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MRSA: An Evolving Pathogen
MRSA: An Evolving Pathogen Mark D. Corriere, MD, FACP, and Catherine F. Decker, MD, FACP, FIDSA Introduction Methicillin-resistant Staphylococcus aureus (MRSA) infections have recently become the focus of intense media attention. MRSA has emerged as a major health problem that is no longer confined to the health care setting.1 Reports of MRSA infections occurring in community settings (eg, day care centers, schools, sports teams) along with reports of deaths in healthy children and adults have heightened public awareness of MRSA. In turn, the lay press has labeled MRSA as the “super bug,” which killed more people in the United States in 2005 than AIDS.2 The fear of infection frequently prompts worried patients to seek medical attention. It has become such a concern to the American public that state legislatures in Maryland, Illinois, Pennsylvania, and New Jersey have proposed measures to target MRSA control, including the mandated use of surveillance cultures to screen hospitalized patients for MRSA and public reporting of MRSA infections.3,4 MRSA infections are not only a significant cause of morbidity and mortality, but they also place a large economic strain on our health care system. It is becoming increasingly important that primary care physicians be aware of the epidemiology, clinical presentation, and treatment of MRSA.
Evolution of MRSA into the Community Staphylococcus aureus is a dynamic and adaptable bacteria that has a remarkable ability to acquire antibiotic resistance quickly. In the preantibiotic era, S. aureus had long been associated with a very high mortality. Penicillin, first introduced in the early 1940s, quickly lowered the mortality rates associated with S. aureus infections. However, by the mid-1940s, strains of penicillin-resistant S. aureus were detected in hospitals. By 1960, S. aureus resistance was commonplace as both community and hospital Disclaimer: The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense, the Department of the Navy, or the naval services at large. Dis Mon 2008;54:751-755 0011-5029/2008 $34.00 ⫹ 0 doi:10.1016/j.disamonth.2008.09.007 DM, December 2008
751
strains demonstrated resistance to penicillin. The introduction of methicillin, a penicillinase-resistant semisynthetic penicillin, quickly solved the problem of penicillin-resistant S. aureus. However, in 1961, less then a year later, MRSA was reported.5-7 The prevalence of MRSA isolates slowly increased over the next three decades, with the majority of isolates being hospital-associated. This changed in 1982 with an outbreak of MRSA among intravenous drug users.8 The predominant pattern of MRSA in the 1980s and 1990s remained a hospital-acquired disease with traditional risk factors.9,10 By the late 1990s, MRSA from a community-acquired source without a history of intravenous drug use began to be described more commonly. A 1998 study clearly demonstrated the increase in community-acquired MRSA. Investigators showed a dramatic change in the prevalence of community-acquired MRSA in pediatric admissions with an increase from 10 per 100,000 in 1988 –1990 to 259 per 100,000 in 1993–1995.11 Not only was the prevalence of community-acquired MRSA increasing, but the devastating mortality of these infections became evident as 4 pediatric deaths from community-acquired MRSA were reported in 1999.12 Once considered predominantly a hospital-acquired infection with only a small number of community-associated cases, the epidemiology of MRSA began to evolve.13 The shift toward more community-acquired infections was highlighted in the 2006 EMERGEncy ID Net Study, which demonstrated that MRSA was the most common identifiable cause of skin and soft tissue infections among patients who presented to emergency departments in 11 U.S. cities. The overall prevalence of MRSA in this population was 59%. Looking specifically at the MRSA isolates in this study shows that 97% were the USA3000 strain (a major clone of community-acquired MRSA).14
Economic Impact S. aureus infections often have devastating effects on both patient outcomes and health care costs. It is estimated that ⬃1% of all inpatients have a discharge diagnosis of S. aureus infection.15,16 Analysis of a 2000 and 2001 database showed that length of stay was three times longer for inpatients with S. aureus infections compared with all other inpatients (14.3 versus 4.5 days; P ⬍ 0.001). Total hospital costs for inpatients with S. aureus infections were more than three times the total for all other inpatients ($48,824 versus $14,141; P ⬍ 0.001).15 Looking specifically at surgical site infections, investigators reported not only an increased length of stay, but also the economic impact of S. aureus infections by reporting 752
DM, December 2008
