METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA)

METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA)

Current Diagnosis

• Health care–associated methicillin-resistant Staphylococcus aureus (HA-MRSA) is endemic in many hospital settings. The strains are polyclonal, resistant to many non–β-lactam antimicrobials, and typically cause pneumonia, line-related infection, surgical site infection, bacteremia, and infrequently skin and soft tissue infections.

• Community-associated strains of MRSA (CA-MRSA) have risen exponentially over the past decade. The strains are clonal, sensitive to many non–β-lactam antimicrobials, harbor multiple virulence factors, and typically cause pyogenic skin and soft tissue infections and occasionally severe necrotizing pneumonia, fasciitis, and multifocal osteomyelitis.

• HA-MRSA infections typically affect patients with multiple comorbidities in the health care setting, but CA-MRSA typically affects previously healthy persons.

• It can be difficult to differentiate infectious syndromes due to β- hemolytic streptococci versus CA-MRSA.]

Current Therapy

• MRSA strains harbor resistance to the β-lactam antimicrobials, including oxacillin, dicloxacillin, cloxacillin,2 nafcillin, methicillin,2 and first-, second-, and third-generation cephalosporins.

• HA-MRSA strains are typically resistant to macrolides, clindamycin (Cleocin), aminoglycosides, and quinolones and are variably resistant to tetracycline and trimethoprim-sulfamethoxazole (Bactrim). They are sensitive to vancomycin (Vancocin) and the lipoglycopeptides, fusidic acid,2 rifampin (Rifadin),1 linezolid (Zyvox), and daptomycin (Cubicin) and ceftaroline (Teflaro).

• CA-MRSA strains are resistant to macrolides and quinolones but usually sensitive to aminoglycosides such as gentamicin (Garamycin), clindamycin, and trimethoprim-sulfamethoxazole in addition to vancomycin (Vancocin) and the lipoglycopeptides,fusidic acid, rifampin (Rifadin), linezolid(Zyvox), daptomycin (Cubicin) and ceftaroline (Teflaro).

• Empiric antimicrobial therapy should be guided by the clinical presentation, and when full sensitivities are available, the antimicrobials may be tailored accordingly.

1  Not FDA approved for this indication.

2  Not available in the United States.

Epidemiology

Staphylococcus aureus is one of the most frequently encountered bacteria causing human infections and may be considered as either methicillin-sensitive S. aureus (MSSA) or methicillin-resistant S. aureus (MRSA). MRSA was first described in 1961 and is not only resistant to the traditional antistaphylococcal β-lactam antibiotics (methicillin,2 nafcillin, oxacillin, cloxacillin,2 dicloxacillin) but also other important β-lactam antibiotics, including the first- to fourth-generation cephalosporins and the carbapenem family, thus eliminating an important class of antibiotics from the clinician’s armamentarium. The only β-lactam that has activity against MRSA is the recently approved advanced-generation cephalosporin agent ceftaroline (Teflaro).

MRSA strains acquired in the hospital or other health care settings have traditionally been referred to as health care–associated MRSA (HA-MRSA) whereas community-associated MRSA (CA-MRSA) has referred to isolates acquired in the community setting and in the absence of traditional hospital or health care exposures for at least 1 year (overnight stays in an acute care or long-term care facility, surgery, dialysis, or presence of a central venous catheter). Recently the term community-onset HA-MRSA has been used to describe the occurrence of MRSA infection in the setting of the presence of a health care exposure within the past year. MRSA has been recognized as a health care–associated pathogen since the 1970s, and became endemic in hospitals in many countries, including the United States, United Kingdom, and many European countries over the next two decades with exceptions being Denmark, the Netherlands, Scandinavia, and Canada. For several decades, MRSA was typically considered a hospital pathogen. Novel and virulent MRSA strains arising in the community and not associated with any traditional health care exposure risks were first encountered in the late 1990s in the United States, Australia, and some European countries and have since risen explosively on a global basis to become the predominant clone of S. aureus associated with community infections. Methicillin resistance among community isolates of S. aureus has been reported as high as 75% in some U.S. communities. More recently livestock-associated MRSA (LA-MRSA) has been reported on a global basis and transmission of these strains from swine, cattle and horses has been implicated as a source of human infections, particularly in farmers, abattoir workers and veterinarians.

