Methicillin-resistant Staphylococcus Aureus Bacteremia Research Articles

Rosmarinic Acid Restores the Ceftiofur Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus by Inhibiting Sortase A.

Methicillin-resistant Staphylococcus aureus (MRSA), one of the most important zoonotic bacterial pathogens, necessitates innovative antibacterial strategies. Rosmarinic acid (RA) possesses various biological functions, including antibacterial and anti-inflammatory effects. This study aimed to explore the synergistic effects and mechanism of RA in conjunction with ceftiofur (CF) against MRSA. Results showed that the combination of RA and CF demonstrated synergistic anti-MRSA activity, conferring protective effects in an MRSA bacteremia mouse model. Mechanistic investigations further established that RA interacts with sortase A (SrtA) through hydrogen bonds, electrostatic, and van der Waals forces at critical sites, leading to the reversible inhibition of SrtA activity. Consequently, this inhibition impeded the ability of MRSA to invade cells and form biofilms. Conclusively, RA directly inhibits SrtA activity, thus enhancing the synergistic anti-MRSA effect of CF. These findings provide a theoretical foundation for the use of RA in combination with CF as a therapeutic strategy for MRSA infections.

Time from Admission to the Onset of Methicillin-Resistant Staphylococcus aureus Bacteremia in a Single Acute Care Hospital in Japan.

The spread of antimicrobial resistant organisms (AROs) poses a major threat to animal and human health. In Japan, the estimated disability-adjusted life years (DALYs) due to ARO infections is 137.9 per 100,000 persons, with methicillin-resistant Staphylococcus aureus (MRSA) being the main contributor. Factors that can contribute to DALYs in Japan include younger age and a higher number of deaths in patients with MRSA bacteremia. Moreover, longer hospital stays may contribute to the higher rates of MRSA bacteremia in Japan than in western countries. We reviewed the diagnostic procedure combination data collected from January 1, 2016 to December 31, 2020, in an acute care hospital in Tokyo, Japan. We found that the median time from admission to MRSA bacteremia onset was 26 days, which is longer than that observed in western countries however similar to that in South Korea. Furthermore, our cohort was older than those in the United States and South Korea, potentially contributing to the higher number of years of life lost in Japan. These results underscore the need to develop strategies to reduce hospitalization rates in Japan. Larger multicenter studies are needed to comprehensively evaluate the economic and health burdens of MRSA bacteremia in Japan.

Association of Antibiotic Route and Outcomes in Children with Methicillin-Resistant Staphylococcus aureus Bacteremic Osteomyelitis.

There remains uncertainty about whether transitioning to oral antibiotic therapy is appropriate for the management of children with methicillin-resistant Staphylococcus aureus (MRSA) bacteremic osteomyelitis. We compared clinical outcomes for children with MRSA osteomyelitis with associated bacteremia who were transitioned to discharge oral antibiotic therapy to those discharged on outpatient parenteral antibiotic therapy (OPAT). We performed a retrospective, multicenter, cohort study of children ≤ 18 years hospitalized with MRSA bacteremic osteomyelitis across four children's hospitals from 2007 to 2018 discharged on oral antibiotic therapy versus OPAT. The primary outcome was treatment failure within 6 months of discharge, defined as any of the following: diagnosis of chronic osteomyelitis, conversion from oral to IV antibiotic route, an operative procedure after the index hospitalization (abscess drainage, bone biopsy, arthrocentesis, or pathologic fracture) and/or recrudescence of MRSA bacteremia. Outcomes were analyzed in an inverse propensity score weighted (IPW) cohort. A total of 106 cases of MRSA bacteremic osteomyelitis were included; 44 (42%) were discharged in the oral antibiotic therapy group and 62 (59%) patients were discharged in the OPAT group. In the IPW cohort, treatment failure within 6 months of discharge occurred in 3.4% of children in the discharge oral therapy group and 16.3% in the OPAT group (P = 0.03). The odds of 6-month composite treatment failure between discharge oral therapy and OPAT were 0.18 (95% CI 0.05-0.61). Discharge oral therapy was not associated with higher rates of treatment failure compared to OPAT for children with MRSA bacteremic osteomyelitis.

