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Methicillin-Resistant Staphylococcus aureus: A Growing Risk in the Hospital and in the Community

February/March 2009, Vol 2, No 2 - Clinical
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Abstract

Methicillin-resistant Staphylococcus aureus is a common and continuously growing cause of nosocomial and community-acquired infections. The type, disease severity, and clinical outcomes of these infections, as well as the genotypic and susceptibility patterns of the bacteria differ according to the setting in which the infection occurs—a healthcare facility or the community setting. The incidence of these infections in the community setting has been growing consistently in the past decade or so. In addition, resistance to the many current antibiotics used to treat these infections is also growing, further complicating management. Rapid-diagnosis tests and new therapeutic agents are constantly under investigation. The authors review the current understanding of the epidemiology, clinical manifestations, and management of methicillin-resistant Staphylococcus aureus infection, including the growing problem of resistance. In addition, they discuss promising diagnostic and therapeutic alternatives, as well as new control strategies to prevent its transmission or the development of infection among carriers.

Am Health Drug Benefits. 2009;2(2):86-95.

Methicillin-resistant Staphylococcus aureus (MRSA) refers to isolates that are resistant to ß-lactam antibiotics (including penicillins and cephalosporins).1 According to the Clinical and Laboratory Standards Institute (CLSI), MRSA is defined as isolates with a methicillin minimum inhibitory concentration (MIC) ≥4 µg/mL; however, S aureus already is considered nonsusceptible to oxacillin if the MIC is >2 µg/mL.2

Methicillin resistance is mediated by the penicillinbinding protein (PBP)-2a encoded by the mecA gene. ß-lactam antibiotics have poor affinity for this altered PBP, and organisms are not killed when exposed to common therapeutic concentrations. The mecA gene is located on a mobile genetic element, the staphylococcal chromosome cassette (SCCmec). Sequencing SCCmec from many MRSA strains reveals that there are at least 5 SCCmec types (I-V) that vary in genetic base-pair construction and size.3
 

Epidemiology

MRSA emerged in England in 1961, 2 years after the introduction of methicillin, and its incidence has increased steadily since then. In the United States, MRSA was first reported in 1968.

Hospital- or healthcare-associated (HA)-MRSA is different from community-associated (CA)-MRSA in terms of epidemiology, phenotype, and genotype. CAMRSA is an important pathogen that has become prevalent during the past decade and, according to some reports, is replacing nosocomial MRSA strains. In one study, during a 7-year period, MRSA bloodstream infections caused by CA-MRSA increased from 26% to 49%.4

HA-MRSA

HA-MRSA is associated with severe infections, with high morbidity and mortality rates, such as ventilatorassociated and hospital-associated pneumonia, surgical site infections, as well as catheter-related infections.

In the early 1990s, MRSA accounted for 20% to 25% of S aureus isolates from hospitalized patients. In 1999, MRSA represented more than 50% of S aureus isolates from patients in intensive care units (ICUs) according to the National Nosocomial Infection Surveillance System.5,6 In 2003, that percentage was approaching 60%. It is now estimated that approximately 70% of all S aureus isolated from ICUs are MRSA.5,6 HA-MRSA carries SCCmec type II and is typified as USA100 or USA200 by pulse-field gel electrophoresis (PFGE).7 The major risk factors associated with HA-MRSA are listed in Table 1.

Table 1
Table 1

CA-MRSA
In the 1980s, MRSA was isolated among injection drug users who had a history of antibiotic exposure. In 1993, a genetically unique MRSA isolate was reported in Australia among aborigines who had no previous contact with a healthcare system. By the mid-1990s, CAMRSA infections emerged in New Zealand, the United Kingdom, France, Finland, Canada, Samoa, and the United States.

