Since its discovery in the 1960s, methicillinresistant

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1 CME Community-Acquired Methicillin-Resistant Staphylococcus aureus: Diagnosis and Treatment Update for Plastic Surgeons D. Heath Stacey, M.D. Barry C. Fox, M.D. Samuel O. Poore, M.D., Ph.D. Michael L. Bentz, M.D. Karol A. Gutowski, M.D. Madison, Wis. Learning Objectives: After studying this article, the participant should be able to: 1. Identify risk factors associated with community-acquired methicillin-resistant Staphylococcus aureus. 2. Recognize the clinical presentation of patients with. 3. Understand the treatment and indications for decolonization of patients who have communityacquired methicillin-resistant S. aureus infections. Summary: Community-acquired methicillin-resistant Staphylococcus aureus has evolved over the past 10 years as a new health threat seen by plastic surgeons and is an increasing cause of soft-tissue infections. This pathogen has several distinct virulence factors and unique antimicrobial susceptibilities that distinguish methicillin-resistant S. aureus from traditional hospital-acquired methicillin-resistant S. aureus. This article reviews the epidemiology, risk factors, clinical presentation, and treatment of. (Plast. Reconstr. Surg. 122: 120e, 2008.) Since its discovery in the 1960s, methicillinresistant Staphylococcus aureus has traditionally been considered a hospital-acquired bacterium that caused severe infections. It is now found in nearly every hospital worldwide. Hospital-acquired methicillin-resistant S. aureus is resistant to penicillin, oxacillin, and methicillin, and nearly always requires treatment with intravenous vancomycin or other newer antibiotics such as linezolid and quinupristin-dalfopristin. Patients with hospital-acquired methicillin-resistant S. aureus infections typically have multiple risk factors and comorbidities, with mortality rates ranging from 20 to 25 percent. 1 The National Nosocomial Infection Surveillance survey reports that 61 percent of all S. aureus in the health care setting is multidrug-resistant. Furthermore, intensive care units From the Divisions of Plastic Surgery and Infectious Disease, University of Wisconsin. Received for publication December 6, 2006; accepted January 12, Online at Plast. Reconstr. Surg. 122: 120e, A passing score on this CME confers 0.5 hours of Patient Safety Credit. The American Society of Plastic Surgeons designates this educational activity for a maximum of one (1) AMA PRA Category 1 credit TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Copyright 2008 by the American Society of Plastic Surgeons DOI: /PRS.0b013e d3f are experiencing an increasing percentage of infections caused by methicillin-resistant S. aureus. 1 Over the past 7 years, a new clinical presentation has developed characterized by patients in the community with no risk factors and no hospital contact presenting with methicillin-resistant S. aureus infections. This new entity, community-acquired methicillin-resistant S. aureus, usually manifests as soft-tissue infections including furuncles, carbuncles, boils, abscesses, cellulitis, or, rarely, necrotizing fasciitis. It is important for plastic surgeons to be able to suspect and recognize this condition and choose the right course of therapy. These isolates of community-acquired methicillin-resistant S. aureus have unique genetic components with novel toxins, and often are surprisingly susceptible to antibiotics that can be given on an outpatient basis. CASE REPORTS Case 1 A 35-year-old woman presented to the plastic surgery service with a 4-day history of pain, swelling, erythema, and purulent drainage on the dorsum of her left long finger (Fig. 1). She reported five instances over several years of infected furuncles Disclosure: The authors have no financial disclosures to report. 120e

2 Volume 122, Number 4 Methicillin-Resistant S. aureus Fig. 1. Case 1. A 35-year-old woman presented with a communityacquired methicillin-resistant S. aureus soft-tissue infection of the left long finger. of the hand. Her boyfriend, who works in pest control, had experienced similar finger infections that were thought to be spider bites. The lesion was unresponsive to outpatient therapy with oral cephalexin and she was admitted to the hospital for intravenous ampicillin-sulbactam and two local drainage procedures. Her initial cultures demonstrated community-acquired methicillin-resistant S. aureus susceptible to clindamycin, gentamicin, rifampin, trimethoprim/sulfamethoxazole, and vancomycin. The patient was switched to intravenous