Specific genetic and molecular distinctions initially distinguished the HA- and CA-MRSA strains (Table 1) and have been used to characterize MRSA strains as likely of community or health care origin. The HA-MRSA strains were found to harbor large staphylococcal cassette chromosome (SCCmec) types known as SCCmec types I, II, or III; to have multidrug resistance to non–β-lactam antimicrobials; to have the absence of specific virulence characteristics such as carriage of the Panton-Valentine Leukocidin (PVL) gene; and to have varying multilocus sequence types (ST5, ST239, ST 247, ST250). On the other hand, the CA-MRSA strains have been found to harbor SCCmec types IV, V, and more recently VI to XII have been described; to have paucidrug resistance to non–β-lactam antimicrobials; to have the presence of specific virulence characteristics such as carriage of the Panton-Valentine Leukocidin gene, and to have multilocus sequence types ST1, ST8, ST80. LA- MRSA strains often are non-typeable or harbor SCCmec V, have high rates of tetracycline resistance, carry multiple virulence factors. and are most often multilocus sequence types ST398 or ST9. However, over the last few years, health care–associated strains have moved into the community and likewise community strains have spread rapidly within hospitals, and the original distinctions between CA-MRSA and HA-MRSA from an epidemiologic perspective has become increasingly blurred. The point of transmission of MRSA is not always possible to identify with certainty, making the classification of CA and HA strains increasingly imprecise.

Table 1

General Features Differentiating HA- and CA-MRSA*

Characteristic HA-MRSA                                                       CA-MRSA
SCCmec types I, II, III IV, V (VI–XII)
Drug resistance to non–β- lactams Multiresistance Pauciresistance
Presence of PVL +
Pathogenicity islands Few Multiple
MLST 5, 45, 239, 247, 250 1, 8, 80, 398†
Pulsotype USA100, 200, 600, 800 USA 300, 400
Age predilection Older Younger
Comorbidities Multiple None
Traditional risk factors Health care contact, prolonged hospital stay, poor hand hygiene, contaminated equipment, invasive procedures, medical devices, recent antibiotic use Crowded community environment, lack of cleanliness, loss of skin integrity, intravenous drug user, homelessness, incarceration, aboriginal, HIV +, contact sports, athletes, military, chronic skin disorder, veterinary worker

Abbreviations: SCCmec = staphylococcal cassette chromosome; MLST = multilocus sequence type; pulsotype = pulsed field electrophoretic type; PVL = Panton-Valentine Leukocidin.

* Features are generalizations only given the appearance of community strains replacing traditional hospital strains in the health care setting and the appearance of typical HA strains in the community setting.

†  ST 398 = untypable “swine-associated”  strains.

Risk Factors

The risk factors for HA-MRSA may be viewed from the perspective of the health care environment and patient-specific risk factors. A major risk factor for acquiring HA-MRSA is exposure to a health care setting and particularly in hospital or other institutional settings where the prevalence of carriage of MRSA among patients is high. Additional risk factors in the health care environment include poor hand hygiene practices among hospital employees, contaminated bedside equipment and surfaces, overcrowding, and reduced health care worker–to–patient ratios. Patient risk factors (see Table 1) include aging, multiple comorbidities, receipt of antibiotics within the preceding 3 months, prolonged duration of hospital stay, admission to a long-term care facility or hospital in the previous year, invasive procedures, and the presence of indwelling catheters or other devices. Initial risk groups for CA-MRSA were injection drug users, homeless populations, incarcerated persons, and indigenous peoples, and the Centers for Disease Control and Prevention suggested the five Cs (Figure 1, Table 2) as contributing factors implicated in the transmission among these groups. The initial risk groups have expanded (Table 3) to include men who have sex with men (MSM), athletes (especially those involved in team and contact sports), military personnel, those with a prior history of abscesses, individuals with chronic skin disorders, individuals with recent antibiotic receipt, underserved urban populations, contact with colonized pets or livestock, and veterinary workers. In the drug-using and underserved urban populations, prevalence and social networking studies have identified hospices, shooting galleries, and crack houses as key sites in which CA-MRSA transmission may occur. Recent outbreaks have been reported in hospital nurseries, daycare settings, nursing home workers, schools, and college dormitories. Sexual transmission has been reported, but it may reflect close skin-to-skin genital contact rather than a true sexually transmitted pathogen. CA-MRSA has now become endemic in the general population in many communities and the elderly and the very young seem to have a predilection for infection, especially if other risk factors are present. Risk groups for LA-MRSA include farmers, their family members and farm hands who are engaged in livestock production, especially swine and cattle, abattoir workers and veterinarians and veterinary assistants. Recent transmission of strains of LA-MRSA has been reported in the hospital setting as well.