Initial outbreaks of CA-MRSA in the United States occurred in Native American children in Minnesota, Nebraska, and North Dakota. Later, CA-MRSA infections were identified in other populations, including homosexual men, incarcerated people, athletes, and soldiers. Compared with HA-MRSA, most CA-MRSA cases contain SCCmec type IV or type V, which encode for resistance to methicillin and other ß-lactam antibiotics, but generally not for other agents. They are typified by a USA300 or USA400 PFGE pattern and frequently carry genes for the cytotoxin Panton-Valentine leukocidin that is associated with the propensity of S aureus to cause tissue necrosis.8

In 3 US communities, 1647 cases of CA-MRSA infection were reported between 2001 and 2002.9 Of all MRSA isolates, 8% to 20% were not associated with traditional risk factors and were classified as CAMRSA.9 Most caused clinically relevant infections that required treatment; many patients were children and required hospitalization.

CA-MRSA infection often presents as skin and softtissue infection (SSTI) in previously healthy individuals. SSTIs may be mild or severe and include pyomyositis or necrotizing fasciitis, osteomyelitis, septic arthritis, Waterhouse-Friderichsen syndrome, pneumonia, and bacteremia.

Table 2
Table 2

The risk factors for CA-MRSA, which differ from those of HA-MRSA, are listed in Table 2. Transmission of MRSA from colonized pets has also been reported.10 In many circumstances, a single risk factor could not be identified.

Pathogenesis

The difference between MRSA and methicillin-sensitive strains is that the former may have acquired a genetic background, which is believed to enhance virulence or the development of more severe and atypical manifestations of the disease.

For diseases caused by S aureus, the pathogenesis is considered to be multifactorial. Progress in molecular biology techniques has allowed identification of many virulence factors (specific genes have been cloned and sequenced, and protein toxins purified); however, it is difficult to determine precisely the role of many of them.

Table 3
Table 3

Staphylococcal infections occur frequently but usually remain localized at the portal of entry by normal host defenses. MRSA colonization is an important risk factor for the development of infection. It is estimated that 20% to 30% of individuals carry S aureus in their nares and in other areas, such as the axillae, groin, or gastrointestinal tract. When the host barriers are broken, "commensal" S aureus may invade deeper structures and produce subsequent infection. Another portal of entry is the respiratory tract. Staphylococcal pneumonia is a severe condition affecting young, previously healthy individuals during or after influenza.11 Table 3 summarizes the most important virulence factors and their roles in the disease.
 

 

CA-MRSA Clinical Syndromes

Almost 80% of CA-MRSA infections in the United States are SSTIs. Abscess and cellulitis are the most common, and 60% of SSTIs seen in emergency departments are produced by MSRA. The median age for CA-MRSA infection in adults ranges from 20 to 47 years, and SSTIs are more frequent among nonwhite men. The majority of CA-MRSA infections, particularly those involving the skin and soft structures, are not severe and are considered to have a low mortality rate (as compared with infections caused by nosocomial MRSA strains); however, severe and life-threatening episodes of invasive CA-MRSA infections have been reported with increased frequency worldwide.12

Less common, but severe forms of disease caused by CA-MRSA are:
 

  • Necrotizing fasciitis, a life-threatening infection that requires urgent surgical and medical therapy; associated conditions or risk factors include previous MRSA infection, hepatitis C, diabetes mellitus, current or past injection drug use, cancer, and HIV infection
  • Pyomyositis, initially considered a tropical disease, is now recognized in areas of temperate climates and especially in patients with HIV and intravenous drug users
  • Necrotizing community-acquired pneumonia (CAP) is associated with influenza, and generally occurs in previously healthy young individuals. During the 2003-2004 influenza season, 15 cases of MRSACAP, with 4 deaths (fatality rate 26.7%), were reported from 9 states.13 In January 2007, the Centers for Disease Control and Prevention (CDC) received reports of 10 cases of severe MRSA-CAP, including 6 deaths, among previously healthy persons in Louisiana and Georgia14
  • Infective endocarditis is a common and often devastating complication of S aureus bacteremia15; risk factors include prosthetic valve, underlying valvular defects, injection drug use, intravascular catheter infection, and persistent bacteremia
  • Septic arthritis and osteomyelitis may be caused by di rect injury or as a complication of S aureus bacteremia
  • Sepsis (with or without Waterhouse-Friderichsen syndrome). Waterhouse-Friderichsen syndrome is characterized by petechial rash, coagulopathy, cardiovascular collapse, and bilateral adrenal hemorrhage. It generally is associated with fulminant meningococcemia; however, 3 fatal cases produced by S aureus were reported in 2005 in children, 2 of which were caused by CA-MRSA.16

HA-MRSA Clinical Syndromes

HA-MRSA infections are associated with prolonged hospital stay, increased mortality, and increased costs. In 2003, 64.4% of S aureus infections in ICUs were associated with methicillin-resistant strains.5,6 MRSA is a suspected pathogen in nearly all types of hospital infections.

