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In a Community Near You: MRSA
By Stan Deresinski, MD, FACP
The evolution of antibiotic resistance in Staphylococcus aureus is an epic saga. Resistance to penicillin was first reported in the 1940s, at a time when the drug still remained in short supply. No reliable effective therapy against penicillin-resistant strains was available until the introduction of methicillin in 1960. There was no time for complacency, however, since resistance to this semisynthetic penicillin was reported the very next year. First detected in the United Kingdom, methicillin-resistant S aureus (MRSA) was soon identified on the continent, with subsequent worldwide spread, causing an ever-increasing number of nosocomial infections. Instead of producing the plasmid-mediated penicillinase that accounts for penicillin resistance, these isolates had acquired an extra penicillin binding protein, PBP 2’, which retained its transpeptidase activity in peptidoglycan synthesis but had reduced affinity for binding of ß-lactam antibiotics.
CA-MRSA: Case Definition
In 1968, the first description of a hospital outbreak of MRSA infection in the United States was reported from Boston City Hospital.1 MRSA then expanded its reach, eventually establishing its current niche in hospitals to the extent that the majority of nosocomial isolates of S aureus in the United States are now methicillin resistant. More recently, S aureus with reduced susceptibility and, in 2 cases, high-level resistance, to vancomycin have made their appearance.2
A similar, albeit delayed, progression of staphylococcal resistance has occurred in the community. The proportion of community-acquired S aureus resistant to penicillin has increased progressively over the decades, reaching 90%. MRSA also appeared in the community, but, in most instances, the affected patients had had contact with health care facilities. The association with health care may be indirect; contacts of individuals with hospital-acquired MRSA are at a significantly increased risk of MRSA colonization.3
Beginning in the middle of the last decade, however, a dramatic change began taking place, with the occurrence of MRSA infections in otherwise healthy individuals with none of the previously known risk factors. These infections, mostly of skin and skin structures, were most commonly identified in children and often occurred in clusters. Outbreaks were reported in Native Americans, prisoners, and competitive athletes. The virulence of these infections was forcefully brought to our attention by a report of the deaths of 4 previously healthy children with community-acquired MRSA (CA-MRSA) infection.4 The CA-MRSA strains, which are distinct from the hospital strains, have accelerated their rate of spread, reaching all regions of the United States and, in some areas, have become dominant community pathogens. For instance, a retrospective review of 60 children with community-acquired S aureus infection admitted to a Houston hospital found that 45% of the isolates were methicillin resistant (IDSA 799).
CDC Recommendations for Prevention of Staphylococcal Skin Infections Among Sports Participants
Source: MMWR Morb Mortal Wkly Rep. 2003;52:793-795.
In northern California, outbreaks of CA-MRSA infections have been identified in county jail prisoners, in men who have sex with men, and in at least one athletic team. Six percent of homeless youth in San Francisco are colonized with CA-MRSA (IDSA 255).
CA-MRSA differs in a number of important ways from the 6 major pandemic clones of MRSA that account for nearly 70% of isolated strains.5 These differences are found in the nature of the gene cassette coding for methicillin resistance, in the carriage of genes encoding resistance to antibiotics of other classes, and, probably, in virulence.
