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Methicillin-resistant Staphylococcus aureus in the Community and the Hospital

Authors: Andrew F. Shorr, MD, MPH   Faculty and Disclosures



Infection is a leading reason for admission of patients to the intensive care unit (ICU). The last decade has witnessed a striking increase in the burden of infection in critically ill patients. Parallel with the growth in infectious disease has been a rise in the rates of antibiotic resistance among many commonly encountered pathogens. Currently, multiple gram-negative pathogens such as Pseudomonas aeruginosa and Acinetobacter spp are resistant to many routinely prescribed anti-infective agents.[1] With respect to gram-positive organisms, Staphylococcus aureus is the leading pathogen of concern. S aureus is now the most frequent cause of hospital-acquired pneumonia and a leading cause of catheter-related bloodstream infections. In particular, methicillin-resistant S aureus (MRSA) challenges critical care physicians daily.

Epidemiology of MRSA Infections in the ICU

More than 70% of S aureus isolated in ICUs is MRSA.[2] Many patients not infected on admission may actually become colonized with MRSA while in the ICU. A recent analysis of a large surgical ICU cohort showed that 8% of patients were colonized with MRSA at the time of admission, and that these subjects can serve as a reservoir for the spread of this pathogen.[3] Beyond the hospital, traditional nosocomial strains of MRSA are increasingly implicated as the cause of "healthcare-associated" infections. These MRSA infections are generally seen in individuals who have ongoing interactions with the healthcare system (eg, dialysis patients) and it is crucial for clinicians to remember that infections may develop in these individuals as outpatients. Hence, when these individuals present to the emergency department from home, they should not be categorized as "community" dwellers for purposes of antibiotic selection, lest they be given antibiotics that lack activity against MRSA.

Complicating the treatment of MRSA is the increase in community-associated MRSA (CA-MRSA). CA-MRSA is a genetically unique form of MRSA that possesses the SCCmec IV gene.[4] Several specific strains comprise CA-MRSA, but the USA 300 strain appears to be most prevalent. Unlike traditional nosocomial MRSA, CA-MRSA produces a toxin (PVL) that can rapidly cause tissue necrosis. There is controversy over the role of PVL as a virulence factor in the evolution of CA-MRSA infections. Some data suggest that PVL is central to the virulence of CA-MRSA, while other data dispute this.[5,6] Regardless of the role of PVL, CA-MRSA has emerged as an issue confronting ICU clinicians.

Originally described as a pathogen mainly in skin infections in children, athletes, and prisoners, CA-MRSA is now reported to cause serious hospital-acquired infections that lead to ICU admission. According to a report from the Centers from Disease Control and Prevention (CDC), CA-MRSA has been recovered in cases of bacteremia, meningitis, and severe pneumonia,[7] and case series have revealed that CA-MRSA may cause a severe, rapidly progressive necrotizing pneumonia in both previously healthy patients and in those with comorbid illness.[8,9] An analysis of MRSA-related bacteremia in Atlanta underscored the evolution of CA-MRSA as a pathogen. Of 116 MRSA-related bloodstream infections in a single hospital, 107 were classified as "hospital-acquired."[10] Despite arising after more than 72 hours of hospitalization, these infections were caused by the USA 300 strain of CA-MRSA in half of cases.

The most comprehensive assessment of MRSA epidemiology was recently published by Klevens and colleagues.[11] These CDC investigators conducted active, population-based surveillance in 9 sites in the United States. MRSA infections were classified as healthcare-associated (either hospital-onset or community-onset) or community-associated (patients without established healthcare risk factors for MRSA). Nearly 40% of infections met the criteria for healthcare-associated infection. The mortality rate in patients with healthcare-associated infections was 4 times greater than in patients with community-associated infections. The authors estimated that annually in the United States there are > 94,000 cases of invasive infection caused by MRSA and 18,650 MRSA-related deaths, exceeding the mortality rate for HIV disease.[11] Of concern, the USA 300 CA-MRSA strain was a leading cause of sepsis, pneumonia, and bacteremia in both healthcare-associated and community-associated infections. Therefore, providers must be cognizant that there are multiple strains of MRSA that may differentially respond to certain antibiotics and can lead to infection. Future trends are difficult to predict as CA-MRSA may not supplant traditional MRSA in the hospital or it could coexist in equilibrium with it. Of importance, these data again underscore the need for physician practice to change in response to shifting microbiologic and epidemiologic trends.