The most common manifestations of HA-MRSA infections are:
 

  • Surgical wound skin and skin structure infection (SSSI)
  • Osteomyelitis and septic arthritis as complications of orthopedic surgery, including prosthetic device infections
  • Bacteremia
  • Healthcare- and ventilator-associated pneumonia.

Treatment of MRSA Infection

Outpatient Drug Therapy
Uncomplicated SSTIs (ie, those without associated sepsis or hemodynamic instability) can be managed with incision and drainage if an abscess is present. Topical antimicrobial therapy sometimes is used to treat limited and superficial MRSA skin infections (eg, impetigo). The most known agents are bacitracin (alone or in combination with polymyxin and neomycin), mupirocin, and retapamulin. Emerging resistance to mupirocin is now being reported worldwide, particularly in healthcare facilities where it is used extensively to prevent infection and transmission from carriers.

Table 4
Table 4

The drug of choice for the ambulatory setting has not been clearly established. Most CA-MRSA are susceptible to doxycycline, minocycline, clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), chloramphenicol, rifampin, and linezolid. Familiarity with local antibiotic patterns and cultures with susceptibility data are critical for tailoring treatment. Table 4 lists oral agents available for the treatment of CA-MRSA.

Susceptibility to erythromycin ranges from 5% to 64% in different geographic areas.11 Clindamycin has good activity against MRSA and is capable of inhibiting bacterial toxin production. Awareness of local clindamycin resistance rates is important. Some experts recommend avoiding use of this antibiotic empirically if the local rate of resistance is 10% to 15%. In addition, isolates that appear susceptible to clindamycin but are resistant to erythromycin by standard susceptibility testing may be capable of inducing resistance to clindamycin. The double disk-diffusion test detects isolates that may become resistant to clindamycin during treatment.

TMP-SMX and tetracyclines are generally not recommended as sole empirical therapy in the treatment of nonpurulent cellulitis, because group A streptococci, which are usually resistant to these antibiotics, may be involved in coinfection. Resistance of group A streptococci to tetracyclines has been well documented, whereas resistance to TMP-SMX remains poorly known.8 Some physicians add an active ß-lactam antibiotic to cover streptococci.

Few data exist on the efficacy of the long-acting tetracyclines (doxycycline and minocycline) against MRSA infection. In one retrospective case series of 24 patients with serious tetracycline-susceptible MRSA infections, clinical cure was achieved in 83% of patients.17

Linezolid is active against almost all isolates of CAMRSA and streptococci; however, it should be reserved for patients who do not respond or cannot tolerate traditional agents. The disadvantages of using linezolid include cost, hematologic side effects, and the potential to induce resistance among S aureus strains.18

Rifampin has excellent activity against MRSA. It has been used with good results in combination with tetracycline or with TMP-SMX, although solid data are not available to support this approach. Rifampin monotherapy is contraindicated due to the rapid emergence of resistant mutants.

Fluoroquinolones should not be used to treat SSTIs caused by MRSA; resistance to ciprofloxacin develops rapidly during therapy and widespread resistance is prevalent in many regions.

Table 5
Table 5

Parenteral Therapy
Parenteral therapy (Table 5) should be considered for patients with severe SSTIs, fever, or with other signs of systemic illness, and patients with diabetes, immunosuppression, or other significant comorbid conditions.

