Community-Associated MRSA — Resistance and Virulence Converge
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《新英格兰医药杂志》
Laypeople and health care professionals alike recognize Staphylococcus aureus as an important cause of disease and understand that antibiotic-resistant strains pose a threat to the community. Before the availability of antibiotics, invasive staphylococcal disease was often fatal, and the introduction of penicillin in the 1940s dramatically improved survival. Although penicillinase-producing strains soon emerged, methicillin and other penicillinase-stable -lactam agents filled the breach. However, methicillin-resistant strains of S. aureus (MRSA), which are resistant to the entire class of -lactam agents, were identified almost immediately and are now found in hospitals worldwide. Despite the growing prevalence of MRSA in hospitals, these strains have been uncommon in the community. The absence of antibiotic selective pressure favoring their survival, detriment to fitness, and attenuated virulence were thought to make the resistant organisms unable to compete in the community.
No longer can MRSA be regarded as an exclusively nosocomial pathogen. Two articles1,2 in this issue of the Journal provide complementary perspectives on what is clearly an epidemic of MRSA in the community. Miller et al.1 provide a view from ground level in their report of 14 cases of S. aureus necrotizing fasciitis, a rare type of staphylococcal infection, occurring within a 15-month period at the Harbor–UCLA Medical Center. Six patients had been hospitalized within the previous year and three had a history of MRSA infection, so whether all these cases represent disease caused by community-associated (or community-acquired) strains, rather than hospital-acquired strains, is debatable.
The molecular analysis of five available isolates most strongly points to a community origin. All contained the pri genes encoding Panton–Valentine leukocidin lukS-PV and lukF-PV, and all were from the same MRSA lineage, a multilocus sequence type (ST) 8 clone designated USA300 by the Centers for Disease Control and Prevention (CDC).3 This clone, which was not seen before 20004 and which is not an archetypal nosocomial MRSA clone5 (although it is related), carries the type IV methicillin-resistance gene cassette element that characterizes community-associated strains. USA300 has caused numerous community outbreaks of MRSA skin infections in several distinct populations, including inmates in Los Angeles and San Francisco jails, men who have sex with men in California, professional football players in St. Louis, and prison inmates in Mississippi, Georgia, and Texas.6 This clone is now the predominant community-associated MRSA clone in San Francisco and presumably Los Angeles as well.
Why this clone and not another has become predominant is a matter of great interest. The case for Panton–Valentine leukocidin, a two-component staphylococcal membrane toxin that targets leukocytes, as the principal virulence factor responsible for the spread of community-associated MRSA is largely circumstantial, but compelling. Isolates containing pvl genes have been epidemiologically linked to recurrent, and often severe, primary skin infections and necrotizing pneumonia.7,8 The pvl genes are rarely found in nosocomial MRSA isolates or methicillin-susceptible community-associated isolates. As with the cases of necrotizing fasciitis described by Miller et al., there is a strong temporal association between a perceived change in disease presentation and the severity and emergence of community-associated MRSA with pvl genes. Both MRSA clones in the United States that are most closely associated with community outbreaks, USA400 (MW2 strain, ST1 lineage) and USA300,6,9 contain pvl genes, as have other successful community-associated MRSA clones (e.g., an ST80 clone in France and an ST30 clone in Australia and the United States).10
It is also possible that pvl genes are only a marker for other virulence or fitness determinants. Community-associated MRSA strains commonly contain a -hemolysin gene and two genes, lukE and lukD, encoding another two-component membrane toxin that is similar in its action to Panton–Valentine leukocidin. Production of Panton–Valentine leukocidin has not been shown to occur during infection or to contribute to the disease process. And other pvl-containing clones, ST30, ST59, and ST1 (MW2 lineage), were circulating in San Francisco before 2000, yet ST8 USA300 is the one that became established, suggesting a substantial contribution of the background genome. The fact that pvl genes are almost invariably found in MRSA strains and not in methicillin-susceptible strains suggests that the methicillin-resistance determinant plays some permissive role.
