Weinstein, Robert A. MD
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.
Describe the role of bacterial factors in infections and explore patient polymorphisms for infection risk.
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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 July 1, 2011. Requests for credit or contact hours must be postmarked no later than January 1, 2012, after which this material is no longer certified for credit.
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Marla Dalton, PE (managing editor), reported no relevant financial relationships.
Thomas M. File, Jr, MD (reviewer), served as an advisor or consultant for Astellas/Theravance, Cerexa/Forest, Merck, Nabriva, Pfizer Inc, and Tetraphase and received grants for clinical research from Cerexa, Cempra, Pfizer Inc, and The Medicines Company.
Robert A. Weinstein, MD (faculty), reported no relevant financial relationships.
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 Merck and Pfizer, Inc; served as a speaker for Genentech; and received grants for clinical research from Cubist Pharmaceuticals, Inc.
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The understanding of bacterial infectious diseases has evolved through the use of 3 scientific approaches: case series, epidemiologic investigation, and molecular analysis (Table 1). The case-series approach evaluates patient risk factors such as diabetes. This approach evaluates pathogens through susceptibility trends (eg, progressive antimicrobial resistance). The second approach-epidemiologic investigation-evaluates population risks (eg, intravenous drug users, health care setting) and identifies pathogens through clonality techniques such as pulsed-field gel electrophoresis typing to determine strain relatedness. The third approach entails more detailed molecular analysis, which has evaluated genetic predisposition of disease in patients (eg, single nucleotide polymorphisms [SNPs]). In the molecular analysis approach, pathogenicity of infecting agents also is studied through analysis of factors such as those affecting colonization and virulence (eg, arginine catabolic mobile elements [ACME] and Panton-Valentine leukocidins [PVLs]).
EPIDEMIOLOGY OF PATHOGENS
The epidemiology of health care-associated pathogens in the 20th and 21st centuries can be described as 4 eras of pathogen activity (Fig. 1). The first era of pathogen activity began with the emergence of streptococcal infections from the mid-1800s through the 1940s. Between 1950 and 1960, staphylococci became the most prevalent hospital pathogens. Gram-negative rods became a problem in the 1970s and have reemerged more recently in the era of multidrug-resistant organisms (eg, extended-spectrum β-lactamases, multidrug-resistant Acinetobacter, Pseudomonas) that includes methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci.
The evolution and spread of community-associated MRSA (CA-MRSA) have been compared with that of penicillin-resistant S. aureus in the 1950s.1 In the 1940s, soon after the introduction of penicillin, penicillin-resistant S. aureus was recognized. In the 1940s through the 1960s, a methicillin-susceptible penicillin-resistant S. aureus strain, phage type 80/81, circled the globe and caused pandemic disease. In the 1960s, methicillin resistance emerged in hospitals in Europe, particularly in England. In the United States, health care-associated MRSA began to emerge in the 1980s. In the early part of the last decade, 2002-2003, CA-MRSA began to emerge across the United States. Reports of CA-MRSA infections occurred in Los Angeles and Chicago within 2 to 3 months of each other. Molecular investigations of CA-MRSA began aggressively. Although much is now known about CA-MRSA, including its epidemiologic and clinical spectrum, possible relations to S. aureus phage type 80/81, and CA-MRSA genetics and virulence mechanisms, the reasons for the rapid cross-continental clonal emergence remain poorly understood.
HEALTH CARE-ASSOCIATED VERSUS CA-MRSA DISTINCTIONS
Historically, genetic strains of health care-associated and CA-MRSA remained separate and distinct. However, recent studies have shown that the CA-MRSA pathogens have begun to comingle among the community, hospital, and health care exposure settings.2 More frequently, community strains are overwhelming and are replacing the hospital strains.
On a genetic level, 2 important elements in the CA-MRSA USA300-currently the most common strain of CA-MRSA in the United States based on pulsed-field gel electrophoresis pattern-appear to be physically linked.3 The interaction between these 2 elements may be responsible for the virulence and resistance demonstrated by CA-MRSA. ACME is a putative pathogenicity island, and the type IV staphylococcal chromosomal cassette mec (SCCmec) confers β-lactam antibiotic class resistance. The ACME enhances growth and survival of USA300, allowing for "genetic hitchhiking" of SCCmec, which provides resistance against β-lactam exposure.
Individual human responses to antibiotic resistance can be understood by studying SNPs in the human chromosome.4 The SNPs occur as a result of a substitution of 1 base (thymine, adenine, guanine, and cytosine) for another, which will change the amino acids and, consequently, the protein encoded by the chromosome. These minor changes may explain the difference in individual responses to infection in humans.