Vancomycin has been the drug of choice for hospitalized patients with invasive MRSA infections. Nevertheless serious problems with vancomycin have been identified. Recent studies have shown emergence of treatment failures in correlation with increasing, but still considered within the "susceptible" range, vancomycin MICs (<0.5 vs 2.0 µg/mL).19,20 Because of the results of those studies, the CLSI changed the susceptibility and resistance breakpoints from ≤4 µg/mL to ≤2 µg/mL for "susceptible" and from 8 µg/mL to 16 µg/mL to 4 µg/mL to 8 µg/mL for "intermediate" resistance.2

A significant concern remains for patients infected with MRSA who have MICs at the upper range of the susceptible zone—the trough levels of vancomycin (15 µg/mL-20 µg/mL) required to treat such patients may result in renal toxicity. In addition, treatment failure has been attributed to vancomycin intermediateresistant S aureus.19 Failure due to strains that exhibit heterogeneous resistance to vancomycin also occurs.19 These strains are missed by routine laboratory methodologies.

Vancomycin-resistant S aureus (VRSA) is now a threatening reality. A total of 7 cases were identified in the United States between 2002 and 2006; 5 in Michigan, 1 in Pennsylvania, and 1 in New York.20 All VRSA isolates carried the vanA gene and had a median vancomycin MIC of 512 µg/mL.20 For patients who fail to respond or cannot tolerate vancomycin, the optimal alternative parenteral agent is not known.

Linezolid, daptomycin, tigecycline, and quinupristindalfopristin are indicated for the treatment of SSTIs. Among this group, only daptomycin also has an indication for bacteremia and endocarditis.

Among the older agents, treatment data for MRSA are limited. Parenteral clindamycin may be given in regions where the likelihood of resistance is low, but this agent is considered bacteriostatic and may not be an effective choice for deep-seated infections. In a 1992 study, investigators compared parenteral TMPSMX with vancomycin for the treatment of invasive S aureus infections in intravenous drug users (43 patients received TMP-SMX and 58 received vancomycin). 21 TMP-SMX proved to be inferior to vancomycin only in cases of methicillin-sensitive S aureus infections. TMP-SMX was successful in treating all MRSA infections, including tricuspid-valve endocarditis. The authors concluded that TMP-SMX could be considered as an alternative to vancomycin in selected cases of MRSA infection.21

Teicoplanin is another glycopeptide with similar efficacy to vancomycin, but with less toxicity; however, it is not available in the United States.

Daptomycin is a cyclic lipopeptide, with rapid bactericidal activity against MRSA produced by depolarization of the bacterial cell membrane. This drug has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated SSTIs at a daily dose of 4 mg/kg, and at a daily dose of 6 mg/kg for the management of bacteremia and rightsided endocarditis. In a randomized trial that included 45 patients with complicated SSTIs caused by MRSA, daptomycin had similar efficacy to vancomycin, with a clinical success rate of 83%.22 In another randomized trial in patients with S aureus bacteremia with or without right-sided endocarditis, daptomycin monotherapy was not inferior to vancomycin plus gentamicin; 53 of 120 patients had a successful outcome with daptomycin compared with 48 of 115 patients who received vancomycin (99 of whom had MRSA infections).23 Daptomycin should not be used to treat pneumonia, because its activity is inhibited by pulmonary surfactant.

Linezolid is an alternative agent to glycopeptides. It inhibits the initiation of protein synthesis at the 50S ribosome. Although bacteriostatic for MRSA, it has excellent bioavailability and tissue penetration, particularly in the epithelial lining fluid of the lungs, making this antibiotic a potentially useful option in cases of MRSA pneumonia.

Tigecycline, a parenteral glycylcycline-minocycline derivative, was approved by the FDA in 2005 for the treatment of complicated SSTIs, including those infected with MRSA. A study that combined data from 2 clinical trials demonstrated tigecycline to be as effective as the combination of vancomycin and aztreonam for the management of complicated SSTIs. For MRSA infections, the cure rate was 78.4% for tigecycline compared with 76.5% for vancomycin plus aztreonam.24

Investigational Antimicrobials
Several new agents are currently under development—dalbavancin, telavancin, and oritavancin are semisynthetic glycopeptides characterized by prolonged plasma half-lives. Dalbavancin is bactericidal against gram-positive cocci, including MRSA, and its estimated half-life of 6 to 12 days permits once-weekly dosing.

