Cutaneous community-acquired methicillin-resistant Staphylococcus aureus infection: a personal perspective of a worldwide epidemic

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a problem of epidemic proportions. Cutaneous manifestations of CA-MRSA frequently accompany this infection and most commonly present as either abscesses or cellulitis or both. This editorial describes my personal insights regarding the diagnosis and treatment of CA-MRSA-associated skin lesions and summarizes some of the salient issues concerning CA-MRSA infection.

In the beginning

In January 2002, I accepted a position as the dermatologist at a University Health Center that catered predominantly to undergraduate college students.

In February 2002, a 28-year-old Asian student presented with left plantar heel pain and had no previous history of trauma to the area; he had been hospitalized for surgery to treat a ruptured appendix 6 months earlier. Examination of the left heel showed a small blackish-red and white patch surrounded by ecchymosis and edema, which measured 15 mm in diameter. Pus and blood were released after incision of the central area and he was administered a course of cephalexin. However the pain persisted. The area appeared as a cystic purple-black 18-mm lesion 2 days later. A tangential excision of the blister roof was performed and the antibiotic was changed to levofloxacin. Microscopic examination of the blister roof showed hemorrhage in the stratum corneum; the bacterial culture of the serosanguinous pus that drained from the site subsequently grew MRSA. The patient continued to experience pain and the lesion site continued to drain purulent fluid and he was therefore hospitalized and placed on intravenous vancomycin treatment therapy. Roentgenograms and bone scan results were negative for osteomyelitis. Within 1 week, the patient’s pain had diminished and the area started to heal; the patient was treated with vancomycin for a total of 5 weeks and the infection site resolved completely. In retrospect, this student’s infection represented CA-MRSA presenting as a soft tissue abscess.

The next week, a 22-year-old Black student, who was a member of the University Varsity football team, presented with an acute paronychia and onchocryptosis of his right big toenail. The bacterial culture from his toe subsequently grew not only MRSA but also group-G β-hemolytic Streptococcus. The patient’s toe infection continued to worsen after starting cephalexin; however, it subsequently cleared following 2 weeks of treatment with clindamycin and rifampin.

In the months following this case, more students with MRSA infections presented for evaluation and treatment. In addition to abscesses, cellulitis and acute paronychia, the morphological appearance of the CA-MRSA infections included erythematous papules and nodules, erythematous pustules (folliculitis) and crusted plaques (impetigo). Some of the students attributed their skin lesions to spider bites; none, however, had actually seen the offending spider.

What is happening?

Before starting my position at the University Health Center, I had encountered only a paucity of patients with MRSA infection. During my tenure at the academic university hospital, most of these individuals had been patients on either the burn or the dialysis units who had hospital-acquired MRSA (HA-MRSA) infection. While in private practice, an elderly woman who resided in a nursing home presented with persistant eczematous skin lesions, which appeared to be secondarily impetiginized; a bacterial culture demonstrated MRSA.

While at the University Health Center, I was diagnosing a new student with MRSA infection approximately every other week. Before I began to work at the Health Clinic, I had previously only seen a small number of patients, perhaps less than five, with MRSA infection and they all had MRSA-associated risk factors. The students with cutaneous-MRSA infections that I was currently seeing were otherwise healthy and most of them did not have any risk factors that were associated with MRSA infection.

Is there something I should know?

I felt like I was the protagonist in a Robin Cook medical thriller. Was there a conspiracy? Were the students being innoculated with MRSA as part of an espionage plot to spread this infection throughout the University, the city, the state or the nation? “Of course not,” I told myself. But I still had no idea why I was seeing so many students with MRSA infection.

Perhaps my treatment rooms in the clinic were the source; yet, some of the affected students had also been initially evaluated in other rooms or at other offices. I even wondered if I was a ‘Typhoid Mary’, an asymptomatic carrier of MRSA, without any clinical stigmata of active infection, who was unknowingly spreading the infection. Yet, a few of the patients had also been seen by the other physicians in the clinic. Furthermore, a bacterial culture of my nostrils was negative.

Back to basics

The number of students with cutaneous-MRSA infection continued to increase. I still had no idea why this infection had become so prevalent in my clinic. So, I began to search for answers.

I started to read. A PubMed search generated a list of articles whose titles mentioned a MRSA infection that was ‘community-associated’. Most of the papers had been published in the pediatric literature, either the general journals or those specializing in infectious disease. Interestingly, many of the reports were generated from academic university pediatric centers from certain cities, such as Chicago (IL, USA) [1], Los Angeles (CA, USA) [2] and Houston (TX, USA) [3].

If MRSA was occurring in the community pediatric population of my city (Houston), perhaps it was not unexpected for it to also be occurring in the young adult patients whom I was seeing. But why some cities and not others? Did the reports merely represent transient ‘local outbreaks’ or were these areas ‘endemic zones’ of CA-MRSA infection?

