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Spotlight
Transmission of antimicrobial resistance in resource-poor healthcare Jodi A. Lindsay Institute of Infection and Immunity, St George’s, University of London, Cranmer Tce, London SW17 0RE, UK
Inter-patient transfer of antimicrobial resistant pathogens is more common in resource-poor healthcare settings. In this age of global resistance, what contributes to the spread of antimicrobial resistant clones? In recent years, whole genome sequencing (WGS) has dramatically improved our understanding of the epidemiology and spread of pathogens causing healthcare-associated infection, including those that are antimicrobial resistant. An example is the spread of methicillin-resistant Staphylococcus aureus (MRSA), a common cause of hospital and community infection that is resistant to the most powerful class of antibiotics for treating and preventing infection. MRSA is endemic in hospitals globally, yet in different geographical areas different clones predominate [1], incidence can vary widely [2], and now new data suggest that MRSA transmission between patients in hospitals is dependent on healthcare resource-levels [3]. WGS is important for epidemiological studies because it can discriminate between isolates belonging to the same closely related clades that dominate in hospitals, allowing detailed transmission mapping that is not possible using more standard typing methods. WGS studies have recently shown that in well-resourced hospitals, transmission of MRSA clones between patients is relatively rare [4]. These studies are best performed by sampling for nasal colonization, which in longitudinal studies is shown to be the reservoir for subsequent infecting isolates. During MRSA outbreaks in western hospitals, low transmission rates make identification of reservoirs difficult, although there have been instances of nasally colonized staff being implicated as outbreak reservoirs [5]. In a new study by Tong et al. [3] of resource-poor intensive care units in rural Thailand, transmission of MRSA between patients was detected at much higher levels. In several cases, patients were admitted with their own clade (>60 SNP variants) of the dominant ST239 MRSA type, and subsequently this clade spread to other patients in the unit, often displacing the patient’s original ST239 clade. The high levels of transmission between patients may be associated with low staffing numbers, 20 SNPs [5]. The authors conclude the patient was colonized with a single ancestor and SNP variants accumulated over a period of months. The implications for epidemiological studies is that sequencing of multiple isolates from the same carrier, particularly if that carrier is the potential reservoir of infecting isolates, may be necessary in order to confirm MRSA hospital transmission pathways. What are the biological reasons for the success of certain clades and their variants? Several antimicrobial resistance genes carried on mobile genetic elements were associated with particular clades, including resistance to aminoglycosides, mupirocin, and quarternary ammonium/disinfectant compounds. However, variation in their presence within clades also suggested these elements can be easily lost, and it is notable that resistance did not accumulate in successful clades. Similar findings in resource-rich healthcare settings suggest the accessory genome during colonisation is highly variable [6], and this is further supported by experimental colonisation models of piglets that demonstrate very high levels of acquisition and loss of mobile genetic elements [7]. Overall, these new studies are suggesting colonisation with mixed populations of closely related MRSA that may rapidly adapt by acquiring SNPs or genetic elements, rather than selection and domination of the fittest variant. The very high antimicrobial resistance burden in resource-poor settings is likely contributing to MRSA transmission between patients both within and outside of healthcare, and has important global implications. The ST239 clone from Asia has been introduced to wellresourced healthcare countries [8], although for reasons unknown these clones have not established themselves for long, and presumably were outcompeted by local MRSA clones and conditions [6]. It is vital to understand transmission pathways, as well as the key factors selecting for resistant clones in different healthcare settings, in the quest to develop evidence-based strategies for reducing antimicrobial resistance. Trends in Microbiology xx (2015) 1–2
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TIMI-1160; No. of Pages 2
Spotlight Disclaimer statement J.A.L. has received fees from Pfizer for consultancy on S. aureus vaccines.