The emergence of CA-MRSA (USA300) necrotizing pneumonia has been reported in young healthy individuals and patients with health care-associated risk factors. Necrotizing pneumonia caused by CA-MRSA is associated with high morbidity and mortality.5 There are multiple factors that contribute to the pathogenicity of CA-MRSA in these illnesses. Virulence factors that contribute significantly to the organism's ability to cause necrotic changes in the lung, high mortality in patients with surgical site infections, and paravalvular abscesses in endocarditis include α-hemolysin, ACME, enterotoxins, phenol-soluble modulins, and PVLs.6
COLONIZATION WITH MRSA
Research over the past several decades has determined that S. aureus is a common colonizer of the human anterior nares and moist skin sites. The population dynamics of methicillin-susceptible S. aureus (MSSA) with regard to nasal colonization are well defined. Approximately 24% of the population is persistently colonized with MSSA in the anterior nares, 47% are intermittent carriers of MSSA, and 29% are never colonized.7 Colonization is also an important risk factor for invasive disease, especially for skin and soft-tissue infections, for which S. aureus is a major cause. Although the MRSA organism has been a major health care-associated pathogen, colonization or infection in the community with MRSA was exceedingly rare, at least until the last 10 years. In contrast, physicians trained in the last 5 years will likely consider that any S. aureus in the community may be an MRSA pathogen.
Nasal carriage of MRSA is an important consideration because people with nasal colonization of MRSA are at a higher risk of developing infection due to MRSA. Individuals with MRSA colonization have a 4-fold or higher risk of infection compared with individuals with MSSA colonization.8 Furthermore, MRSA infections tend to occur within the first 3 months of detection of nasal colonization. Datta and Huang9 reported that approximately 14% of patients became infected with MRSA within 1 to 3 months after colonization compared with 5% of patients within 3 to 6 months and 4% within 6 to 9 months.
Susceptibility to S. aureus nasal carriage has been associated with an SNP in the serine protease C1 inhibitor gene at amino acid position 480.10 The valine/valine SNP genotype at this location in the gene versus a valine/methionine genotype was associated with S. aureus noncarriers.
RATES OF MRSA INFECTIONS IN THE UNITED STATES
There is no national surveillance for outpatient staphylococcal infections in the United States. However, a Centers for Disease Control and Prevention (CDC) report evaluated health care-associated and CA-MRSA infection rates from 9 surveillance sites in the United States in 2005.11 Approximately 9000 observed cases of invasive MRSA infection were reported. The majority of these cases were health care-associated (approximately 85%), and 14% were community-associated. Of the health care-associated infections, the majority (58%) were considered to be community-onset infections. Projected estimates for the US population indicated that approximately 95,000 cases of MRSA infections and 19,000 deaths due to MRSA occurred during 2005. To put these numbers in perspective, the rate of invasive MRSA in the United States in 2005 (31.8 per 100,000) was greater than the combined rate for invasive pneumococcal disease (14.1 per 100,000), invasive group A streptococcal disease (3.6 per 100,000), invasive meningococcal disease (0.35 per 100,000), and invasive Haemophilus influenzae infections (1.4 per 100,000).12
Unlike outpatient infections, there is an established national surveillance system for selected inpatient infections in the United States. Approximately 1300 to 1500 hospitals in the United States (approximately 25% of all US hospitals) report the number of infections to the CDC. Of all the health care-associated infections reported to the CDC from January 2006 to October 2007 (by 463 hospitals), S. aureus was ranked as the number 2 overall cause of hospital-acquired infections, the number 1 cause of surgical site infections and ventilator-associated pneumonia, and the number 4 cause of central line-associated bloodstream infections.13
A GLOBAL PERSPECTIVE OF MRSA AND ENDOCARDITIS
In a prospective cohort study of 61 hospitals in 28 countries, S. aureus was reported as the most common cause of health care-associated endocarditis (health care-associated, 47%; non-health care-associated, 42%; P = 0.30).14 A high proportion of these patients had MRSA (health care-associated, 57%; non-health care-associated, 41%; P = 0.014) A multivariate analysis in that study revealed the following risk factors for death in patients with native valve endocarditis: health care-associated infection, age, diabetes, S. aureus, paravalvular abscess, surgery, stroke, heart failure, and new conduction abnormality.
MRSA AND HEALTH OUTCOMES
A review of studies that evaluated health outcomes (hospital length of stay, hospital charges, and mortality) was conducted in patients with MRSA surgical site infections.15 Patients with MRSA infections had an average hospital length of stay of 29 days that cost approximately $118,000 and resulted in a 21% mortality rate (Table 2). In comparison, the mortality rate of inpatients in hospitals is approximately 3%. Compared with uninfected controls and patients with MSSA, these outcomes with MRSA were significantly worse, confirming that MRSA infections are associated with excess morbidity in hospitalized patients.
