- Email: [email protected]
MRSA – seeing the bigger picture
Journal of Hospital Infection 93 (2016) 364e365 Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Commentary
MRSA e seeing the bigger picture
The evolution and spread of antimicrobial resistance is now widely recognized as a global public health challenge.1 It is generally perceived that the emergence and rapid spread of multidrug-resistant Gram-negative bacilli (MDRGNB), together with a lack of new agents in development to treat infections arising from these organisms, are issues of particular current concern.2 However, alongside these more recent threats, it is important that we do not lose sight of the considerable morbidity and mortality attributable to infections with resistant Gram-positive organisms, especially meticillin-resistant Staphylococcus aureus (MRSA). In many ways the development of antibiotic resistance in S. aureus provides a paradigm for the evolution of antimicrobial resistance in general. The successive introduction of effective antimicrobial agents has been paralleled by the emergence of ‘waves’ of antibiotic-resistant S. aureus.3 Thus the introduction of penicillin was followed rapidly by the emergence of penicillin-resistant strains in hospitals by the mid-1940s, and within the wider community in the following decade. Similarly meticillin resistance was first reported only a year after the introduction of the penicillinase-stable agent meticillin. Whereas these original MRSA strains circulated to some extent in a number of hospitals, mainly within Europe, they did not become established in the community and gradually waned during the 1970s. However, the following two decades were marked by the emergence and global spread of a number of highly successful MRSA lineages within hospitals and other healthcare facilities, many of which remain important today. Increasing use of glycopeptides for the treatment of MRSA and other Gram-positive organisms, especially for intravascular device-associated infections, has been associated with the emergence of MRSA strains with varying degrees of reduced susceptibility to these agents. More recently we have witnessed the widespread emergence of communityassociated MRSA (CA-MRSA) in many regions of the world. It is also increasingly recognized that there are significant animal reservoirs of MRSA. These so-called livestock-associated MRSA serve not only as a further source of human infections, but also as a significant ecological niche in which novel antimicrobial resistance and virulence traits may be selected. The increasingly complex evolutionary and epidemiological relationships and interchange between healthcare, community, and livestock/environmental reservoirs challenge many of our traditional assumptions about sources and spread of MRSA.
They serve to highlight the limitations of conventional hospitalbased investigational epidemiology approaches to case attribution and the design and implementation of control measures. For example, Park et al. demonstrated that approximately half of nasal MRSA isolates from newly admitted patients at a tertiary referral centre in South Korea in the periods 2007e8, 2009e10 and 2013e14 were of sequence type (ST) 72.4 ST72 is an important CA-MRSA clone in South Korea and had previously been shown to be the predominant clone among MRSA isolated from the anterior nares of healthy South Korean children attending daycare centres in 2008. Although rarely isolated in Europe, Potel et al. found, in a retrospective survey of MRSA isolated between 2003 and 2011 from outpatients attending 24 community healthcare centres in the northwest of Spain, that ST72 accounted for 41 out of 457 strains.5 Moreover, the proportion of ST72 isolates increased significantly from 4.5% in the first half of the study (2003e2007) to 11% in the second study period (2007e2011), and the authors note that spread of this strain within the hospital setting occurred. Whereas hospitalassociated MRSA predominated overall, the proportion of CAMRSA strains increased significantly from 6% in the first study period to 21% in the second study period. Unfortunately, due to design limitations the study could not distinguish infections arising within the hospital from those arising in the community. Similarly the authors could only speculate on possible links between Spain and South Korea, although interestingly they noted that ST72 MRSA had been isolated in swine, cattle and pig carcasses in Korea. These studies, and the example of the ST72 clone, provide a specific illustration of the more general phenomenon of the increasing interplay of MRSA clones previously associated with specific ecological niches. This increasingly complex relationship between MRSA strains of diverse origins and infections acquired and/or presenting in the community or in the healthcare setting is a challenge for conventional approaches for epidemiological investigation, particularly for what have traditionally been viewed as nosocomial infections. Conventional hospital-based investigational epidemiology has its limitations as it can only link cases with an apparent epidemiological association. Equally, data available at national communicable disease surveillance centres or on reference laboratory request forms may contain too little information to identify epidemiological links. However, Donker and colleagues have elegantly demonstrated how the linkage of geo-temporal data with MRSA multiple-locus variable-number tandem repeat analysis (MLVA) data at a national level in The Netherlands allowed them to draw conclusions about the existence of unknown reservoirs outside of hospitals and the differential transmissibility of MRSA clones within healthcare settings.6 Specifically it permitted