a doubling of the mean hospital charge for patients with no infection compared with those with methicillin-sensitive S. aureus (MSSA) infections ($34,395 versus $73,165; P ⬍ 0.001).17 In some institutions, MRSA accounts for ⬎50% of all S. aureus infections.18 Comparing the economic burden of MSSA infections with MRSA infections can further demonstrate the impact of this problem. In 2005, in a retrospective cohort study in an urban U.S. hospital, the average length of stay for patients with MRSA infections was 20.1 days compared with 13.7 days in patients with MSSA infections (P ⬍ 0.001). The study also demonstrated an increased overall hospital cost in MRSA-infected patients compared with MSSAinfected patients ($22,735 versus $11,205; P ⬍ 0.001).19 Similar findings in surgical site infections included a marked increase in mean hospital charges for MRSA-infected patients compared with MSSA-infected patients ($118,414 versus $73,165; P ⬍ 0.001).17
Morbidity and Mortality As a clinician, early recognition of MRSA infections is critical to assure prompt initiation of appropriate antibiotic therapy. Failure to recognize risk factors for MRSA can lead to delay in appropriate treatment, which can have devastating consequences. Not only do MRSA infections lead to higher lengths of stay and more cost then MSSA infections, but more importantly, MRSA infections lead to a higher mortality. A 2003 meta-analysis that included 31 studies showed a significant increase in mortality with MRSA bacteremia compared with MSSA bacteremia (odds ratio 1.93; 95% CI 1.54 –2.42; P ⬍ 0.001).20 Mortality among patients with S. aureus surgical site infections was increasingly higher when compared with uninfected patients (mortality 2.1%), MSSA-infected patients (mortality 6.7%), and MRSA-infected patients (mortality 20.7%) (P ⬍ 0.001).17 A delay in initiation of therapy is associated with a further increase in mortality, making it more important for clinicians to have a heightened awareness for MRSA infection and to be prepared to treat it.19
Conclusion The growing threat of MRSA is becoming increasingly recognized by the public and health care providers. In 2008, MRSA has evolved to be commonplace in the community and hospital setting. MRSA infections are yet another major factor in the spiraling costs of health care. It is imperative that clinicians have a high index of suspicion for MRSA so they can promptly initiate the appropriate antibiotic therapy. Failure to act quickly can lead to increased morbidity and mortality for patients. As more virulent strains and increasing resistance occur due to the dynamic DM, December 2008
753
nature of this organism, MRSA will remain a growing menace to patients and clinicians. Focused continued education of physicians should improve recognition and treatment, decrease unnecessary antibiotic use, and help reduce the spread of MRSA.
REFERENCES 1. 2. 3.
4. 5. 6. 7. 8.
9. 10. 11.
12.
13. 14. 15. 16. 17.
18.
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Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin resistant Staphylococcus aureus infections in the United States. J Am Med Assoc 2007;298:1763-71. Flynn N, Cohen SH. The continuing saga of MRSA. J Infect Dis 2008;197:1217-9. Weber SG, Huang SS, Oriola S, et al. Legislative mandates for use of active surveillance cultures to screen for methicillin resistant Staphylococcus aureus and vancomycin resistant Enterococci: position statement from the joint SHEA and APIC Task Force. Inf Control Hosp Epidemiol 2007;28:249-60. Diekema DJ, Climo M. Preventing MRSA infections. J Am Med Assoc 2008;299:1190-2. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001;7:178-82. Stewart GT, Holt RJ. Evolution of natural resistance to the new penicillins. Br Med J 1963;1(5326):308-11. Benner EJ, Kayser FH. Growing clinical significance of methicillin resistant Staphylococcus aureus. Lancet 1968;2:741. Saravolatx LD, Markowitz N, Arking L, et al. Methicillin-resistant Staphylococcus aureus: epidemiologic observations during a community acquired outbreak. Ann Intern Med 1982;96(1):11-6. Brumfitt W, Hamilton-Miller J. Methicillin-resistant Staphylococcus aureus. N Engl J Med 1989;320:1188-96. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998;339:520-32. Herold BC, Immergluck LC, Maranan MC, et al. Community acquired methicillin resistant Staphylococcus aureus in children with no identified predisposing risk. J Am Med Assoc 1998;279:593-8. Centers for Disease Control. Four pediatric deaths from community acquired methicillin resistant Staphylococcus aureus: Minnesota and North Dakota, 19971999. J Am Med Assoc 1999;282:1122-5. Enright MC, Robinson DA, Randle G, et al. The evolutionary history of methicillin resistant Staphylococcal aureus (MRSA). Proc Natl Acad Sci U S A 2002;99:7687. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355:666-74. Noskin GA, Krishnadasan A, Gorwitz RJ, et al. The burden of Staphylococcus aureus infections on hospitals in the United States. Arch Intern Med 2005;16:1756-61. Rubin RJ, Harrington CA, Poon A, et al. The economic impact of Staphylococcus aureus infection in New York City hospitals. Emerg Infect Dis 1999;5:9-17. Engeman JJ, Carmilli Y, Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis 2003;36:592-9. Pfaller MA, Jones RN, Doern GV, et al. Survey of blood stream infections attributable to gram positive cocci: frequency of occurrence and antimicrobial susceptibility of isolates collected in 1997 in the United States, Canada, and DM, December 2008
19.