I discovered from my reading that some of the patients infected with CA-MRSA had risk factors similar to those with HA-MRSA. These included prior antibiotic use, hospitalization (with or without admission to the intensive care unit), or surgery – often within the previous year, similar to the student I had seen with the CA-MRSA soft tissue infection of his heel whose appendix had also been removed earlier that year. Other MRSA-associated risk factors include:

•	Individuals who have diabetes mellitus or other chronic illnesses, who are immunosuppressed, use intravenous drugs or have a previous documentation of MRSA;
•	Patients who are undergoing dialysis, on ventillators (via endotrachial or tracheostomy tubes), receiving enteral (via nasogastric or gastrostomy tube) or parenteral feedings or recipients of invasive indwelling devices or chronic Foley catheters;
•	Individuals who are day care attendants, in contact with a healthcare worker or nursing home resident and residents in long-term care facilities.

However, several of the patients with cutaneous CA-MRSA infection did not have MRSA-related risk factors [4–8,101].

I also discovered that the bacterial strain responsible for CA-MRSA is genomically distinct from that which caused HA-MRSA. The methicillin-resistant gene (mecA gene) mediates methicillin resistance in S. aureus by encoding the methicillin-resistant penicillin-binding protein 2a (PBP2a), which is responsible for β-lactam resistance. The staphylococcal cassette chromosome (SCC) is the genetic element that carries the mecA gene. In contrast to HA-MRSA infection, which is associated with SCCmec types I, II and III, CA-MRSA infection has the type IV SCCmec. Since my initial review of the literature, recent studies have also demonstrated at least two type V SCCmec varieties that can also be associated with CA-MRSA infection [1,5,7–10,101].

The presence of associated exotoxins is another important distinction between the CA-MRSA strains and those associated with HA-MRSA infection. The most common toxin associated with CA-MRSA bacterial isolates is the Panton-Valentine leukocidin (PVL) toxin, a staphylococcal leukocidal toxin, which is lethal to neutrophils. Clinically, PVL toxin is important as it is not only associated with severe necrotizing pneumonia but is also a potent dermonecrotic toxin, which accounts for the predilection of CA-MRSA strains to cause skin and soft tissue infections [5,11–13].

Initial revelations

After 7 months at the Health Center, I had diagnosed and treated ten students with cutaneous CA-MRSA. During this period of time, a total of 19 patients with S. aureus skin infection had been seen in my clinic. I was astonished by the 53% prevalence rate of methicillin-resistance.

Razelle Kurzrock and myself described these observations as a ‘Brief Report’ in the February 2004 issue of the Journal of the American Academy of Dermatology[14]. This was the first study describing the pleomorphic cutaneous manifestations of CA-MRSA skin infection that was published in the dermatological literature. The more common clinical CA-MRSA skin lesions: abscess, cellulitis or both (which did not improve after empirical cephalexin therapy), were emphasized and the less frequent morphologies of cutaneous CA-MRSA infection were also noted. Resistance to multiple antibiotics was observed in those patients who had associated MRSA risk factors; however, most of the students were young, healthy and without risk factors for MRSA. Half of the students required surgical intervention (e.g., incision and drainage) of their infectious lesions and all of the students’ CA-MRSA-related skin lesions resolved after definitive systemic antimicrobial treatment, which was based on the in vitro susceptibility studies of the cultured MRSA strain [14].

Importantly, my observations from this initial group of patients modified my approach to the evaluation of individuals with suspected skin infections. During my training in dermatology, it was considered an acceptable management strategy to begin empirical therapy – usually without performing a bacterial culture of the lesion – with a β-lactamase-resistant first-generation cephalosporin (e.g., cephalexin) or a penicillinase-resistant penicillin (e.g., dicloxacillin). Now, a bacterial culture of the cutaneous lesion is performed at the initial visit for all patients with a suspected skin infection. Yet, I still typically prefer to begin empirical systemic-antibiotic treatment with an agent that will adequately treat methicillin-sensitive S. aureus, such as cephalexin, and subsequently change my antimicrobial therapy, if necessary, based on the susceptiblity results of the bacterial culture. More recently, however, there are several investigators who recommend that the initial selection of oral antibiotics for empirical treatment of uncomplicated skin and soft tissue infection be an agent to which most MRSA strains are susceptible (e.g., trimethoprim-sulfamethoxazole, clindamycin or tetracycline) in geographical areas with high rates of outpatient CA-MRSA infections [1,3,5,11,15].