Clinical trials evaluating the efficacy of dalbavancin demonstrated that it is not inferior to vancomycin in the treatment of catheter-related infection caused by grampositive pathogens (including MRSA). The success rate for dalbavancin was 87% versus 50% for vancomycin.25 Dalbavancin was also as effective as linezolid for the treatment of complicated SSTIs, with a success rate of 91% compared with 89% for linezolid in patients with MRSA infections.26

Ceftobiprole is an advanced-generation pyrolidinone cephalosporin with capacity to bind to PBP-2a. The results of 2 multicenter noninferiority trials involving approximately 1600 patients with complicated SSSIs (cSSSIs) were reported recently. The first trial included patients with gram-positive cSSSI; cure rates were 93.3% and 93.5% for ceftobiprole treatment and vancomycin treatment, respectively. The second trial included a broad range of cSSSIs; clinical cure rate among patients with MRSA infections who received ceftobiprole was 91.4% compared with 86.1% for vancomycin plus ceftazidime.27

Ceftaroline, another new broad-spectrum cepha losporin, is currently under investigation (in phase 2 and 3 clinical trials) in patients with S aureus cSSSIs.

Immunointervention
Pooled staphylococcal antibody preparations that neutralize staphylococcal superantigen toxins are being prepared for the treatment of toxic shock syndrome. Telfibazumab is a humanized monoclonal antibody directed at microbial surface compounds recognizing adhesive matrix molecule clumping factor A, a protein on the S aureus surface that binds to human fibrinogen. This drug is being investigated for the treatment of S aureus infections and also for potential prevention of disease.28

StaphVAX, a promising S aureus polysaccharide conjugate vaccine, has been demonstrated to offer protection against S aureus bacteremia in dialysis patients. However, the effect is temporary, requiring a booster dose every 6 months.29 In a recent (yet to be published) phase 3, confirmatory study involving more than 3500 hemodialysis patients, StaphVAX did not offer any more benefit than placebo, and therefore, its development has been halted.30

 

New Test for Rapid Diagnosis of S aureus Bacteremia

Based on a fluorescent in-situ hybridization (FISH) assay with peptide nucleic-acid (PNA) probes that target specific sequences of S aureus 16S rRNA, the new PNA FISH test allows for rapid diagnosis of S aureus bacteremia. The performance of the PNA FISH assay was evaluated using 285 blood cultures that had gram-positive cocci resembling staphylococci on Gram's stain. The sensitivity, specificity, and positive and negative predictive values of the PNA FISH test for the rapid identification of S aureus directly from positive blood culture bottles were 100%, 99.4%, 99.2%, and 100%, respectively. Results are available within 3 hours after blood cultures turn positive.31

The impact of the rapid differentiation of S aureus from coagulase-negative staphylococci in blood cultures using PNA FISH was evaluated in a recent retrospective, cost-effective analysis.32 When comparing the PNA FISH assay results with those for a control group (53 and 34 patients, respectively), a significant reduction was found with use of the new assay in median length of hospital stay from 6 to 4 days, as well as a trend toward reduced vancomycin use, with a decreased cost of $4000 per patient.32

Continued Emergence of Resistance in S aureus

S aureus has developed resistance to most antibiotics, including penicillin, methicillin, linezolid, and daptomycin, rather rapidly. Resistant strains were reported from around the world, within 1 or 2 years after the introduction of each of these agents. With vancomycin, the history was different; after the introduction of vancomycin in 1958, the first vancomycin intermediateresistant S aureus was found in 1997 in Japan (39 years later). The first truly resistant isolate (ie, VRSA) was identified in Detroit, Michigan, in 2002. According to the CLSI, vancomycin intermediate-resistant S aureus (or glycopeptide intermediate-resistant S aureus) and VRSA are defined as having MICs of 4 µg/mL to 8 µg/mL, and ≥16 µg/mL, respectively.2

In VRSA strains, resistance is mediated by the presence of operons that encode enzymes that eliminate precursors with high affinity to vancomycin. In glycopeptide intermediate-resistant S aureus strains, reduced susceptibility is the result of the production of increased numbers of D-Ala-D-Ala residues on the nascent cell wall that serve as dead-end binding sites for vancomycin. The result is a reduced vancomycin diffusion coefficient and sequestration of this drug within the cell wall by these false targets.33

