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Why Has Methicillin-Resistant Staphylococcus aureus Become Such a Successful Pathogen in Adults?

Moellering, Robert C. Jr MD

Infectious Diseases in Clinical Practice: September 2010 - Volume 18 - Issue 5 - p 286-291
doi: 10.1097/IPC.0b013e3181efebca
NFID Clinical Updates

Staphylococcus aureus is a pathogen that has caused human disease for centuries, and despite efforts to control it via modern antibiotics, this organism has persisted and continues to cause major clinical problems throughout the world. A remarkably versatile pathogen, it has virulence mechanisms that enable it to cause a broad variety of serious infections in man, and it has the ability to acquire new exogenous genes, which make it possible for it to adapt to a variety of changing environmental conditions and to modulate its pathogenicity. It can establish a symptomatic carriage that permits widespread dissemination. It has shown a remarkable ability to develop resistance to the major antibiotics directed against it including the penicillins. The development of methicillin resistance in staphylococci has resulted in organisms that continue to plague patients in institutionalized settings and elsewhere. More recently, there has been a worldwide outbreak (currently most prominent in the United States) of infections due to community-associated methicillin-resistant staphylococci. The factors that have made it possible for this to occur are defined in this article.

From the Harvard Medical School, Boston, MA.

Correspondence to: Robert C. Moellering, Jr, MD, Harvard University Medical School, 110 Francis St, Suite 6A1102 Bates Ave, Suite 1120, Boston, MA 02215. E-mail:

The author served as an advisor or consultant for Cubist Pharmaceuticals, Inc; Pfizer Inc; Wyeth; and Theravance.

This CME activity is supported by an unrestricted educational grant from Cubist Pharmaceuticals.

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Infectious disease physicians, nurses, hospital epidemiologists, clinical microbiologists, pharmacists, public health authorities, practicing physicians, and other health care professionals interested in the treatment of serious infections due to methicillin-resistant Staphylococcus aureus (MRSA).

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Describe the epidemiology, pathogenesis, and clinical characteristics of MRSA infections in the adult population.

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Credit is based on the approximate time it should take to read this publication and complete the assessment and evaluation. A minimum assessment score of 80% is required. Publication date is September 1, 2010. Requests for credit or contact hours must be postmarked no later than March 1, 2011, after which this material is no longer certified for credit.

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Lauren Ero, MS (managing editor), reports no relevant financial relationships.

Thomas M. File, Jr, MD (reviewer), served as an advisor or consultant for Astellas/Theravance, Cerexa/Forest, Ortho-McNeil, Protez, Merck, Nabriva, and Pfizer and received grants for clinical research from Cerexa, Ortho-McNeil, Protez, Pfizer, Boehringer Ingelheim, Gilead, and Tibotic.

Robert C. Moellering, Jr, MD (faculty), served as an advisor or consultant for Cubist Pharmaceuticals, Inc, Pfizer Inc, Wyeth, and Theravance.

Marguerite Jackson, PhD, RN (reviewer), owns stock, stock options, or bonds from Cellestis, Inc.

Susan J. Rehm, MD (senior editor), served as an advisor or consultant for Cubist Pharmaceuticals, Inc, and Pfizer Inc; served as a speaker for Cubist Pharmaceuticals, Inc, and Roche; and received grants for clinical research from Cubist Pharmaceuticals, Inc.

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Outbreaks of the community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 clone across the United States in recent years suggest that we are in the midst of an almost unprecedented epidemic. These CA-MRSA infections, which are often serious and invasive, are becoming commonplace and have been reported in many states including California, Georgia, Texas, Pennsylvania, Mississippi, and Minnesota.1-3 A rise in CA-MRSA-related illnesses in both the community and the hospital setting over the last 10 years has prompted research efforts to better understand the unique nature of the organism and its impact in these settings.