As time goes on

I continued to evaluate and treat students with CA-MRSA skin infections at my clinic. In addition to performing bacterial cultures (obtained with or without incision and drainage of the infectious lesion) and starting systemic antimicrobial therapy, I also wanted to initiate topical interventions to promote lesion resolution and prevent infection recurrence. The protocol I finally developed involved daily baths while receiving oral antibiotics – with special attention to the affected body area – using either a topical antibacterial liquid soap (7.5 or 10.0% povidine-iodine) or detergent (4% chlorhexidine gluconate). After complete resolution of the cutaneous CA-MRSA infection, the frequency of bathing with an antibacterial agent was tapered, initially to three-times weekly (every other day) for 2 weeks and subsequently to twice weekly (every 3 or 4 days) for an additional 2 weeks before stopping the baths with the topical antibacterial agent [16].

I also continued to follow the literature on this subject. I realized that most of the reports, including some of my own, only described either individual patients or the features observed in groups of patients who had presented to tertiary centers [17–20]. They did not focus on the office-based management for individuals with cutaneous CA-MRSA lesions who were presenting to their local physician.

Furthermore, the number of papers published on CA-MRSA was increasing exponentially – not only from multiple cities within the USA but also from several countries throughout the world. CA-MRSA was now a problem of global proportion. In the July 2004 issue of the Journal of the American Academy of Dermatology, a ‘Commentary’ by myself and Marc E Grossman was the first publication in the medical literature describing CA-MRSA skin infections as ‘an emerging epidemic’ [16]; subsequently, several investigators have also recognized that CA-MRSA infection is a worldwide epidemic [21–27]. The Commentary also provided a succinct approach to the evaluation and management of cutaneous lesions associated with CA-MRSA, including the selection of systemic antimicrobial agents and the initiation of topical treatment [16].

An epiphany: another risk group

Each month new observations with regards to the epidemiology of CA-MRSA infections are being noted. For example, several groups of individuals have been identified who appear to be at increased risk of developing CA-MRSA infection [5,16,28]. They included children (including newborns) [29], men who have sex with men [2], military personnel [30], parenteral substance abusers [28], prisoners in correctional facilities [28] and select ethnic populations (e.g., Alaska natives [11], native American Indians [28], Canadian aborigines [28] and Pacific islanders [31]).

Random reports had also been published describing cutaneous CA-MRSA infection in athletes, yet a definitive association had not been established. By June 2004, I had noted that more than 20% of the students with CA-MRSA skin infections had been athletes. Two of the ten individuals originally reported in February 2002 [14] – the football player whose cutaneous CA-MRSA infection presented as an acute paronychia and a 19-year-old White female volleyball player whose CA-MRSA skin lesion appeared as an abscess with surrounding cellulitis on her right thigh – were members of the university varsity teams [16]. A third student whom I subsequently described was a 19-year-old male Black weightlifter with CA-MRSA-associated axillary abscess with cellulitis [32]; furthermore, two additional weightlifters were also seen with axillary CA-MRSA skin lesions and shared use of colonized common equipment (e.g., the bench press in the university recreation center) was suspected as the source of bacterial infection. The other two student athletes included varsity female players on either the basketball team or the volleyball team. In June 2005, the Southern Medical Journal published a paper in which I summarized my observations regarding cutaneous CA-MRSA infection in the seven students who were participants in athletic activities at the university [33].

CA-MRSA skin infections have subsequently been observed in athletes who participate in baseball or softball, basketball, canoeing, fencing, football, rugby, cross country running, soccer, volleyball, weight lifting and wrestling. Cutaneous CA-MRSA infection is more common in those individuals who participated in competitive contact sports and occurs in high school, college and professional athletes. Potential mechanisms for the transmission of CA-MRSA skin infections in sports participants include physical contact, skin damage and sharing of equipment (e.g., the bench press in the weightlifters) or clothing [33,34].

What have I learned?

Since January 2002, my personal journey with regards to the evaluation and treatment of cutaneous CA-MRSA infection has been both emotionally fulfilling and intellectually intriguing. I have been able to provide compassionate care to my patients. Also, I have had the unique opportunity to make clinical observations and to report my findings, some of which have been the first descriptions of these phenomenons in the dermatological or medical literature.

Conclusion: some current concepts

CA-MRSA infection is a global problem of epidemic proportion. It has been described in cities from at least 31 states both within and outside of the continental USA (Box 1)[35]. It has also been reported in at least 34 nations throughout the world (Box 2)[35].

Several groups of individuals appear to be at increased risk of developing CA-MRSA infection. They include athletes, certain ethnic populations, children, homosexual men, intravenous drug abusers, military personnel and prisoners. However, many of the patients who develop cutaneous CA-MRSA lesions do not have infection-associated risk factors.

Cutaneous lesions of CA-MRSA are pleomorphic. The most common presentations of CA-MRSA infectious lesions are abscesses, cellulitis or both; in this setting, it is not uncommon for the patient to misinterpret their CA-MRSA-related lesion as spider or insect bites [2,14,30,36]. Other manifestations of CA-MRSA skin infection are impetigo, folliculitis and acute paronychia.