The article by Fridkin et al. from the CDC2 gives a broader view of the burden of disease caused by community-associated MRSA. In this population- and laboratory-based surveillance study conducted in Baltimore, Atlanta, and Minnesota, the investigators found that between 8 percent and 20 percent of cases of MRSA could not be attributed to a hospital source by means of a chart review or interviews of the patients. The clinically relevant question, however, is what proportion of all cases of community-associated S. aureus infection are likely to be caused by MRSA, because if this number is small, then the overall effect on treatment of suspected cases of staphylococcal infection will be limited. If the approximately 3 percent rate of bacteremia2 in community-associated staphylococcal infections is independent of the methicillin-resistance phenotype, assuming an incidence of 17 cases of community-associated bacteremia per 100,000 persons,11 then the case rate for all community-associated S. aureus infections is about 600 per 100,000. Therefore, in the Atlanta metropolitan area, 5 percent of community-associated staphylococcal infections may be caused by methicillin-resistant strains not originating in hospitals. Because hospital strains also cause community-associated disease, the impact of methicillin resistance on therapeutic decision making is, in fact, greater than this number indicates.
An increasing burden of MRSA disease, especially if caused by clones that cause more severe, invasive infections, will have an enormous influence on the clinical approach to suspected staphylococcal infection. At a minimum, vigilance and a decrease in the threshold for obtaining cultures to document MRSA are warranted. Patients who are seriously ill and hospitalized for suspected staphylococcal infection should be treated with an antibiotic that is active against these strains. Vancomycin is still the preferred antibiotic for empirical coverage and definitive therapy, but whether it should remain so is questionable. It is a less effective antistaphylococcal agent than the penicillins, and increased use will further exacerbate problems with vancomycin-resistant enterococci and staphylococci. Antimicrobial agents shown to be more effective than vancomycin in well-designed, randomized, controlled trials could and, one hopes, will displace vancomycin as the drug of choice.
Issues concerning outpatient management of suspected staphylococcal skin and soft-tissue infections in communities in which MRSA is prevalent are murky. The inexpensive oral agents trimethoprim–sulfamethoxazole, doxycycline, and clindamycin, to which community-associated MRSA strains are often susceptible in vitro, have little or no track record to demonstrate their clinical effectiveness. At a cost of several hundred to more than a thousand dollars per treatment course, linezolid, which is approved by the Food and Drug Administration for the treatment of MRSA infections, is frankly not a consideration in most cases. Whether initial therapy with an antibiotic active against MRSA even affects the outcome of skin and soft-tissue infections is uncertain.
In the study by Fridkin et al., patients who were prescribed an antimicrobial agent to which the isolate was not susceptible actually had fewer follow-up visits and were less likely to have a new antimicrobial prescribed than those given a drug to which the isolate was susceptible, although the difference did not achieve statistical significance except among those undergoing incision and drainage. Data from my institution12 suggest that with adequate surgical drainage, skin and soft-tissue infections severe enough to warrant hospitalization resolve regardless of whether the antimicrobial agent given to the patient has in vitro activity. As rates of community-associated MRSA infection rise, as they inexorably will, clinical trials will be sorely needed to determine the precise role of antimicrobial agents in the treatment of uncomplicated skin and soft-tissue infections and to identify which agents are most clinically effective and cost-effective.
Dr. Chambers reports having received consulting fees from Pfizer and grant support from Cubist Pharmaceuticals.
Source Information
From the Division of Infectious Diseases, San Francisco General Hospital, University of California–San Francisco, San Francisco.
References
Miller LG, Perdreau-Remington F, Reig G, et al. Fourteen patients with necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005;352:1445-1453.
Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 2005;352:1436-1444.
McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 2003;41:5113-5120.
Carleton HA, Diep BA, Charlebois ED, Sensabaugh GF, Perdreau-Remington F. Community-adapted methicillin-resistant Staphylococcus aureus (MRSA): population dynamics of an expanding community reservoir of MRSA. J Infect Dis 2004;190:1730-1738.
Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci U S A 2002;99:7687-7692.
Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med 2005;352:468-475.
Lina G, Piemont Y, Godail-Gamot F, et al. Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis 1999;29:1128-1132.
Gillet Y, Issartel B, Vanhems P, et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 2002;359:753-759.
Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290:2976-2984.