Prevention Strategies for Reducing MRSA Infection Rates in the ICU

A change in practice necessitates an emphasis on prevention. For the 2 leading disease states related to MRSA, catheter-related bloodstream infections (CRBSI) and ventilator-associated pneumonia (VAP), evidence-based preventive strategies exist. Lena Napolitano, MD,[12] of Ann Arbor Michigan, reviewed findings from a recent collaborative cohort study conducted predominantly in ICUs in Michigan, documenting the effectiveness of some of these preventive options. For CRBSI, a multifaceted approach that emphasized hand hygiene, use of full-barrier drapes, chlorhexidine skin preparation, avoidance of catheterization of the femoral vein, and removal of unnecessary catheters substantially reduced the rate of CRBSIs.[13] In fact, in the multiple hospitals that participated in the study, CRBSI rates were reduced by nearly two thirds. In reviewing their local experience with CRBSIs, Dr. Napolitano noted that with an aggressive, multifaceted approach they had eliminated CRBSIs in their surgical ICU. For nearly 2 years they had not had a case of CRBSI.

There are also several approaches to prevention of pneumonia, but it is important to appreciate the pathogenesis of VAP. There are 2 prerequisites for the development of VAP: bacterial colonization of the aerodigestive tract followed by microaspiration of contaminated secretions into the lower airway. It should also be noted that the presence of the endotracheal (ET) tube itself is a key risk factor for VAP, as it facilitates both colonization and microaspiration. Therefore, protocols for spontaneous breathing trials in ventilated patients that reduce sedation also decrease rates of VAP because they foster earlier liberation from mechanical ventilation.[14] Alternatively, broader reliance on noninvasive ventilation in appropriate settings offers protection from VAP because it allows one to avoid the risk associated with ET tube intubation.[14]

Beyond ventilator management, Dr. Napolitano commented that several simple practices can alter rates of VAP. For example, one can address concerns with upper airway colonization by using chlorhexidine to decolonize the upper airway. In a prospective, randomized trial, use of a 0.12% chlorhexidine rinse several times daily reduced the incidence of VAP and decreased mortality.[15] A recent meta-analysis also supports the use of chlorhexidine, which is relatively in expensive and safe.[16]

Maintaining the patient in a semirecumbent position helps prevent microaspiration. The most comprehensive randomized study of this strategy demonstrated that caring for patients in a semirecumbent vs flat position decreased VAP rates from 34% to 8% (P = .003).[17] However, Dr. Napolitano noted that realistically, it is often a challenge to keep the head of the patient's bed elevated.

In light of issues with compliance, Dr. Napolitano advocated for preventive paradigms that do not require active effort on the part of the healthcare team. One such intervention is early tracheostomy. Early tracheostomy has been shown in both randomized studies and meta-analysis to limit the burden of VAP and to reduce the hospital length of stay.[18] As a result, Dr. Napolitano has changed her practice to earlier use of tracheostomy (eg, at 48 hours vs 14 days). Another strategy is the use of ET tubes specifically designed to address VAP. These tubes are an attractive alternative because their effectiveness does not increase the burden of nursing or physician care. Several years ago an ET tube that allowed continuous aspiration of subglottic secretions became available. Several studies revealed that this redesigned ET tube prevented VAP.[19] However, it only seemed to prevent VAP caused by low-pathogenicity organisms such as Haemophilus influenzae. Moreover, the lumen though which secretions were aspirated often became clogged, rendering it ineffective. Building on this approach, a silver-coated ET tube has been developed that prevents the accumulation of biofilm in the airway. In animal and preliminary human studies, this ET tube delayed colonization and prevented the onset of VAP. A recently completed large, randomized trial showed that this ET tube significantly reduced the rate of VAP and hence, represents a new treatment alternative.[20]

Pharmacologic Options for Treatment of MRSA

Should prevention fail, therapeutic decisions may be challenging. Marin Kollef, MD,[21] of St. Louis, Missouri, reviewed current pharmacologic options for treatment of MRSA-related pneumonia. Currently available potential options include vancomycin, quiupristin/dalfopristin, linezolid, daptomycin, and tigecycline. Alternative agents for treatment of CA-MRSA include clindamycin, rifampin, and trimethoprim-sulfamethoxazole. Although vancomycin has been the mainstay of treatment for decades, Dr. Kollef expressed concerns regarding the continuing efficacy of vancomycin.

