Samuel Marquez, MD, MA*
Surgical Critical Care Fellow
University of Minnesota
Minneapolis, Minnesota, USA

Greg Beilman, MD**
Professor and Vice Chair of Surgery
Chief of Surgical Critical Care
University of Minnesota Medical Center
Minneapolis, Minnesota, USA

Methicillin-resistant Staphylococcus aureus (MRSA) first emerged as a pathogen in the early 1960s. It has been cultured and isolated in soft tissue infections with increasing frequency within a broad range of healthcare settings. S. aureus gains its resistance via a gene complex known as staphylococcal cassette chromosome mec (SCCmec), which contains the mecA methicillin-resistance gene.

MRSA has continued to evolve within two distinct settings with marked clinical and genetic characteristics. Healthcare associated MRSA (HA-MRSA) first evolved as a pathogen in the 1960s and is common in patients with multiple medical comorbidities and prolonged hospitalization. Risk factors for HA-MRSA infection include immunosuppression, diabetes, and recent or frequent hospitalization. Interestingly, in the late 1990s, a new community-associated MRSA (CA-MRSA) was recognized worldwide. It was first described, and continues to be identified, in individuals without significant typical risk factors for HA-MRSA. Importantly, however, the incidence of CA-MRSA is not distributed uniformly throughout a community. Most patients with confirmed CA-MRSA come from subsets of people with low economic status, individuals in close living conditions, children and young adults, and minority groups. (1,2) Although the distinctions between CA-MRSA and HA-MRSA increasingly overlap, their biologic and genetic distinctions remain unchanged. (2) Between 1998 and 2003, MRSA isolates increased dramatically, with CA-MRSA accounting for a significant amount of the upturn. (1)

There are a number of distinctions that separate HA-MRSA and CA-MRSA. On the level of biologic behavior, CA-MRSA isolates tend to be susceptible to antimicrobial classes other than penicillin. Most CA-MRSA remains susceptible to clindamycin and trimethoprim/sulfamethoxazole. However, reports now show that some CA-MRSA clones are demonstrating resistance patterns toward these antibiotics. A key feature of many of these isolates is an inducible resistance to clindamycin, carried by the erm gene. It is important to be suspicious of this situation, detected with a D-test in the microbiological laboratory. In the D-test, erythromycin and clindamycin disks are dropped on a plate 15 mm apart. MRSA with the erm gene show and, when exposed to erythromycin, develop resistance to clindamycin and demonstrate the characteristic flattening on the erythromycin side of the clindamycin disk (thus the “D” shape).

On the genetic level, notable differences are also present. SCCmec typing, pulsed-field gel electrophoresis (PFGE), and the presence of the toxin Panton-Valentine leukocidin (PVL) are three commonly used methods of classifying and tracking MRSA clones. (3) SCCmec IV accounts for 78% of CA-MRSA cases and SCCmec II accounts for 78% of HAMRSA cases. Community acquired strains are frequently PVL positive (69%), whereas hospital-acquired strains are positive infrequently (4.8%). More than 95% of PVL-positive MRSA are SCCmec IVa. PFGE is used to evaluate the DNA banding pattern of MRSA; the banding pattern type USA300 accounts for nearly all CA-MRSA. (4)

It is hypothesized that it is the PVL toxin that makes CA-MRSA strains pathogenic. The mechanism of how PVL might contribute to or be responsible for the increased virulence of CA-MRSA is still not well elucidated. In nearly all published series of MRSA-associated necrotizing soft tissue infections (NSTI), the species are PVL positive. (5)

Severe and necrotizing soft tissue infections have been lumped together under various names, including gas gangrene, necrotizing fasciitis and many others. Given these variable descriptors, it would seem that these infections would best be described based on the soft tissue layer(s) involved (e.g., skin, adipose tissue, fascia or muscle) and the causative organism. NSTI traditionally is caused by group A Streptococcus, Clostridium perfringens, or a mixture of aerobic and anaerobic organisms (Table 1). The reported mortality for NSTI historically has been in the range of 30% to 80%, with 100% morbidity due to the need for multiple disfiguring procedures.