20.
Latin America for the SENTRY Antimicrobial Surveillance Program. SENTRY Participants Group. Diagn Microbiol Infect Dis 1999;33:283-97. Lodise TP, McKinnon PS. Clinical and economic impact of methicillin resistance in patients with Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis 2005;52:113-22. Cosgrove SE, Sakoulus G, Parencevich EN, et al. Comparison of mortality associated with methicillin resistant and methicillin susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;36:53-9.
DM, December 2008
755
Evolution of MRSA into the Community Staphylococcus aureus is a dynamic and adaptable bacteria that has a remarkable ability to acquire antibiotic resistance quickly. In the preantibiotic era, S. aureus had long been associated with a very high mortality. Penicillin, first introduced in the early 1940s, quickly lowered the mortality rates associated with S. aureus infections. However, by the mid-1940s, strains of penicillin-resistant S. aureus were detected in hospitals. By 1960, S. aureus resistance was commonplace as both community and hospital Disclaimer: The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense, the Department of the Navy, or the naval services at large. Dis Mon 2008;54:751-755 0011-5029/2008 $34.00 ⫹ 0 doi:10.1016/j.disamonth.2008.09.007 DM, December 2008
751
strains demonstrated resistance to penicillin. The introduction of methicillin, a penicillinase-resistant semisynthetic penicillin, quickly solved the problem of penicillin-resistant S. aureus. However, in 1961, less then a year later, MRSA was reported.5-7 The prevalence of MRSA isolates slowly increased over the next three decades, with the majority of isolates being hospital-associated. This changed in 1982 with an outbreak of MRSA among intravenous drug users.8 The predominant pattern of MRSA in the 1980s and 1990s remained a hospital-acquired disease with traditional risk factors.9,10 By the late 1990s, MRSA from a community-acquired source without a history of intravenous drug use began to be described more commonly. A 1998 study clearly demonstrated the increase in community-acquired MRSA. Investigators showed a dramatic change in the prevalence of community-acquired MRSA in pediatric admissions with an increase from 10 per 100,000 in 1988 –1990 to 259 per 100,000 in 1993–1995.11 Not only was the prevalence of community-acquired MRSA increasing, but the devastating mortality of these infections became evident as 4 pediatric deaths from community-acquired MRSA were reported in 1999.12 Once considered predominantly a hospital-acquired infection with only a small number of community-associated cases, the epidemiology of MRSA began to evolve.13 The shift toward more community-acquired infections was highlighted in the 2006 EMERGEncy ID Net Study, which demonstrated that MRSA was the most common identifiable cause of skin and soft tissue infections among patients who presented to emergency departments in 11 U.S. cities. The overall prevalence of MRSA in this population was 59%. Looking specifically at the MRSA isolates in this study shows that 97% were the USA3000 strain (a major clone of community-acquired MRSA).14
Economic Impact S. aureus infections often have devastating effects on both patient outcomes and health care costs. It is estimated that ⬃1% of all inpatients have a discharge diagnosis of S. aureus infection.15,16 Analysis of a 2000 and 2001 database showed that length of stay was three times longer for inpatients with S. aureus infections compared with all other inpatients (14.3 versus 4.5 days; P ⬍ 0.001). Total hospital costs for inpatients with S. aureus infections were more than three times the total for all other inpatients ($48,824 versus $14,141; P ⬍ 0.001).15 Looking specifically at surgical site infections, investigators reported not only an increased length of stay, but also the economic impact of S. aureus infections by reporting 752
DM, December 2008
a doubling of the mean hospital charge for patients with no infection compared with those with methicillin-sensitive S. aureus (MSSA) infections ($34,395 versus $73,165; P ⬍ 0.001).17 In some institutions, MRSA accounts for ⬎50% of all S. aureus infections.18 Comparing the economic burden of MSSA infections with MRSA infections can further demonstrate the impact of this problem. In 2005, in a retrospective cohort study in an urban U.S. hospital, the average length of stay for patients with MRSA infections was 20.1 days compared with 13.7 days in patients with MSSA infections (P ⬍ 0.001). The study also demonstrated an increased overall hospital cost in MRSA-infected patients compared with MSSAinfected patients ($22,735 versus $11,205; P ⬍ 0.001).19 Similar findings in surgical site infections included a marked increase in mean hospital charges for MRSA-infected patients compared with MSSA-infected patients ($118,414 versus $73,165; P ⬍ 0.001).17
