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The Epidemiology and Clinical Manifestations of Community-Acquired Methicillin-Resistant Staphylococcus aureus
Author(s)
Ravindran A. Padmanabhan, MD
Thomas G. Fraser, MD
Department Of Infectious Diseases
The Cleveland Clinic Foundation
Cleveland
Oh

A 65-year-old male with no significant past medical history, recently returned from a trip to the Democratic Republic of the Congo, presented with pain, swelling, and ulceration of his right lower leg. The symptoms had progressed despite oral amoxicillin/clavulanate. Evaluation at the time of admission revealed a large fluid collection in the anterior calf with extensive subcutaneous edema. Blood cultures were positive for methicillin–resistant S. aureus susceptible to clindamycin, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, gentamicin, and tetracycline. His infection was successfully treated with surgical debridement, wound care, and vancomycin.

In 1941, Skinner and colleagues described the seriousness of S. aureus bloodstream infections in their series of 122 consecutive patients. The mortality rate was greater than 80% (1). Despite early success with penicillin the subsequent decades have shown this organism to be capable of elaborating resistance mechanisms that make therapy increasingly difficult (2). Methicillin resistance, which first appeared in the 1960s, has come to characterize many of the S. aureus isolates that are identified in the hospital. Recently, distinct strains of methicillin-resistant S. aureus (MRSA) are more commonly being identified in patients presenting for care from the community. This review will discuss recent developments in the clinical presentation and epidemiology of community-acquired MRSA in adults.

Definitions and Epidemiology

For infection control and epidemiological purposes, infections have been traditionally termed nosocomial if they 1) were not incubating at the time of presentation, 2) developed more than 72 hours after hospital admission, or 3) occurred in patients who were recently discharged from the hospital or who reside in a long-term care or skilled nursing facility. Beyond epidemiology, these definitions have been useful in helping the practicing clinician to employ effective empirical antibiotic therapy. The delivery of health care has evolved, however, and the distinction between outpatients and inpatients has been blurred. A broader term that has been suggested for infectious maladies in experienced patients who have moved in and out of the hospital is “healthcare associated” infections (3).

The evolving understanding of the origin of an infection has influenced efforts to define community MRSA. The term “community onset” or “community associated” MRSA can be used to describe a methicillin-resistant S. aureus infection that began incubating outside the hospital. If a patient has historical ties to a traditional treatment setting, the infection is most likely healthcare associated. Notable risk factors include hospitalization or stay in a nursing facility within the past year, use of broad-spectrum antibiotics, surgery, dialysis, intravenous drug use, or the presence of an indwelling vascular catheter. A MRSA infection in a patient presenting from home without any healthcare risk factors can be deemed “community acquired” MRSA (CaMRSA) (4).

A further understanding of CaMRSA can be gleaned from molecular studies of the organism. Methicillin resistance is mediated by a genetic element called staphylococcal cassette chromosome mecA (SCCmecA). MecA codes for a novel penicillin binding protein, PBP 2a, which is not inhibited by beta-lactam antibiotics (2). There are at least 5 types of SCCmecA. Types I through III are typically present in nosocomial MRSA strains. CaMRSA is distinguishable by the presence of SCCmecA IV (4-6).

Another distinctive feature of CaMRSA is the presence of the Panton-Valentine leukocidin (PVL). Previous work has shown that only 2–3% of strains of S. aureus produce this toxin (7). However this virulence factor, encoded by the genes lukS-PV and lukF-PV, appears to be expressed much more commonly in CaMRSA.

The difficulties with defining CaMRSA have influenced attempts to understand its prevalence. The key question in reviewing the available studies is how rigorous an attempt was made to exclude those patients who had significant healthcare contact. Salgado and colleagues performed a meta-analysis to try to determine the prevalence of true CaMRSA. They found that a significant number of subjects included in prevalence studies had identifiable healthcare risk factors, and that when this was accounted for, the overall prevalence of CaMRSA was less than 0.24% (8). The burden of CaMRSA infection will vary however based on location, and certain areas of the United States have demonstrated a higher prevalence. Researchers from the Emerging Infections Program Network examined CaMRSA in Atlanta, Baltimore, and Minnesota and found the prevalence to range from 8% to 20% (9). Of note, only 41% of suspected cases of CaMRSA were confirmed through interviews.

 

 

So what is CaMRSA? An acceptable working definition is a methicillin-resistant S. aureus infection occurring in a patient without a history of healthcare risk factors due to an isolate carrying SCCmecA type IV. The isolate is also likely to express the PVL virulence factor. This definition combines what is known about both the clinical and molecular epidemiology of these strains. Further research and time is likely to result in modifications to our understanding of this emerging phenomenon.

Antibiotic Susceptibility Patterns

CaMRSA strains have unique susceptibility patterns compared with traditional MRSA strains. As noted above, SCCmecA codes for methicillin resistance in S. aureus. SCCmecA types II and III are large genetic elements that usually code for resistance to multiple antibiotics. In contrast, type IV is smaller and results in decreased susceptibility to betalactams alone. CaMRSA strains are identifiable as being susceptible to clindamycin, trimethoprim-sulfamethoxazole, and the aminoglycosides (4). Susceptibility to clindamycin must be interpreted cautiously in strains that are erythromycin resistant. If erythromycin resistance is due to an inactivating enzyme (a ribosomal methylase) resistance to clindamycin can be induced. This macrolide-lincosamide-streptogramin–inducible phenotype can be identified in the microbiology lab by performing an erythromycin induction test (D-test). Clinical failures have been described when clindamycin has been used in the presence of this inducible phenotype (10).

Outbreaks

As with many infectious diseases, outbreaks first brought the problem of CaMRSA to wider attention. The first well-described outbreak occurred in the early 1980s among intravenous drug users in Detroit (11). Reports in the early 1990s focused on MRSA infections in young children without risk factors for resistant infection (12). Overwhelming, fatal sepsis due to MRSA was described in 4 pediatric patients in Minnesota and North Dakota. A fulminant, necrotizing pneumonia characterized 3 of the cases (13). Subsequently numerous outbreaks have been described among prison inmates, sexual partners, and competitive sports participants (14-16).