http://dx.doi.org/10.1016/j.jhin.2016.05.017 0195-6701/ª 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Commentary / Journal of Hospital Infection 93 (2016) 364e365 identification of transmission chains involving more than one institution that had otherwise been unrecognized. This is an excellent example of the power and added value of linking large routinely collected datasets to provide insights at both local and national levels. The results of the study also suggested that the current clinical risk-based assessment used for screening for MRSA in Dutch patients may require further refinement. It is important to recognize that the appropriateness of screening criteria may change with time, reflecting changes in the underlying epidemiology. Our ability to understand and monitor the complex emergence and spread of MRSA, and hence to design and assess the effectiveness of intervention measures, is crucially dependent on the availability of effective, efficient, and affordable subtyping. Traditional molecular epidemiological approaches for the study of MRSA have used a range of techniques. These include multi-locus sequence typing to define specific sequence types and clonal complexes for phylogenetic purposes, pulsed-field gel electrophoresis and MLVA for evaluation of more recent evolution among groups of strains (particularly in investigation of putative outbreaks), spa typing (which can be useful for phylogenetic and epidemiological studies), and SCCmec typing that has been useful in understanding the evolution of the various MRSA lineages. All of the foregoing techniques have limitations. However, our understanding of the phylogeny and epidemiology of MRSA is currently being transformed by the application of whole genome sequencing (WGS).7 Due to reductions in cost, and the wider availability of bioinformatics tools and expertise, this technology is currently transitioning from the research domain to application in clinical practice. Ugolotti et al. demonstrate the additional information that could be derived by the application of this technology for analysing nosocomial MRSA infections among hospitalized paediatric patients.8 However, this was essentially a ‘proof of concept’ validation study that retrospectively analysed outbreak-associated strains that had previously been characterized by other typing techniques within a single institution. The study did, however, demonstrate that typing resolution was significantly increased, and at the same time accurate prediction of the presence of known virulence and antibiotic resistance genes was possible. However, as has been elegantly demonstrated by Donker et al., the power and value of molecular subtyping is considerably enhanced when data are shared beyond the institutional level, and especially when these data are linked to other datasets.6 This may occur at regional, national, and international levels. WGS technology and the portability of the data produced is well suited to this ‘scalability’ of analysis. The potential for such an approach for routine public
365
health pathogen surveillance of S. aureus at an international level has recently been demonstrated.9 It is increasingly apparent that there is a much bigger picture emerging with respect to our understanding of the origins, evolution and spread of MRSA. We increasingly have the tools to allow us to see that picture, but the clarity and fidelity of the view will depend upon linking genomic datasets of MRSA isolates from human, animal and environmental sources, together with other national epidemiological and clinical datasets. Increasingly that will be an organizational, ethical, political and legal challenge, rather than a scientific one.
References 1. O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. London: Wellcome Trust/HM Government; May 2016. 2. Gray JW, Mahida N. How do you solve a problem like multidrugresistant Gram-negative bacteria? J Hosp Infect 2016;92:1e2. 3. Chambers HF, DeLeo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009;7:629e641. 4. Park SY, Chung DR, Yoo JR, et al. Sequence type 72 communityassociated meticillin-resistant Staphylococcus aureus emerged as a predominant clone of nasal colonization in newly admitted patients. J Hosp Infect 2016;93:386e389. ´ lvarez M. Molecular character5. Potel C, Rey S, Otero S, Rubio J, A ization and clonal diversity of meticillin-resistant Staphylococcus aureus isolated from the community in Spain: emergence of clone sequence type 72. J Hosp Infect 2016;93:382e385. 6. Donker T, Bosch T, Ypma RJF, et al. Monitoring the spread of meticillin-resistant Staphylococcus aureus in The Netherlands. J Hosp Infect 2016;93:366e374. 7. Price JR, Didelot X, Crook DW, Llewelyn MJ, Paul J. Whole genome sequencing in the prevention and control of Staphylococcus aureus infection. J Hosp Infect 2013;83:14e21. 8. Ugolotti E, Larghero P, Vanni I, et al. Whole-genome sequencing as standard practice for the analysis of clonality in outbreaks of meticillin-resistant Staphylococcus aureus in a paediatric setting. J Hosp Infect 2016;93:375e381. 9. Aanensen DM, Feil EJ, Holden MT, et al. Whole-genome sequencing for routine pathogen surveillance in public health: a population snapshot of invasive Staphylococcus aureus in Europe. mBio 2016;7(3):e00444e16.