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Staphylococcus aureus is a constantly evolving and incredibly versatile pathogen. It has virulence and quorum-sensing mechanisms that enable it to cause a broad variety of serious infections in man. The genetic diversity of the organism is remarkable. It has the ability to acquire new exogenous genes, which allow it to adapt to a variety of changing environmental conditions and to modulate its pathogenicity. It can establish asymptomatic carriage, which permits widespread dissemination among human hosts. It also has a remarkable propensity to acquire resistance to multiple antimicrobial agents, which causes therapeutic challenges for physicians.

The predominant CA-MRSA clone in the US community is now USA300 rather than USA400. In a rat model of necrotizing pneumonia, USA300 isolates were shown to be more lethal than USA400 isolates in terms of more severe pneumonia and higher bacterial density in the lung.4 Greater expression of regulatory genes (ie, agr, saeRS, sarA, hla, and pvl) associated with the virulence factors Panton-Valentine leukocidin (PVL) and α-hemolysin occurred with USA300 versus USA400 isolates.4,5

The USA300 MRSA strain has several characteristics that give it selective advantages over other MRSA clones. First, most USA300 strains have the type IV SCCmec chromosomal cassette, which is smaller than types I to III found in hospital-acquired MRSA. Smaller cassettes may offer an advantage in terms of speed of replicating DNA. Second, CA-MRSA-including USA300-carries fewer antibiotic resistant genes than hospital-acquired MRSA. Third, the doubling time of USA300 is shorter than standard strains, by approximately 1.25-fold. Fourth, the linkage of arginine catabolic element with SCCmec type IV in USA300 confers increased fitness and/or pathogenicity. Arginine catabolic mobile element (ACME), which is a putative pathogenicity island, is genetically linked to SCCmec in USA300, suggesting interconnection between antibiotic resistance and pathogenicity. In a rabbit model of bacteremia, Diep et al6 showed that the deletion of SCCmec did not affect competitive fitness of the organism. In contrast, the deletion of ACME reduced pathogenicity of the USA300 MRSA strain, indicating a significant role of ACME in the ability of USA300 to cause serious infections.

The DNA sequencing of the MRSA genome in 2001 provided some interesting insights into the organism.7 Whole-genome sequences of 2 related S. aureus strains were determined: N315 (MRSA; isolated in 1982) and Mu50 (vancomycin intermediate S. aureus, isolated in 1997). The organism has approximately 2600 genes (open reading frames). Remarkably, a significant number of these genes are not staphylococcal genes. They have been acquired from other organisms. The genome contained 11 genes with encoded resistance to more than 9 classes of antibiotics. Most of these were on plasmids or mobile genetic elements. Three classes of new "pathogenicity islands"-or collections of genes-were identified: a toxic shock syndrome toxin family of islands, exotoxin islands, and enterotoxin islands. Seventy candidate genes for new virulence factors were also discovered.

Although most CA-MRSA strains in the United States, including USA300, have the PVL genes, the presence of PVL genes alone is probably not a factor in the predominance and virulence of the organism in the community. Zhang et al8 identified the coexistence of 2 USA400 sibling strains with and without the PVL genes in a large Canadian health care region. The strains shared identical genotypic and phenotypic properties and similar clinical characteristics. These data suggest that the presence of PVL genes alone does not explain the predominance of the CA-MRSA organism.

The genome sequence of the MW2 strain of CA-MRSA, which caused fatal bacteremia in a 16-month-old female Native American from North Dakota in 1998, was ascertained.9 It was determined that the methicillin resistance gene (mecA) was carried on the type IVa cassette (SCCmec IVa). The SCCmec IVa did not contain multiple resistance genes (as does type II SCCmec from N315 and Mu50). However, 19 additional genes were found in the MW2 genome, all but two of which were found in 4 of the 7 genomic islands of MW2. Eighteen of these were toxins (including PVL) not found in the N315, Mu50, or COL strains. In contrast to N315 and Mu50, MW2 has almost no transposons or insertion sequences. Chongtrakool and colleagues10 diagrammed the various staphylococcal chromosome cassettes that are associated with methicillin resistance. The CA-MRSA SCCmec type IV cassettes are considerably smaller than the hospital-associated strains.

