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Painful nodule with induration and spreading erythema.

A young woman presented with a 2-day history of a 2- to 3-cm erythematous painful papule on her right flank, which she thought was a spider bite. Initially, the lesion was a nodule that was warm, tender, and fluctuant on palpation. Clinically the lesion was most consistent with an abscess, spider bite, or inflamed cyst. The lesion was incised, drained, and cultured. Empiric therapy with cephalexin was started. Within 24 hours, the patient presented to the dermatology clinic with a low-grade fever (38.3[degrees]C, 101[degrees]F), and the lesion had become more tender. The erythema had spread to 20 cm, and the central induration had spread to 9 cm (Figure).

What is the most likely diagnosis? What is the most appropriate therapy at this point?

DIAGNOSIS: Methicillin-resistant Staphylococcus aureus (MRSA).


Staphylococcus aureus is responsible for the majority of skin and soft tissue infections (1). When the patient presented with evidence of extension of infection (<24 hours on cephalexin), empiric therapy with levofloxacin and linezolid was instituted. The patient was no longer febrile after 12 hours on the new regimen, and the culture and sensitivity testing confirmed MRSA sensitive to levofloxacin, tetracycline, and trimethoprim-sulfamethoxazole.

Since the inception of penicillin therapy, S. aureus has been adapting to maintain its stature as a cutaneous pathogen (Table 1). Researchers in an urban California emergency department screened 137 adults who presented with localized cutaneous infections (i.e., cellulitis, furunculosis, or wound infections) and found that 79 had staphylococcal infections. Sixty-one (77%) of those infections were methicillin resistant (5). Currently, there is a worldwide epidemic of MRSA infections. Historically, MRSA was a hospital-acquired pathogen (HA-MRSA) with subsequent "spillover" into the community (6). However, it is now apparent that the community-acquired pathogen (CA-MRSA) is a distinctive entity (7).

Virulence of MRSA

The virulence of MRSA is dictated primarily by antibiotic resistance genes and toxin production (Table 2). Some of the mechanisms of antibiotic resistance are known on a molecular level. The staphylococcal antibiotic resistance genes are found on a genomic island termed the staphylococcal cassette chromosome (SCC) (9-11). The antibiotic resistance genes have been categorized as SCCmec types I through V based on their antibiotic specificity. SCCmec types I, IV, and V are involved in beta-lactam (methicillin) resistance and primarily code for the regulatory, structural, and recombinase genes required (1, 12). SCCmec types II and III code for genes involved in non-betalactam antibiotics (trimethoprim-sulfamethoxazole, clindamycin, and tetracycline) (10-13).

Interestingly, HA-MRSA contains distinct SCCmec types, plasmids encoding resistance to various antibiotics, as well as heavy metal resistance elements (7). HA-MRSA characteristically lacks the toxin genes frequently associated with CA-MRSA. Increased virulence in CA-MRSA has been attributed to the presence of staphylococcal enterotoxins B and C, toxic shock syndrome toxin-1 (TSST-1) and, most importantly, Panton-Valentine leukocidin (PVL) (Table 3). TSST-1 and the enterotoxins are "superantigens" that activate T cells expressing major histocompatibility complex class II molecules via the variable portion of the beta chain of the T-cell receptor. CA-MRSA cutaneous infections associated with abscess formation and tissue necrosis are increasingly associated with the presence of PVL (17, 18).


Bacterial culture and sensitivity testing is required for diagnosis and appropriate therapeutic intervention for cutaneous staphylococcal infections. Clues to the diagnosis of cutaneous CA-MRSA include personal contacts with CA-MRSA (day care centers [19], assisted-living homes, college dormitories), colonization with MRSA, and a history of incarceration (20). Intriguing new data suggest that receipt of conjugate pneumococcal vaccine may induce a shift in nasal flora towards S. aureus colonization, including MRSA, with a risk of invasive infections (21). Risk factors for CA-MRSA necrotizing fasciitis include injection drug use, previous MRSA infection, diabetes, hepatitis C, malignancy, and HIV infection (22).


Appropriate therapy for S. aureus infections varies with the age of the patient and should be dictated by local culture and sensitivity data. Cultures are imperative for adequate therapy--the days of empiric first-generation cephalosporin antibiotics for presumed staphylococcal infections are over in many major geographic areas. For cutaneous and soft tissue CA-MRSA infections, surgical incision and drainage are critical (23, 24). Recently, investigators at Children's Medical Center in Dallas, Texas, determined that for pediatric patients with CA-MRSA abscesses <5 cm in diameter, incision and drainage constituted effective therapy even when patients received antibiotics to which the isolate was not susceptible (25).