Vandenesch F, Naimi T, Enright MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 2003;9:978-984.
Morin CA, Hadler JL. Population-based incidence and characteristics of community-onset Staphylococcus aureus infections with bacteremia in 4 metropolitan Connecticut areas, 1998. J Infect Dis 2001;184:1029-1034.
Young DM, Harris HW, Charlebois ED, et al. An epidemic of methicillin-resistant Staphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg 2004;139:947-951.(Henry F. Chambers, M.D.)
No longer can MRSA be regarded as an exclusively nosocomial pathogen. Two articles1,2 in this issue of the Journal provide complementary perspectives on what is clearly an epidemic of MRSA in the community. Miller et al.1 provide a view from ground level in their report of 14 cases of S. aureus necrotizing fasciitis, a rare type of staphylococcal infection, occurring within a 15-month period at the Harbor–UCLA Medical Center. Six patients had been hospitalized within the previous year and three had a history of MRSA infection, so whether all these cases represent disease caused by community-associated (or community-acquired) strains, rather than hospital-acquired strains, is debatable.
The molecular analysis of five available isolates most strongly points to a community origin. All contained the pri genes encoding Panton–Valentine leukocidin lukS-PV and lukF-PV, and all were from the same MRSA lineage, a multilocus sequence type (ST) 8 clone designated USA300 by the Centers for Disease Control and Prevention (CDC).3 This clone, which was not seen before 20004 and which is not an archetypal nosocomial MRSA clone5 (although it is related), carries the type IV methicillin-resistance gene cassette element that characterizes community-associated strains. USA300 has caused numerous community outbreaks of MRSA skin infections in several distinct populations, including inmates in Los Angeles and San Francisco jails, men who have sex with men in California, professional football players in St. Louis, and prison inmates in Mississippi, Georgia, and Texas.6 This clone is now the predominant community-associated MRSA clone in San Francisco and presumably Los Angeles as well.
Why this clone and not another has become predominant is a matter of great interest. The case for Panton–Valentine leukocidin, a two-component staphylococcal membrane toxin that targets leukocytes, as the principal virulence factor responsible for the spread of community-associated MRSA is largely circumstantial, but compelling. Isolates containing pvl genes have been epidemiologically linked to recurrent, and often severe, primary skin infections and necrotizing pneumonia.7,8 The pvl genes are rarely found in nosocomial MRSA isolates or methicillin-susceptible community-associated isolates. As with the cases of necrotizing fasciitis described by Miller et al., there is a strong temporal association between a perceived change in disease presentation and the severity and emergence of community-associated MRSA with pvl genes. Both MRSA clones in the United States that are most closely associated with community outbreaks, USA400 (MW2 strain, ST1 lineage) and USA300,6,9 contain pvl genes, as have other successful community-associated MRSA clones (e.g., an ST80 clone in France and an ST30 clone in Australia and the United States).10
It is also possible that pvl genes are only a marker for other virulence or fitness determinants. Community-associated MRSA strains commonly contain a -hemolysin gene and two genes, lukE and lukD, encoding another two-component membrane toxin that is similar in its action to Panton–Valentine leukocidin. Production of Panton–Valentine leukocidin has not been shown to occur during infection or to contribute to the disease process. And other pvl-containing clones, ST30, ST59, and ST1 (MW2 lineage), were circulating in San Francisco before 2000, yet ST8 USA300 is the one that became established, suggesting a substantial contribution of the background genome. The fact that pvl genes are almost invariably found in MRSA strains and not in methicillin-susceptible strains suggests that the methicillin-resistance determinant plays some permissive role.
The article by Fridkin et al. from the CDC2 gives a broader view of the burden of disease caused by community-associated MRSA. In this population- and laboratory-based surveillance study conducted in Baltimore, Atlanta, and Minnesota, the investigators found that between 8 percent and 20 percent of cases of MRSA could not be attributed to a hospital source by means of a chart review or interviews of the patients. The clinically relevant question, however, is what proportion of all cases of community-associated S. aureus infection are likely to be caused by MRSA, because if this number is small, then the overall effect on treatment of suspected cases of staphylococcal infection will be limited. If the approximately 3 percent rate of bacteremia2 in community-associated staphylococcal infections is independent of the methicillin-resistance phenotype, assuming an incidence of 17 cases of community-associated bacteremia per 100,000 persons,11 then the case rate for all community-associated S. aureus infections is about 600 per 100,000. Therefore, in the Atlanta metropolitan area, 5 percent of community-associated staphylococcal infections may be caused by methicillin-resistant strains not originating in hospitals. Because hospital strains also cause community-associated disease, the impact of methicillin resistance on therapeutic decision making is, in fact, greater than this number indicates.