First, vancomycin has poor lung penetration[22]; hence, current guidelines recommend the use of higher doses (eg, 15 mg/kg aiming for a trough level of 15-20 microgram (mcg)/mL) of vancomycin for treatment for pneumonia.[23] Second, much of the vancomycin in serum is protein bound and therefore, is not active in killing. Third, this recommendation is not based on randomized controlled trials but rather expert opinion, and several analyses reveal that increasing the dose of vancomycin to overcome poor lung penetration may not be an effective strategy.[24,25] Reporting data from his own institution, Dr. Kollef stated that subjects with steady-state vancomycin trough levels within the target range were no more likely to survive than those whose steady-state trough levels were below the target level.[24] Confirming this finding, a study by Hidayat and colleagues[25] showed no improvement in cure rates with higher doses of vancomycin, again raising the concern that optimizing vancomycin dosing may not be a practical alternative. Fourth, although vancomycin resistance to S. aureus is diminishingly rare, the minimum inhibitory concentrations (MICs) needed to kill S aureus in vitro are shifting. In the 1990s, the vancomycin MICs for 90% of isolates (MIC90s) for S aureus in general and MRSA specifically were well below the breakpoints for nonsusceptibility. In 2006, the vancomycin MIC breakpoints for S aureus were lowered (from ≤ 4 mcg/mL to ≤ 2 mcg/mL for "susceptible," from 8-16 mcg/mL to 4-8 mcg/mL for "intermediate," and from ≥ 32 mcg/mL to ≥ 16 mcg/mL for "resistant") to increase detection of heterogeneously resistant isolates of S aureus.[25] In microbiology surveillance studies, it has been shown that the rate of higher-MIC S aureus isolates is changing. For example, the prevalence of MIC90 2 mcg/mL isolates ranges from 10% to 50% of all MRSA.[26,27] This shift toward higher MIC90 organisms is worrisome because other data show that failure rates for vancomycin against such pathogens approaches 90%.[28] Finally, vancomycin, because of its mechanism of action, does not affect toxin production in CA-MRSA. As noted earlier, toxin production by CA-MRSA may represent a major source of virulence, and hence, there are theoretical reasons to believe that, as we do in necrotizing fascitis, adding toxin-inhibiting antibiotics may be important in the treatment of CA-MRSA.

Alternatives to Vancomycin

What are the alternatives to vancomycin? A number of novel agents are in clinical trials, including advanced cephalosporins, newer glycopeptides, and others. Some preliminary data highlight how complicated interpreting the data from these trials will be. For example, a study with ceftobiprole, a cephalosporin with antiMRSA and antipseudomonal activity, suggests that ceftobiprole is effective in hospital-acquired pneumonia, but not in VAP.[29] Likewise, a trial of tigecycline, which is approved for intraabdominal and skin infections, failed to meet the study's primary endpoint in hospital-acquired pneumonia.

Of the currently approved agents, daptomycin is approved for use in bacteremia and skin infections. Dapotmycin is not used to treat pneumonia because it is inactivated by surfactant, underscoring the need for our clinical decision making to be driven by evidence from clinical trials. One might have believed that daptomycin, which is bactericidal against MRSA, would be a good choice; however, the clinical trial data show that in vitro predictions do not translate into clinical findings and that "cidality" may not be a crucial issue in treating infections in intact hosts. In addition, Dr. Kollef expressed concern that despite daptomycin's bactericidal activity against MRSA, daptomycin-resistant MRSA emerged in the largest study of daptomycin vs vancomycin for bloodstream infections.[30]

Clindamycin may have a role in pneumonia caused by CA-MRSA strains. As with all agents used to treat CA-MRSA, there are no randomized, controlled trials to guide us. A potential advantage of clindamycin is that it inhibits toxin production. However, Dr. Kollef noted that inducible resistance (when a strain appears susceptible to in vitro testing) can be seen with clindamycin in the treatment of CA-MRSA. When that testing is repeated in the presence of erythromycin, true resistance may become apparent. Because of this, Dr. Kollef cautioned against broad utilization of clindamycin for pneumonia caused by MRSA.

Like clindamycin, linezolid, an oxidalizone, inhibits protein synthesis and thus toxin production. Several randomized trials have compared linezolid with vancomycin for the treatment of pneumonia. In a pooled analysis of these trials, linezolid was associated with greater rates of bacterial eradication of MRSA and with improved survival.[31] This analysis has been criticized for several reasons, including its retrospective nature and that vancomycin was not dosed to trough levels of 15 to 20 mcg/mL. Anticipating this criticism, Dr. Kollef noted that when these trials were conducted there were no concerns regarding higher-MIC90 MRSA isolates. In the end, Dr. Kollef emphasized the need to focus on evolving issues with the efficacy of vancomycin for serious infections in the ICU. He predicted that linezolid and newer agents will be increasingly used in the care of critically ill patients. Therefore, and most important, ICU clinicians must keep abreast of the changing evidence in this field.