A microbiological definition of daptomycin resistance has not been established yet; however, a value of MIC >1.0 µg/mL is considered nonsusceptible in accordance with the CLSI guidelines.2

Wild-type S aureus with MICs of >1.0 µg/mL are rare but have been recovered from patients who had previously received either vancomycin, daptomycin, or, in some cases, had not received antibiotics previously. At this time, multiple studies have reported that 90% of S aureus isolates in healthcare settings still have daptomycin MICs <0.5 µg/mL.34 It is thought that glycopeptide exposure induces the formation of a thicker cell wall, thus preventing the diffusion of daptomycin into the bacteria. In addition, mutations in certain genes, such as MPRF (which encodes lysylphosphatidylglycerol synthetase), YYCG (which encodes sensor histidine kinase), and RPOB/RPOC (encode ß and ß' subunits of RNA polymerase), were found in S aureus strains with daptomycin MIC of more than 1.0 µg/mL.35

Linezolid resistance is associated with mutations in the central loop of domain V in the 23S ribosomal RNA, and increased MICs are associated with greater numbers of mutations. The most frequent mutation associated with linezolid resistance in both staphylococci and enterococci strains is G2576T. Another mutation (T2500A) was characterized in a single patient isolate of MRSA. Recently, the presence of the CFR gene (a gene encoding an rRNA methyltransferase, and is called CFR for chloramphenicol-florfenicol resistance) has been identified in a clinical MRSA isolate (designated CM-05) from Colombia.33,36 Linezolid resistance in MRSA is still considered rare.
 

Controlling MRSA Infection

Optimal measures for the prevention of MRSA infections remain under investigation. The most common source of HA-MRSA is colonized or infected patients; the most important mode of transmission is via hands, especially from healthcare personnel. Basic infection control practices are integral to the prevention and control of MRSA in healthcare settings. In its "Information about MRSA for Healthcare Personnel" and the Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007, the CDC emphasizes several standard and contact precautions to prevent the transmission of MRSA.37

Community-associated infections can recur in individuals and can spread within families. Clinicians should educate patients or their caretakers, and when possible, household members, on methods to limit further spread of infection. The CDC has recommended the following measures in an effort to prevent the spread of CAMRSA infections in the community37:
 

  • Keep hands clean by washing thoroughly with soap and water or by using an alcohol-based hand sanitizer
  • Keep cuts and scrapes clean and covered with a bandage until healed
  • Avoid contact with other people's wounds or bandages
  • Avoid sharing personal items, such as towels, washcloths, razors, clothing, or uniforms.


To date, no data support the use of agents to eliminate colonization in patients with MRSA infection or their contacts. However, it may be reasonable to attempt decolonization if a patient has had multiple recurrences of MRSA infection or ongoing MRSA transmission is occurring in a well-defined, closely associated cohort (such as a household).38

The role of early screening for MRSA colonization in hospitalized patients is unclear. In a recent study involving more than 21,000 surgical patients, 2 MRSA control strategies (rapid screening on admission plus standard infection control measures vs standard infection control alone) were used to determine the effect of an early MRSA detection strategy on nosocomial MRSA infection rates. Rapid MRSA screening on admission did not reduce the rate of nosocomial MRSA infection.39

 

Conclusion

MRSA now represents a common infectious agent in any environment. More virulent than ever, MRSA keeps producing high rates of morbidity and mortality. MRSA also has the ability to become easily resistant every time a new therapeutic agent is introduced, except for vancomycin, which was considered useful for the past 40 years; however, increasing rates of treatment failure with strains reported to have MICs in the "susceptible" range have been widely documented. The continuous emergence of resistant strains has created an enormous difficulty for the management of MRSA infections. It is now crucial to make the diagnosis very early and in an effective way. Many potent antibiotics are being developed as well as promising vaccines; however, control measures to identify populations at risk and strategies to prevent transmission should play an essential aspect of care.

Disclosure Statement
Dr Levine is on the Speakers' Bureau of Cubist Pharmaceuticals and Novartis; receives research support from Cubist and Theravance Therapeutics (Astellas); and is on the advisory board of Cubist, Merck & Co, Novartis, and Theravance.

