Vancomycin-intermediate Staphylococcus aureus (VISA) and its precursor hetero-VISA (hVISA) were discovered almost 20 years ago and have continued to be a stumbling block in the chemotherapy of ...methicillin-resistant S. aureus (MRSA). Unlike vancomycin resistance mediated by the van gene in enterococci and staphylococci, VISA is generated by accumulation of mutations. It displays diverse and intriguing genetic mechanisms underlying its resistance phenotype. Here we make a brief note on our recent understanding of the genetics of hVISA, VISA and the newly discovered phenotype ‘slow VISA’ (sVISA).
•Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is considered as one of the main causes in treatment failure of vancomycin.•Infection with hVISA bacteria was higher in bacteremic ...patients than other infections (9.4% vs. 5.5%).•A total of 1136 articles were retrieved due to searching the global databases.•SCCmec I, SCCmec II, and SCCmec III are considered as the most common SCCmec types in community-acquired MRSA strains.•SCCmec IV and SCCmec V are common in hospital-acquired MRSA (HA-MRSA) strains.
Heterogeneous vancomycin-intermediate Staphylococcus aureus is considered one of the main causes in treatment failure of vancomycin, which leads to poor clinical outcomes. Herein, we comprehensively evaluated characteristics such as global prevalence, trend, and genetic backgrounds of these strains.
In this study, we conducted a meta-analysis based on PRISMA checklist 2020. In the beginning, global databases were searched to achieve the studies related to the prevalence of hVISA in clinical isolates of methicillin-resistant Staphylococcus aureus. After retrieving the eligible English studies, the prevalence of hVISA isolates and their trend changes were assessed using event rate with 95% confidence intervals.
In the present study, the prevalence of 114 801 MRSA isolates (of 124 studies) was 64%. According to our results, although the frequency of infection with hVISA is increasing in recent years, there is not a significant difference between Asian countries and Europe/America (6.1% vs. 6.8%). In addition, infection with hVISA bacteria was higher in bacteraemic patients than other infections (9.4% vs. 5.5%), which increases hospitalization, treatment costs, and mortality in these patients. Isolates harbouring SCCmec types II and III are most common genotypes in hVISA strains.
The prevalence of hVISA is increasing, which will reduce the effectiveness of vancomycin treatment in the coming years. The presence of hVISA stains in blood samples was higher than the other samples, which is threatening for bacteraemic patients. The results of the current study indicate a universal program to identify and control the spread of such strains in nosocomial infections.
Heteroresistant vancomycin intermediate Staphylococcus aureus (hVISA) testing is recommended when therapeutic failure is suspected in the clinics. In our research, we aimed to investigate the ...prevalence of hVISA among methicilline-resistant S. aureus (MRSA) isolates in our university hospital and compared three methods for detection of hVISA.
One hundred MRSA clinical isolates were collected in our medical microbiology laboratory between 01.04.2018 and 01.10.2019. For screening of hVISA, we used two screening agar plates and used one commercial medium; brain heart infusion agar (BHI) plates containing 4 µg/mL vancomycin and 16 g/Lt casein (BHIA-VC; Satola's test), BHI agar plates containing 4 µg/mLvancomycin (BHIAV), and commercially obtained vancomycin resistant Enterococci (VRE) agar for detetection of hVISA. Colonies which could grow on plates were counted manually at 24th and 48th hours.
Among 100 MRSA isolates, 43 (43%) were found as hVISA using Satola's test. BHIAV and VRE agar screening test results were found 70% and 4%, respectively. Finally, at the step, MIC values of 20 (47%) hVISA isolates reduced to 2 µg/mL after sub culturing for the gradient test.
We found higher rates of hVISA comparing other studies in Turkey. Both VRE agar and BHIAV screening test failed to detect hVISA properly. Meropenem in combination with vancomycin inhibited the growth of 90% hVISA isolates in our study.
•We review current understanding VISA and hVISA genetics.•We review factors promoting evolution of VISA and loss of resistance phenotype.•We review virulence and other impacts of hVISA and VISA.