The molecule that accounts for methicillin resistance, PBP 2’, is encoded by the mecA gene. This gene is carried on a large mobile genetic element called staphylococcal cassette chromosome mec (SCCmec) that is integrated in the chromosome of MRSA. Four distinct types of SCCmec are known with types SCCmec I, II, and III found in most hospital-associated MRSA. SCCmec I and II generally also encode resistance to other antibiotics, accounting for the usual multidrug-resistant phenotype of hospital MRSA. One or the other of these genes is believed to have been introduced into S aureus at least 20 times, with the resultant emergence of methicillin resistance in at least 5 phylogenetically distinct lineages.6 In contrast, CA-MRSA carries SCCmec type IV, a genetic element significantly smaller than the other 3 and which does not carry other antibiotic resistance genes. Most CA-MRSA maintains susceptibility to tetracyclines, trimethoprim/sulfamethoxazole, and clindamycin. Some strains that are reported by the laboratory to be susceptible to clindamycin but resistant to erythromycin may, however, exhibit inducible resistance to clindamycin, a phenomenon that can be detected with the "D test."7
While being less likely to be multidrug resistant than hospital strains, clinical observations and molecular studies suggest CA-MRSA may be more virulent. Thus, sequencing of the entire genome of a single CA-MRSA strain (MW2) that caused fatal sepsis in a 16-month-old girl from North Dakota4 detected 19 virulence genes not detected in the genomes of 5 hospital MRSA strains. These include a number of superantigens, such as staphylococcal enterotoxin H and the amphipathic bicomponent leukotoxin, Panton-Valentine leukocidin (PVL).
PVL, which appears to be carried on temperate phage, has been detected in the vast majority of SCCmec IV CA-MRSA isolates. It has been associated with increased severity of skin infections and with necrotizing pneumonia.8,9 In addition to lysing leukocytes by forming pores in their cell membranes, intradermal injection of PVL causes demonecrosis in experimental animals.10 In addition, some (but not all) studies suggest that CA-MRSA has greater replicative fitness as reflected in shorter doubling times than hospital strains.11
The increasing incidence of infections with MRSA, both community and hospital acquired, have a number of important implications.
· It is increasingly important that cultures be obtained in outpatients with possible staphylococcal infections.
· In outpatient community-onset staphylococcal infection prior to the availability of susceptibility data, consideration may be given to the use of antibiotics other than ß-lactams.
· In all patients with MRSA infection or colonization, strenuous efforts must be made to avoid transmission to other patients. Most such transmission occurs via the hands of health care workers. Wash your hands!
· Antibiotic use, both appropriate and inappropriate, leads to the emergence of antibiotic-resistant bacteria. In the case of MRSA, this is the consequence not only of the use of ß-lactams but also fluoroquinolones. Only use antibiotics when indicated.
Dr. Deresinski, MD, FACP Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.
1. Barrett FF, et al. Methicillin-resistant Staphylococcus aureus at Boston City Hospital. Bacteriologic and epidemiologic observations. N Engl J Med. 1968;279:441-448.
2. Chang S, et al. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med. 2003;348:1342-1347.
3. Calfee DP, et al. Spread of methicillin-resistant Staphylococcus aureus (MRSA) among household contacts of individuals with nosocomially acquired MRSA. Infect Control Hosp Epidemiol. 2003;24:422-426.
4. CDC. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus: Minnesota and North Dakota, 1997-1999. MMWR Morb Mortal Wkly Rep. 1999;48:707-710.
5. De Sousa A, de Lancastre H. Evolution of sporadic isolates of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals and their similarities to isolates of community-acquired MRSA. J Clin Microbiol. 2003;41:3806-3815.
6. Enright MC, et al. The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci USA. 2002;99:7687-7692.
7. Siberrry GK, et al. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis. 2003;37:1257-1260.
8. Dufour P, et al. Community-acquired methicillin-resistant Staphylococcus aureus infections in France: Emergence of a single clone that produces Panton-Valentine leukocidin. Clin Infect Dis. 2002;35:819-824.
9. Gillet Y, et al. Association between Staphylococcus aureus strains carrying gene for Panto-Valentine leukocidin and highly lethal necrotizing pneumonia in young immunocompetent patients. Lancet. 2002;359:753-759.
10. Cribier B, et al. Staphylococcus aureus leukocidin: A new virulence factor for cutaneous infections? An epidemiological and experimental study. Dermatology. 1992;185:175-180.
11. Okuma K, et al. Dissemination of new Staphylococcus aureus clones in the community. J Clin Microbiol. 2002;40:4289-4294.