Two well-documented outbreaks have been described in football players. Begier and colleagues identified an outbreak that involved 10 players on the same college football team. Molecular typing demonstrated all recovered isolates to be of the same strain and to carry SCCmecA and the PVL gene. The case-control analysis showed an association between infection and playing wide receiver or cornerback, turf burns, and body shaving (17). An investigation of 8 MRSA infections among professional football players similarly showed all recovered strains to be clonal and to harbor SCCmecA IV and the PVL locus. In contrast to the college outbreak, these investigators found an association between being a lineman or a linebacker and disease. Turf burns were again a significant risk factor (18).

Both of these outbreaks, although geographically separate, were found to be due to the same strain of MRSA, clone USA300-0114. This clone has also been demonstrated as the predominant cause of CaMRSA in other communities (15,19). This would seem to indicate greater fitness of this particular strain that has allowed it to spread widely (20).

Clinical Manifestations

In general, CaMRSA has been reported to cause a similar spectrum of disease as methicillin-susceptible S. aureus (MSSA). As mentioned above, it appears to be seen mostly in otherwise healthy, young individuals. In the population based surveillance project of Fridkin et al., 77% of patients with community MRSA had skin and soft tissue infections (9). Invasive disease was observed in 6%. Similarly, Naimi and colleagues found skin and soft tissue infections in 75% of the subjects in their study of community-associated MRSA in Minnesota (21).

There is concern that CaMRSA may be associated with a greater likelihood of disease compared with other S. aureus strains. Ellis et al. prospectively evaluated active-duty soldiers found to be colonized with CaMRSA. Of the 24 colonized, 38% or 9 individuals developed soft-tissue infections as compared with 3% of those colonized with MSSA. Eight of nine affected patients had abscesses. All 9 of the available clinical isolates were positive for the PVL gene and the presence of this virulence factor was associated with an increased risk of invasive disease (22). Other authors have found an association between PVL-carrying strains of S. aureus and disease and it is perhaps this characteristic, not methicillin resistance, that assists the organism in causing disease in otherwise healthy individuals (23,24). The observed high prevalence of the PVL virulence factor among CaMRSA has been described as the “convergence of resistance and virulence” (25).

 

 

Severe disease has also been described due to strains of CaMRSA. Francis described 4 patients with necrotizing pneumonia due to CaMRSA similar to the pediatric cases referred to above. The isolates from all 4 patients carried PVL and SCCmecA IV genes and were of the USA300 strain group (26). Of note, all 4 patients initially had influenza-like illnesses, demonstrating again the association between influenza and staphylococcal pneumonia. This also signifies these presentations were potentially vaccine preventable. Recently, necrotizing fasciitis caused by CaMRSA strains, all again characterized as having PVL genes, has been described (27). This new phenomenon expands the differential diagnosis of causes of this life-threatening soft-tissue syndrome and influences empirical antibiotic selection.

A 41-year-old with Crohn’s disease treated with infliximab undergoes ventral hernia repair. She has a past surgical history of multiple abdominal surgeries. Three weeks postoperatively she is readmitted with a superinfected hematoma requiring operative drainage. Cultures reveal MRSA, susceptible to erythromycin, clindamycin, vancomycin, gentamicin, tetracycline, and trimethoprim-sulfamethoxazole.

The work to date on this new aspect of resistance in S. aureus intimates a trend similar to that previously experienced with penicillin resistance. Penicillinase-producing strains, first recognized in 1944, became increasingly common among hospital isolates after the second World War (28,29). By the 1970s, penicillin-resistant staphylococci had become widespread in the Community as well. Currently, identification of a penicillin-susceptible S. aureus isolate is uncommon.

The potential for further increases in the prevalence of methicillin resistance among staphylococci lies with the SCCmecA complex. Acquisition of this determinant from another resistant clone of either S. aureus or a coagulase-negative staphylococcus is the necessary first step in the process of becoming methicillin resistant. Types I through III are large, and this has been an obstacle to frequent transfers to MSSA strains. The result of this dynamic is that hospital-acquired MRSA to this point has descended from a relatively small number of clones as compared with the wide heterogeneity seen in susceptible S. aureus (30). As mentioned above, SCCmecA IV is smaller and can therefore more easily insert into many different MSSA strains without a loss of fitness. In fact type IV strains have been shown in vitro to replicate faster than hospital MRSA strains (20). This may allow MRSA to begin to displace MSSA as the predominant community phenotype in a manner similar to that in which penicillin-susceptible S. aureus was replaced.

A similar phenomenon may occur in hospitals wherein a typical CaMRSA strain may become the predominant hospital clone. This has been described already in 1 hospital where SCCmecA IV became the major determinant of methicillin resistance in the hospital (31). The trend was identifiable by a “more susceptible” antibiogram of MRSA strains. Future epidemiological surveillance will be necessary as the potential exists for resistant strains to continue to cross the increasingly more permeable barrier between traditional healthcare and the community.

Management

Increasing resistance to S. aureus has several implications for clinicians. Fundamental principles in the management of infectious syndromes become even more important, particularly source control of suppurative foci through debridement and drainage. An added benefit of such procedures is that they facilitate the establishment of a microbiological diagnosis. Clinicians and microbiologists will need to continue to work together closely so as to be aware of resistance trends in their community. In situations where the pathogen is not identified and treatment is prescribed empirically, follow-up is crucial.

Obviously, the emergence of CaMRSA has limited antibiotic choices. Clindamycin, trimethoprim-sulfamethoxazole, and doxycycline remain therapeutic options in the appropriate clinical situation. The severe clinical manifestations described above require consideration of empirical vancomycin in the treatment of patients presenting seriously ill with infectious syndromes that could be potentially due to S. aureus while awaiting culture results. The most extensive experience for inpatient use is with this agent. Linezolid, daptomycin, and quinupristin-dalfopristin are newer agents with activity against MRSA that have been reviewed elsewhere (32,33). Growing experience with these agents has provided options in situations where vancomycin cannot be used. It has also emphasized some of their limitations. Daptomycin and quinupristin-dalfopristin are only given parenterally, while linezolid can be given both orally and intravenously. Expense impacts the use of all three especially outside the hospital. Treatment-limiting cytopenias and peripheral and optic neuropathy have been described with linezolid when it is has been employed for extended courses of therapy. Daptomycin is inhibited by surfactant and therefore should not be used for suspected pulmonary infections. Quinupristin-dalfopristin’s use can be limited by disabling myalgias and the need for central venous access. More data about the use of these newer agents for invasive infections are needed before they can be considered superior to vancomycin.