vancomycin and oral clindamycin. She was taken to the operating room and was found to have a subcutaneous abscess with surrounding necrotic tissue requiring drainage and debridement. The process was limited to the subcutaneous space without involvement of tendon, extensor sheath, bone, or joint. She was discharged from the hospital on postoperative day 3, completed a 7-day course of intravenous vancomycin and a 10-day course of oral clindamycin, and performed warm soaks every 4 hours for 3 days. At her follow-up 10 days after discharge, the inflammation and pain had resolved. Case 2 A 13-month-old girl presented to the pediatric plastic surgery service for excision of a tumor of the right great toe and fullthickness skin grafting. She was discharged to home on postoperative day 1 in good condition. Her postoperative course was uncomplicated and she returned to daycare shortly after discharge. On postoperative day 21, her mother noted erythema and exudate near the skin-graft site. Cultures of the wound bed grew, susceptible to clindamycin, trimethoprim/sulfamethoxazole, rifampin, and vancomycin. After starting rifampin, the patient s mother notified the daycare institution and was told that another child was on rifampin, raising the possibility that this was acquired at daycare. The patient was treated with a 14-day course of rifampin and clindamycin and had resolution of the inflammatory sinus with complete graft healing and salvage. Case 3 A 21-year-old man was involved in a work-related accident with blunt trauma to his left index finger and spilling of an industrial solvent on his hand. On the day of the injury, his hand was irrigated thoroughly in the emergency department and oral amoxicillin-clavulanate was started. The patient followed up with the plastic surgery service 5 days later with significant pain, swelling, erythema, and discharge from two open wounds involving the left index and middle fingers (Fig. 2). Plain films of the hand demonstrated no evidence of foreign body or bony destruction. On the day of admission, his hand was thoroughly irrigated and debrided of necrotic tissue and fat. The infection was primarily superficial, with no involvement of tendon, bone, or joint. Wound cultures grew community-acquired methicillin-resistant S. aureus that was susceptible to rifampin, trimethoprim/sulfamethoxazole, clindamycin, and vancomycin. Intravenous clindamycin and rifampin were begun and he was discharged to home on a 14-day course of oral rifampin and clindamycin. Two weeks later, he presented for follow-up and was nearly healed. He had no tenderness, erythema, drainage, or discharge and had returned to work with no restrictions 2 days earlier. DEFINITION AND GENETICS When community-acquired methicillin-resistant S. aureus initially appeared, it was thought that these strains were hospital-acquired methicillin-resistant S. aureus strains that reached the community. Community-acquired methicillin-resistant S. aureus was first differentiated from hospital-acquired methicillin-resistant S. aureus by classifying communityacquired methicillin-resistant S. aureus infections as ones in which cultures became positive for methicillin-resistant S. aureus within 24 to 72 hours of hospitalization. 2 Later studies found that true community-acquired methicillin-resistant S. aureus had unique virulence factors and antimicrobial suscep- Fig. 2. Case 3. A 21-year-old man presented with a communityacquired methicillin-resistant S. aureus infection of the left index and middle fingers. 121e

3 Plastic and Reconstructive Surgery October 2008 tibilities. Table 1 summarizes the differences between hospital- and community-acquired methicillin-resistant S. aureus. 3 Methicillin-resistant S. aureus has a mutated penicillin-binding protein 2a coded on a gene called meca that gives it resistance to methicillin and all -lactam antibiotics. All methicillin-resistant S. aureus isolates contain the mobile chromosomal staphylococcal cassette cartridge (SCCmec), which houses the meca gene. There are five types of SCCmec. Hospital-acquired methicillin-resistant S. aureus strains contain SCCmec types I, II, III, and V 4, and community-acquired methicillin-resistant S. aureus strains contain a smaller version of SCCmec type IV. 5 The smaller size of the SCCmec type IV is responsible for the wider susceptibility of the community-acquired methicillin-resistant S. aureus to antimicrobials, as it does not carry the genes for other drug resistance. This genetic package gives resistance always to methicillin and almost always to erythromycin, in addition to other drugs that may be used to treat an infection. 