Outpatient staphylococcal infections of the skin can be treated with a variety of agents. Recently, MRSA infections reported by sentinel hospitals and reference laboratories in three US cities from 2001 through 2002 were categorized by researchers at the Centers for Disease Control and Prevention (26). CA-MRSA accounted for 8% to 20% of the total; >75% of these infections involved skin or soft tissue. Of CA-MRSA isolates, 97% were sensitive to trimethoprim-sulfamethoxazole, 87% to clindamycin, 88% to tetracycline, and 65% to cipro-floxacin (26). Trimethoprim-sulfamethoxazole is one of the most common antibiotics utilized for outpatient MRSA infections; however, resistance has been noted in up to 29.5% of CA-MRSA isolates in parts of Europe (27, 28). In the pediatric population, clindamycin is commonly used; however, the incidence of inducible resistance may be 20% or higher, especially when it is used as monotherapy (29). CA-MRSA appears to be most susceptible in vitro to minocycline as compared with doxycycline (30). Finally, the "respiratory" fluoroquinolones such as levofloxacin, gatifloxacin, and moxifloxacin have been successfully used for CA-MRSA (1). Ciprofloxacin use should be avoided in CA-MRSA because of its inferior activity against gram-positive bacteria and the propensity for rapid development of resistance (31).

In general, vancomycin is the drug of choice for moderate to severe methicillin-resistant staphylococcal infections (3). Historically, in methicillin-sensitive staphylococcal infections, however, the beta-lactam antibiotics are associated with faster clinical responses as well as more rapid clearing of bacteremia when compared with vancomycin (32). In keeping with history, vancomycin-resistant MRSA has been documented, especially in MRSA-colonized patients with prolonged exposure to vancomycin and indwelling devices ("hardware" infections) (33). For such patients, linezolid is indicated for the treatment of adults and children with MRSA and vancomycin-resistant enterococcal infections involving skin, soft tissue, or lungs. Unlike vancomycin, linezolid is 100% bioavailable, allowing for easy oral dosing (34).


Since colonization with CA-MRSA is a risk factor for the development of invasive disease (35), patients must be evaluated and treated for this as well. While CA-MRSA may reside in the nose, axilla, groin, and navel, eradication of nasal colonization is key to successful decolonization (36). One local protocol for decolonization includes topical mupirocin to the nares twice daily; chlorhexidine body scrubs daily; and trimethoprim-sulfamethoxazole (double strength) twice daily for 5 days. Additionally, since direct contact is the primary mode of transmission for staphylococcal infections, alcohol-based hand sanitizers may be helpful, as they have been shown to decrease colonization and transmission of pathogens within the household setting (37).


This report is dedicated to the founder of BUMC Proceedings, George J. Race, MD, PhD, who has provided inspiration and motivation to generations of physicians at Baylor University Medical Center, Dallas, Texas.

(1.) Deresinski S. Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis 2005;40:562-573.

(2.) Rammelkamp CH, Maxon T. Resistance of Staphylococcus aureus to the action of penicillin. Proc Soc Exp Biol Med 1942;51:386-389.

(3.) Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001;7:178-182.

(4.) Hartman B, Tomasz A. Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus. Antimicrob Agents Chemother 1981;19: 726-735.

(5.) Frazee BW, Lynn J, Charlebois ED, Lambert L, Lowery D, Perdreau-Remington F. High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg Med 2005;45: 311-320.

(6.) Tacconelli E, Venkataraman L, De Girolami PC, D'Agata EM. Methicillin-resistant Staphylococcus aureus bacteraemia diagnosed at hospital admission: distinguishing between community-acquired versus healthcare-associated strains. J Antimicrob Chemother 2004;53:474-479.

(7.) Aires de Sousa M, de Lencastre H. Evolution of sporadic isolates of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals and their similarities to isolates of community-acquired MRSA. J Clin Microbiol 2003;41:3806-3815.

(8.) Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus--Minnesota and North Dakota, 1997-1999. JAMA 1999;282:1123-1125.

(9.) Katayama Y, Ito T, Hiramatsu K. A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 2000;44:1549-1555.

(10.) Hiramatsu K, Watanabe S, Takeuchi F, Ito T, Baba T. Genetic characterization of methicillin-resistant Staphylococcus aureus. Vaccine 2004;22(Suppl 1):S5-S8.

(11.) Robinson DA, Enright MC. Multilocus sequence typing and the evolution of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 2004;10: 92-97.

(12.) Ito T, Ma XX, Takeuchi F, Okuma K, Yuzawa H, Hiramatsu K. Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase, ccrC. Antimicrob Agents Chemother 2004;48:2637-2651.

(13.) O'Brien FG, Lim TT, Chong FN, Coombs GW, Enright MC, Robinson DA, Monk A, Said-Salim B, Kreiswirth BN, Grubb WB. Diversity among community isolates of methicillin-resistant Staphylococcus aureus in Australia. J Clin Microbiol 2004;42:3185-3190.

(14.) Szmigielski S, Prevost G, Monteil H, Colin DA, Jeljaszewicz J. Leukocidal toxins of staphylococci. Zentralbl Bakteriol 1999;289:185-201.

(15.) Kaneko J, Kamio Y. Bacterial two-component and hetero-heptameric pore-forming cytolytic toxins: structures, pore-forming mechanism, and organization of the genes. Biosci Biotechnol Biochem 2004;68:981-1003.