Clinical characteristics and genomic changes of recurrent Methicillin‐Resistant Staphylococcus aureus bacteremia

BackgroundRecurrent or persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia presents significant clinical challenges. Comprehensive genomic-scale studies on the genetic changes in MRSA that correspond to refractory bacteremia are lacking. MethodFrom 2011 to 2019, MRSA blood isolates were collected from patients with persistent or recurrent bacteremia at a teaching hospital in southern Taiwan. Whole-genome sequencing (WGS) captured the genomic changes in strains responsible for refractory bacteremia, and the altered susceptibilities to specific antimicrobial agents were assessed through measurements of minimal inhibitory concentrations (MICs). ResultA total of 35 MRSA blood isolates from 15 patients with recurrent or persistent bacteremia were analyzed. Reduced susceptibilities to at least one anti-MRSA agent developed in strains from seven (46.7 %) patients. Of them, a non-synonymous mutation on a global regulator mgrA was associated with reduced daptomycin susceptibility, while an increase in vancomycin MIC was linked to mutations in genes encoding LCP family protein. A 16-fold increase in MIC to fusidic acid was connected to a mutation in the elongation factor G. These recurrent strains commonly exhibited a loss or acquisition of adhesion genes that were involved in biofilm formation, including fnbA, fnbB, and sdrD, and easG series genes of type VII secretion system. ConclusionChanges in the susceptibility of successive strains to common anti-MRSA agents were frequently observed in recurrent MRSA bacteremia. These changes were linked to modifications in genes of regulatory cascade, peptidoglycan binding, adhesion, and type VII secretion system.

Clinical outcome of combination of vancomycin and ceftaroline versus vancomycin monotherapy for treatment of methicillin resistant Staphylococcus aureus bloodstream infection

BackgroundThe role of combination therapies for serious methicillin-resistant Staphylococcus aureus (MRSA) infections is widely debated.MethodsThis retrospective cohort study included adults with MRSA bacteraemia treated between January 1, 2013, to December 31, 2022. Patients receiving combination therapy with vancomycin and ceftaroline were matched in a 2:1 ratio with those on vancomycin monotherapy based on bacteraemia source and illness severity. The primary outcome was frequency of bacteraemia recurrence. Secondary outcomes were all cause 30/90-day mortality, recurrence or mortality at 30/90 days and in hospital length of stay.ResultsOf 57 patients included, 37 (65%) were in the combination group. The overall intensive care unit admission rate was 63.2% (36/57) and the Pitt Bacteraemia Score was 1 [0–4] at the time of diagnosis. The most common source of infection was endovascular/endocarditis (n = 36, 63.2%). Demographic and clinical characteristics were similar between the monotherapy and combination group of patients, except for higher body mass index (32.5 [25.5–36.4] vs. 24.4 [20.9–29], p = 0.004) and a greater immunosuppression prevalence (3 (15%) vs. 0 (0%), p = 0.039) in monotherapy group. There was no significant difference in bacteraemia recurrence (3 (15%) vs. 4 (10.8%), p = 0.7) or all-cause 30-day mortality (3 (15%) vs. 4 (10.8%), p = 0.7) between the two groups.ConclusionThe results of this study are limited by a retrospective observational design; however, combination of vancomycin and ceftaroline for MRSA bacteraemia was not associated with lower bacteraemia recurrence or mortality compared to vancomycin monotherapy.

Developing and reporting a healthcare-associated infection composite score for health system board review