6 There are many heterogeneous strains of community-acquired methicillin-resistant S. aureus because of the easy horizontal genetic transfer of the small SCCmec type IV. This stands in stark comparison to the handful of strains of hospital-acquired methicillin-resistant S. aureus. The increase in over the past several years is likely attributable to the many community-based strains of methicillin-sensitive S. aureus acquiring the SCCmec type IV gene. 4 Other authors also note that SCCmec type Table 1. Comparison of Hospital- and Community-Acquired Methicillin-Resistant S. aureus* HA-MRSA CA-MRSA Health care contact Yes No Mean age at infection Older Younger Skin and soft-tissue infection 25% 75% Antibiotic resistance Many agents Some agents Resistance gene SCCmec types I, II, III, V SCCmec type IV Strain type USA 100 and 200 USA 300 and 400 PVL toxin gene Rare (5%) Almost 100% HA-MRSA, hospital-acquired methicillin-resistant S. aureus; CA- MRSA, ; PVL, Panton-Valentine leukocidin. *Data from Borlaug, G., Davis, J. P., and Fox, B. C. Community associated methicillin-resistant Staphylococcus aureus: Guidelines for clinicalmanagementandcontroloftransmission. Availableat: dhfs.wisconsin.gov/communicable/pdf_files/camrsaguide_1105. pdf. Madison, Wisconsin: Wisconsin Division of Public Health, IV may have originated from Staphylococcus epidermidis species. 7 Of clinical importance is that almost 100 percent of community-acquired methicillin-resistant S. aureus strains contain the Panton-Valentine leukocidin (PVL) gene allowing for production of a necrotizing, cell membrane pore-forming cytotoxin that targets leukocytes and erythrocytes Panton-Valentine leukocidin is responsible for the localized invasiveness in community-acquired methicillin-resistant S. aureus soft-tissue infections. In contrast, only 5 percent of methicillin-sensitive S. aureus and hospital-acquired methicillin-resistant S. aureus isolates contain the PVL gene. EPIDEMIOLOGY When community-acquired methicillin-resistant S. aureus is responsible for clinically relevant soft-tissue infections, 25 percent of cases require hospitalization. 6 The estimated annual incidence from a prospective population based study was 18 to 26 cases per 100,000 persons. 6 Other studies found that up to 20 percent of methicillin-resistant S. aureus isolates are not associated with traditional risk factors and are considered community acquired (Table 2). 3 There may be a higher incidence of communityacquired methicillin-resistant S. aureus among cer- Table 2. Risk Factors Associated with Community-Acquired Methicillin-Resistant S. aureus* The following risk factors should increase suspicion for CA-MRSA in patients presenting with compatible signs and symptoms: History of methicillin-resistant S. aureus infection or colonization in patient or close contact High prevalence of CA-MRSA in local community or patient population Recurrent skin disease Crowded living conditions (e.g., homeless shelters, military barracks) History of incarceration Participation in contact sports Skin or soft-tissue infection with poor response to -lactam antibiotics Recent and/or frequent antibiotic use Injection drug use Member of Native American, Pacific Island, Alaskan Native populations Child younger than 2 years old Male with history of having sex with men Shaving of body hair CA-MRSA,. *Data from Borlaug, G., Davis, J. P., and Fox, B. C. Community associated methicillin-resistant Staphylococcus aureus: Guidelines for clinicalmanagementandcontroloftransmission. Availableat: dhfs.wisconsin.gov/communicable/pdf_files/camrsaguide_1105. pdf. Madison, Wisconsin: Wisconsin Division of Public Health, See text for details. 122e

4 Volume 122, Number 4 Methicillin-Resistant S. aureus tain ethnic populations, including Pacific Islanders, African Americans, and Alaskan Natives. 6,11,12 Diabetes and human immunodeficiency virus are also associated with higher rates of infection. 6 Children younger than 2 years have an increased incidence of causing skin and soft-tissue infections, up to 70 percent in some studies. 13 Four deaths reported in children that were caused by community-acquired methicillin-resistant S. aureus infections were the original sentinel cases for community-acquired methicillin-resistant S. aureus. 14 Other groups at risk include prisoners, military recruits, men who have sex with men, victims of unsterile tattooing practices, and intravenous drug abusers. 