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From a historical perspective, S. aureus resistance to penicillin occurred very rapidly with the clinical use of that drug, which made it quickly obsolete for treatment of S. aureus infections. Although methicillin has been used for many years (since 1959), it took only 2 years from the first clinical use of that agent for the emergence of the first strains of methicillin-resistant staphylococci. In other countries outside the United States, MRSA organisms were primarily seen in hospitals and chronic care facilities. The first report of 2 cases of MRSA nosocomial infections in the United States was in 1967. The first reports of larger numbers of cases of MRSA in the United States occurred between 1975 and 1980 in large tertiary-care hospitals, especially burn units and intensive care units. By 1980, there was an increase in MRSA prevalence in US nursing homes and in the community setting.11-13 By 2004, more than 60% of S. aureus in most US hospitals were methicillin-resistant (Fig. 1) (Table 1).14





Until recently, most MRSA outbreaks were considered nosocomial infections as a result of clonal spread in the hospital or in nursing homes in the community. Community-acquired MRSA infections have become more commonplace and have been reported not only in the United States, but also around the world in countries such as the United Kingdom, Australia, New Zealand, France, Finland, Canada, and Samoa. These CA-MRSA organisms are fully virulent, and many of them have caused fatal infections, especially in children.15-17

Outbreaks of CA-MRSA in the United States began among Native American children in Minnesota, Nebraska, and North Dakota. Subsequent outbreaks from 2000 to 2005 occurred in the populations listed in Table 2.



The incidence of serious infections owing to CA-MRSA is increasing. New syndromes associated with CA-MRSA have included necrotizing skin infections ("spider bites"), necrotizing fasciitis, septic thrombophlebitis of the extremities, pelvic syndrome (septic arthritis of the hips, pelvic osteomyelitis, pelvic abscesses, and septic thrombophlebitis), Waterhouse-Friderichsen syndrome, and rapidly progressive necrotizing pneumonia. Pelvic syndrome occurs most commonly in children. The CA-MRSA organism is quite virulent in these settings, particularly in children.18

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The prevalence of CA-MRSA is rapidly increasing in the United States. The incidence of CA-MRSA increased at Texas Children's Hospital in Houston from 71.5% in 2001 to 76.4% in 2004. The rate of increase was greater for MRSA versus methicillin-sensitive S. aureus isolates.19 At Emory University Hospital in Atlanta, Ga, MRSA accounted for 72% of community-acquired S. aureus episodes; 63% of S. aureus isolates were identified as CA-MRSA organisms.20 In August 2004, MRSA was the most commonly identifiable cause of skin and soft-tissue infections reported from 11 university-affiliated emergency departments in the United States.21 The overall prevalence of MRSA was 59% (ranging from 15% to 74%). The USA300 clone is the predominant MRSA isolate in the United States.

Rapid dissemination of new CA-MRSA clones has occurred in the United States and in other countries. In a study of multiple CA-MRSA strains that carried SCCmec type IV from the United States and from Australia, researchers determined that the CA-MRSA strains multiplied much faster than health care-associated MRSA and were resistant to fewer non-β-lactam antibiotics. The doubling time of CA-MRSA was shorter (28 minutes) than that for health care-associated MRSA (39 minutes).22

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From the outset of the CA-MRSA epidemic over the past decade, there has been widespread dissemination of this organism in the outpatient setting. Furthermore, the rapid introduction of the organism into the hospital setting has blurred the distinction between CA-MRSA and hospital-associated MRSA. It is possible that the USA300 strain may become the dominant strain in hospitals as well as in the community because of its unique characteristics (Table 3).