Background One strategy for supporting a hospital or health system's board of directors (Board), with their quality oversight responsibility is to review the organization's performance on quality measures. But for large systems, the number of measures needing review is quite burdensome and makes priority setting difficult. Our goal was to develop a scoring method that summarizes multiple quality measures together, while still maintaining the Board's opportunity to examine individual measures where there are specific concerns. Methods We calculated an overall health system-level composite performance score using six publicly reported healthcare-associated infections reported by the Centers for Medicare and Medicaid Services on their Care Compare website [central-line associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), surgical site infections (SSIs) for colon surgery and abdominal hysterectomy, hospital-onset Methicillin-resistant Staphylococcus aureus bacteremia (MRSA), and hospital-onset Clostridioides difficile ( C. diff)], where relative weights assigned to each infection type reflect the severity of patient harm. We also calculated a health-system composite performance target. For individual infection types, we calculated system-wide scores and targets and categorized individual hospital performance into three performance categories. Results The health system's composite score between 2015 and 2019 ranged from a high of 1.10 to a low of 0.71. The health system's composite score in 2017–2019 was better than the composite target. Of the 34 measures used to calculate the 2019 composite score, 20 were better than internal standardized infection ratio (SIR) targets, seven were between internal targets and SIR of 1.0, and seven were worse than SIR of 1.0. Discussion The Board communicated they find this composite score reporting approach helpful for streamlining their understanding of HAI performance, as compared to traditional approaches of reporting out individual performance measures. Approaches that streamline Board review of quality and safety performance are important as we hold Board members accountable for overseeing quality, seek greater engagement from the Board, and work to minimize measure review overload.

Complete genome sequencing of three methicillin-resistant Staphylococcus aureus isolated from the blood of patients with persistent bacteremia.

We report the complete genome sequences of three molecular types of methicillin-resistant Staphylococcus aureus (MRSA) clinical strains isolated from the blood of three patients diagnosed with persistent MRSA bacteremia: KNIH_5618 (ST5-t5076-SCCmecII), KNIH_5844 (ST72-t664-SCCmecIV), and KNIH_6268 (ST89-t375-SCCmecII). These genome sequences contribute to an enhanced understanding of the underlying causes of persistent MRSA infection.

In vitro identification of underutilized β-lactam combinations against methicillin-resistant Staphylococcus aureus bacteremia isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an in vitro high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC95) for all isolates tested and lowered daptomycin IC95 below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin IC95s were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce IC95s and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC95. These analyses rationalize further in vivo evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.

Impact of the First Twenty-Four-Hour Area Under the Concentration-Time Curve/Minimum Inhibitory Concentration of Vancomycin on Treatment Outcomes in Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia.

Vancomycin regimens are designed to achieve an area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) ratio ranging between 400 and 600 µg·h/mL in the steady state. However, in cases of critical infections such as bacteremia requiring an early treatment approach, the clinical course may be affected by the AUC/MIC before reaching the steady state, that is, the AUC/MIC values 24 h after the first dose (first 24-h AUC/MIC). This study evaluated the relationship between the first 24-h AUC/MIC and the clinical course of methicillin-resistant Staphylococcus aureus (MRSA) infection. We retrospectively reviewed the records of patients with MRSA bacteremia in a university hospital between 2015 and 2022. The first 24-h AUC/MIC cutoff was set at 300 µg·h/mL based on the results of early response, and eligible patients were divided into groups with a first 24-h AUC/MIC either < 300 µg·h/mL (< 300 group, n = 32) or ≥ 300 µg·h/mL (≥ 300 group, n = 38). The primary endpoint was the rate of treatment efficacy, and the secondary endpoints were time to clinical and bacteriological improvement and 30-day survival rate. Treatment efficacy and 30-day survival rates were not significantly different between the two groups (78.1% vs. 79.0%, P = 0.933 and 83.9% vs. 87.2%, P = 0.674, respectively). Among patients who showed treatment efficacy, the median time to clinical and bacteriological improvement was 11.5 days and 8.0 days in the < 300 and ≥ 300 groups, respectively; compared to the ≥ 300 group, the < 300 group had a significantly longer time to improvement (P = 0.001). The first 24-h AUC/MIC had no effect on the treatment efficacy and 30-day survival rates. However, the time to clinical and bacteriological improvement was significantly prolonged in the < 300 group, indicating that the first 24-h AUC/MIC does not affect the rate of therapeutic efficacy but may affect the treatment period.