J.E. Coia* Scottish MRSA Reference Service, Scottish Microbiology Reference Laboratories, Glasgow, UK * Address: New Lister Building, 10e16 Alexandra Parade, Glasgow G31 2ER, UK. Tel.: þ44 141 211 0589. E-mail address: [email protected] Available online 4 June 2016
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Commentary
MRSA e seeing the bigger picture
The evolution and spread of antimicrobial resistance is now widely recognized as a global public health challenge.1 It is generally perceived that the emergence and rapid spread of multidrug-resistant Gram-negative bacilli (MDRGNB), together with a lack of new agents in development to treat infections arising from these organisms, are issues of particular current concern.2 However, alongside these more recent threats, it is important that we do not lose sight of the considerable morbidity and mortality attributable to infections with resistant Gram-positive organisms, especially meticillin-resistant Staphylococcus aureus (MRSA). In many ways the development of antibiotic resistance in S. aureus provides a paradigm for the evolution of antimicrobial resistance in general. The successive introduction of effective antimicrobial agents has been paralleled by the emergence of ‘waves’ of antibiotic-resistant S. aureus.3 Thus the introduction of penicillin was followed rapidly by the emergence of penicillin-resistant strains in hospitals by the mid-1940s, and within the wider community in the following decade. Similarly meticillin resistance was first reported only a year after the introduction of the penicillinase-stable agent meticillin. Whereas these original MRSA strains circulated to some extent in a number of hospitals, mainly within Europe, they did not become established in the community and gradually waned during the 1970s. However, the following two decades were marked by the emergence and global spread of a number of highly successful MRSA lineages within hospitals and other healthcare facilities, many of which remain important today. Increasing use of glycopeptides for the treatment of MRSA and other Gram-positive organisms, especially for intravascular device-associated infections, has been associated with the emergence of MRSA strains with varying degrees of reduced susceptibility to these agents. More recently we have witnessed the widespread emergence of communityassociated MRSA (CA-MRSA) in many regions of the world. It is also increasingly recognized that there are significant animal reservoirs of MRSA. These so-called livestock-associated MRSA serve not only as a further source of human infections, but also as a significant ecological niche in which novel antimicrobial resistance and virulence traits may be selected. The increasingly complex evolutionary and epidemiological relationships and interchange between healthcare, community, and livestock/environmental reservoirs challenge many of our traditional assumptions about sources and spread of MRSA.
They serve to highlight the limitations of conventional hospitalbased investigational epidemiology approaches to case attribution and the design and implementation of control measures. For example, Park et al. demonstrated that approximately half of nasal MRSA isolates from newly admitted patients at a tertiary referral centre in South Korea in the periods 2007e8, 2009e10 and 2013e14 were of sequence type (ST) 72.4 ST72 is an important CA-MRSA clone in South Korea and had previously been shown to be the predominant clone among MRSA isolated from the anterior nares of healthy South Korean children attending daycare centres in 2008. Although rarely isolated in Europe, Potel et al. found, in a retrospective survey of MRSA isolated between 2003 and 2011 from outpatients attending 24 community healthcare centres in the northwest of Spain, that ST72 accounted for 41 out of 457 strains.5 Moreover, the proportion of ST72 isolates increased significantly from 4.5% in the first half of the study (2003e2007) to 11% in the second study period (2007e2011), and the authors note that spread of this strain within the hospital setting occurred. Whereas hospitalassociated MRSA predominated overall, the proportion of CAMRSA strains increased significantly from 6% in the first study period to 21% in the second study period. Unfortunately, due to design limitations the study could not distinguish infections arising within the hospital from those arising in the community. Similarly the authors could only speculate on possible links between Spain and South Korea, although interestingly they noted that ST72 MRSA had been isolated in swine, cattle and pig carcasses in Korea. These studies, and the example of the ST72 clone, provide a specific illustration of the more general phenomenon of the increasing interplay of MRSA clones previously associated with specific ecological niches. This increasingly complex relationship between MRSA strains of diverse origins and infections acquired and/or presenting in the community or in the healthcare setting is a challenge for conventional approaches for epidemiological investigation, particularly for what have traditionally been viewed as nosocomial infections. Conventional hospital-based investigational epidemiology has its limitations as it can only link cases with an apparent epidemiological association. Equally, data available at national communicable disease surveillance centres or on reference laboratory request forms may contain too little information to identify epidemiological links. However, Donker and colleagues have elegantly demonstrated how the linkage of geo-temporal data with MRSA multiple-locus variable-number tandem repeat analysis (MLVA) data at a national level in The Netherlands allowed them to draw conclusions about the existence of unknown reservoirs outside of hospitals and the differential transmissibility of MRSA clones within healthcare settings.6 Specifically it permitted