FIGURE 1    The five Cs implicated in transmission of  CA-MRSA.

(Adapted from the U.S. Centers for Disease Control and Prevention.)

Table 2

Risk Factor Associations Reported for CA-MRSA Infections

 

Adapted from Barton-Forbes et al. (2006).

Table 3

Principles of Empiric Treatment of Minor Skin and Soft Tissue Infections (Folliculitis, Furuncles, Small Abscesses without Cellulitis, Impetigo, Secondarily Infected Lesions Such as Eczema, Ulcers, or Wounds) Where the Etiology Is Unknown but May Include MRSA as a Possibility

 2  Not available in the United States.

Pathophysiology

The resistance to the antistaphylococcal β-lactam antibiotics in MRSA strains is imparted by the presence of an altered configuration for a specific penicillin-binding protein (PBP) known as PBP2a in the cell wall of staphylococci. Normally the PBPs would act as a site for the attachment of the active moieties of the β-lactam agent, which then would inhibit further cell wall assembly. The alteration in the configuration of PBP2a occurs as the result of the presence of the SCCmec gene in S. aureus which confers resistance to the β-lactam antibiotics. The origins of the mec gene and its insertion into the SCCmec element are not known with certainty. Once the MRSA strains acquired resistance to the antistaphylococcal β-lactam antibiotics in the health care setting, it is not difficult to appreciate how it emerged as a predominant pathogen in the hospital setting over the years, with increasing acuity of illness in the patient populations and increased use of broad-spectrum antimicrobials.

The appearance and rapid spread of CA-MRSA with the clinical impression of more virulent and lethal infections than what had been seen with traditional HA-MRSA strains may be explained by several factors. The SCCmec IV genetic element is very widely distributed among S. aureus isolates, which may explain its appearance in multiple settings globally, and these strains appear to have more rapid growth rates than typical HA-MRSA strains, larger numbers of virulence factors, pathogenicity islands, and higher levels of expression of the virulence factors produced. Recently α-type phenol- soluble modulins were described in strains of CA-MRSA, which are produced at very high levels and are potent lysins of neutrophils.

High levels of α-toxin production by these strains, which act as pore- forming toxins for multiple cell types, may also contribute to their virulence. The vast majority of CA-MRSA strains also produce the genes for PVL and it functions as a dermonecrotic factor in skin lesions, a potent cell lysin in high concentrations, and a potent inflammatory mediator in lower concentrations. However, there is controversy about the role of PVL as a single predominant virulence factor, because strains of CA-MRSA that have this gene knocked out have demonstrated no difference in pathogenicity in both vertebrate and invertebrate animal models and in human settings when the PVL is not present.

Prevention

Controlling the spread of either HA-, CA- or LA-MRSA, from an infected or colonized person to others in the hospital, family, or community is a key goal of prevention. In the hospital setting, strict adherence to hand hygiene, application of barrier precautions (gloves, gowns, and private rooms) for patients colonized or infected with MRSA, environmental and equipment cleaning, and antimicrobial stewardship are the key preventive strategies. Active surveillance cultures to identify colonized patients and decolonization may be effective in selected settings but its general application is controversial. In the community setting, practicing hygienic measures including good personal hygiene, consistent hand hygiene, ensuring all draining skin and soft tissue lesions have adequate dressings, not sharing potentially contaminated personal articles, and keeping the household environment hygienic are important. Public health organizations may also contribute to the prevention of CA-MRSA by instituting education programs targeting health care providers and individuals in high-risk groups in the community and by promoting appropriate antimicrobial use. In sports settings, in addition to the basic hygienic measures mentioned previously, avoidance of sharing of towels and other personal items, showering after every practice or tournament, cleaning of communal showering and bathing areas, and cleaning or laundering of equipment after each use are also important.