Morbidity and Mortality As a clinician, early recognition of MRSA infections is critical to assure prompt initiation of appropriate antibiotic therapy. Failure to recognize risk factors for MRSA can lead to delay in appropriate treatment, which can have devastating consequences. Not only do MRSA infections lead to higher lengths of stay and more cost then MSSA infections, but more importantly, MRSA infections lead to a higher mortality. A 2003 meta-analysis that included 31 studies showed a significant increase in mortality with MRSA bacteremia compared with MSSA bacteremia (odds ratio 1.93; 95% CI 1.54 –2.42; P ⬍ 0.001).20 Mortality among patients with S. aureus surgical site infections was increasingly higher when compared with uninfected patients (mortality 2.1%), MSSA-infected patients (mortality 6.7%), and MRSA-infected patients (mortality 20.7%) (P ⬍ 0.001).17 A delay in initiation of therapy is associated with a further increase in mortality, making it more important for clinicians to have a heightened awareness for MRSA infection and to be prepared to treat it.19
Conclusion The growing threat of MRSA is becoming increasingly recognized by the public and health care providers. In 2008, MRSA has evolved to be commonplace in the community and hospital setting. MRSA infections are yet another major factor in the spiraling costs of health care. It is imperative that clinicians have a high index of suspicion for MRSA so they can promptly initiate the appropriate antibiotic therapy. Failure to act quickly can lead to increased morbidity and mortality for patients. As more virulent strains and increasing resistance occur due to the dynamic DM, December 2008
753
nature of this organism, MRSA will remain a growing menace to patients and clinicians. Focused continued education of physicians should improve recognition and treatment, decrease unnecessary antibiotic use, and help reduce the spread of MRSA.
REFERENCES 1. 2. 3.
4. 5. 6. 7. 8.
9. 10. 11.
12.
13. 14. 15. 16. 17.
18.
754
Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin resistant Staphylococcus aureus infections in the United States. J Am Med Assoc 2007;298:1763-71. Flynn N, Cohen SH. The continuing saga of MRSA. J Infect Dis 2008;197:1217-9. Weber SG, Huang SS, Oriola S, et al. Legislative mandates for use of active surveillance cultures to screen for methicillin resistant Staphylococcus aureus and vancomycin resistant Enterococci: position statement from the joint SHEA and APIC Task Force. Inf Control Hosp Epidemiol 2007;28:249-60. Diekema DJ, Climo M. Preventing MRSA infections. J Am Med Assoc 2008;299:1190-2. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001;7:178-82. Stewart GT, Holt RJ. Evolution of natural resistance to the new penicillins. Br Med J 1963;1(5326):308-11. Benner EJ, Kayser FH. Growing clinical significance of methicillin resistant Staphylococcus aureus. Lancet 1968;2:741. Saravolatx LD, Markowitz N, Arking L, et al. Methicillin-resistant Staphylococcus aureus: epidemiologic observations during a community acquired outbreak. Ann Intern Med 1982;96(1):11-6. Brumfitt W, Hamilton-Miller J. Methicillin-resistant Staphylococcus aureus. N Engl J Med 1989;320:1188-96. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998;339:520-32. Herold BC, Immergluck LC, Maranan MC, et al. Community acquired methicillin resistant Staphylococcus aureus in children with no identified predisposing risk. J Am Med Assoc 1998;279:593-8. Centers for Disease Control. Four pediatric deaths from community acquired methicillin resistant Staphylococcus aureus: Minnesota and North Dakota, 19971999. J Am Med Assoc 1999;282:1122-5. Enright MC, Robinson DA, Randle G, et al. The evolutionary history of methicillin resistant Staphylococcal aureus (MRSA). Proc Natl Acad Sci U S A 2002;99:7687. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355:666-74. Noskin GA, Krishnadasan A, Gorwitz RJ, et al. The burden of Staphylococcus aureus infections on hospitals in the United States. Arch Intern Med 2005;16:1756-61. Rubin RJ, Harrington CA, Poon A, et al. The economic impact of Staphylococcus aureus infection in New York City hospitals. Emerg Infect Dis 1999;5:9-17. Engeman JJ, Carmilli Y, Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis 2003;36:592-9. Pfaller MA, Jones RN, Doern GV, et al. Survey of blood stream infections attributable to gram positive cocci: frequency of occurrence and antimicrobial susceptibility of isolates collected in 1997 in the United States, Canada, and DM, December 2008
19.
20.
Latin America for the SENTRY Antimicrobial Surveillance Program. SENTRY Participants Group. Diagn Microbiol Infect Dis 1999;33:283-97. Lodise TP, McKinnon PS. Clinical and economic impact of methicillin resistance in patients with Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis 2005;52:113-22. Cosgrove SE, Sakoulus G, Parencevich EN, et al. Comparison of mortality associated with methicillin resistant and methicillin susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;36:53-9.
DM, December 2008
755