18F-FDG whole-body PET/CT for the evaluation of suspected native valve infective endocarditis

18F-FDG-PET/CT is indicated in the workup of patients with suspected infective endocarditis to detect intra-cardiac and disseminated infections, as well as its source. We present the case of a 66-year-old female patient known for recurrent diabetic foot infection, with equivocal TTE results and persistent MRSA bacteremia despite medical management. PET/CT revealed evidence of left foot osteomyelitis. Whole body PET/CT diagnosed native mitral valve infective endocarditis (IE) and right lower lobe segmental pulmonary artery uptake, consistent with septic pulmonary embolism (PE).

In-situ repair of a mycotic thoracoabdominal aortic aneurysm caused by MRSA bacteremia using cryopreserved artery and autogenous vein

Mycotic aortic aneurysm (MAA) is a rare disease process associated with high morbidity and mortality, especially if left untreated. Currently, there is no consensus on optimal management for MAA but early diagnosis is vital for improving chances of survival. Treatment with antibiotics is recommended followed by surgical repair. We present the unique case of a 33-year-old male who presented with a mycotic thoracoabdominal aneurysm that was treated via open in-situ repair with cryopreserved artery, celiac and superior mesenteric artery bypasses, and ligation of bilateral renal arteries. The patient subsequently underwent a successful kidney transplant several years later and currently remains dialysis free. CT imaging at 1-year and 5-years demonstrated patent bypasses without evidence of re-infection or aneurysmal changes to the cryopreserved arterial graft. This case underscores the myriad of challenges associated with managing MAA, while also presenting the opportunities to surmount these challenges through a personalized and multidisciplinary treatment approach.

Short versus long duration of ceftaroline combination therapy and outcomes in persistent or high-grade MRSA bacteremia: A retrospective single-center study.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high mortality rates. Despite antibiotic therapy, persistent bacteremia is challenging to treat. Combination therapy with ceftaroline has emerged as a potential treatment option; however, the optimal duration and clinical implications after bacteremia clearance are unknown. This retrospective cohort study examined patients with high-grade or persistent MRSA bacteremia who were treated with ceftaroline combination therapy at the University of New Mexico Hospital between January 2014 and June 2021. Patients were categorized into short- (<7 days) or long-duration (≥7 days) groups based on the duration of combination therapy after bacteremia clearance. Outcomes included 30-day all-cause mortality, bacteremia recurrence, post-bacteremia clearance length of stay, and adverse events. A total of 32 patients were included in this study. The most common sources of bacteremia were bone/joint and endovascular (28.1%, 9/32 each). The median duration of combination therapy after clearance was seven days (IQR 2.8, 11). Patients in the long-duration group had a lower Charlson comorbidity index (1.0 vs 5.5, p = 0.017) than those in the short-duration group. After adjusting for confounders, there was no significant difference in the 30-day all-cause mortality between the groups (AOR 0.17, 95% CI 0.007-1.85, p = 0.18). No association was found between combination therapy duration and recurrence (OR 2.53, 95% CI 0.19-inf, p = 0.24) or adverse drug events (OR 3.46, 95% CI 0.39-74.86, p = 0.31). After controlling for total hospital length of stay, there was no significant difference in the post-bacteremia clearance length of stay between the two groups (p = 0.37). Prolonging ceftaroline combination therapy after bacteremia clearance did not significantly improve outcomes in patients with persistent or high-grade MRSA bacteremia. The limitations of this study warrant cautious interpretation of its results. Larger studies are needed to determine the optimal duration and role of combination therapy for this difficult-to-treat infection.

Tensor modeling of MRSA bacteremia cytokine and transcriptional patterns reveals coordinated, outcome-associated immunological programs.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a common and life-threatening infection that imposes up to 30% mortality even when appropriate therapy is used. Despite in vitro efficacy determined by minimum inhibitory concentration breakpoints, antibiotics often fail to resolve these infections in vivo, resulting in persistent MRSA bacteremia. Recently, several genetic, epigenetic, and proteomic correlates of persistent outcomes have been identified. However, the extent to which single variables or their composite patterns operate as independent predictors of outcome or reflect shared underlying mechanisms of persistence is unknown. To explore this question, we employed a tensor-based integration of host transcriptional and cytokine datasets across a well-characterized cohort of patients with persistent or resolving MRSA bacteremia outcomes. This method yielded high correlative accuracy with outcomes and immunologic signatures united by transcriptomic and cytokine datasets. Results reveal that patients with persistent MRSA bacteremia (PB) exhibit signals of granulocyte dysfunction, suppressed antigen presentation, and deviated lymphocyte polarization. In contrast, patients with resolving bacteremia (RB) heterogeneously exhibit correlates of robust antigen-presenting cell trafficking and enhanced neutrophil maturation corresponding to appropriate T lymphocyte polarization and B lymphocyte response. These results suggest that transcriptional and cytokine correlates of PB vs. RB outcomes are complex and may not be disclosed by conventional modeling. In this respect, a tensor-based integration approach may help to reveal consensus molecular and cellular mechanisms and their biological interpretation.