12,15,16 Carter et al. 17 reported 11 cases of communityacquired methicillin-resistant S. aureus facial abscesses and, surprisingly, eight of the 11 abscesses were resistant to clindamycin. Karanas et al. 18 reported four cases of hand infections caused by in patients with no risk factors. Communityacquired methicillin-resistant S. aureus has also been reported in a felon, demonstrating the importance of sending all pus for culture to ensure appropriate antibiotic coverage. 19 A professional football team had 9 percent of its players infected with a single strain of community-acquired methicillin-resistant S. aureus. 20 These football players were receiving 10 times the number of antimicrobial prescriptions dispensed to the general public, suggesting that prolonged antibiotic use might be a risk factor. Community-acquired methicillin-resistant S. aureus is likely underreported because many skin infections are not cultured. The prevalence of colonization with S. aureus and with methicillin-resistant S. aureus is 32 percent and 0.8 percent, respectively, in noninstitutionalized persons in the U.S. population. 21 The prevalence of communityacquired methicillin-resistant S. aureus colonization in the general population is approximately 1 to 1.3 percent 2,21 and may account for 5 percent of all hospitalized patients with methicillin-resistant S. aureus. 2 Persons older than 65 years, women, diabetics, and persons who have been in a longterm health care facility in the past year are more likely to be colonized with methicillin-resistant S. aureus. 21 Transmission occurs by person-to-person contact and by indirect contact with inanimate objects. Community-acquired methicillin-resistant S. aureus infections have occurred among postpartum women and in orthopedic patients, 22,23 and caused a necrotizing pneumonia in an otherwise healthy adult. 24 Recent nasal acquisition of community-acquired methicillin-resistant S. aureus has been associated with an up to 10 times increased risk of developing a skin or soft-tissue infection. 25,26 Persons previously colonized with S. aureus may have a lower relative risk of developing an infection, suggesting that immunity may be induced by colonization in some individuals. 26 CLINICAL FINDINGS AND DIAGNOSIS Whereas hospital-acquired methicillin-resistant S. aureus is often associated with severe systemic infections, community-acquired methicillin-resistant S. aureus presents as a skin and soft-tissue infection 75 percent of the time. 28 This may manifest as furuncles, carbuncles, boils, abscesses, or occasionally necrotizing fasciitis. 8,27 Skin lesions often are described as appearing initially like spider bites before progressing further (Fig. 1). Spread of infection is usually restricted to tissue planes and does not lead to a deeper infection. In addition, preexisting wounds may become infected with community-acquired methicillin-resistant S. aureus. In our practice, we have seen an increasing number of soft-tissue infections and hand infections caused by community-acquired methicillin-resistant S. aureus. Progression of wound infection to sepsis and shock is rare. TREATMENT At our institution, we follow recommendations published by the Centers for Disease Control and Prevention 1 in 2006 and similar recommendations suggested by the Wisconsin Division of Public Health when treating community-acquired methicillin-resistant S. aureus 3 (Fig. 3). Abscesses should be incised and drained with material sent for aerobic culture. Abscess drainage alone suffices in patients with a soft-tissue abscess less than 5 cm in diameter and who are not systemically ill. 29 There is no benefit in using antibiotics for cutaneous abscesses if adequate drainage is performed 30 ; however, this does not apply to patients with cellulitis. In a patient with comorbidities, moderate illness, or a soft-tissue infection larger than 5 cm in diameter, antibiotic therapy should be started after incision and drainage. If community-acquired methicillin-resistant S. aureus is suspected but there is not a definite abscess, antibiotic treatment should be started. If this course is chosen, the patient should follow up 48 to 72 hours after treatment has begun, as the aggressiveness of the com- 123e

5 Fig. 3. Treatment algorithm for. SSTI, skin and soft-tissue infection. (From Borlaug, G., Davis, J. P., and Fox, B. C. Community associated methicillin-resistant Staphylococcus aureus: Guidelines for clinical management and control of transmission. Available at: CAMRSAGuide_1105.pdf. Madison, Wis.: Wisconsin Division of Public Health, Reprinted with permission from the Wisconsin Division of Public Health.) 124e

