystem

Applied and Environmental Microbiology ◽

10.1128/aem.02287-14 ◽

2014 ◽

Vol 80 (22) ◽

pp. 7028-7035 ◽

Cited By ~ 16

Author(s):

Sébastien Nouaille ◽

Lucie Rault ◽

Sophie Jeanson ◽

Pascal Loubière ◽

Yves Le Loir ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Lactic Acid ◽

Lactococcus Lactis ◽

Response Regulator ◽

Food Poisoning ◽

Accessory Gene ◽

Content Type ◽

Accessory Gene Regulator ◽

Virulence Regulator ◽

Reducing Properties

ABSTRACTStaphylococcus aureusis a major cause of food poisoning outbreaks associated with dairy products, because of the ingestion of preformed enterotoxins. The biocontrol ofS. aureususing lactic acid bacteria (LAB) offers a promising opportunity to fight this pathogen while respecting the product ecosystem. We had previously established the ability ofLactococcus lactis, a lactic acid bacterium widely used in the dairy industry, to downregulate a major staphylococcal virulence regulator, the accessory gene regulator (agr) system, and, as a consequence,agr-controlled enterotoxins. In the present paper, we have shown that the oxygen-independent reducing properties ofL. lactiscontribute toagrdownregulation. Neutralizing lactococcal reduction by adding potassium ferricyanide or maintaining the oxygen pressure constant at 50% releasedagrdownregulation in the presence ofL. lactis. This downregulation still occurred in anS. aureus srrAmutant, indicating that the staphylococcal respiratory response regulator SrrAB was not the only component in the signaling pathway. Therefore, this study clearly demonstrates the ability ofL. lactisreducing properties to interfere with the expression ofS. aureusvirulence, thus highlighting this general property of LAB as a lever to control the virulence expression of this major pathogen in a food context and beyond.

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Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05453-11 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3712-3719 ◽

Cited By ~ 19

Author(s):

Brian T. Tsuji ◽

Tanya Brown ◽

Ridhi Parasrampuria ◽

Daniel A. Brazeau ◽

Alan Forrest ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Growth Control ◽

Study Endpoint ◽

Infection Model ◽

Accessory Gene ◽

Bacterial Killing ◽

Content Type ◽

Accessory Gene Regulator ◽

Pharmacodynamic Profile ◽

The Impact

ABSTRACTFront loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded byagr) in methicillin-resistantStaphylococcus aureus(MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 106CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log10CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of −6.15 and −6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27× increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.

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Identification and characterization of msa (SA1233), a gene involved in expression of SarA and several virulence factors in Staphylococcus aureus

Microbiology ◽

10.1099/mic.0.29071-0 ◽

2006 ◽

Vol 152 (9) ◽

pp. 2559-2572 ◽

Cited By ~ 26

Author(s):

Karthik Sambanthamoorthy ◽

Mark S. Smeltzer ◽

Mohamed O. Elasri

Keyword(s):

Staphylococcus Aureus ◽

Virulence Factors ◽

Protein A ◽

Laboratory Strain ◽

Reporter System ◽

Accessory Gene ◽

Accessory Gene Regulator ◽

Genes Encoding ◽

Membrane Spanning ◽

The Impact

The staphylococcal accessory regulator (sarA) plays a central role in the regulation of virulence in Staphylococcus aureus. To date, studies involving sarA have focused on its activity as a global regulator that modulates transcription of a wide variety of genes (>100) and its role in virulence. However, there is also evidence to suggest the existence of accessory elements that modulate SarA production and/or function. A reporter system was developed to identify such elements, and a new gene, msa (SA1233), mutation of which results in reduced expression of SarA, was identified and characterized. Additionally, it was shown that mutation of msa resulted in altered transcription of the accessory gene regulator (agr) and the genes encoding several virulence factors including alpha toxin (hla) and protein A (spa). However, the impact of mutating msa was different in the laboratory strain RN6390 and the clinical isolate UAMS-1. For instance, mutation of msa caused a decrease in spa and hla transcription in RN6390 but had a different effect in UAMS-1. The strain-dependent effects of the msa mutation were similar to those observed previously, which suggests that msa may modulate the production of specific virulence factors through its impact on sarA. Interestingly, sequence analysis of Msa suggests that it is a putative membrane protein with three membrane-spanning regions, indicating that Msa might interact with the environment. The findings show that msa is involved in the expression of SarA and several virulence factors.

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The Impact of Infectious Disease Specialist Consultation for Staphylococcus aureus Bloodstream Infections: A Systematic Review

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw048 ◽

2016 ◽

Vol 3 (2) ◽

Cited By ~ 35

Author(s):

Julie Paulsen ◽

Erik Solligård ◽

Jan Kristian Damås ◽

Andrew DeWan ◽

Bjørn Olav Åsvold ◽

...

Keyword(s):

Infectious Disease ◽

Systematic Review ◽

Staphylococcus Aureus ◽

Meta Analysis ◽

Management Strategies ◽

Bloodstream Infections ◽

Risk Of Bias ◽

Infectious Disease Specialist ◽

The Impact ◽

Disease Specialist

Abstract Staphylococcus aureus is a common cause of severe bloodstream infection. We performed a systematic review to assess whether consultation with infectious disease specialists decreased all-cause mortality or rate of complications of S aureus bloodstream infections. The review also assessed parameters associated with the quality of management of the infection. We searched for eligible studies in PubMed, Embase, Scopus, and clinical trials.gov as well as the references of included studies. We identified 22 observational studies and 1 study protocol for a randomized trial. A meta-analysis was not performed because of the high risk of bias in the included studies. The outcomes are reported in a narrative review. Most included studies reported survival benefit, in the adjusted analysis. Recommended management strategies were carried out significantly more often among patients seen by an infectious disease specialist. Trials, such as cluster-randomized controlled trials, can more validly assess the studies at low risk of bias.

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