...Resistance to new antimicrobials is generally recognized in Staphylococcus aureus soon after they are released for clinical use. In the case of vancomycin, which was first released in the 1950s, resistance was not reported until the mid 1990s, with the description of vancomycin-intermediate S. aureus (VISA), and heterogenous-VISA (hVISA). Unraveling the complex genetic and cell wall structural changes conferring low-level vancomycin resistance in S. aureus has proved challenging. However the recent advances in high throughput whole-genome sequencing has played a key role in determining the breadth of bacterial chromosomal changes linked with resistance. Diverse mutations in a small number of staphylococcal regulatory genes, in particular walKR, graRS, vraSR and rpoB, have been associated with hVISA and VISA. Only a small number of these mutations have been experimentally proven to confer the resistance phenotype and some of these only partially contribute to resistance. It also appears that the evolution of VISA from VSSA is a step-wise process. Transcriptomics studies, and analysis of host pathogen interactions, indicate that the evolution of vancomycin-susceptible S. aureus to VISA is associated not only with antibiotic resistance, but with other changes likely to promote persistent infection. These include predicted alterations in central metabolism, altered expression of virulence associated factors, attenuated virulence in vivo, and alterations in susceptibility to host innate immune responses, together with reduced susceptibility to other antibiotics. In fact, current data suggests that hVISA and VISA represent a bacterial evolutionary state favoring persistence in the face of not only antibiotics, but also the host environment. The additional knowledge of staphylococcal biology that has been uncovered during the study of hVISA and VISA is significant. The present review will detail the current understanding of the evolutionary process in the generation of hVISA and VISA, and explore the diverse additional changes that occur in these strains.
For more than 4 decades, vancomycin has been the antibiotic of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections. Recently, infections due to isolates with high but susceptible ...vancomycin minimum inhibitory concentrations have been associated with additional treatment failures and patient mortality. These poorer outcomes may in part be explained by the inability of attaining appropriate vancomycin levels in these patients. However, assumptions that these poor outcomes are solely due to failure to achieve optimal serum levels of vancomycin are premature. The availability of effective alternatives further erodes the position of vancomycin as first-line therapy. The emergence of resistance and cost considerations, however, favor a more measured approach when using alternative antimicrobials. Collectively, the current available data suggest that the optimal therapy for MRSA infections remains unclear. In the absence of further data, the Infectious Diseases Society of America guidelines remain relevant and inform clinicians of best practice for treating patients with MRSA infections.
Purpose
The extensive use of vancomycin has led to the development of
Staphylococcus aureus
strains with varying degrees of resistance to vancomycin. The present study aimed to explore the molecular ...causes of vancomycin resistance by conducting a proteomics analysis of subcellular fractions isolated from vancomycin-intermediate resistant
S. aureus
(VISA) and vancomycin-sensitive
S. aureus
(VSSA) strains.
Methods
We conducted proteomics analysis of subcellular fractions isolated from 2 isogenic
S. aureus
strains: strain 11 (VSSA) and strain 11Y (VISA). We used an integrated quantitative proteomics approach assisted by bioinformatics analysis, and comprehensively investigated the proteome profile. Intensive bioinformatics analysis, including protein annotation, functional classification, functional enrichment, and functional enrichment-based cluster analysis, was used to annotate quantifiable targets.
Results
We identified 128 upregulated proteins and 21 downregulated proteins in strain 11Y as compared to strain 11. The largest group of differentially expressed proteins was composed of enzymatic proteins associated with metabolic and catalytic activity, which accounted for 32.1% and 50% of the total proteins, respectively. Some proteins were indispensable parts of the regulatory networks of
S. aureus
that were altered with vancomycin treatment, and these proteins were related to cell wall metabolism, cell adhesion, proteolysis, and pressure response.
Conclusion
Our proteomics study revealed regulatory proteins associated with vancomycin resistance in
S. aureus
. Some of these proteins were involved in the regulation of cell metabolism and function, which provides potential targets for the development of strategies to manage vancomycin resistance in
S. aureus
.
Brain-heart infusion agar supplemented with 4 µg/mL of vancomycin (BHI-V4) was commonly used for the detection of heterogeneous (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA). ...However, its diagnostic value remains unclear. This study aims to compare the diagnostic accuracy of BHI-V4 with population analysis profiling with area under the curve (PAP-AUC) in hVISA/VISA.