Impact of Povidone Application to Nares in Addition to Chlorhexidine Bath in Critically Ill Patients on Nosocomial Bacteremia and Central Line Blood Stream Infection.

Nosocomial Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in a significant increase in morbidity and mortality in hospitalized patients. We aimed to analyze the impact of applying 10% povidone iodine (PI) twice daily to both nares in addition to chlorhexidine (CHG) bathing on nosocomial (MRSA) bacteremia in critically ill patients. A quality improvement study was completed with pre and post-design. The study period was from January 2018 until February 2020 and February 2021 and June 2021. The control period (from January 2018 to May 2019) consisted of CHG bathing alone, and in the intervention period, we added 10% PI to the nares of critically ill patients. Our primary outcome is rates of nosocomial MRSA bacteremia, and our secondary outcome is central line associated blood stream infection (CLABSI) and potential cost savings. There were no significant differences in rates of MRSA bacteremia in critically ill patients. Nosocomial MRSA bacteremia was significantly lower during the intervention period on medical/surgical areas (MSA). CLABSIs were significantly lower during the intervention period in critically ill patients. There were no Staphylococcus aureus CLABSIs in critical care area (CCA)during the intervention period. The intervention showed potential significant cost savings. The application of 10% povidone iodine twice a day in addition to CHG bathing resulted in a significant decrease in CLABSIs in critically ill patients and a reduction in nosocomial MRSA in the non-intervention areas. Further trials are needed to tease out individual patients who will benefit from the intervention.

Combination of Antistaphylococcal β-Lactam With Standard Therapy Compared to Standard Therapy Alone for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia: A Post Hoc Analysis of the CAMERA2 Trial Using a Desirability of Outcome Ranking Approach.

Desirability of outcome ranking (DOOR) is an emerging approach to clinical trial outcome measurement using an ordinal scale to incorporate efficacy and safety endpoints. We applied a previously validated DOOR endpoint to a cohort of CAMERA2 trial participants with methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). Participants were randomly assigned to standard therapy, or to standard therapy plus an antistaphylococcal β-lactam (combination therapy). Each participant was assigned a DOOR category, within which they were further ranked according to their hospital length of stay (LOS) and duration of intravenous antibiotic treatment. We calculated the probability and the generalized odds ratio of participants receiving combination therapy having worse outcomes than those receiving standard therapy. Participants assigned combination therapy had a 54.5% (95% confidence interval [CI], 48.9%-60.1%; P = .11) probability and a 1.2-fold odds (95% CI, .95-1.50; P = .12) of having a worse outcome than participants on standard therapy. When further ranked according to LOS and duration of antibiotic treatment, participants in the combination group had a 55.6% (95% CI, 49.5%-61.7%) and 55.3% (95% CI, 49.2%-61.4%) probability of having a worse outcome than participants in the standard treatment group, respectively. When considering both efficacy and safety, treatment of MRSAB with a combination of standard therapy and a β-lactam likely results in a worse clinical outcome than standard therapy. However, a small benefit of combination therapy cannot be excluded. Most likely the toxicity of combination therapy outweighed any benefit from faster clearance of bacteremia.

