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Policy implementation for methicillin-resistant Staphylococcus aureus in seven European countries: a comparative analysis from 1999 to 2015.

ABSTRACT: Background: Policies to reduce methicillin-resistant Staphylococcus aureus (MRSA) infections, both healthcare-acquired (HA-MRSA) and livestock-associated (LA-MRSA) are implemented Europe-wide, but evaluations are difficult for countries yet to implement such policies. A descriptive study was conducted, describing multinational MRSA rates and policy implementation, focusing on MRSA mandatory surveillance. We also investigated antibiotic use and MRSA rates and the use of veterinary antibiotics. Methods: This study used Europe-wide surveillance data on infectious diseases (EARS-Net), antibiotic consumption (ESAC-Net), and veterinary medicine (ESVAC). We visualized LA- and HA-MRSA related policies and MRSA rates from 1999 to 2015 in seven European countries. Changes in MRSA rates after implementation of an MRSA mandatory surveillance policy were investigated by setting each country as rate of 1.0 and compared countries with and without such policy. Correlations between antibiotic use and MRSA rates from 1999 to 2012 were investigated using defined daily dose. Sales data were used to investigate veterinary antibiotic use. Results: MRSA rates were 1-45.4% across the seven countries between 1999 and 2015. MRSA rates changed between 0.61 and 0.24 after the implementation of mandatory surveillance policies within a 6-12 year span. The rate of decrease rate in implemented and non-implemented countries ranged from 10% in Spain to 76% in the UK. The correlation between MRSA rate and cephalosporin consumption was r = 0.419, and for fluoroquinolones r = 0.305. Mean annual sales of veterinary cephalosporin and quinolone antibiotics were lowest in the UK (0.8 mg/PCU) and highest in Spain (9.7 mg/PCU) between 2009 and 2014. Conclusions: There were similar but different health policy implications in the seven countries regarding LA- and HA-MRSA. Although causation could not be defined, some policies such as mandatory surveillance may be helpful for countries that have yet to implement an MRSA policy. Further investigations are needed to evaluate each policies.

SUBMITTER: Kinoshita T

PROVIDER: S-EPMC5533128 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:UNLABELLED:Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations. IMPORTANCE:With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection of strains of the S. aureus CC80 lineage. Our study determined that a single descendant of a PVL-positive methicillin-sensitive ancestor circulating in sub-Saharan Africa rose to become the dominant CA-MRSA clone in Europe, the Middle East, and North Africa. In the transition from a methicillin-susceptible lineage to a successful CA-MRSA clone, it simultaneously became resistant to fusidic acid, a widely used antibiotic for skin and soft tissue infections, thus demonstrating the importance of antibiotic selection in the success of this clone. This finding furthermore highlights the significance of horizontal gene acquisitions and underscores the combined importance of these factors for the success of CA-MRSA.

Project description:ObjectivesMethicillin-resistant Staphylococcus aureus (MRSA) infections impose a considerable burden on health systems, yet there is remarkable variation in the global incidence and epidemiology of MRSA. The MACOTRA consortium aimed to identify bacterial markers of epidemic success of MRSA isolates in Europe using a representative MRSA collection originating from France, the Netherlands and the United Kingdom.MethodsOperational definitions of success were defined in consortium meetings to compose a balanced strain collection of successful and sporadic MRSA isolates. Isolates were subjected to antimicrobial susceptibility testing and whole-genome sequencing; genes were identified and phylogenetic trees constructed. Markers of epidemiological success were identified using genome-based time-scaled haplotypic density analysis and linear regression. Antimicrobial usage data from ESAC-Net was compared with national MRSA incidence data.ResultsHeterogeneity of MRSA isolate collections across countries hampered the use of a unified operational definition of success; therefore, country-specific approaches were used to establish the MACOTRA strain collection. Phenotypic antimicrobial resistance varied within related MRSA populations and across countries. In time-scaled haplotypic density analysis, fluoroquinolone, macrolide and mupirocin resistance were associated with MRSA success, whereas gentamicin, rifampicin and trimethoprim resistance were associated with sporadicity. Usage of antimicrobials across 29 European countries varied substantially, and β-lactam, fluoroquinolone, macrolide and aminoglycoside use correlated with MRSA incidence.DiscussionOur results are the strongest yet to associate MRSA antibiotic resistance profiles and antibiotic usage with the incidence of infection and successful clonal spread, which varied by country. Harmonized isolate collection, typing, resistance profiling and alignment with antimicrobial usage over time will aid comparisons and further support country-specific interventions to reduce MRSA burden.

Project description:Methicillin resistant Staphylococcus aureus (MRSA) infection is becoming refractory to existing antibiotic therapy owing to the inherent ability of S. aureus to develop rapid resistance and is considered a major threat to public health. We found that a natural isolate of Bacillus pumilus from the Columbia River Estuary produces a strong anti-MRSA compound, amicoumacin A. As amicoumacin A has been reported to exhibit anti-microbial, anti-inflammatory, and anti-ulcer activities, we sought to uncover its mechanism of action. Genome-wide transcriptome analysis of S. aureus COL in response to amicoumacin A showed alteration in the expression of genes involved in several cellular processes including cell envelope turnover, cross-membrane transport, virulence, metabolism, and general stress response. The most highly induced gene was lrgA, encoding an antiholin-like product, which has been shown to be induced in response to a collapse of membrane potential. In order to gain further insight into the mechanism of action of amicoumacin A, a whole genome comparison of wild-type COL and amicoumacin A-resistant mutants isolated by serial passage method was carried out. Single point mutations resulting in codon substitutions were uncovered in several distinct genes: ksgA, RNA dimethyltranferase; fusA, elongation factor G; dnaG, primase, ; lacD, tagatose 1,6-bisphosphate aldolase, ; and SACOL0611, encoding a putative glycosyl transferase gene. Based on these results, a candidate approach was undertaken to recreate the same amino acid substitution individually in FusA and KsgA, each of which resulted in two-fold resistance towards amicoumacin A. The fusA gene is known as the site for fusidic acid- resistant mutations; however the codon substitutions in EF-G that cause amicoumacin A resistance and fusidic acid resistance occur in separate domains and do not bring about cross resistance. Taken together, these results suggest that amicoumacin A might cause perturbation of the cell membrane and lead to energy dissipation. Decreased rates of cellular metabolism including protein synthesis and DNA replication in resistant strains might allow cells to compensate for membrane dysfunction and thus increase cell survivability.

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Policy implementation for methicillin-resistant Staphylococcus aureus in seven European countries: a comparative analysis from 1999 to 2015.

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