The protocol of this study was registered in INPLASY (INPLASY2023120069). The PubMed and Cochrane Library databases were searched from inception to October 2023. Review Manager 5.4 was used for data visualization in the quality assessment, and STATA17.0 (MP) was used for statistical analysis.
In total, eight publications including 2153 strains were incorporated into the meta-analysis. Significant heterogeneity was evident although a threshold effect was not detected across the eight studies. The summary receiver operating characteristic (SROC) was 0.77 (95% confidence interval CI, 0.74-0.81). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic score and diagnostic odds ratio were 0.59 (95% CI: 0.46-0.71), 0.96 (95%CI: 0.83-0.99), 14.0 (95% CI, 3.4-57.1), 0.43 (95%CI, 0.32-0.57), 3.48(95%CI, 2.12-4.85) and 32.62 (95%CI, 8.31-128.36), respectively.
Our study showed that BHI-V4 had moderate diagnostic accuracy for diagnosing hVISA/VISA. However, more high-quality studies are needed to assess the clinical utility of BHI-V4.
Hetero-resistance vancomycin intermediate Staphylococcus aureus (hVISA) is phenotype, which on in-vitro susceptibility test is vancomycin susceptible (VSSA) but has a minority population of ...vancomycin intermediate (VISA). hVISA is responsible for vancomycin treatment failure. Population Analysis Profile- Area under Curve (PAP-AUC) is a test for detection of hVISA; however, this test is unsuitable for clinical microbiology laboratory. Tests, such as Brain Heart Infusion Agar with 6 μg/ml vancomycin (BHIA6V), E test and Macromethod E Test (MET) are available; however reported to have variable results.
58 clinical isolates of Methicillin resistant S aureus (MRSA) having MIC of vancomycin more than 1 μg/ml by E test and agar dilution were analyzed by PAP-AUC, BHIA6V and MET.
The prevalence of hVISA was 6.9%. hVISA isolates were having vancomycin E test MIC >2 μg/ml. Sensitivity of BHIA6V, MET and E test with MIC >2 μg/ml were 0.75, 0.67 and 1.0 respectively; however, positive predictive values (PPV) were 0.43, 0.4 and 0.27 respectively with PAP-AUC. PAP-AUC ratio correlated with MIC by E test and MET.
There is need for screening MRSA isolates showing in-vitro vancomycin susceptibility ≤2 μg/ml by agar dilution method for detection of hVISA. PAP-AUC test is unsuitable for routine laboratory testing. BHIA6V, MET and E test can be used for screening, however have low PPV.
Ceftobiprole is a broad-spectrum cephalosporin that demonstrates activity against Staphylococcus aureus resistant to methicillin, including strains with reduced susceptibility to glycopeptides and ...lipopeptides. The addition of this agent provides a potential therapeutic option for difficult-to-treat infections. Synergy has been demonstrated between β-lactams combined with glycopeptides and lipopeptides against S. aureus. This study sought to determine whether ceftobiprole was synergistic with daptomycin, vancomycin or standard-of-care combination agents (gentamicin or rifampicin) against methicillin-resistant S. aureus (MRSA) strains with varying degrees of vancomycin susceptibility.
Broth microdilution MICs of ceftobiprole, daptomycin, vancomycin, rifampicin and gentamicin were evaluated for 20 MRSA isolates. Combination MICs were additionally evaluated in the presence of subinhibitory concentrations of ceftobiprole to assess synergism. Time-kill curves for five representative isolates were performed utilizing combinations of ceftobiprole plus daptomycin, vancomycin, rifampicin and gentamicin to further quantify the degree of synergy for each regimen.
Ceftobiprole plus daptomycin represented the most potent combination with a 4-fold decrease in MIC and synergy against all strains evaluated in time-kill evaluations. Additionally, binding studies demonstrated enhanced daptomycin binding in the presence of subinhibitory concentrations of ceftobiprole.
The use of combination therapy with ceftobiprole may provide a needed addition for the treatment of Gram-positive infections resistant to daptomycin or vancomycin. Consistent with what has been observed with other β-lactams, ceftobiprole increased bodipy-tagged daptomycin binding on the surface of S. aureus, potentially explaining this potent synergy observed in time-kill evaluations. More detailed evaluation of ceftobiprole is warranted to better characterize observed synergy.
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