Ceftaroline Fosamil for the Treatment of Methicillin-Resistant Staphylococcus Aureus Bacteremia: A Real-World Comparative Clinical Outcomes Study.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in substantial morbidity and mortality. As current treatments often lead to unsatisfactory outcomes, evidence guiding alternative treatment options is needed. This study evaluated real-world clinical outcomes of ceftaroline fosamil for the treatment of MRSA bacteremia. This retrospective study included adults hospitalized with MRSA bacteremia between 2011 and 2019. Patients were classified according to treatment with ceftaroline fosamil (ceftaroline), vancomycin, or daptomycin: Group 1, ceftaroline; Group 2, vancomycin or daptomycin (without ceftaroline); Group 3, combination therapy with ≥ 2 of these three agents. Clinical outcomes were compared using propensity-score-adjusted odds ratios (ORs) from logistic regression models. Overall, 24,479 patients were included (Group 1, n=532; Group 2, n=21,555; Group 3, n=2392). Mean age was 59.6, 60.8, and 57.4 years in Groups 1, 2, and 3, respectively. Mean post-index treatment length of stay was 8.8, 8.8, and 8.0 days, respectively. The most frequent line of therapy was ceftaroline first-line (42.1%), vancomycin or daptomycin first-line (95.4%), and combination therapy third-line or later (67.8%) in Groups 1, 2, and 3, respectively. Compared with Group 2, Groups 1 and 3 had similar favorable clinical responses {odds ratio [OR]=1.18 [95% confidence interval (CI) 0.98-1.44], p=0.08; OR=1.20 [95% CI 0.97-1.47], p=0.09, respectively} and were less likely to switch treatment (both p<0.001). Compared with Group 2, Group 1 was more likely to undergo 30-day all-cause readmission [OR=1.38 (95% CI 1.06-1.80), p=0.02], whereas this was less likely for Group 3 [OR=0.77 (95% CI 0.58-1.00), p=0.05]. Patients receiving ceftaroline more often had favorable clinical responses than those receiving vancomycin or daptomycin monotherapy. In the absence of large-scale randomized controlled trials, these real-world data provide insights into the potential role of ceftaroline for treating MRSA bacteremia.

The 3′ UTR of vigR is required for virulence in Staphylococcus aureus and has expanded through STAR sequence repeat insertions

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are alarmingly common, and treatment is confined to last-line antibiotics. Vancomycin is the treatment of choice for MRSA bacteremia, and treatment failure is often associated with vancomycin-intermediate S.aureus isolates. The regulatory 3' UTR of the vigR mRNA contributes to vancomycin tolerance and upregulates the autolysin IsaA. Using MS2-affinity purification coupled with RNA sequencing, we find that the vigR 3' UTR also regulates dapE, a succinyl-diaminopimelate desuccinylase required for lysine and peptidoglycan synthesis, suggesting a broader role in controlling cell wall metabolism and vancomycin tolerance. Deletion of the 3' UTR increased virulence, while the isaA mutant is completely attenuated in a wax moth larvae model. Sequence and structural analyses of vigR indicated that the 3' UTR has expanded through the acquisition of Staphylococcus aureus repeat insertions that contribute sequence for the isaA interaction seed and may functionalize the 3' UTR.

Validation of a new risk stratification system-based management for methicillin-resistant Staphylococcus aureus bacteraemia: analysis of a multicentre prospective study.

Distinguishing between complicated and uncomplicated Staphylococcus aureus bacteraemia (SAB) is therapeutically essential. However, this distinction has limitations in reflecting the heterogeneity of SAB and encouraging targeted diagnostics. Recently, a new risk stratification system for SAB metastatic infection, involving stepwise approaches to diagnosis and treatment, has been suggested. We assessed its applicability in methicillin-resistant SAB (MRSAB) patients. We retrospectively analysed data of a 3-year multicentre, prospective cohort of hospitalised patients with MRSAB. We classified the patients into three risk groups: low, indeterminate, and high, based on the new system and compared between-group management and outcomes. Of 380 patients with MRSAB, 6.3% were classified as low-, 7.6% as indeterminate-, and 86.1% as high-risk for metastatic infection. No metastatic infection occurred in the low-, 6.9% in the indeterminate-, and 19.6% in the high-risk groups (P < 0.001). After an in-depth diagnostic work-up, patients were finally diagnosed as 'without metastatic infection (6.3%)', 'with metastatic infection (17.4%)', and 'uncertain for metastatic infection (76.3%)'. 30-day mortality increased as the severity of diagnosis shifted from 'without metastatic infection' to 'uncertain for metastatic infection' and 'with metastatic infection' (P = 0.09). In multivariable analysis, independent factors associated with metastatic complications were suspicion of endocarditis in transthoracic echocardiography, clinical signs of metastatic infection, Pitt bacteraemia score ≥ 4, and persistent bacteraemia. The new risk stratification system shows promise in predicting metastatic complications and guiding work-up and management of MRSAB. However, reducing the number of cases labelled as 'high-risk' and 'uncertain for metastatic infection' remains an area for improvement.