 

 

Dr. Fraser may be reached at [email protected].

Dr. Fraser is a member of the Wyeth Emerging Pathogens speakers’ bureau and has participated in a local advisory panel for GlaxoSmithKline. There is no conflict of interest to disclose for this work.

References

  1. Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med. 1941;68:851-75.

  2. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003;111:1265-73.

  3. Friedman ND, Kaye KS, Stout JE, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137:791-7.

  4. Said-Salim B, Mathema B, Kreiswirth BN. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen. Infect Control Hosp Epidemiol. 2003;24:451-5.

  5. 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;190:1730-8.

  6. Daum RS, Ito T, Hiramatsu K, et al. A novel methicillin-resistance cassette in community-acquired methicillin resistant Staphylococcus aureus isolates of diverse genetic backgrounds. J Infect Dis. 2002:186;1344-7.

  7. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000;13:16-34.

  8. Salgado CD, Farr BM, Calfee DP. Community-acquired methicillin-resistant Staphylococcus aureus: a metaanalysis of prevalence and risk factors. Clin Infect Dis. 2003;36:131-9.

  9. Fridkin SK, Hageman JC, Morrison M, et al. Methicillinresistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436-44.

  10. Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis. 2003;37:1257-60.

  11. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med. 1982;96:11-6.

  12. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-598.

  13. Centers for Disease Control and Prevention. Four pediatric deaths from community acquired methicillin resistant Staphylococcus aureus—Minnesota and North Dakota, 1997-1999. MMWR Morb Mortal Wkly Rep. 1999;48:707-10.

  14. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus infections in correctional facilities—Georgia, California, and Texas, 2001-2003. MMWR Morb Mortal Wkly Rep. 2003;52:992-6.

  15. Centers for Disease Control and Prevention. Public Health Dispatch: outbreaks of community-associated methicillin-resistant Staphylococcus aureus skin infections—Los Angeles County, California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2003;52:88.

  16. Lindenmayer JD, Schoenfeld S, O’Grady R, Carney JK. Methicillin-resistant Staphylococcus aureus in a high school wrestling team and the surrounding community. Arch Int Med. 1998;158:895-9.

  17. Begier EM, Frenette K, Barrett NL, et al. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis. 2004;39:1446-53.

  18. Kazakova SV, Hagerman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med. 2005;352: 468-75.

  19. 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;41:5113-20.

  20. Deresinski S. Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis. 2005;40:562-73.

  21. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 2003;290:2976-84.

  22. Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis. 2004;39:971-9.

  23. Yamasaki O, Kaneko J, Morizane S, et al. The association between Staphylococcus aureus strains carrying panton-valentine leukocidin genes and the development of deep-seated follicular infection. Clin Infect Dis. 2005;40:381-5.

  24. Hsu LY, Koh TH, Kurup A, Low J, Chlebicki MP, Tan BH. High incidence of Panton-Valentine leukocidin-producing Staphylococcus aureus in a tertiary care public hospital in Singapore. Clin Infect Dis. 2005;40:486-9.

  25. Chambers HF. Community-associated MRSA–resistance and virulence converge. N Engl J Med. 2005;352:1485-7.

  26. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005;40:100-7.

  27. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-53.

  28. Kirby WMM. Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science. 1944;99:452-3.

  29. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001;7:178-82.

  30. Kreiswirth B, Kornblum J, Arbeit RD, et al. Evidence for a clonal origin of methicillin resistance in Staphylococcus aureus. Science. 1993;259:227-30.

  31. Donnio PY, Preney L, Gautier-Lerestif AL, Avril JL, Lafforgue N. Changes in staphylococcal chromosome type and antibiotic resistance profile in methicillin-resistant Staphylococcus aureus isolates from a French hospital over an 11 year period. J Antimicrob Chemother. 2004;53:808-13.

  32. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis. 2003;36: 473-81.

  33. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38: 994-1000.

Issue
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Author(s)
Ravindran A. Padmanabhan, MD
Thomas G. Fraser, MD
Department Of Infectious Diseases
The Cleveland Clinic Foundation
Cleveland
Oh
Author(s)
Ravindran A. Padmanabhan, MD
Thomas G. Fraser, MD
Department Of Infectious Diseases
The Cleveland Clinic Foundation
Cleveland
Oh

A 65-year-old male with no significant past medical history, recently returned from a trip to the Democratic Republic of the Congo, presented with pain, swelling, and ulceration of his right lower leg. The symptoms had progressed despite oral amoxicillin/clavulanate. Evaluation at the time of admission revealed a large fluid collection in the anterior calf with extensive subcutaneous edema. Blood cultures were positive for methicillin–resistant S. aureus susceptible to clindamycin, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, gentamicin, and tetracycline. His infection was successfully treated with surgical debridement, wound care, and vancomycin.

In 1941, Skinner and colleagues described the seriousness of S. aureus bloodstream infections in their series of 122 consecutive patients. The mortality rate was greater than 80% (1). Despite early success with penicillin the subsequent decades have shown this organism to be capable of elaborating resistance mechanisms that make therapy increasingly difficult (2). Methicillin resistance, which first appeared in the 1960s, has come to characterize many of the S. aureus isolates that are identified in the hospital. Recently, distinct strains of methicillin-resistant S. aureus (MRSA) are more commonly being identified in patients presenting for care from the community. This review will discuss recent developments in the clinical presentation and epidemiology of community-acquired MRSA in adults.

Definitions and Epidemiology

For infection control and epidemiological purposes, infections have been traditionally termed nosocomial if they 1) were not incubating at the time of presentation, 2) developed more than 72 hours after hospital admission, or 3) occurred in patients who were recently discharged from the hospital or who reside in a long-term care or skilled nursing facility. Beyond epidemiology, these definitions have been useful in helping the practicing clinician to employ effective empirical antibiotic therapy. The delivery of health care has evolved, however, and the distinction between outpatients and inpatients has been blurred. A broader term that has been suggested for infectious maladies in experienced patients who have moved in and out of the hospital is “healthcare associated” infections (3).

