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Keywords:

  • Community-acquired methicillin-resistant Staphylococcus aureus;
  • epidemiology;
  • hospital-acquired methicillin-resistant Staphylococcus aureus;
  • infection control;
  • methicillin-resistant Staphylococcus aureus;
  • review

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

Methicillin-resistant Staphylococcus aureus (MRSA) has become a worldwide problem, although its prevalence varies considerably among countries. The epidemiology of MRSA is now changing; infections are no longer confined to the hospital setting, but also appear in healthy community-dwelling individuals without established risk factors for the acquisition of MRSA. Reported prevalence rates of community-acquired MRSA (CA-MRSA) vary widely among studies—largely because of the different definitions employed and different settings in which the studies have been performed. At present, molecular epidemiological definitions, based on staphylococcal cassette chromosome mec (SCCmec) typing and phylogenetic analyses of the MRSA isolates, are considered the most reliable means by which to distinguish between hospital-acquired MRSA (HA-MRSA) and CA-MRSA. CA-MRSA has been isolated predominantly from skin and soft tissue infections, such as abscesses, cellulitis, folliculitis and impetigo. Although CA-MRSA infections are usually mild, they may also be severe, and can result in hospitalisation and even death. CA-MRSA strains differ from the major pandemic clones of MRSA that account for the majority of epidemic HA-MRSA strains. Differences are found in SCCmec types, bacterial growth rate, and the distribution of antibiotic resistance genes and toxin genes. Mathematical models have shown that CA-MRSA has a high potential to become endemic in the community, and this will impact significantly on the control of MRSA in the hospital setting. Well-designed, community-based studies with adequate risk factor analysis are required to further elucidate the epidemiology of CA-MRSA and to improve strategies to control MRSA in both the community and hospital settings.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

Methicillin-resistant Staphylococcus aureus (MRSA) has traditionally been considered a healthcare-associated pathogen in patients with established risk factors [1–3]. More recently, however, MRSA infections have been described in community-dwelling patients without established risk factors for the acquisition of MRSA [4–15]. The emergence of this community-acquired MRSA (CA-MRSA) as a clinically significant pathogen necessitates reconsideration of current empirical treatment with β-lactam antibiotics for community-acquired S. aureus infections and current control strategies for MRSA in hospitals. The objective of this article is to summarise the current knowledge concerning CA-MRSA that is relevant to the development of future infection control strategies.

Mechanism of resistance

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

MRSA strains harbour the mecA gene, which encodes the low-affinity penicillin-binding protein 2a (PBP2a). The production of PBP2a confers resistance to otherwise inhibitory concentrations of all β-lactam antibiotics. The mecA gene is carried on a mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec), which is integrated in the chromosome of S. aureus. Phylogenetic analyses of international collections of MRSA and methicillin-susceptible S. aureus isolates have revealed that methicillin resistance has emerged in five phylogenetically distinct lineages, and on multiple occasions within a given phylogenetic lineage [16]. Up to now, five types of SCCmec have been identified, which differ in size and genetic composition. Notably, SCCmec type IV has been found in twice as many clones as any other SCCmec type, and it is this SCCmec type that is most commonly found in clones from patients with CA-MRSA infections [16].

Definitions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

Several definitions for CA-MRSA infections have been proposed [17]. Epidemiological definitions have commonly been based on the timing of isolation of MRSA in relation to the time of admission to the hospital (that is, MRSA isolates were classified as community-acquired if they were cultured within the first 48–72 h of hospitalisation or in a community setting) [17,18]. However, colonisation with S. aureus (both methicillin-susceptible S. aureus and MRSA) can persist for months to years [19,20], and is asymptomatic in the majority of individuals. Consequently, clinical infections may develop in a setting different from that in which the organism was initially acquired [21]. A meta-analysis of studies reporting the prevalence of CA-MRSA indicated that at least 85% of hospitalised patients who met the time-based definition for CA-MRSA infection, and 47.5% of healthy community members found to be colonised with MRSA, had at least one healthcare-associated risk factor for acquisition [17]. This suggests that at least some of the isolates were healthcare-acquired, and that the use of time-based definitions may lead to overestimation of the true prevalence of MRSA originating in the community. Therefore, others have classified MRSA infections as community-acquired only if no healthcare-associated risk factors were identified [7,12,22,23]. Healthcare-associated risk factors include recent hospitalisation or surgery, dialysis, residence in a long-term care facility, and the presence of a permanent indwelling catheter or percutaneous medical device at the time of culture [6,14].