The molecular epidemiology and clinical implication of methicillin-resistant Staphylococcus aureus (MRSA) sequence types in pediatric bacteremia: a restrospective observational study, 2016-2021.

While there is a high burden of methicillin-resistant Staphylococcus aureus (MRSA) infections among pediatric patients, studies on the molecular epidemiology of MRSA infections in Korean children since the 2010s are lacking. This study aimed to investigate the molecular genotypes and clinical characteristics of MRSA isolates from children with MRSA bacteremia at Asan Medical Center Children's Hospital from 2016 to 2021. Clinical data were retrospectively reviewed, and the molecular types of MRSA were determined using multilocus sequence typing (MLST) and Staphylococcal cassette chromosome mec (SCCmec) typing. The overall methicillin resistance rate of S. aureus bacteremia was 44.8% (77/172); 49.5% in the period 2016-2018 (period 1) and 37.3% in the period 2019-2021 (period 2) (P = 0.116). Community-acquired infections accounted for only 3.9% of cases. The predominant ST group was ST72 group (67.6%), followed by ST5 group (18.9%) and ST1 group (5.4%). The proportion of ST5 was significantly lower in period 2 compared to period 1 (P = 0.02). Compared to the ST5 and ST1 groups, the ST72 group exhibited lower overall antibiotic resistance and multidrug-resistant (MDR) rates (12.0% [6/50] in ST72 group vs. 100.0% [14/14] in ST5 group vs. 50.0% [2/4] in ST1 group; P < 0.001). In the multivariate analysis, the ST1 group was an independent risk factor for 30-day all-cause mortality (aOR, 44.12; 95% CI, 3.46-562.19). The ST72-MRSA strain remained the most frequently isolated genotype in Korean children, while the ST1 group emerged as an independent risk factor for 30-day all-cause mortality in pediatric MRSA bacteremia. Ongoing efforts to uncover the evolving epidemiology of MRSA are essential for developing effective strategies for prevention and treatment.

Daptomycin and Ceftaroline Combination Therapy in Complicated Endovascular Infections Caused by Methicillin-Resistant Staphylococcus epidermidis.

Background In complicated endovascular infections by methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis (MRSE), when first-line therapy with vancomycin (VAN) or daptomycin (DAP) fails, combination therapy with ceftaroline (CFT) and DAP has been shown to be a useful approach as salvage therapy for persistent MRSA bacteremia. Objectives This study aimed to describe experience with daptomycin and ceftaroline combination therapy in MRSE-complicated endovascular infections. Methods A single-center retrospective review of consecutive patients with MRSE-complicated endovascular infections treated with ≥72 hours of DAP+CFT at any time during the course of treatment, from January 1, 2016 to December 31, 2020, at Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal, was conducted. The exclusion criteria were known resistance to daptomycin or ceftaroline, total time of combination therapy <72 hours and loss to follow-up. Results We identified seven cases that matched our criteria: five endocarditis and two central venous catheter infections. Six patients switched to combination therapy due to treatment failure with first-line agents - three due to persistent bacteremiaand three due to progression of infection despite negative blood cultures. Effective surgical source control took one to four weeks to occur. Three patients died during the treatment, one from progression of the disease and two due to another infection. Conclusions We consider the DAP+CFT combination therapy to be a valid and safe therapeutic choice in complicated patients, such as those with severe infection, poor functional status, and impossibility or delay of surgical source control. However, conclusions on the role of combination therapy should be careful due to the low number of patients and the several confounding factors.