Clinical Manifestations

The specific clinical infections associated with MRSA parallel those associated with MSSA. Almost any body site, organ, or appendage may be affected by infections due to S. aureus, but there are specific predilections associated with HA- and CA-MRSA. In the hospital or other health care setting, the most commonly encountered sites of infection include pneumonia, line-related infection, surgical site infection, bacteremia, and less often skin and soft tissue infections, whereas in the community setting, the most common sites (> 80%) are skin and soft tissue infections (furuncles, cellulitis, and soft tissue abscesses) and less commonly severely invasive infections such as necrotizing pneumonia, necrotizing fasciitis, multifocal osteomyelitis/septic arthritis, epidural abscess, pelvic septic thrombophlebitis, and bacteremia with toxic shock syndrome. The skin and soft tissue infections often affect young previously healthy patients and are characteristically very painful and pyogenic with an initial black eschar that patients presume was a “spider bite” as the initiating process.

Diagnosis

The diagnosis of MRSA infections is based on the clinical presentation and the isolation of the causative organism from purulent discharge, sputum, or urine or from specimens obtained from normally sterile body fluids (joint fluid, abscess or tissue aspirates, blood). The organism appears on Gram stain as a Gram-positive organism in clusters and is usually seen in association with neutrophils and may be either intracellular or extracellular. The organism is very hardy and grows readily on typical media in the microbiology laboratory within 24 to 48 hours. Some laboratories are using rapid agglutination tests to detect the PBP2a protein or polymerase chain reaction (PCR)–based techniques to provide same-day or next-day identification. In settings where no cultures have been obtained or in the setting of toxic shock syndrome where cultures are often negative, the diagnosis may be difficult and only suspected based on a typical clinical presentation.

Treatment

MRSA strains harbor resistance to the β-lactam antimicrobials, including oxacillin, dicloxacillin, cloxacillin,2  nafcillin, methicillin,2  and first-, second-, and third-generation cephalosporins. The new advanced-generation cephalosporin antimicrobial ceftaroline (Teflaro) has activity against MRSA strains. The majority of HA-MRSA strains are resistant to macrolides, clindamycin (Cleocin), aminoglycosides, and quinolones and are variably resistant to tetracycline and trimethoprim-sulfamethoxazole (Bactrim), depending on local epidemiologic patterns. They are sensitive to vancomycin (Vancocin) and the lipoglycopeptides such as dalbavancin (Dalvance), telavancin (Vibativ) and oritavancin (Orbactiv) and usually sensitive to fusidic acid,2 rifampin (Rifadin), linezolid (Zyvox) and daptomycin (Cubicin). For hospitalized patients where S. aureus is considered a possible etiology of any major infectious syndrome, it should be considered as methicillin resistant until proven otherwise and empiric choices of vancomycin or a lipoglycopeptides such as dalbavancin (Dalvance), telavancin (Vibativ) or oritavancin (Orbitactiv), linezolid (Zyvox) or tedizolid (Sivextro), daptomycin (Cubicin) or ceftaroline (Teflaro) considered as appropriate to the presenting syndrome. CA-MRSA strains are resistant to macrolides and quinolones but usually sensitive to aminoglycosides such as gentamicin (Garamycin), clindamycin, and trimethoprim-sulfamethoxazole, but the resistance patterns vary depending on local resistance patterns. In addition these strains are sensitive to vancomycin (Vancocin) and the lipoglycopeptides, fusidic acid, rifampin (Rifadin), linezolid (Zyvox), daptomycin (Cubicin) and ceftaroline (Teflaro). LA-MRSA strains are almost always resistant to tetracyclines, often resistant to quinolones, macrolides, clindamycin and variably resistant to aminoglycosides and trimethoprim-sulfamethoxazole. In addition these strains are sensitive to vancomycin (Vancocin) and the lipoglycopeptides, fusidic acid, rifampin (Rifadin), linezolid (Zyvox), daptomycin (Cubicin) and ceftaroline (Teflaro). Treatment guidelines for MRSA with a focus on the ambulatory setting have been published in Canada, the United Kingdom, and the United States and provide both empiric choices for common infectious presentations of unknown etiology and definitive treatment once an etiology of MRSA is known. The treatment options for both empiric and definitive use where MRSA is considered or proven are presented in Tables 3 through 6 and represent a constellation of the various guidelines that have been published.

Table 4

Principles of Empiric Treatment of Non–Life-Threatening Skin and Soft Tissue Infections Other Than Minor Skin Infections Where the Etiology Is Unknown but May Include MRSA as a Possibility

Abbreviation: IDSA = Infectious Diseases Society of  America.