In summary, S. aureus continues to evolve, and the molecular mechanisms that drive these changes are not completely understood. However, it is clear that colonization is the most common risk factor for infection, and genetic studies have been able to suggest to some extent which individuals may be carriers of S. aureus. Bacteremia and endocarditis are commonly caused by S. aureus and are associated with high morbidity and mortality. There are worse outcomes with MRSA than with MSSA infections. Molecular research is beginning to illuminate mechanisms that facilitate enhanced virulence in MRSA infections. However, the complete molecular explanations for these events are unknown, and our understanding will continue to evolve with ongoing research.
1. Kennedy AD, Otto M, Braughton KR, et al. Epidemic community-associated methicillin-resistant Staphylococcus aureus
: recent clonal expansion and diversification. Proc Natl Acad Sci U S A
2. Popovich KJ, Weinstein RA. Commentary: the graying of methicillin-resistant Staphylococcus aureus
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3. 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
4. Christensen K, Murray JC. What genome-wide association studies can do for medicine. N Engl J Med
5. Hidron AI, Low CE, Honig EG, et al. Emergence of community-acquired methicillin-resistant Staphylococcus aureus
strain USA300 as a cause of necrotizing community-onset pneumonia. Lancet Infect Dis
6. Wang R, Braughton KR, Kretschmer D, et al. Identification of novel cytolic peptides as key virulence determinants for community-associated MRSA. Nat Med
7. Van Belkum A, Verkaik NJ, de Vogel CP, et al. Reclassification of Staphylococcus aureus
nasal carriage types. J Infect Dis
8. Safdar N, Bradley EA. The risk of infection after nasal colonization with Staphylococcus aureus
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9. Datta R, Huang SS. Risk of infection and death due to methicillin-resistant Staphylococcus aureus
in long-term carriers. Clin Infect Dis
10. Emonts M, de Jongh CE, Houwing-Duistermaat JJ, et al. Association between nasal carriage of Staphylococcus aureus
and the human complement cascade activator serine protease C1 inhibitor (C1INH) valine vs. methionine polymorphism at amino acid position 480. FEMS Immunol Med Microbiol
11. Klevins MR, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus
infections in the United States. JAMA
12. Banckroft EA. Antimicrobial resistance. JAMA
13. Hidron AI, Edwards JR, Patel J, et al. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol
14. Benito N, Mirό JM, de Lazzari E, et al. Health care-associated native valve endocarditis: importance of non-nosocomial acquisition. Ann Intern Med
15. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis
. 2006;42(suppl 2):S82-S89.
A minimum assessment score of 80% is required.
1) The following 2 genetic elements in the CA-MRSA USA300 isolate appear to be physically linked and may be responsible for virulence and β-lactam antibiotic class resistance:
A. type IV staphylococcal chromosomal cassette mec (SCCmec) and phenol-soluble modulins
B. arginine catabolic mobile element and Panton-Valentine leukocidin
C. enterotoxins and type IV staphylococcal chromosomal cassette mec (SCCmec)
D. arginine catabolic mobile element and type IV staphylococcal chromosomal cassette mec (SCCmec)
2) MRSA infections tend to occur within ___ months of detection of nasal colonization.
A. 3 months
B. 3-6 months
C. 6-9 months
D. 9-12 months
3) In Cosgrove's study (Clin Infect Dis 2006;42:S82-S89), health outcomes in patients with MRSA-related surgical site infections were compared with those in uninfected controls and patients with MSSA. In this study, patients with MRSA:
A. had an increased hospital length of stay and a lower mortality rate.
B. had a higher mortality rate and incurred lower hospital charges.
C. incurred higher hospital charges and had an increased hospital length of stay.
D. incurred higher hospital charges and had a lower mortality rate.
4) According to reports from the CDC, of all health care-associated infections, S. aureus was ranked as
A. the number 5 overall cause of hospital-acquired infections.
B. the number 1 cause of surgical site infections and ventilator-associated pneumonia.
C. the number 3 cause of central line-associated bloodstream infections.
D. the number 2 cause of surgical site infections.
5) The ______ SNP genotype in the serine protease C1 inhibitor gene at amino acid position 480 was associated with ______.
A. valine/methionine; S. aureus noncarriers
B. valine/valine; S. aureus carriers
C. valine/methionine; S. aureus carriers
D. valine/valine; S. aureus noncarriers
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