Surgical intervention (incision and drainage) for abscesses, systemic antibiotic therapy and adjuvant topical antibacterial treatment are the management fundamentals for CA-MRSA skin lesions. In addition, a bacterial culture of the lesion to confirm identification and to determine antimicrobial susceptibility should be performed at the initial visit. If necessary, the patient’s systemic antimicrobial treatment can then be appropriately altered based upon the reported antibiotic sensitivity.

Potential mechanisms for the acquisition and transmission of cutaneous CA-MRSA infection have been identified. They include direct skin-to-skin transmission of MRSA resulting from physical contact, damage to the skin’s surface, which results in nonintact epithelium that facilitates pathogen entry at that location, sharing of personal items (e.g., equipment or clothing) that have not been cleaned or laundered between users and, therefore, provide a vehicle for bacterial transmission and humid environment. Personal measures (e.g., hand washing and improved hygiene), environmental measures (e.g., appropriately cleaning and disinfecting equipment as part of a regularly scheduled routine for athletes), and healthcare measures (e.g., educating potential patients and their families about the presentation of cutaneous CA-MRSA infections and the first-aid measures to be performed on suspected skin wounds) that strive to eliminate the causes of bacterial acquisition and transmission may be useful for preventing the spread of CA-MRSA skin infection [33–35,102].

Summary

CA-MRSA infection is a worldwide epidemic. Cutaneous CA-MRSA lesions frequently accompany this infection. Individuals at an increased risk of developing CA-MRSA infection include athletes, certain ethnic populations, children, homosexual men, intravenous drug abusers, military personnel and prisoners; yet, many of the patients who develop cutaneous CA-MRSA lesions do not have infection-associated risk factors. The cutaneous lesions of CA-MRSA are pleomorphic. Abscess, cellulitis or both are the most common presentations of CA-MRSA infection; in this setting, it is not uncommon for the patient to misinterpret their infectious lesions as spider or insect bites. Impetigo, folliculitis and acute paronychia are other manifestations of CA-MRSA skin infection. The management of CA-MRSA skin infection includes incision and drainage of abscesses, systemic antibiotic therapy and adjuvant topical antibacterial treatment. A bacterial culture of the lesion to confirm identification and determine antimicrobial susceptibility should be preformed at the initial visit. If necessary, the patient’s systemic antimicrobial treatment can then be appropiately altered based upon the reported antibiotic sensitivity. Potential mechanisms for the acquisition and transmission of cutaneous CA-MRSA infection include direct skin-to-skin transmission of MRSA, damage to the skin’s surface, sharing of personal items and a humid environment. Personal, environmental and healthcare measures that strive to eliminate the causes of bacterial acquisition and transmission may be useful for preventing the spread of CA-MRSA infection.

Box 1. States (and cities) in which community–acquired methicilin–resistant Staphylococcus aureus has been reported in the USA.

Continental USA

•	Northcentral states: Illinois (Chicago) Indiana Iowa (Ottumwa) Minnesota (Minneapolis-St. Paul) North Dakota (Fargo) Ohio (Cleveland) Wisconsin (Franklin)

•	Northeastern states: Conneticut (Fairfield and Hartford) Maryland (Baltimore) Massachusetts (Springfield) New Jersey New York (Buffalo) Pennsylvania (Bethlehem, Pittsburg and Williamsport) Rhode Island Vermont Washington DC

•	Southcentral states: Missouri (St. Louis) Texas (Corpus Christi, Dallas, Fort Sam Houston, Houston, Pasadena and San Antonio)

•	Southeastern states: Florida (Miami) Georgia (Atlanta) Kentucky (Louisville) Mississippi South Carolina (Fort Jackson) Virginia (Norfolk and Portsmith) West Virginia

•	Western states: Arizona (Phoenix) California (Los Angeles, Oakland, Palo Alto, San Diego, San Francisco, Stanford and Torrance) Colorado (Denver) New Mexico (Albuquerque)

Noncontinental USA

•

Alaska

•	Hawaii (Honolulu)

Box 2. Nations in which community–acquired methicillin–resistant Staphylococcus aureus has been reported.

Continents

•	Africa – South Africa

•	Asia – China, Hong Kong, India, Israel, Japan, Saudi Arabia, Singapore, Taiwan and Turkey

•	Europe – Austria, Belgium, Finland, Germany, Greece, Italy, The Netherlands, Poland, Portugal, Spain, Switzerland and UK

•	North America – Canada, Mexico and USA

•	Oceania – Australia, New Zealand and Samoa

•	South America – Argentina, Brazil, Chile and Columbia