However, discounting the possible community origin of MRSA infections in patients with healthcare-associated risk factors may lead to an underestimation of the true prevalence of CA-MRSA, as patients with prior healthcare exposure may be at increased risk of colonisation and infection by a true community-dwelling pathogen (e.g., due to outpatient antibiotic use, immunosuppression, or long-term intravenous access) [24]. Moreover, CA-MRSA isolates have recently been reported to have spread into hospitals, causing nosocomial infections [21,24,25]. Definitions based on epidemiological information are therefore insufficient to distinguish between CA-MRSA and hospital-acquired MRSA (HA-MRSA). The use of antibiotic resistance profiles in discriminating between CA-MRSA and HA-MRSA can also be questioned; although antibiotic resistance in CA-MRSA isolates is often limited to β-lactam antibiotics, multidrug resistance has been reported [26].

At present, molecular epidemiological definitions, based on SCCmec typing and phylogenetic analyses, are considered the most reliable. According to these definitions, an MRSA strain is classified as community-acquired if the SCCmec type IV (or V) is present and if it is phylogenetically unrelated to previously known HA-MRSA clonal lineages [16].

Epidemiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

MRSA has become a worldwide problem, although its prevalence varies considerably among countries. Consistently high prevalence rates are found in the USA, South America, Japan and southern Europe, whereas prevalence rates are low in Scandinavia, The Netherlands and Switzerland [27–29]. Several investigators have suggested that the epidemiology of MRSA is changing, as infections are increasingly reported in healthy community-dwelling individuals without healthcare-associated risk factors for the acquisition of MRSA [4,7,17,24,30]. Clusters and outbreaks of these so-called CA-MRSA infections have been described in more-or-less ‘closed populations’, such as native Americans [5], men who have sex with men [10], prison inmates [10,31,32], children attending childcare centres [9], military recruits [33], and competitive sports participants [10,11,34]. Moreover, CA-MRSA has now been introduced from its site of origin in the community into the hospital setting [24,25,35,36]. At some hospitals, CA-MRSA strains are even displacing classic hospital-acquired strains of MRSA [21].

Reported prevalence rates of CA-MRSA vary widely among studies, in part because of the use of different definitions to distinguish between CA-MRSA and HA-MRSA, but also because of the different settings in which studies have been performed. It should be noted that relatively few studies have been conducted among randomly selected healthy members of the community. Most studies have been based on hospitalised patients, or patients upon admission to the hospital, which has probably resulted in an overestimation of the ‘true’ prevalence of CA-MRSA.

A meta-analysis of studies reporting prevalence rates of CA-MRSA has recently been conducted [17]. The pooled prevalence of CA-MRSA among MRSA isolates from hospitalised patients was 30.2% in 27 retrospective studies and 37.3% in five prospective studies. Among community members without healthcare contacts, the pooled MRSA colonisation rate was 0.2%. European data are limited: the prevalence of MRSA nasal carriage was found to be 0.7% in a Portuguese surveillance study among young and healthy individuals from the community [37]; the prevalence of CA-MRSA upon admission to the hospital has been reported to be 0.1% in Switzerland [38], and 0.03% in The Netherlands [39].

Data concerning potential risk factors for the acquisition of CA-MRSA are limited. CA-MRSA-infected patients have been found to be younger than patients with HA-MRSA infections [12,13]. However, this finding may well reflect the fact that hospitalised patients represent a selected group of older individuals. Previous exposure to antimicrobial agents has been associated with an increased risk for CA-MRSA infections in some studies [15,40], but not in others [38].

Clinical spectrum of disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

The spectrum of clinical infections caused by CA-MRSA is similar to that caused by methicillin-susceptible S. aureus[5,7], but clearly distinct from that caused by HA-MRSA. Whereas HA-MRSA commonly causes bloodstream infections and infections of the urinary and respiratory tracts, CA-MRSA has predominantly been isolated from skin and soft tissue infections, such as abscesses, cellulitis, folliculitis and impetigo [5,6,10–12,14]. Although CA-MRSA infections are commonly mild, they may also be severe, and can result in hospitalisation and/or death [4]. For example, necrotising fasciitis caused by CA-MRSA has recently been reported as an emerging clinical entity [41]. In addition to skin and soft tissue infections, severe necrotising pneumonia due to CA-MRSA has occasionally been described in young patients without known healthcare-associated risk factors for the acquisition of MRSA [14]. The observed clinical spectrum of infections caused by CA-MRSA has been associated with the presence of Panton–Valentine leukocidin genes, which code for the production of cytotoxins that cause tissue necrosis and leukocyte destruction [13,42–44]. However, other exotoxin genes or combinations of genes could also be important pathogenic factors [13].