http://dx.doi.org/10.1016/j.jhin.2016.05.017 0195-6701/ª 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Commentary / Journal of Hospital Infection 93 (2016) 364e365 identification of transmission chains involving more than one institution that had otherwise been unrecognized. This is an excellent example of the power and added value of linking large routinely collected datasets to provide insights at both local and national levels. The results of the study also suggested that the current clinical risk-based assessment used for screening for MRSA in Dutch patients may require further refinement. It is important to recognize that the appropriateness of screening criteria may change with time, reflecting changes in the underlying epidemiology. Our ability to understand and monitor the complex emergence and spread of MRSA, and hence to design and assess the effectiveness of intervention measures, is crucially dependent on the availability of effective, efficient, and affordable subtyping. Traditional molecular epidemiological approaches for the study of MRSA have used a range of techniques. These include multi-locus sequence typing to define specific sequence types and clonal complexes for phylogenetic purposes, pulsed-field gel electrophoresis and MLVA for evaluation of more recent evolution among groups of strains (particularly in investigation of putative outbreaks), spa typing (which can be useful for phylogenetic and epidemiological studies), and SCCmec typing that has been useful in understanding the evolution of the various MRSA lineages. All of the foregoing techniques have limitations. However, our understanding of the phylogeny and epidemiology of MRSA is currently being transformed by the application of whole genome sequencing (WGS).7 Due to reductions in cost, and the wider availability of bioinformatics tools and expertise, this technology is currently transitioning from the research domain to application in clinical practice. Ugolotti et al. demonstrate the additional information that could be derived by the application of this technology for analysing nosocomial MRSA infections among hospitalized paediatric patients.8 However, this was essentially a ‘proof of concept’ validation study that retrospectively analysed outbreak-associated strains that had previously been characterized by other typing techniques within a single institution. The study did, however, demonstrate that typing resolution was significantly increased, and at the same time accurate prediction of the presence of known virulence and antibiotic resistance genes was possible. However, as has been elegantly demonstrated by Donker et al., the power and value of molecular subtyping is considerably enhanced when data are shared beyond the institutional level, and especially when these data are linked to other datasets.6 This may occur at regional, national, and international levels. WGS technology and the portability of the data produced is well suited to this ‘scalability’ of analysis. The potential for such an approach for routine public
365
health pathogen surveillance of S. aureus at an international level has recently been demonstrated.9 It is increasingly apparent that there is a much bigger picture emerging with respect to our understanding of the origins, evolution and spread of MRSA. We increasingly have the tools to allow us to see that picture, but the clarity and fidelity of the view will depend upon linking genomic datasets of MRSA isolates from human, animal and environmental sources, together with other national epidemiological and clinical datasets. Increasingly that will be an organizational, ethical, political and legal challenge, rather than a scientific one.
References 1. O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. London: Wellcome Trust/HM Government; May 2016. 2. Gray JW, Mahida N. How do you solve a problem like multidrugresistant Gram-negative bacteria? J Hosp Infect 2016;92:1e2. 3. Chambers HF, DeLeo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009;7:629e641. 4. Park SY, Chung DR, Yoo JR, et al. Sequence type 72 communityassociated meticillin-resistant Staphylococcus aureus emerged as a predominant clone of nasal colonization in newly admitted patients. J Hosp Infect 2016;93:386e389. ´ lvarez M. Molecular character5. Potel C, Rey S, Otero S, Rubio J, A ization and clonal diversity of meticillin-resistant Staphylococcus aureus isolated from the community in Spain: emergence of clone sequence type 72. J Hosp Infect 2016;93:382e385. 6. Donker T, Bosch T, Ypma RJF, et al. Monitoring the spread of meticillin-resistant Staphylococcus aureus in The Netherlands. J Hosp Infect 2016;93:366e374. 7. Price JR, Didelot X, Crook DW, Llewelyn MJ, Paul J. Whole genome sequencing in the prevention and control of Staphylococcus aureus infection. J Hosp Infect 2013;83:14e21. 8. Ugolotti E, Larghero P, Vanni I, et al. Whole-genome sequencing as standard practice for the analysis of clonality in outbreaks of meticillin-resistant Staphylococcus aureus in a paediatric setting. J Hosp Infect 2016;93:375e381. 9. Aanensen DM, Feil EJ, Holden MT, et al. Whole-genome sequencing for routine pathogen surveillance in public health: a population snapshot of invasive Staphylococcus aureus in Europe. mBio 2016;7(3):e00444e16.
J.E. Coia* Scottish MRSA Reference Service, Scottish Microbiology Reference Laboratories, Glasgow, UK * Address: New Lister Building, 10e16 Alexandra Parade, Glasgow G31 2ER, UK. Tel.: þ44 141 211 0589. E-mail address: [email protected] Available online 4 June 2016