 

References

1. van Belkum A, Verbrugh H. 40 years of methicillin resistant Staphylococcus aureus. BMJ. 2001;323:644-645.
2. Division of Healthcare Quality Promotion, National Center for Preparedness, Detection, and Control of Infectious Diseases. Laboratory detection of oxacillin/methicillin-resistant Staphylococcus aureus. February 2005. www.cdc.gov/ncidod/dhqp/ar_lab_mrsa.html. Accessed July 29, 2008.
3. Ito T, Kuwahara K, Hiramatsu K. Staphylococcal cassette chromosome mec (SCCmec) analysis of MRSA. Methods Mol Biol. 2007;391:87-102.
4. Popovich K, Weinstein R, Hota B. Are community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains? Clin Infect Dis. 2008;46:787-794.
5. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. Management of multidrugresistant organisms in healthcare settings, 2006. www.cdc.gov/ncidod/dhqp/pdf/ar/mdroguideline2006.pdf. Accessed January 2, 2009.
6. Klevens RM, Morrison M, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections, in the United States. JAMA. 2007;298: 1763-1571.
7. McDougal LK, Steward CD, Killgore GE, et al. Pulse-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol. 2003;41:5113-5120.
8. Diep BA, Gill SR, Chang RF, et al. Complete genome sequence of USA300, an epidemic clone of community-acquired methicillin-resistant Staphylococcus aureus. Lancet. 2006;367:731-739.
9. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005; 352:1436-1444.
10. Sing A, Tuschak C, Hormansdorfer S. Methicillin-resistant Staphylococcus aureus in a family and its pet cat. N Engl J Med. 2008;358: 1200-1201.
11. Kallen AJ, Brunkard J, Moore Z, et al. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med. June 5, 2008. Epub ahead of print.
12. Stryjewski ME, Chambers HF. Skin and soft-tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008;46(suppl 5):S368-S377.
13. Hageman JC, Uyeki TM, Francis JS, et al. Severe communityacquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006;12:894-899.
14. Centers for Disease Control and Prevention: MMWR. Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza in Louisiana and Georgia, December 2006–January 2007. JAMA. 2007;297:2070-2072.
15. Millar BC, Prendergast BD, Moore JE. Community-associated MRSA (CA-MRSA): an emerging pathogen in infective endocarditis. J Antimicrob Chemother. 2008;61:1-7.
16. Adem PV, Montgomery CP, Husain AN, et al. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children. N Engl J Med. 2005;353:1245-1251.
17. Ruhe JJ, Monson T, Bradsher RW, et al. Use of long-acting tetracyclines for methicillin-resistant Staphylococcus aureus infections: case series and review of the literature. Clin Infect Dis. 2005;40:1429-1434.
18. Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis. 2002;34:1481-1490.
19. Charles PG, Ward PB, Johnson PD, et al. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004;38:448-451.
20. Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant Staphylococcus aureus in the United States, 2002-2006. Clin Infect Dis. 2008;46:668-674.
21. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med. 1992;117:390-398.
22. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38:1673-1681.
23. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-665.
24. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis. 2005;41(suppl 5):S341-S353.
25. Raad I, Darouiche R, Vasquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005;40:374-380.
26. Jauregui LE, Babazadeh Seltzer E, et al. Randomized, double-blind comparison of once weekly dalbavancin versus twice daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis. 2005;41:1407-1415.
27. Deresinski SC. The efficacy and safety of ceftobiprole in the treatment of complicated skin and skin structure infections: evidence from 2 clinical trials. Diagn Microbiol Infect Dis. 2008;61:103-109.
28. John JF Jr. Drug evaluation: tefibazumab—a monoclonal antibody against staphylococcal infection. Curr Opin Mol Ther. 2006;8:455-460.
29. Shinefield HR, Black S. Prevention of Staphylococcus aureus infections: advances in vaccine development. Expert Rev Vaccines. 2005;4:669-676.
30. Schaffer AC, Lee JC. Vaccination and passive immunisation against Staphylococcus aureus. Int J Antimicrob Agents. 2008;32(suppl 1):S71-S78.
31. González V, Padilla E, Giménez M, et al. Rapid diagnosis of Staphylococcus aureus bacteremia using S aureus PNA FISH. Eur J Clin Microbiol Infect Dis. 2004;23:396-398.
32. Forrest GN, Mehta S, Weekes E, et al. Impact of rapid in situ hybridization testing on coagulase-negative staphylococci positive blood cultures. J Antimicrob Chemother. 2006;58:154-158.
33. Sakoulas G, Moellering RC Jr. Increasing antibiotic resistance among methicillin-resistant Staphylococcus aureus strains. Clin Infect Dis. 2008;46(suppl 5):S360-S367.
34. Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis. 2007; 45:601-608.
35. Sharma M, Riederer K, Chase P, et al. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2008;27:433-437.
36. Arias CA, Vallejo M, Reyes J, et al. Clinical and microbiological aspects of linezolid resistance mediated by the cfr gene encoding a 23sRNA methyltransferase. J Clin Microbiol. 2008;46:892-896.
37. Centers for Disease Control and Prevention. Information about MRSA for healthcare personnel. Updated October 2007. www.cdc.gov/ncidod/dhqp/ar_mrsa_healthcareFS.html. Accessed August 8, 2008.
38. Strategies for clinical management of MRSA in the community: summary of an experts' meeting convened by the Centers for Disease Control and Prevention. March 2006. www.cdc.gov/ncidod/dhqp/pdf//ar/CAMRSA_ExpMtgStrategies.pdf. Accessed August 8, 2008.
39. Harbarth S, Fankhauser C, Schrenzel J, et al. Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA. 2008;299:1149-1157.