The evolving understanding of the origin of an infection has influenced efforts to define community MRSA. The term “community onset” or “community associated” MRSA can be used to describe a methicillin-resistant S. aureus infection that began incubating outside the hospital. If a patient has historical ties to a traditional treatment setting, the infection is most likely healthcare associated. Notable risk factors include hospitalization or stay in a nursing facility within the past year, use of broad-spectrum antibiotics, surgery, dialysis, intravenous drug use, or the presence of an indwelling vascular catheter. A MRSA infection in a patient presenting from home without any healthcare risk factors can be deemed “community acquired” MRSA (CaMRSA) (4).

A further understanding of CaMRSA can be gleaned from molecular studies of the organism. Methicillin resistance is mediated by a genetic element called staphylococcal cassette chromosome mecA (SCCmecA). MecA codes for a novel penicillin binding protein, PBP 2a, which is not inhibited by beta-lactam antibiotics (2). There are at least 5 types of SCCmecA. Types I through III are typically present in nosocomial MRSA strains. CaMRSA is distinguishable by the presence of SCCmecA IV (4-6).

Another distinctive feature of CaMRSA is the presence of the Panton-Valentine leukocidin (PVL). Previous work has shown that only 2–3% of strains of S. aureus produce this toxin (7). However this virulence factor, encoded by the genes lukS-PV and lukF-PV, appears to be expressed much more commonly in CaMRSA.

The difficulties with defining CaMRSA have influenced attempts to understand its prevalence. The key question in reviewing the available studies is how rigorous an attempt was made to exclude those patients who had significant healthcare contact. Salgado and colleagues performed a meta-analysis to try to determine the prevalence of true CaMRSA. They found that a significant number of subjects included in prevalence studies had identifiable healthcare risk factors, and that when this was accounted for, the overall prevalence of CaMRSA was less than 0.24% (8). The burden of CaMRSA infection will vary however based on location, and certain areas of the United States have demonstrated a higher prevalence. Researchers from the Emerging Infections Program Network examined CaMRSA in Atlanta, Baltimore, and Minnesota and found the prevalence to range from 8% to 20% (9). Of note, only 41% of suspected cases of CaMRSA were confirmed through interviews.

 

 

So what is CaMRSA? An acceptable working definition is a methicillin-resistant S. aureus infection occurring in a patient without a history of healthcare risk factors due to an isolate carrying SCCmecA type IV. The isolate is also likely to express the PVL virulence factor. This definition combines what is known about both the clinical and molecular epidemiology of these strains. Further research and time is likely to result in modifications to our understanding of this emerging phenomenon.

Antibiotic Susceptibility Patterns

CaMRSA strains have unique susceptibility patterns compared with traditional MRSA strains. As noted above, SCCmecA codes for methicillin resistance in S. aureus. SCCmecA types II and III are large genetic elements that usually code for resistance to multiple antibiotics. In contrast, type IV is smaller and results in decreased susceptibility to betalactams alone. CaMRSA strains are identifiable as being susceptible to clindamycin, trimethoprim-sulfamethoxazole, and the aminoglycosides (4). Susceptibility to clindamycin must be interpreted cautiously in strains that are erythromycin resistant. If erythromycin resistance is due to an inactivating enzyme (a ribosomal methylase) resistance to clindamycin can be induced. This macrolide-lincosamide-streptogramin–inducible phenotype can be identified in the microbiology lab by performing an erythromycin induction test (D-test). Clinical failures have been described when clindamycin has been used in the presence of this inducible phenotype (10).

Outbreaks

As with many infectious diseases, outbreaks first brought the problem of CaMRSA to wider attention. The first well-described outbreak occurred in the early 1980s among intravenous drug users in Detroit (11). Reports in the early 1990s focused on MRSA infections in young children without risk factors for resistant infection (12). Overwhelming, fatal sepsis due to MRSA was described in 4 pediatric patients in Minnesota and North Dakota. A fulminant, necrotizing pneumonia characterized 3 of the cases (13). Subsequently numerous outbreaks have been described among prison inmates, sexual partners, and competitive sports participants (14-16).

Two well-documented outbreaks have been described in football players. Begier and colleagues identified an outbreak that involved 10 players on the same college football team. Molecular typing demonstrated all recovered isolates to be of the same strain and to carry SCCmecA and the PVL gene. The case-control analysis showed an association between infection and playing wide receiver or cornerback, turf burns, and body shaving (17). An investigation of 8 MRSA infections among professional football players similarly showed all recovered strains to be clonal and to harbor SCCmecA IV and the PVL locus. In contrast to the college outbreak, these investigators found an association between being a lineman or a linebacker and disease. Turf burns were again a significant risk factor (18).

Both of these outbreaks, although geographically separate, were found to be due to the same strain of MRSA, clone USA300-0114. This clone has also been demonstrated as the predominant cause of CaMRSA in other communities (15,19). This would seem to indicate greater fitness of this particular strain that has allowed it to spread widely (20).

Clinical Manifestations

In general, CaMRSA has been reported to cause a similar spectrum of disease as methicillin-susceptible S. aureus (MSSA). As mentioned above, it appears to be seen mostly in otherwise healthy, young individuals. In the population based surveillance project of Fridkin et al., 77% of patients with community MRSA had skin and soft tissue infections (9). Invasive disease was observed in 6%. Similarly, Naimi and colleagues found skin and soft tissue infections in 75% of the subjects in their study of community-associated MRSA in Minnesota (21).

There is concern that CaMRSA may be associated with a greater likelihood of disease compared with other S. aureus strains. Ellis et al. prospectively evaluated active-duty soldiers found to be colonized with CaMRSA. Of the 24 colonized, 38% or 9 individuals developed soft-tissue infections as compared with 3% of those colonized with MSSA. Eight of nine affected patients had abscesses. All 9 of the available clinical isolates were positive for the PVL gene and the presence of this virulence factor was associated with an increased risk of invasive disease (22). Other authors have found an association between PVL-carrying strains of S. aureus and disease and it is perhaps this characteristic, not methicillin resistance, that assists the organism in causing disease in otherwise healthy individuals (23,24). The observed high prevalence of the PVL virulence factor among CaMRSA has been described as the “convergence of resistance and virulence” (25).