An increasing burden of MRSA disease, especially if caused by clones that cause more severe, invasive infections, will have an enormous influence on the clinical approach to suspected staphylococcal infection. At a minimum, vigilance and a decrease in the threshold for obtaining cultures to document MRSA are warranted. Patients who are seriously ill and hospitalized for suspected staphylococcal infection should be treated with an antibiotic that is active against these strains. Vancomycin is still the preferred antibiotic for empirical coverage and definitive therapy, but whether it should remain so is questionable. It is a less effective antistaphylococcal agent than the penicillins, and increased use will further exacerbate problems with vancomycin-resistant enterococci and staphylococci. Antimicrobial agents shown to be more effective than vancomycin in well-designed, randomized, controlled trials could and, one hopes, will displace vancomycin as the drug of choice.
Issues concerning outpatient management of suspected staphylococcal skin and soft-tissue infections in communities in which MRSA is prevalent are murky. The inexpensive oral agents trimethoprim–sulfamethoxazole, doxycycline, and clindamycin, to which community-associated MRSA strains are often susceptible in vitro, have little or no track record to demonstrate their clinical effectiveness. At a cost of several hundred to more than a thousand dollars per treatment course, linezolid, which is approved by the Food and Drug Administration for the treatment of MRSA infections, is frankly not a consideration in most cases. Whether initial therapy with an antibiotic active against MRSA even affects the outcome of skin and soft-tissue infections is uncertain.
In the study by Fridkin et al., patients who were prescribed an antimicrobial agent to which the isolate was not susceptible actually had fewer follow-up visits and were less likely to have a new antimicrobial prescribed than those given a drug to which the isolate was susceptible, although the difference did not achieve statistical significance except among those undergoing incision and drainage. Data from my institution12 suggest that with adequate surgical drainage, skin and soft-tissue infections severe enough to warrant hospitalization resolve regardless of whether the antimicrobial agent given to the patient has in vitro activity. As rates of community-associated MRSA infection rise, as they inexorably will, clinical trials will be sorely needed to determine the precise role of antimicrobial agents in the treatment of uncomplicated skin and soft-tissue infections and to identify which agents are most clinically effective and cost-effective.
Dr. Chambers reports having received consulting fees from Pfizer and grant support from Cubist Pharmaceuticals.
Source Information
From the Division of Infectious Diseases, San Francisco General Hospital, University of California–San Francisco, San Francisco.
References
Miller LG, Perdreau-Remington F, Reig G, et al. Fourteen patients with necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005;352:1445-1453.
Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 2005;352:1436-1444.
McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 2003;41:5113-5120.
Carleton HA, Diep BA, Charlebois ED, Sensabaugh GF, Perdreau-Remington F. Community-adapted methicillin-resistant Staphylococcus aureus (MRSA): population dynamics of an expanding community reservoir of MRSA. J Infect Dis 2004;190:1730-1738.
Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci U S A 2002;99:7687-7692.
Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med 2005;352:468-475.
Lina G, Piemont Y, Godail-Gamot F, et al. Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis 1999;29:1128-1132.
Gillet Y, Issartel B, Vanhems P, et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 2002;359:753-759.
Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290:2976-2984.
Vandenesch F, Naimi T, Enright MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 2003;9:978-984.
Morin CA, Hadler JL. Population-based incidence and characteristics of community-onset Staphylococcus aureus infections with bacteremia in 4 metropolitan Connecticut areas, 1998. J Infect Dis 2001;184:1029-1034.
Young DM, Harris HW, Charlebois ED, et al. An epidemic of methicillin-resistant Staphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg 2004;139:947-951.(Henry F. Chambers, M.D.)