Stakeholder Perspective
Prevention and Control of Methicillin-Resistant Staphylococcus aureus

MEDICAL/PHARMACY DIRECTORS: The medical and operational complexities of responding to antimicrobial resistance, convincingly demonstrated by the nearly 50 years of human experience with methicillin-resistant Staphylococcus aureus (MRSA), are well described in this expansive review.


Formerly encountered only in tertiary care or long-term care settings, MRSA has become a significant infection control challenge in nearly all healthcare settings. The boundaries surrounding healthcare-associated (HA)-MRSA infections have rapidly dissolved with the recent evolution of strains that cause disease in persons within the community. These new community-associated (CA)-MRSA strains have unique virulence factors that may facilitate the transmission of the microbe and the development of disease. Outbreaks of infection have occurred in group settings in the community, such as prisons, schools, military barracks, and households.

The cost of treating hospitalized patients with HA-MRSA infections is nearly double that of treating hospitalized patients without these infections, and the cost for treating CA-MRSA infections exceeds the cost of treating infections with methicillin-sensitive strains. These increased costs pose formidable challenges for health plans and insurers, and represent a growing burden on the US healthcare industry as a whole.

Antimicrobial treatment for MRSA is complex, dynamic, and subject to localized pressures, thereby requiring constant attention by pharmacy and formulary decision makers. The continuing emergence of additional resistance capacity as we use new drugs is especially troublesome and mandates adherence to standards of judicious use of current antimicrobial therapies.

Recent advances have increased the number of new and promising antimicrobials in our armamentarium pipeline. Ensuring that effective therapies successfully reach use in practice is as difficult now as it always has been. Attempts to develop effective vaccines against virulence factors of S aureus have had mixed results, and no new vaccine appears ready for use yet.

In the face of these complex medical challenges, nonpharmaceutical approaches, specifically, proven infection control measures, may represent our best chance to control the spread of MRSA in both the healthcare and community settings. Educating healthcare workers and family members in the basics of hand washing may represent the greatest weapon against drug-resistant microbes.

Addressing the many issues of multidrug-resistant organisms, such as MRSA, requires a long-term commitment from physicians, pharmacists, health plan directors, epidemiologists, and benefits designers. Policies and procedures for antimicrobial use and payer coverage must always consider the current local resistance patterns. Only when our response is coordinated and inclusive will we tip the balance against MRSA and for our patients.

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Last modified: August 30, 2021