6 Volume 122, Number 4 Methicillin-Resistant S. aureus munity-acquired methicillin-resistant S. aureus may lead to development of an abscess. If material has not been sent for culture and antibiotics are to be started, an assessment of risk factors and local prevalence of community-acquired methicillin-resistant S. aureus should be considered. Risk factors associated with community-acquired methicillin-resistant S. aureus should be sought for in the history. If any of these risk factors are present (Table 2), the clinician should begin an antibiotic that favors treatment of community-acquired methicillin-resistant S. aureus rather than methicillin-sensitive S. aureus. Some authors recommend treatment coverage for methicillin-resistant S. aureus when the local prevalence rate is greater than 15 percent. 13 In urban populations, up to 50 percent of abscesses treated in the emergency room may be attributable to. 12 One recent prospective study found that 65 percent of patients with soft-tissue infections that were cultured and eventually grew community-acquired methicillin-resistant S. aureus were initially given an antibiotic not active against methicillin-resistant S. aureus (usually a -lactam). 11 Because there is no multidrug resistance in strains, several antibiotic options are available for treatment (Table 3). Trimethoprim/sulfamethoxazole double strength and doxycycline are reasonable choices for initial empiric antibiotic therapy. Ninety to 95 percent of community-acquired methicillin-resistant S. aureus strains are susceptible to trimethoprim/sulfamethoxazole double strength and doxycycline, but these agents are not active against group A Streptococcus species, which are a common cause of cellulitis (especially in children) and erysipelas. Clindamycin has a susceptibility rate of 70 to 80 percent in community-acquired methicillin-resistant S. aureus strains and is broadly effective against Gram-positive organisms. It can be given initially intravenous and switched to an oral regimen without a change in bioavailability. Up to 33 percent of community-acquired methicillin-resistant S. aureus isolates may be resistant to clindamycin in some populations 31 ; therefore, if the local prevalence of clindamycin resistance is greater than 10 to 15 percent, clindamycin generally should not be used for empiric therapy of staphylococcal infections in adults. However, because clindamycin is active against both community-acquired methicillin-resistant S. aureus and group A streptococcus, it is frequently the best first choice of therapy in pediatric patients. 29 Laboratories routinely test S. aureus strains for resistance to clindamycin, doxycycline, macrolides, trimethoprim/sulfamethoxazole, gentamicin, and -lactams. Many strains are resistant to macrolides but appear to be sensitive to clindamycin. The typical automated susceptibility tests run by the standard laboratory will not ferret out these strains with inducible clindamycin resistance. The laboratory must test for the inducible macrolide-lincosamide-streptogramin phenotype (MLS B ) by performing a double-disk diffusion test (D-test), which takes the laboratory an additional 24 hours to complete. D-test positive strains are clindamycin resistant. Table 3. Recommended Antimicrobial Agents for CA-MRSA Skin and Soft-Tissue Infections* Antimicrobial Agent TMP-SMX DS (160 mg/800 mg) Percentage of CA-MRSA Strains Susceptible Dosage (Adult) Notes DS tab every 8 12 hr May need to add -lactam if suspect group A Streptococcus infection Doxycycline mg load, then 100-mg tab every 12 hr May need to add -lactam if suspect group A Streptococcus infection Clindamycin mg tab every 6 hr Indicated only if negative D test, or isolate sensitive also to erythromycin; covers most Gram-positive organisms CA-MRSA, community-associated methicillin-resistant S. aureus; TMP-SMX, trimethoprim/sulfamethoxazole; DS, double strength. *Data from Borlaug, G., Davis, J. P., and Fox, B. C. Community associated methicillin-resistant Staphylococcus aureus: Guidelines for clinical management and control of transmission. Available at: Madison, Wis.: Wisconsin Division of Public Health, 2005; Fridkin, S. K., Hageman, J. C., Morrison, M., et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N. Engl. J. Med. 352: 1436, 2005; and Naimi, T. S., LeDell, K. H., Como-Sabetti, K., et al. Comparison of communityand health care-associated methicillin-resistant Staphylococcus aureus infection. J.A.M.A. 290: 2976, Duration of therapy, 7 to 14 days. Should be accompanied by incision and drainage if is abscess present. Use weight-adjusted dosing guidelines for pediatric patients. Higher doses may be considered in obese patients. 125e