Genotypic and phenotypic characteristics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

CA-MRSA strains differ from the major pandemic clones of MRSA that account for the majority of epidemic HA-MRSA strains [22,45,46]. Differences are found in SCCmec types, the presence of additional antibiotic resistance genes, bacterial growth rate and the distribution of toxin genes (Table 1).

Table 1.  Characteristics of staphylococcal cassette chromosome mec (SCCmec) types I–V [13,22,45–48]
SCCmecStaphylococcus aureus carrying specified SCCmec type
TypeSize (kb)Presence of other antibiotic resistance genesOrigin of isolatesMean doubling time (min)Presence of PVL genes
  1. PVL, Panton–Valentine leukocidin.

I34NoHospital36Infrequent
II53YesHospital32Infrequent
III67YesHospital42Infrequent
IV21–24NoCommunity28Frequent
V28NoCommunityUnknownUnknown

Recent studies have indicated that well-defined CA-MRSA strains carry SCCmec type IV or V [22,45,47], whereas the majority of HA-MRSA strains carry SCCmec type I, II or III [48,49]. SCCmec types IV and V are relatively small in size; for SCCmec type IV, this appears to have resulted in its increased mobility and therefore greater potential for horizontal spread to diverse S. aureus genetic backgrounds, compared with other SCCmec types [16,22,45,50–53].

In contrast to the multidrug resistance that is usually seen in HA-MRSA strains, antibiotic resistance in CA-MRSA strains is often limited to β-lactam antibiotics [5,14,54]. This is consistent with the absence of antibiotic resistance genes other than mecA in SCCmec types IV and V, as compared to the accumulation of multiple additional antibiotic resistance genes in SCCmec types II and III [22,45,47,48].

CA-MRSA strains carrying SCCmec type IV have been reported to have a higher growth rate than HA-MRSA strains [22], which may have enhanced the ecologic fitness of CA-MRSA.

Several studies have indicated that the presence of Panton–Valentine leukocidin genes is common among CA-MRSA strains from different genetic backgrounds, whereas these genes are rare among HA-MRSA strains [13,43,46].

Threats and prevention

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

The future impact of the emergence of CA-MRSA on the occurrence of MRSA infections in both the community and hospital settings is of great interest. Some authors predict that MRSA will become the most prevalent type of S. aureus in the near future, and that this will mirror the emergence of penicillin resistance in S. aureus in the 1950s and 1960s (Fig. 1) [30]. Dissemination of penicillin-resistant strains from the hospital setting into the community occurred at a time when the rate of penicillin resistance among hospital patients with staphylococcal disease approached 50%. This is comparable to the current rate of methicillin resistance among hospitalised patients with staphylococcal infections in US hospitals [29]. However, contrary to the view that the majority of CA-MRSA isolates result from the spread of hospital-acquired strains into the community, it appears that community-based strains are migrating into the hospital setting [21,24,25,35,36], and that MRSA in the community is independent of a hospital reservoir.

image

Figure 1. Prevalence of penicillin resistance among Staphylococcus aureus in hospitals and in the community, 1940–1974. The prevalence of S. aureus strains resistant to penicillin within hospitals rose dramatically in the 1940s and 1950s. However, penicillin-resistant community-acquired strains of S. aureus were not reported until 1949, when the rate of penicillin resistance in hospitals approached 50%. The prevalence of penicillin-resistant S. aureus in communities continued to increase throughout the ensuing 20 years, finally approaching the resistance rates seen among hospital strains. Adapted from Chambers [30] and Salgado [17].

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Mathematical models have been used to predict the future epidemiology of MRSA and to determine effective control strategies. With the use of such models, it has been shown that the presence of a community reservoir has a major impact on the control of MRSA in the hospital [55–57]. In open communities, it will take years or even decades to see substantial reductions in the frequency of antibiotic resistance solely as a result of more prudent (reduced) use of antibiotics [57]. Furthermore, isolation of infected patients and contact tracing will be hardly effective within the community setting, because of the high frequency of transmission by asymptomatic colonised individuals [56]. Therefore, CA-MRSA has a high potential to become endemic in the community unless additional control measures are introduced, e.g., screening of asymptomatic individuals. Conversely, in the hospital setting, the frequency of resistance may be reduced substantially by restricting the input of resistant bacteria through the implementation of appropriate infection control and other measures [57].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References

Although our understanding of CA-MRSA is increasing, well-designed community-based studies with adequate risk factor analysis are required to further elucidate the epidemiology of CA-MRSA and to improve strategies to control MRSA in both the community and hospital setting.

References

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  2. Abstract
  3. Introduction
  4. Mechanism of resistance
  5. Definitions
  6. Epidemiology
  7. Clinical spectrum of disease
  8. Genotypic and phenotypic characteristics
  9. Threats and prevention
  10. Conclusion
  11. References
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