  1. Fridkin SK, Hill HA, Volkova NV, et al. Intensive Care Antimicrobial Resistance Epidemiology Project Hospitals. Temporal changes in prevalence of antimicrobial resistance in 23 US hospitals. Emerg Infect Dis. 2002;8:697-701. Abstract
  2. Klevens RM, Edwards JR, Tenover FC, et al. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992-2003. Clin Infect Dis. 2006;42:389-391. Abstract
  3. Warren DK, Guth RM, Coopersmith CM, et al. Epidemiology of methicillin-resistant Staphylococcus aureus colonization in a surgical intensive care unit. Infect Control Hosp Epidemiol. 2006;27:1032-1040. Abstract
  4. Herman RA, Kee VR, Moores KG, Ross MB. Etiology and treatment of community-associated methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm. 2008;65:219-225. Abstract
  5. Tristan A, Ferry T, Durand G, et al. Virulence determinants in community and hospital methicillin-resistant Staphylococcus aureus. J Hosp Infect. 2007;65:S105-S109.
  6. Boyle-Vavra S, Daum RS. Community-acquired methicillin-resistant Staphylococcus aureus: the role of Panton-Valentine leukocidin. Lab Invest. 2007;87:3-9. Abstract
  7. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436-1444. Abstract
  8. Ebert MD, Sheth S, Fishman EK. Necrotizing pneumonia caused by community-acquired methicillin-resistant Staphylococcus aureus: an increasing cause of "mayhem in the lung." Emerg Radiol. 2008 Feb 15; [Epub ahead of print]
  9. Vayalumkal JV, Whittingham H, Vanderkooi O, et al. Necrotizing pneumonia and septic shock: suspecting CA-MRSA in patients presenting to Canadian emergency departments. CJEM. 2007;9:300-303. Abstract
  10. Seybold U, Kourbatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis. 2006;42:647-656. Abstract
  11. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763-1771. Abstract
  12. Napolitano LM. Community-acquired and healthcare-associated MRSA: implications for practice. Prevention strategies to reduce the rate of MRSA infections in critical care. Paper presented at the Society of Critical Care Medicine (SCCM) 37th Critical Care Congress; February 4, 2008; Honolulu, Hawaii.
  13. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006;355:2725-2732. Abstract
  14. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371:126-134. Abstract
  15. Koeman M, van der Ven AJ, Hak E, et al. Oral decontamination with chlorhexidine reduces the incidence of ventilator-associated pneumonia. Am J Respir Crit Care Med. 2006;173:1348-1355. Abstract
  16. Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med. 2007;35:595-602. Abstract
  17. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354:1851-1858. Abstract
  18. Delaney A, Bagshaw SM, Nalos M. Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systematic review and meta-analysis. Crit Care. 2006;10:R55.
  19. Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S. Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med. 2005;118:11-18. Abstract
  20. Kollef MH. Limitations of vancomycin in the management of resistant staphylococcal infections. Clin Infect Dis. 2007;45:S191-S195. Abstract
  21. Kollef MH. Community-acquired and healthcare-associated MRSA: implications for practice. Evidence-based management of MRSA infections in the critical care setting. Paper presented at the Society of Critical Care Medicine (SCCM) 37th Critical Care Congress; February 4, 2008; Honolulu, Hawaii.
  22. Bard. Bard receives clearance to market Agento(TM) IC silver-coated endotracheal tube. Available at: Accessed February 20, 2008.
  23. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. Abstract
  24. Jeffres MN, Isakow W, Doherty JA, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest. 2006;130:947-955. Abstract
  25. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166:2138-2144. Abstract
  26. Rhee KY, Gardiner DF, Charles M. Decreasing in vitro susceptibility of clinical Staphylococcus aureus isolates to vancomycin at the New York Hospital: quantitative testing redux. Clin Infect Dis. 2005;40:1705-1706. Abstract
  27. Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis. 2007;44:1208-1215. Abstract
  28. Moise-Broder PA, Sakoulas G, Eliopoulos GM, et al. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis. 2004;38:1700-1705. Abstract
  29. Basilea Pharmaceutica Ltd. Basilea announces positive top-line data from phase III study of ceftobiprole in hospital-acquired pneumonia. Available at: Accessed February 20, 2008.
  30. Fowler VG Jr, Boucher HW, Corey GR, et al., for the Staphylococcus aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-665. Abstract
  31. Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double blind studies comparing linezolid with vancomycin. Intensive Care Med. 2004;30:388-394. Abstract
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