Global prevalence and distribution of vancomycin resistant, vancomycin intermediate and heterogeneously vancomycin intermediate Staphylococcus aureus clinical isolates: a systematic review and meta-analysis

Vancomycin-resistant Staphylococcus aureus (VRSA), Vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA) are subject to vancomycin treatment failure. The aim of the present study was to determine their precise prevalence and investigate prevalence variability depending on different years and locations. Several international databases including Medline (PubMed), Embase and Web of Sciences were searched (data from 1997 to 2019) to identify studies that addressed the prevalence of VRSA, VISA and hVISA among human clinical isolates around the world. Subgroup analyses and meta-regression were conducted to indicate potential source of variation. Publication bias was assessed using Egger’s test. Statistical analyses were conducted using STATA software (version 14.0). Data analysis showed that VRSA, VISA and hVISA isolates were reported in 23, 50 and 82 studies, with an overall prevalence of 1.5% among 5855 S. aureus isolates, 1.7% among 22,277 strains and 4.6% among 47,721 strains, respectively. The overall prevalence of VRSA, VISA, and hVISA before 2010 was 1.2%, 1.2%, and 4%, respectively, while their prevalence after this year has reached 2.4%, 4.3%, and 5.3%. The results of this study showed that the frequency of VRSA, VISA and hVISA after 2010 represent a 2.0, 3.6 and 1.3-fold increase over prior years. In a subgroup analysis of different strain origins, the highest frequency of VRSA (3.6%) and hVISA (5.2%) was encountered in the USA while VISA (2.1%) was more prevalent in Asia. Meta-regression analysis showed significant increasing of VISA prevalence in recent years (p value ≤ 0.05). Based on the results of case reports (which were not included in the calculations mentioned above), the numbers of VRSA, VISA and hVISA isolates were 12, 24 and 14, respectively, among different continents. Since the prevalence of VRSA, VISA and hVISA has been increasing in recent years (especially in the Asian and American continents), rigorous monitoring of vancomycin treatment, it’s the therapeutic response and the definition of appropriate control guidelines depending on geographical regions is highly recommended and essential to prevent the further spread of vancomycin-resistant S. aureus.

the prevalence of VRSA, ViSA and hViSA isolates among human clinical isolates. Out    Meta-regression analysis. The results of meta-regression showed that the prevalence of VISA was significantly increase by increasing published year (p value < 0.05, Supplementry information figure S1). The results of this analysis indicated that by increasing the published year of study, the prevalence of VRSA and hVISA  www.nature.com/scientificreports/ increased, but this increase was statistically non-significant (p value > 0.05; Table 3 and Supplementry information Figure S1).