7 Plastic and Reconstructive Surgery October 2008 In patients with severe soft-tissue infections who require hospitalization, intravenous antibiotic therapy should be chosen. Vancomycin or one of the newer antistaphylococcal antibiotics (linezolid, quinupristin-dalfopristin, tigecycline, and daptomycin) should be used while awaiting culture results. Linezolid is available as an oral formulation, which is helpful transitioning to outpatient treatment. A recent report highlights the importance of considering community-acquired methicillin-resistant S. aureus as a monomicrobial cause of necrotizing fasciitis. 8 This is a relatively new entity, as typically necrotizing fasciitis is caused by multiple microbial organisms. In a series of 14 patients with infections, 86 percent grew methicillin-resistant S. aureus strains positive for the SCCmec type IV and PVL genes. All were susceptible to clindamycin, trimethoprim/sulfamethoxazole, and rifampin. None of the patients died and the necrotizing fasciitis presented as a subacute illness, developing over several days, suggesting that community-acquired methicillin-resistant S. aureus is a less virulent cause of necrotizing fasciitis. DECOLONIZATION FOR METHICILLIN-RESISTANT S. AUREUS Colonization of S. aureus occurs mainly in the anterior nares. Health care workers are thought to be the main reservoir of methicillin-resistant S. aureus, and transmission occurs through hand contact. Host colonization with methicillin-resistant S. aureus results in a 10-fold increased risk of infection when compared with colonization with methicillin-sensitive S. aureus. 26,32,33 Topical mupirocin in the nares has been shown to eradicate methicillinresistant S. aureus colonization in health care workers and patients for a short time. 34 This effect may be lost over time as individuals become recolonized, and prolonged use of mupirocin has been associated with resistance. In community-acquired methicillin-resistant S. aureus, there is minimal evidence at this time to support decolonization protocols in the community. Possible candidates for treatment with topical intranasal mupirocin include patients with recurrent methicillin-resistant S. aureus soft-tissue infections or high-risk contacts of patients with methicillin-resistant S. aureus softtissue infections. 35 Table 4 reviews some of the measures that can be taken to control and prevent the spread of community-acquired methicillin-resistant S. aureus. Table 4. Measures to Prevent CA-MRSA Infections* Personal hygiene Shower daily Wash hands frequently Keep wounds covered Avoid contact with wound drainage Environmental control Clean shared equipment (e.g., athletic equipment) Clean contaminated surfaces Use a barrier to bare skin when in contact with shared equipment Health care associated control Use antimicrobials judiciously Diagnose and treat methicillin-resistant S. aureus lesions early Educate patients about wound care Consider decolonization Consult with an infectious disease specialist when appropriate CA-MRSA,. *Data from Kowalski, T. J., Berbari, E. F., and Osmon, D. R. Epidemiology, treatment, and prevention of community-acquired methicillin-resistant Staphylococcus aureus infections. Mayo Clin. Proc. 80: 1201, CONCLUSIONS Community-acquired methicillin-resistant S. aureus is an emerging source of soft-tissue infections with associated morbidity affecting plastic surgery patients. Community-acquired methicillin-resistant S. aureus strains usually produce the Panton-Valentine leukocidin toxin and cause significant damage to soft tissues, leading to abscesses, highlighting the importance of sending material for culture and susceptibility. Appropriate treatment should not be delayed if communityacquired methicillin-resistant S. aureus is suspected as the source based on patient risk factors and the clinical picture. Once cultures have been sent, empiric treatment should be started. Most patients may be treated on an outpatient basis because the majority of infections are usually localized and respond rapidly to treatment. The clinician should have a high index of suspicion to correctly diagnose and treat these infections. The nationwide epidemic of community-acquired methicillin-resistant S. aureus is likely to increase in prevalence. D. Heath Stacey, M.D. Division of Plastic Surgery University of Wisconsin 3334 Bradbury Road Madison, Wis dheathstacey@gmail.com REFERENCES 1. Centers for Disease Control. Healthcare-associated methicillin resistant Staphylococcus aureus (MRSA). Available at: Accessed e

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Proc. 80: 1201, e