References 1 Stefani, S. et al. (2012) Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int. J. Antimicrob. Agents 39, 273–282 2 World Health Organization (2014) Antimicrobial resistance: global report on surveillance 2014. http://apps.who.int/iris/bitstream/10665/ 112642/1/9789241564748_eng.pdf?ua=1 3 Tong, S.Y.C. et al. (2015) Genome sequencing defines phylogeny and spread of methicillin-resistant Staphylococcus aureus in a high transmission setting. Genome Res. 25, 111–118
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4 Price, J.R. et al. (2014) Whole genome sequencing shows that patient-topatient transmission rarely accounts for acquisition of Staphylococcus aureus in an intensive care unit. Clin. Infect. Dis. 58, 609–618 5 Harris, S.R. et al. (2013) Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study. Lancet Infect. Dis. 13, 120–136 6 Knight, G.M. et al. (2012) Shift in dominant hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) clones over time. J. Antimicrob. Chemother. 67, 2514–2522 7 McCarthy, A.J. et al. (2014) Extensive horizontal gene transfer during Staphylococcus aureus co-colonization in vivo. Genome Biol. Evol. 6, 2697–2708 8 Harris, S.R. et al. (2010) Evolution of MRSA during hospital transmission and intercontinental spread. Science 327, 469–474
Spotlight
Transmission of antimicrobial resistance in resource-poor healthcare Jodi A. Lindsay Institute of Infection and Immunity, St George’s, University of London, Cranmer Tce, London SW17 0RE, UK
Inter-patient transfer of antimicrobial resistant pathogens is more common in resource-poor healthcare settings. In this age of global resistance, what contributes to the spread of antimicrobial resistant clones? In recent years, whole genome sequencing (WGS) has dramatically improved our understanding of the epidemiology and spread of pathogens causing healthcare-associated infection, including those that are antimicrobial resistant. An example is the spread of methicillin-resistant Staphylococcus aureus (MRSA), a common cause of hospital and community infection that is resistant to the most powerful class of antibiotics for treating and preventing infection. MRSA is endemic in hospitals globally, yet in different geographical areas different clones predominate [1], incidence can vary widely [2], and now new data suggest that MRSA transmission between patients in hospitals is dependent on healthcare resource-levels [3]. WGS is important for epidemiological studies because it can discriminate between isolates belonging to the same closely related clades that dominate in hospitals, allowing detailed transmission mapping that is not possible using more standard typing methods. WGS studies have recently shown that in well-resourced hospitals, transmission of MRSA clones between patients is relatively rare [4]. These studies are best performed by sampling for nasal colonization, which in longitudinal studies is shown to be the reservoir for subsequent infecting isolates. During MRSA outbreaks in western hospitals, low transmission rates make identification of reservoirs difficult, although there have been instances of nasally colonized staff being implicated as outbreak reservoirs [5]. In a new study by Tong et al. [3] of resource-poor intensive care units in rural Thailand, transmission of MRSA between patients was detected at much higher levels. In several cases, patients were admitted with their own clade (>60 SNP variants) of the dominant ST239 MRSA type, and subsequently this clade spread to other patients in the unit, often displacing the patient’s original ST239 clade. The high levels of transmission between patients may be associated with low staffing numbers, 20 SNPs [5]. The authors conclude the patient was colonized with a single ancestor and SNP variants accumulated over a period of months. The implications for epidemiological studies is that sequencing of multiple isolates from the same carrier, particularly if that carrier is the potential reservoir of infecting isolates, may be necessary in order to confirm MRSA hospital transmission pathways. What are the biological reasons for the success of certain clades and their variants? Several antimicrobial resistance genes carried on mobile genetic elements were associated with particular clades, including resistance to aminoglycosides, mupirocin, and quarternary ammonium/disinfectant compounds. However, variation in their presence within clades also suggested these elements can be easily lost, and it is notable that resistance did not accumulate in successful clades. Similar findings in resource-rich healthcare settings suggest the accessory genome during colonisation is highly variable [6], and this is further supported by experimental colonisation models of piglets that demonstrate very high levels of acquisition and loss of mobile genetic elements [7]. Overall, these new studies are suggesting colonisation with mixed populations of closely related MRSA that may rapidly adapt by acquiring SNPs or genetic elements, rather than selection and domination of the fittest variant. The very high antimicrobial resistance burden in resource-poor settings is likely contributing to MRSA transmission between patients both within and outside of healthcare, and has important global implications. The ST239 clone from Asia has been introduced to wellresourced healthcare countries [8], although for reasons unknown these clones have not established themselves for long, and presumably were outcompeted by local MRSA clones and conditions [6]. It is vital to understand transmission pathways, as well as the key factors selecting for resistant clones in different healthcare settings, in the quest to develop evidence-based strategies for reducing antimicrobial resistance. Trends in Microbiology xx (2015) 1–2
1
TIMI-1160; No. of Pages 2
Spotlight Disclaimer statement J.A.L. has received fees from Pfizer for consultancy on S. aureus vaccines.
References 1 Stefani, S. et al. (2012) Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int. J. Antimicrob. Agents 39, 273–282 2 World Health Organization (2014) Antimicrobial resistance: global report on surveillance 2014. http://apps.who.int/iris/bitstream/10665/ 112642/1/9789241564748_eng.pdf?ua=1 3 Tong, S.Y.C. et al. (2015) Genome sequencing defines phylogeny and spread of methicillin-resistant Staphylococcus aureus in a high transmission setting. Genome Res. 25, 111–118
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Trends in Microbiology xxx xxxx, Vol. xxx, No. x
4 Price, J.R. et al. (2014) Whole genome sequencing shows that patient-topatient transmission rarely accounts for acquisition of Staphylococcus aureus in an intensive care unit. Clin. Infect. Dis. 58, 609–618 5 Harris, S.R. et al. (2013) Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study. Lancet Infect. Dis. 13, 120–136 6 Knight, G.M. et al. (2012) Shift in dominant hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) clones over time. J. Antimicrob. Chemother. 67, 2514–2522 7 McCarthy, A.J. et al. (2014) Extensive horizontal gene transfer during Staphylococcus aureus co-colonization in vivo. Genome Biol. Evol. 6, 2697–2708 8 Harris, S.R. et al. (2010) Evolution of MRSA during hospital transmission and intercontinental spread. Science 327, 469–474