 

 

Severe disease has also been described due to strains of CaMRSA. Francis described 4 patients with necrotizing pneumonia due to CaMRSA similar to the pediatric cases referred to above. The isolates from all 4 patients carried PVL and SCCmecA IV genes and were of the USA300 strain group (26). Of note, all 4 patients initially had influenza-like illnesses, demonstrating again the association between influenza and staphylococcal pneumonia. This also signifies these presentations were potentially vaccine preventable. Recently, necrotizing fasciitis caused by CaMRSA strains, all again characterized as having PVL genes, has been described (27). This new phenomenon expands the differential diagnosis of causes of this life-threatening soft-tissue syndrome and influences empirical antibiotic selection.

A 41-year-old with Crohn’s disease treated with infliximab undergoes ventral hernia repair. She has a past surgical history of multiple abdominal surgeries. Three weeks postoperatively she is readmitted with a superinfected hematoma requiring operative drainage. Cultures reveal MRSA, susceptible to erythromycin, clindamycin, vancomycin, gentamicin, tetracycline, and trimethoprim-sulfamethoxazole.

The work to date on this new aspect of resistance in S. aureus intimates a trend similar to that previously experienced with penicillin resistance. Penicillinase-producing strains, first recognized in 1944, became increasingly common among hospital isolates after the second World War (28,29). By the 1970s, penicillin-resistant staphylococci had become widespread in the Community as well. Currently, identification of a penicillin-susceptible S. aureus isolate is uncommon.

The potential for further increases in the prevalence of methicillin resistance among staphylococci lies with the SCCmecA complex. Acquisition of this determinant from another resistant clone of either S. aureus or a coagulase-negative staphylococcus is the necessary first step in the process of becoming methicillin resistant. Types I through III are large, and this has been an obstacle to frequent transfers to MSSA strains. The result of this dynamic is that hospital-acquired MRSA to this point has descended from a relatively small number of clones as compared with the wide heterogeneity seen in susceptible S. aureus (30). As mentioned above, SCCmecA IV is smaller and can therefore more easily insert into many different MSSA strains without a loss of fitness. In fact type IV strains have been shown in vitro to replicate faster than hospital MRSA strains (20). This may allow MRSA to begin to displace MSSA as the predominant community phenotype in a manner similar to that in which penicillin-susceptible S. aureus was replaced.

A similar phenomenon may occur in hospitals wherein a typical CaMRSA strain may become the predominant hospital clone. This has been described already in 1 hospital where SCCmecA IV became the major determinant of methicillin resistance in the hospital (31). The trend was identifiable by a “more susceptible” antibiogram of MRSA strains. Future epidemiological surveillance will be necessary as the potential exists for resistant strains to continue to cross the increasingly more permeable barrier between traditional healthcare and the community.

Management

Increasing resistance to S. aureus has several implications for clinicians. Fundamental principles in the management of infectious syndromes become even more important, particularly source control of suppurative foci through debridement and drainage. An added benefit of such procedures is that they facilitate the establishment of a microbiological diagnosis. Clinicians and microbiologists will need to continue to work together closely so as to be aware of resistance trends in their community. In situations where the pathogen is not identified and treatment is prescribed empirically, follow-up is crucial.

Obviously, the emergence of CaMRSA has limited antibiotic choices. Clindamycin, trimethoprim-sulfamethoxazole, and doxycycline remain therapeutic options in the appropriate clinical situation. The severe clinical manifestations described above require consideration of empirical vancomycin in the treatment of patients presenting seriously ill with infectious syndromes that could be potentially due to S. aureus while awaiting culture results. The most extensive experience for inpatient use is with this agent. Linezolid, daptomycin, and quinupristin-dalfopristin are newer agents with activity against MRSA that have been reviewed elsewhere (32,33). Growing experience with these agents has provided options in situations where vancomycin cannot be used. It has also emphasized some of their limitations. Daptomycin and quinupristin-dalfopristin are only given parenterally, while linezolid can be given both orally and intravenously. Expense impacts the use of all three especially outside the hospital. Treatment-limiting cytopenias and peripheral and optic neuropathy have been described with linezolid when it is has been employed for extended courses of therapy. Daptomycin is inhibited by surfactant and therefore should not be used for suspected pulmonary infections. Quinupristin-dalfopristin’s use can be limited by disabling myalgias and the need for central venous access. More data about the use of these newer agents for invasive infections are needed before they can be considered superior to vancomycin.

 

 

Dr. Fraser may be reached at [email protected].

Dr. Fraser is a member of the Wyeth Emerging Pathogens speakers’ bureau and has participated in a local advisory panel for GlaxoSmithKline. There is no conflict of interest to disclose for this work.

References

  1. Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med. 1941;68:851-75.

  2. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003;111:1265-73.

  3. Friedman ND, Kaye KS, Stout JE, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137:791-7.

  4. Said-Salim B, Mathema B, Kreiswirth BN. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen. Infect Control Hosp Epidemiol. 2003;24:451-5.

  5. 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;190:1730-8.

  6. Daum RS, Ito T, Hiramatsu K, et al. A novel methicillin-resistance cassette in community-acquired methicillin resistant Staphylococcus aureus isolates of diverse genetic backgrounds. J Infect Dis. 2002:186;1344-7.

  7. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000;13:16-34.

  8. Salgado CD, Farr BM, Calfee DP. Community-acquired methicillin-resistant Staphylococcus aureus: a metaanalysis of prevalence and risk factors. Clin Infect Dis. 2003;36:131-9.

  9. Fridkin SK, Hageman JC, Morrison M, et al. Methicillinresistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436-44.

  10. Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis. 2003;37:1257-60.

  11. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med. 1982;96:11-6.

  12. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-598.

  13. Centers for Disease Control and Prevention. Four pediatric deaths from community acquired methicillin resistant Staphylococcus aureus—Minnesota and North Dakota, 1997-1999. MMWR Morb Mortal Wkly Rep. 1999;48:707-10.