CA-MRSA as a sole causative agent in NSTI was first described widely in 2005. In a series examining soft tissue infections attributable to CA-MRSA in young military personnel, we described a case of NSTI caused by this organism. (1) Also in 2005, Miller et al described 14 cases of NSTI attributable to CA-MRSA. (6) Of the patients in that series, only five had specimens available for detailed genotype analyses. All were CA-MRSA, carried type IV SCCmec elements, were PVL-positive and had the USA300 DNA banding pattern. No deaths were reported in this group. The most recent series, from the University of Colorado Health Sciences Center, noted that 16.7% of their NSTI cases between 2004 and 2006 were caused by CA-MRSA clones that were USA300- and PVL-positive. (7)

Another interesting feature of NSTI caused by CAMRSA is that up to one-third of cases originally were believed to be spider bites, even in areas where spiders typically associated with necrotic bites, such as the brown recluse spider, are not endemic. Several studies have evaluated brown recluse spiders as a potential carrier of MRSA, with an overwhelmingly negative conclusion. (6-7) It is more likely that the appearance of these two conditions is similar enough that patients, in particular, attribute the lesion to a spider bite. However, such bites typically are necrotic without purulence, allowing the astute clinician to distinguish these lesions.

One of the fundamental tenets of treating NSTI is aggressive and early surgical debridement, with many cases requiring several debridements and multiple procedures to completely eradicate infection. Because outcome is critically related to early debridement, patients with suspected NSTI should be evaluated immediately by a surgeon without significant delay for radiologic evaluation. Diagnosis is typically made in the operating room, usually after finding dishwater edema fluid and discovering the easy separation of fascia from overlying soft tissue. Confirmation of the diagnosis can be made in questionable cases if frozen section evaluation reveals polymorphonuclear leukocytes infiltrating the fascia. Debridement should include all involved fascia, muscle and short tissue, and should be repeated daily until no progression of infection is identified.

Antimicrobial coverage for NSTI historically has not included agents with activity against MRSA, but given the increasing incidence of this specific organism in multiple areas of the world, antimicrobial coverage should be broad and should include agents with activity against MRSA. Initial selection of an antibiotic regimen should include agents with coverage against Gram-negative bacteria, Clostridium species, β-hemolytic Streptococcus species, and MRSA (Table 2). Many authors suggest including agents that inhibit protein synthesis (e.g., clindamycin, daptomycin or linezolid). Antimicrobial coverage should be tailored appropriately when culture results become available.

Many hospitals are isolating CA-MRSA patients, blurring the line of distinction between CA-MRSA and HAMRSA. Despite their outlined differences, the treatment algorithm currently does not differ between these two distinct types of organisms. This may change if new agents are developed with the ability to inhibit PVL toxin activity.

In summary, CA-MRSA is an increasingly common causative organism in NSTI. Agents selected for initial empiric treatment should include those with activity against MRSA. Population susceptibility and genetic and biologic response profiles of CA MRSA differ from those of HA-MRSA and should be noted; however, the clinical management is identical. Early and repeated surgical debridement with cultures for source control, as well as early and appropriate antimicrobial coverage, remain mandatory components for the management of these tissue infections.


References

1. Beilman GJ, et al. Emerging infections with community-associated methicillin-resistant Styphylococcus aureus in outpatients at an Army Community Hospital. Surg Infect.  2005;6:87-92.

2. Gorwitz RJ, Jernigan DB, Powers JH, Jernigan JA, and Participants in the Centers for Disease Control and Prevention Convened Experts’ Meeting on Management of MRSA in the Community. Strategies for clinical management of MRSA in the community: Summary of an experts’ meeting convened by the Centers for Disease Control and Prevention. 2006. http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca.html. Accessed January 30, 2009.

3. Deurenberg RH, et al. The evolution of Staphylococcus aureus. Infect Genetic Evolution. 2008;8:747-763.

4. Houssein J, et al. Staphylococcus aureus skin/soft tissue infection: the impact of SCCmec Type & PV. Scand J Infect Dis. 2008;40:601-606.

5. Diep BA, et al. Contribution of Panton-Valentine leukocidin in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. PLoS ONE 2008;3(9):e3198. 

6. Miller LG, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-1453.

7. Young LM, et al.  Community-acquired methicillin-resistant Staphylococcus aureus emerging as an important cause of necrotizing fasciitis. Surg Infect. 2008;9:469-474.

Bibliography

Salgado C, et al. Community-acquired methicillin-resistant Staphylococcus aureus: a meta-analysis of prevalence and risk factors. Clin Infect Dis. 2003;36:131-139.

Eady EA, et al. Staphylococcal resistance revisited. Curr Opin Infect Dis. 2003;16(2):103-124.

Jung SI, et al. Antimicrobial susceptibility and clonal relatedness between community and hospital-acquired methicillin-resistant Staphylococcus aureus from blood cultures. J Microbiol. 2006;44:336-343.

Patel M, et al. Prevalence of inducible clindamycin resistance among community and hospital-associated Staphylococcus aureus isolates. J Clin Microbiol. 2006;44:2481-2484.

Disclosures

*Author has no disclosures to report

**Author has no disclosures to report