The prevalence of CA-MRSA and subsequent mortality owing to MRSA-related illnesses are increasing in US hospitals. Many strains of S. aureus in the hospital setting now seem to be community-associated strains. Numerous hospitals throughout the country document that the prevalence of CA-MRSA is increasing among hospitalized patients.

Hospitalizations related to MRSA in the United States more than doubled from 1999 to 2005, partially owing to the introduction of CA-MRSA into the hospital setting.23 Among patients with health care-related risk factors, 18% to 28% were infected with CA-MRSA USA300. In Chicago hospitals, CA-MRSA caused an increase in the percentage of hospital onset bacteremias from 24% in 2000 to 49% in 2006.24 A recent study of 9 San Francisco medical centers from 2004 to 2005 showed an annual increase of CA-MRSA disease that has now surpassed hospital-associated disease, with USA300 ranking as the predominant clone. The USA300 clone constituted almost 80% of CA-MRSA and 43% of hospital-associated MRSA in San Francisco.25

Mathematical models can predict the rapidity of dissemination of CA-MRSA in hospitals and suggest possible control measures. D'Agata and colleagues26 developed a deterministic mathematical model that characterized the factors contributing to the replacement of hospital-associated MRSA with CA-MRSA and quantified interventions for control in the hospital. The model strongly suggests that CA-MRSA will become the dominant strain in hospitals as a result of documented expanding community reservoirs and a larger in-hospital population of carriers (Table 4).



Because the CA-MRSA organism causes serious disease, patients may require a longer duration of hospitalization, and the impact of the disease may be greater on the typically older, more debilitated inpatient population. Strategies toward reducing the spread of MRSA infections such as hand hygiene and screening for MRSA carriers are effective strategies; however, hand hygiene is emphasized as the key to reducing the spread of MRSA infections in the health care setting.

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In conclusion, more than 70 years after the discovery of the first effective antistaphylococcal agents, S. aureus has not been subdued. Staphylococcus aureus continues to pose unique problems for researchers and clinicians. The CA-MRSA USA300 clone has unique characteristics that make it a versatile and lethal pathogen. Dissemination of CA-MRSA is widespread throughout the community. The distinction between community-associated and hospital-associated MRSA is rapidly blurring in the United States. The increased prevalence of the MRSA USA300 clone in hospitals has prompted researchers to create mathematical models in an attempt to predict and slow the spread of this virulent organism in health care settings.