  14. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus infections in correctional facilities—Georgia, California, and Texas, 2001-2003. MMWR Morb Mortal Wkly Rep. 2003;52:992-6.

  15. Centers for Disease Control and Prevention. Public Health Dispatch: outbreaks of community-associated methicillin-resistant Staphylococcus aureus skin infections—Los Angeles County, California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2003;52:88.

  16. Lindenmayer JD, Schoenfeld S, O’Grady R, Carney JK. Methicillin-resistant Staphylococcus aureus in a high school wrestling team and the surrounding community. Arch Int Med. 1998;158:895-9.

  17. Begier EM, Frenette K, Barrett NL, et al. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis. 2004;39:1446-53.

  18. Kazakova SV, Hagerman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med. 2005;352: 468-75.

  19. 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;41:5113-20.

  20. Deresinski S. Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis. 2005;40:562-73.

  21. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 2003;290:2976-84.

  22. Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis. 2004;39:971-9.

  23. Yamasaki O, Kaneko J, Morizane S, et al. The association between Staphylococcus aureus strains carrying panton-valentine leukocidin genes and the development of deep-seated follicular infection. Clin Infect Dis. 2005;40:381-5.

  24. Hsu LY, Koh TH, Kurup A, Low J, Chlebicki MP, Tan BH. High incidence of Panton-Valentine leukocidin-producing Staphylococcus aureus in a tertiary care public hospital in Singapore. Clin Infect Dis. 2005;40:486-9.

  25. Chambers HF. Community-associated MRSA–resistance and virulence converge. N Engl J Med. 2005;352:1485-7.

  26. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005;40:100-7.

  27. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-53.

  28. Kirby WMM. Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science. 1944;99:452-3.

  29. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001;7:178-82.

  30. Kreiswirth B, Kornblum J, Arbeit RD, et al. Evidence for a clonal origin of methicillin resistance in Staphylococcus aureus. Science. 1993;259:227-30.

  31. Donnio PY, Preney L, Gautier-Lerestif AL, Avril JL, Lafforgue N. Changes in staphylococcal chromosome type and antibiotic resistance profile in methicillin-resistant Staphylococcus aureus isolates from a French hospital over an 11 year period. J Antimicrob Chemother. 2004;53:808-13.

  32. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis. 2003;36: 473-81.

  33. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38: 994-1000.

A 65-year-old male with no significant past medical history, recently returned from a trip to the Democratic Republic of the Congo, presented with pain, swelling, and ulceration of his right lower leg. The symptoms had progressed despite oral amoxicillin/clavulanate. Evaluation at the time of admission revealed a large fluid collection in the anterior calf with extensive subcutaneous edema. Blood cultures were positive for methicillin–resistant S. aureus susceptible to clindamycin, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, gentamicin, and tetracycline. His infection was successfully treated with surgical debridement, wound care, and vancomycin.

In 1941, Skinner and colleagues described the seriousness of S. aureus bloodstream infections in their series of 122 consecutive patients. The mortality rate was greater than 80% (1). Despite early success with penicillin the subsequent decades have shown this organism to be capable of elaborating resistance mechanisms that make therapy increasingly difficult (2). Methicillin resistance, which first appeared in the 1960s, has come to characterize many of the S. aureus isolates that are identified in the hospital. Recently, distinct strains of methicillin-resistant S. aureus (MRSA) are more commonly being identified in patients presenting for care from the community. This review will discuss recent developments in the clinical presentation and epidemiology of community-acquired MRSA in adults.

Definitions and Epidemiology

For infection control and epidemiological purposes, infections have been traditionally termed nosocomial if they 1) were not incubating at the time of presentation, 2) developed more than 72 hours after hospital admission, or 3) occurred in patients who were recently discharged from the hospital or who reside in a long-term care or skilled nursing facility. Beyond epidemiology, these definitions have been useful in helping the practicing clinician to employ effective empirical antibiotic therapy. The delivery of health care has evolved, however, and the distinction between outpatients and inpatients has been blurred. A broader term that has been suggested for infectious maladies in experienced patients who have moved in and out of the hospital is “healthcare associated” infections (3).

The evolving understanding of the origin of an infection has influenced efforts to define community MRSA. The term “community onset” or “community associated” MRSA can be used to describe a methicillin-resistant S. aureus infection that began incubating outside the hospital. If a patient has historical ties to a traditional treatment setting, the infection is most likely healthcare associated. Notable risk factors include hospitalization or stay in a nursing facility within the past year, use of broad-spectrum antibiotics, surgery, dialysis, intravenous drug use, or the presence of an indwelling vascular catheter. A MRSA infection in a patient presenting from home without any healthcare risk factors can be deemed “community acquired” MRSA (CaMRSA) (4).

A further understanding of CaMRSA can be gleaned from molecular studies of the organism. Methicillin resistance is mediated by a genetic element called staphylococcal cassette chromosome mecA (SCCmecA). MecA codes for a novel penicillin binding protein, PBP 2a, which is not inhibited by beta-lactam antibiotics (2). There are at least 5 types of SCCmecA. Types I through III are typically present in nosocomial MRSA strains. CaMRSA is distinguishable by the presence of SCCmecA IV (4-6).

Another distinctive feature of CaMRSA is the presence of the Panton-Valentine leukocidin (PVL). Previous work has shown that only 2–3% of strains of S. aureus produce this toxin (7). However this virulence factor, encoded by the genes lukS-PV and lukF-PV, appears to be expressed much more commonly in CaMRSA.

The difficulties with defining CaMRSA have influenced attempts to understand its prevalence. The key question in reviewing the available studies is how rigorous an attempt was made to exclude those patients who had significant healthcare contact. Salgado and colleagues performed a meta-analysis to try to determine the prevalence of true CaMRSA. They found that a significant number of subjects included in prevalence studies had identifiable healthcare risk factors, and that when this was accounted for, the overall prevalence of CaMRSA was less than 0.24% (8). The burden of CaMRSA infection will vary however based on location, and certain areas of the United States have demonstrated a higher prevalence. Researchers from the Emerging Infections Program Network examined CaMRSA in Atlanta, Baltimore, and Minnesota and found the prevalence to range from 8% to 20% (9). Of note, only 41% of suspected cases of CaMRSA were confirmed through interviews.