* The IDSA guideline suggests to differentiate purulent and nonpurulent cellulitis and reserve empiric therapy for β-hemolytic streptococci only in nonpurulent cellulitis but acknowledges it is an area of controversy. The U.K. and Canadian guidelines explicitly recommend coverage for β-hemolytic streptococci and do not differentiate cellulitis into different  types.

Table 5

Principles of Empiric Treatment of Life-Threatening Infections Where the Etiology Is Unknown but May Include MRSA as a Possibility

Table 6

Guidelines for the Management of MRSA Infections

 

Abbreviations: ICU = intensive care unit; IVIG = intravenous immunoglobulin; MRSA = methicillin-resistant Staphylococcus aureus; TMP-SMX = trimethoprim- sulfamethoxazole.

1 Not FDA approved for this indication. Dosing has varied in published reports and specific dosing guidelines are not available.

2  Not available in the United States.

3  Exceeds dosage recommended by the  manufacturer.

* Patients with risk factors, as a part of an outbreak investigation, patients with slowly responding or recurrent lesions.

† The IDSA guideline suggests to differentiate purulent and nonpurulent cellulitis and reserve empiric therapy for β-hemolytic streptococci only in nonpurulent cellulitis but acknowledges it is an area of controversy. The U.K. and Canadian guidelines explicitly recommend empiric coverage for β-hemolytic streptococci and do not differentiate cellulitis into different   types.

§  Choice of antimicrobial therapy depends on local susceptibility  patterns.

‡  Not recommended for pediatric patients under 8 years of age or in  pregnancy.

References

1.     Barton-Forbes M., Hawkes M., Moore D., et al. Guidelines for the prevention and management of community associated methicillin resistant Staphylococcus aureus (CA-MRSA): a perspective for Canadian Health Care Practitioners. Can J Infect Dis Med Microbiol. 2006;17(Suppl. C):1B–24B.

2.    Chambers H.F., Deleo F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol. 2009;7:629–641. doi:10.1038/nrmicro2200.

3.     David M.Z., Daum R.S. Community-associated methicillin resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–687. doi:10.1128/CMR.00081-09.

4.    Fluit A.C. Livestock-associated Staphylococcus aureus. Clin Microbiol Infect. 2012;18:735–744. doi:10.1111/j.1469- 0691.2012.03846.x.

5.     Gorwitz R.J., Jernigan D.B., Powers J.H., et al. Strategies for clinical management of MRSA in the community: summary of an experts’ meeting convened by the Centers for Disease Control and Prevention. 2006. 2006. Available at, www.cdc.gov/ncidod/dhqp/pdf/ar/CAMRSA_ExpMtgStrategi (accessed 02.01.13).

6.      Gould F.K., Brindle R., Chadwick P.R., et al. Guidelines (2008) for the prophylaxis and treatment of methicillin resistant Staphylococcus aureus (MRSA) infections in the United Kingdom. J Antimicrob Chemother. 2009;63:849–861. doi:10.1093/jac/dkp065.

7.    Kaplan S.L., Hulten K.G., Gonzalez B.E., et al. Three-year surveillance of community-acquired Staphylococcus aureus infections in children. Clin Infect Dis. 2005;40:1785–1791.

8.    Klevens R.M., Morrison M.A., Nadle J., et al. Invasive methicillin resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763–1771.

9.       Köck R., Becker K., Cookson B., et al. Methicillin resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe. Euro Surveill. 2010;15:19688.

10.       Liu C., Bayer A., Cosgrove S.E., et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin resistant staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52:285–292. doi:10.1093/cid/cir034.

11.    Miller LG, Daum RS, Creech CB, et al. Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections, N Engl J Med 372(12):1093–103, 2015.

12.     Muto C.A., Jernigan J.A., Ostrowsky B.E., et al. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus. Infect Control Hosp Epidemiol. 2003;24:362–386.

13.     Nathwani D., Morgan M., Masterton R.G., et al. Guidelines for UK practice for the diagnosis and management of methicillin resistant Staphylococcus aureus (MRSA) infections presenting in the community. J Antimicrob Chemother. 2008;61:976–994. doi:10.1093/jac/dkn096.

2  Not available in the United  States.

2  Not available in the United  States.

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