Discussion
Frequent use of vancomycin as the drug of choice for treatment of infections caused by multidrug-resistant MRSA has putatively led to selection of the is isolates with reduced susceptibility to vancomycin 15, 203 . In this study we report the prevalence of VRSA, VISA and hVISA around the world. The global prevalence of VRSA, VISA and hVISA isolates was 1.5%, 1.7%, and 4.6%, respectively.  Table S1, presence of vanA in VRSA strains by PCR showed that 69% (55/79) of the VRSA strains were vanA positive. This elevated rate of vanA in these bacteria indicates that the resistance determinant was possibly acquired from a vancomycin-resistant Enterococcus species or from one of the other vanA positive organisms living in the human gastro-intestinal tract. Absence of vanA in the other isolates suggests that cell wall thickening and possibly vancomycin affinity trapping may be responsible for the development of vancomycin resistance in these isolates 19 . Furthermore, many studies reported a failure to detect the vanB gene.
Regarding VISA and hVISA strains, although, there is no clear overall genetic explanation for these phenotypes 15 , the main mechanisms of reduced susceptibility to vancomycin among VISA strains are mutations in cell wall-associated genes (thickened cell wall with an increased number of peptidoglycan layers) 204,205 , and/ or in the ribosomal gene rpoB 203 . The prolonged usage of vancomycin can lead to changes in cell wall patterning or reduced expression of penicillin-binding proteins. This may accumulate from heterogeneous to selected homogeneous VISA-type resistance 203,206 . Noteworthy, when the cell wall gets thicker, the vancomycin MIC level increases 207,208 . Because of enhanced selective pressure, evolution of hVISA/VISA strains is more rapid in the hospital setting than in the community and therefore VISA is considered a more significant clinical problem than VRSA 209 . Furthermore, the results of meta-regression results showed the prevalence of the VISA was significantly increase over the time compare to the VRSA and hVISA. It seems that the real incidence of hVISA/ VISA strains is much higher than the present reports and hence there is a clear need for the development of new diagnostic methods for detecting hVISA/VISA. This also includes the development for new antimicrobial susceptibility tests (AST). For instance, in several studies, the PAP-AUC gold standard AST method was not used due to its time-consumption and technical difficulty. Other methods such as Disk Diffusion testing are unable to detect and distinguish these strains 9 . In overall, all studies used the culture-based methods such as E-test, PAP-AUC, broth dilution, and agar dilution. Moreover, some studies beside the culture-based methods, used PCR for detection of resistant-related gene. Since global scale sort of the same type and frequency of methods was used, the differences between developed and developing countries cannot be hypothetically addressed towards the use of different AST systems.
VRSA and/or VISA with resistance to multiple other antibiotics, including β-lactams, have been isolated from livestock animals that highlights the abuse of antibiotic in that sector and the suspected use of antibiotics as a food supplement 210,211 . The potential reasons for the emergence or detecting more resistant strains during recent years include: more frequent use of vancomycin for treatment of MRSA infections, better use of diagnostics, The prevalence of VRSA in Asia, Europe, America and Africa was 1.2%, 1.1%, 3.6% and 2.5%, respectively. By the way, 65 strains of VRSA were found in Asia versus only 5 VRSA in America. The prevalence of VISA in Asia was higher than on the other continents. It should be noted that 67% (327/485) of vancomycin-resistant strains were reported from Iran and India. Therefore, our data shows that the Asian data are biased towards two countries but also that the emergence of VRSA in India and Iran warrants active microbiological surveillance and careful monitoring of vancomycin therapy. There are several factors involved in the higher number of VRSA and a higher prevalence of VISA in Asia, in comparison to Europe/America countries. Most of the Asian countries are developing countries with lower public hygiene standards and different attitudes towards antimicrobial treatments. Furthermore, population density can lead to more MRSA infections through enhanced microbial transmission. Higher vancomycin use for the treatment of infections can play a role as well 15 .
Previous studies have helped to identify risk factors that may contribute to VISA emergence such as previous MRSA colonization, hemodialysis dependence, long-term use of vancomycin, hospitalization in ICU and use of indwelling devices. There is no clarity on the precise clinical consequences of vancomycin non-susceptibility among S. aureus strains. Although some meta-analyses have addressed the association between elevated vancomycin MICs and worse clinical outcomes 214,215 , a recent prospective cohort study suggested exactly the opposite 216 . Previous studies have also demonstrated a correlation between increased vancomycin MICs and daptomycin resistance in VISA isolates 217,218 . Furthermore, decreased vancomycin susceptibility is associated with increased susceptibility to beta-lactams. Therefore, the combination of vancomycin and beta-lactams can be a good option for treatment of hVISA or VISA infections 198,219 . On the other hand, those correlated resistances  www.nature.com/scientificreports/ can lead to problems in elucidating the role of the individual resistance marker in disease severity. Since there is an emerging and increasing rate of resistance to vancomycin, thorough monitoring of the success of vancomycin treatment is essential. 220 . The majority of VRSA strains belonged to same clonal complex (CC) such as CC5 in the USA. Interestingly, there is high prevalence of the CC5 in healthcare settings. Unlike VRSA, hVISA/VISA has been associated with many clones such as CC5, CC8, CC30, and CC45 221 . Antibiotics such as trimethoprim-sulfamethoxazole, tetracyclines, fluoroquinolones, and clindamycin are alternative treatment choices for community-acquired MRSA infections. New drugs such as linezolid, daptomycin, tigecycline, and sodium fusidate are suggested for isolates with a vancomycin MIC of greater than 2 μg/mL 198 . Finally, in order to control the spread of vancomycin resistant staphylococci, contact precautions, disinfection of care equipment and the environment, plus adequate antimicrobial stewardship are highly recommended [222][223][224] .   Scientific RepoRtS | (2020) 10:12689 | https://doi.org/10.1038/s41598-020-69058-z www.nature.com/scientificreports/