 

 

So what is CaMRSA? An acceptable working definition is a methicillin-resistant S. aureus infection occurring in a patient without a history of healthcare risk factors due to an isolate carrying SCCmecA type IV. The isolate is also likely to express the PVL virulence factor. This definition combines what is known about both the clinical and molecular epidemiology of these strains. Further research and time is likely to result in modifications to our understanding of this emerging phenomenon.

Antibiotic Susceptibility Patterns

CaMRSA strains have unique susceptibility patterns compared with traditional MRSA strains. As noted above, SCCmecA codes for methicillin resistance in S. aureus. SCCmecA types II and III are large genetic elements that usually code for resistance to multiple antibiotics. In contrast, type IV is smaller and results in decreased susceptibility to betalactams alone. CaMRSA strains are identifiable as being susceptible to clindamycin, trimethoprim-sulfamethoxazole, and the aminoglycosides (4). Susceptibility to clindamycin must be interpreted cautiously in strains that are erythromycin resistant. If erythromycin resistance is due to an inactivating enzyme (a ribosomal methylase) resistance to clindamycin can be induced. This macrolide-lincosamide-streptogramin–inducible phenotype can be identified in the microbiology lab by performing an erythromycin induction test (D-test). Clinical failures have been described when clindamycin has been used in the presence of this inducible phenotype (10).

Outbreaks

As with many infectious diseases, outbreaks first brought the problem of CaMRSA to wider attention. The first well-described outbreak occurred in the early 1980s among intravenous drug users in Detroit (11). Reports in the early 1990s focused on MRSA infections in young children without risk factors for resistant infection (12). Overwhelming, fatal sepsis due to MRSA was described in 4 pediatric patients in Minnesota and North Dakota. A fulminant, necrotizing pneumonia characterized 3 of the cases (13). Subsequently numerous outbreaks have been described among prison inmates, sexual partners, and competitive sports participants (14-16).

Two well-documented outbreaks have been described in football players. Begier and colleagues identified an outbreak that involved 10 players on the same college football team. Molecular typing demonstrated all recovered isolates to be of the same strain and to carry SCCmecA and the PVL gene. The case-control analysis showed an association between infection and playing wide receiver or cornerback, turf burns, and body shaving (17). An investigation of 8 MRSA infections among professional football players similarly showed all recovered strains to be clonal and to harbor SCCmecA IV and the PVL locus. In contrast to the college outbreak, these investigators found an association between being a lineman or a linebacker and disease. Turf burns were again a significant risk factor (18).

Both of these outbreaks, although geographically separate, were found to be due to the same strain of MRSA, clone USA300-0114. This clone has also been demonstrated as the predominant cause of CaMRSA in other communities (15,19). This would seem to indicate greater fitness of this particular strain that has allowed it to spread widely (20).

Clinical Manifestations

In general, CaMRSA has been reported to cause a similar spectrum of disease as methicillin-susceptible S. aureus (MSSA). As mentioned above, it appears to be seen mostly in otherwise healthy, young individuals. In the population based surveillance project of Fridkin et al., 77% of patients with community MRSA had skin and soft tissue infections (9). Invasive disease was observed in 6%. Similarly, Naimi and colleagues found skin and soft tissue infections in 75% of the subjects in their study of community-associated MRSA in Minnesota (21).

There is concern that CaMRSA may be associated with a greater likelihood of disease compared with other S. aureus strains. Ellis et al. prospectively evaluated active-duty soldiers found to be colonized with CaMRSA. Of the 24 colonized, 38% or 9 individuals developed soft-tissue infections as compared with 3% of those colonized with MSSA. Eight of nine affected patients had abscesses. All 9 of the available clinical isolates were positive for the PVL gene and the presence of this virulence factor was associated with an increased risk of invasive disease (22). Other authors have found an association between PVL-carrying strains of S. aureus and disease and it is perhaps this characteristic, not methicillin resistance, that assists the organism in causing disease in otherwise healthy individuals (23,24). The observed high prevalence of the PVL virulence factor among CaMRSA has been described as the “convergence of resistance and virulence” (25).

 

 

Severe disease has also been described due to strains of CaMRSA. Francis described 4 patients with necrotizing pneumonia due to CaMRSA similar to the pediatric cases referred to above. The isolates from all 4 patients carried PVL and SCCmecA IV genes and were of the USA300 strain group (26). Of note, all 4 patients initially had influenza-like illnesses, demonstrating again the association between influenza and staphylococcal pneumonia. This also signifies these presentations were potentially vaccine preventable. Recently, necrotizing fasciitis caused by CaMRSA strains, all again characterized as having PVL genes, has been described (27). This new phenomenon expands the differential diagnosis of causes of this life-threatening soft-tissue syndrome and influences empirical antibiotic selection.

A 41-year-old with Crohn’s disease treated with infliximab undergoes ventral hernia repair. She has a past surgical history of multiple abdominal surgeries. Three weeks postoperatively she is readmitted with a superinfected hematoma requiring operative drainage. Cultures reveal MRSA, susceptible to erythromycin, clindamycin, vancomycin, gentamicin, tetracycline, and trimethoprim-sulfamethoxazole.

The work to date on this new aspect of resistance in S. aureus intimates a trend similar to that previously experienced with penicillin resistance. Penicillinase-producing strains, first recognized in 1944, became increasingly common among hospital isolates after the second World War (28,29). By the 1970s, penicillin-resistant staphylococci had become widespread in the Community as well. Currently, identification of a penicillin-susceptible S. aureus isolate is uncommon.

The potential for further increases in the prevalence of methicillin resistance among staphylococci lies with the SCCmecA complex. Acquisition of this determinant from another resistant clone of either S. aureus or a coagulase-negative staphylococcus is the necessary first step in the process of becoming methicillin resistant. Types I through III are large, and this has been an obstacle to frequent transfers to MSSA strains. The result of this dynamic is that hospital-acquired MRSA to this point has descended from a relatively small number of clones as compared with the wide heterogeneity seen in susceptible S. aureus (30). As mentioned above, SCCmecA IV is smaller and can therefore more easily insert into many different MSSA strains without a loss of fitness. In fact type IV strains have been shown in vitro to replicate faster than hospital MRSA strains (20). This may allow MRSA to begin to displace MSSA as the predominant community phenotype in a manner similar to that in which penicillin-susceptible S. aureus was replaced.