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1. Chambers HF. Community-associated MRSA-resistance and virulence converge. N Engl J Med. 2005;352(14):1485-1487.
2. Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med. 2005;352(5):468-475.
3. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-acquired methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352(14):1445-1453.
4. Montgomery CP, Boyle-Vavra S, Adem PV, et al. Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia. J Infect Dis. 2008;198(4):561-570.
5. Wardenburg BJ, Bae T, Otto M, et al. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med. 2007;13(12):1405-1406.
6. Diep BA, Stone GG, Basuino L, et al. The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus. J Infect Dis. 2008;197(11):1523-1530.
7. Kuroda M, Ohta T, Uchiyama I, et al. Whole genome sequencing of methicillin-resistant Staphylococcus aureus. Lancet. 2001;357(9264):1225-1240.
8. Zhang K, McClure JA, Elsayed S, et al. Coexistence of Panton-Valentine leukocidin-positive and -negative community-associated methicillin-resistant Staphylococcus aureus USA400 sibling strains in a large Canadian health-care region. J Infect Dis. 2008;197(2):195-204.
9. Baba T, Takeuchi F, Kuroda M, et al. Genome and virulence determinants of high virulence community-acquired MRSA. Lancet. 2002;359(9320):1819-1827.
10. Chongtrakool P, Ito T, Ma XX, et al. Staphylococcal cassette chromosome mec (SCCmec) typing of methicillin-resistant Staphylococcus aureus strains isolated in 11 Asian countries: a proposal for a new nomenclature for SCCmec elements. Antimicrob Agents Chemother. 2006;50(3):1001-1012.
11. Westh H, Jarløv JO, Kjersem H, et al. The disappearance of multiresistant Staphylococcus aureus in Denmark: changes in strains of the 83A complex between 1969 and 1989. Clin Infect Dis. 1992;14(6):1186-1194.
12. Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev. 1997;10(4):781-791.
13. Bradley SF. Methicillin-resistant Staphylococcus aureus: long-term care concerns. Am J Med. 1999;106(5A):2S-10S.
14. National Nosocomial Infections Surveillance System (NNIS). Accessed July 28, 2010.
15. Bradley SF, Terpenning MS, Ramsey MA, et al. Methicillin-resistant Staphylococcus aureus: colonization and infection in a long-term care facility. Ann Intern Med. 1991;115(6):417-422.
16. Groom AV, Wolsey DH, Naimi TS, et al. Community-acquired methicillin-resistant Staphylococcus aureus in a rural American Indian community. JAMA. 2001;286(10):1201-1205.
17. Ma XX, Ito T, Tiensasitorn C, et al. Novel type of staphylococcal cassette chromosome mec identified in community-acquired methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother. 2002;46(4):1147-1152.
18. Moellering RC Jr. The growing menace of community-acquired methicillin-resistant Staphylococcus aureus. Ann Intern Med. 2006;144(5):368-370.
19. Kaplan SL, Hulten KG, Gonzalez BE, et al. Three-year surveillance of community-acquired Staphylococcus aureus infections in children. Clin Infect Dis. 2005;40(12):1785-1791.
20. King MD, Humphrey BJ, Wang YF, et al. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med. 2006;144(5):309-317.
21. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355(7):666-674.
22. Okuma K, Iwakawa K, Turnidge JD, et al. Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community. J Clin Microbiol. 2002;40(11):4289-4294.
23. Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis. 2007;13(12):1840-1846.
24. Popovich KJ, Weinstein RA, Hota B. Are community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains? Clin Infect Dis. 2008;46(6):787-794.
25. Liu C, Graber CJ, Karr M, et al. A population-based study of the incidence and molecular epidemiology of methicillin-resistant Staphylococcus aureus disease in San Francisco, 2004-2005. Clin Infect Dis. 2008;46(11):1637-1646.
26. D'Agata EM, Webb GF, Horn MA, et al. Modeling the invasion of community-acquired methicillin-resistant Staphylococcus aureus into hospitals. Clin Infect Dis. 2009;48(3):274-284.
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Self Assessment Examination

A minimum assessment score of 80% is required.

Which of the following characteristics give the USA300 CA-MRSA strain selective advantages over other MRSA clones?

Type II SCCmec chromosomal cassette

More antibiotic resistance genes than hospital-acquired MRSA

Doubling time is shorter than standard strains, by approximately 1.25-fold

The linkage of arginine catabolic element with SCCmec type IV in USA300 confers increased pathogenicity.

C and D only

Syndromes associated with CA-MRSA include all but which of the following?

Septic thrombophlebitis

Pelvic syndrome in children

Waterhouse-Friderichsen syndrome

All of the above

B and C only

Which of the following statements regarding MRSA are true?

A significant number of genes in the MRSA genome are not staphylococcal genes.

The presence of PVL genes in MRSA strains is probably a factor in the predominance and virulence of the organism in the community.

Mathematical models suggest that CA-MRSA will become the dominant S. aureus strain in hospitals.

All of the above

A and C only

The predominant community CA-MRSA strain responsible for outbreaks reported in recent years has been identified by pulsed-field gel electrophoresis as





none of the above

Which of the following statements regarding CA-MRSA is false?

The USA400 MRSA strain is associated with greater regulatory expression of PVL and α-hemolysin than the USA-300 strain.

The MRSA organism has approximately 2600 genes.

The methicillin resistance gene (mecA) is carried on the type IVa cassette (SCCmec IVa).

All of the above

B and C only

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Staphylococcus aureus; methicillin resistance; pathogenicity; USA300

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