A similar phenomenon may occur in hospitals wherein a typical CaMRSA strain may become the predominant hospital clone. This has been described already in 1 hospital where SCCmecA IV became the major determinant of methicillin resistance in the hospital (31). The trend was identifiable by a “more susceptible” antibiogram of MRSA strains. Future epidemiological surveillance will be necessary as the potential exists for resistant strains to continue to cross the increasingly more permeable barrier between traditional healthcare and the community.

Management

Increasing resistance to S. aureus has several implications for clinicians. Fundamental principles in the management of infectious syndromes become even more important, particularly source control of suppurative foci through debridement and drainage. An added benefit of such procedures is that they facilitate the establishment of a microbiological diagnosis. Clinicians and microbiologists will need to continue to work together closely so as to be aware of resistance trends in their community. In situations where the pathogen is not identified and treatment is prescribed empirically, follow-up is crucial.

Obviously, the emergence of CaMRSA has limited antibiotic choices. Clindamycin, trimethoprim-sulfamethoxazole, and doxycycline remain therapeutic options in the appropriate clinical situation. The severe clinical manifestations described above require consideration of empirical vancomycin in the treatment of patients presenting seriously ill with infectious syndromes that could be potentially due to S. aureus while awaiting culture results. The most extensive experience for inpatient use is with this agent. Linezolid, daptomycin, and quinupristin-dalfopristin are newer agents with activity against MRSA that have been reviewed elsewhere (32,33). Growing experience with these agents has provided options in situations where vancomycin cannot be used. It has also emphasized some of their limitations. Daptomycin and quinupristin-dalfopristin are only given parenterally, while linezolid can be given both orally and intravenously. Expense impacts the use of all three especially outside the hospital. Treatment-limiting cytopenias and peripheral and optic neuropathy have been described with linezolid when it is has been employed for extended courses of therapy. Daptomycin is inhibited by surfactant and therefore should not be used for suspected pulmonary infections. Quinupristin-dalfopristin’s use can be limited by disabling myalgias and the need for central venous access. More data about the use of these newer agents for invasive infections are needed before they can be considered superior to vancomycin.

 

 

Dr. Fraser may be reached at [email protected].

Dr. Fraser is a member of the Wyeth Emerging Pathogens speakers’ bureau and has participated in a local advisory panel for GlaxoSmithKline. There is no conflict of interest to disclose for this work.

References

  1. Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med. 1941;68:851-75.

  2. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003;111:1265-73.

  3. Friedman ND, Kaye KS, Stout JE, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137:791-7.

  4. Said-Salim B, Mathema B, Kreiswirth BN. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen. Infect Control Hosp Epidemiol. 2003;24:451-5.

  5. 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;190:1730-8.

  6. Daum RS, Ito T, Hiramatsu K, et al. A novel methicillin-resistance cassette in community-acquired methicillin resistant Staphylococcus aureus isolates of diverse genetic backgrounds. J Infect Dis. 2002:186;1344-7.

  7. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000;13:16-34.

  8. Salgado CD, Farr BM, Calfee DP. Community-acquired methicillin-resistant Staphylococcus aureus: a metaanalysis of prevalence and risk factors. Clin Infect Dis. 2003;36:131-9.

  9. Fridkin SK, Hageman JC, Morrison M, et al. Methicillinresistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436-44.

  10. Siberry GK, Tekle T, Carroll K, Dick J. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis. 2003;37:1257-60.

  11. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med. 1982;96:11-6.

  12. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-598.

  13. Centers for Disease Control and Prevention. Four pediatric deaths from community acquired methicillin resistant Staphylococcus aureus—Minnesota and North Dakota, 1997-1999. MMWR Morb Mortal Wkly Rep. 1999;48:707-10.

  14. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus infections in correctional facilities—Georgia, California, and Texas, 2001-2003. MMWR Morb Mortal Wkly Rep. 2003;52:992-6.

  15. Centers for Disease Control and Prevention. Public Health Dispatch: outbreaks of community-associated methicillin-resistant Staphylococcus aureus skin infections—Los Angeles County, California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2003;52:88.

  16. Lindenmayer JD, Schoenfeld S, O’Grady R, Carney JK. Methicillin-resistant Staphylococcus aureus in a high school wrestling team and the surrounding community. Arch Int Med. 1998;158:895-9.

  17. Begier EM, Frenette K, Barrett NL, et al. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis. 2004;39:1446-53.

  18. Kazakova SV, Hagerman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med. 2005;352: 468-75.

  19. 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;41:5113-20.

  20. Deresinski S. Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis. 2005;40:562-73.

  21. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 2003;290:2976-84.

  22. Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis. 2004;39:971-9.

  23. Yamasaki O, Kaneko J, Morizane S, et al. The association between Staphylococcus aureus strains carrying panton-valentine leukocidin genes and the development of deep-seated follicular infection. Clin Infect Dis. 2005;40:381-5.

  24. Hsu LY, Koh TH, Kurup A, Low J, Chlebicki MP, Tan BH. High incidence of Panton-Valentine leukocidin-producing Staphylococcus aureus in a tertiary care public hospital in Singapore. Clin Infect Dis. 2005;40:486-9.

  25. Chambers HF. Community-associated MRSA–resistance and virulence converge. N Engl J Med. 2005;352:1485-7.

  26. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005;40:100-7.

  27. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-53.

  28. Kirby WMM. Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science. 1944;99:452-3.

  29. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001;7:178-82.

  30. Kreiswirth B, Kornblum J, Arbeit RD, et al. Evidence for a clonal origin of methicillin resistance in Staphylococcus aureus. Science. 1993;259:227-30.

  31. Donnio PY, Preney L, Gautier-Lerestif AL, Avril JL, Lafforgue N. Changes in staphylococcal chromosome type and antibiotic resistance profile in methicillin-resistant Staphylococcus aureus isolates from a French hospital over an 11 year period. J Antimicrob Chemother. 2004;53:808-13.

  32. Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis. 2003;36: 473-81.

  33. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38: 994-1000.

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