(16.) Gillet Y, Issartel B, Vanhems P, Fournet JC, Lina G, Bes M, Vandenesch F, Piemont Y, Brousse N, Floret D, Etienne J. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 2002;359:753-759.

(17.) Konig B, Prevost G, Piemont Y, Konig W. Effects of Staphylococcus aureus leukocidins on inflammatory mediator release from human granulocytes. J Infect Dis 1995;171:607-613.

(18.) Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 2000;13:16-34.

(19.) Shahin R, Johnson IL, Jamieson F, McGeer A, Tolkin J, Ford-Jones EL. Methicillin-resistant Staphylococcus aureus carriage in a child care center following a case of disease. Toronto Child Care Center Study Group. Arch Pediatr Adolesc Med 1999;153:864-868.

(20.) Centers for Disease Control and Prevention (CDC). Methicillin-resistant Staphylococcus aureus infections in correctional facilities--Georgia, California, and Texas, 2001-2003. MMWR Morb Mortal Wkly Rep 2003;52:992-996.

(21.) Regev-Yochay G, Dagan R, Raz M, Carmeli Y, Shainberg B, Derazne E, Rahav G, Rubinstein E. Association between carriage of Streptococcus pneumoniae and Staphylococcus aureus in children. JAMA 2004;292:716-720.

(22.) Miller LG, Perdreau-Remington F, Rieg G, Mehdi S, Perlroth J, Bayer AS, Tang AW, Phung TO, Spellberg B. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005;352:1445-1453.

(23.) Iyer S, Jones DH. Community-acquired methicillin-resistant Staphylococcus aureus skin infection: a retrospective analysis of clinical presentation and treatment of a local outbreak. J Am Acad Dermatol 2004;50:854-858.

(24.) Young DM, Harris HW, Charlebois ED, Chambers H, Campbell A, Perdreau-Remington F, Lee C, Mankani M, Mackersie R, Schecter WP. An epidemic of methicillin-resistant Staphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg 2004;139:947-951; discussion 951-953.

(25.) Lee MC, Rios AM, Aten MF, Mejias A, Cavuoti D, McCracken GH Jr, Hardy RD. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J 2004;23:123-127.

(26.) Fridkin SK, Hageman JC, Morrison M, Sanza LT, Como-Sabetti K, Jernigan JA, Harriman K, Harrison LH, Lynfield R, Farley MM; Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 2005;352:1436-1444.

(27.) Adra M, Lawrence KR. Trimethoprim/sulfamethoxazole for treatment of severe Staphylococcus aureus infections. Ann Pharmacother 2004;38:338-341.

(28.) Fokas Sp, Fokas St, Markatou F, Lauranou E, Kalkani M, Dionysopoulou M. Staphylococcus aureus community-acquired infections. Antibiotic resistance rates and macrolide resistance phenotypes [abstract]. Clin Microbiol Infect 2004;10(Suppl 3):134.

(29.) Frank AL, Marcinak JF, Mangat PD, Tjhio JT, Kelkar S, Schreckenberger PC, Quinn JP. Clindamycin treatment of methicillin-resistant Staphylococcus aureus infections in children. Pediatr Infect Dis J 2002;21:530-534.

(30.) Klein NC, Cunha BA. Tetracyclines. Med Clin North Am 1995;79:789-801.

(31.) Entenza JM, Vouillamoz J, Glauser MP, Moreillon P. Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus. Antimicrob Agents Chemother 1997;41:1662-1667.

(32.) McKinnon PS, Lodise TP Jr, Rybak MJ. Impact of initial treatment with vancomycin versus a beta-lactam on outcomes and costs of methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) [abstract]. In Program and Abstracts of the 40th Annual Meeting of the Infectious Diseases Society of America, 2002:146.

(33.) Cosgrove SE, Carroll KC, Perl TM. Staphylococcus aureus with reduced susceptibility to vancomycin. Clin Infect Dis 2004;39:539-545.

(34.) Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2002;34:1481-1490.

(35.) Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of community-acquired methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis 2004;39:971-979.

(36.) Phillips E et al. Randomized controlled trial of combination therapy versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus (MRSA) colonization. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 30-November 2, 2004, Washington DC.

(37.) Sandora TJ, Taveras EM, Shih M-C, Resnick EA, Lee GM, Ross-Degnan D, Goldmann DA. Hand sanitizer reduces illness transmission in the home [abstract]. In Program and Abstracts of the 42nd Annual Meeting of the Infectious Diseases Society of America, 2004:52.

Elizabeth Race, MD, MPH, Cindy Berthelot, MS, and Jennifer Clay Cather, MD

From the Division of Infectious Diseases, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas (Race), the University of Texas Southwestern Medical School (Berthelot), and the Division of Dermatology, Department of Internal Medicine, Baylor University Medical Center (Cather), Dallas, Texas.

Corresponding author: Elizabeth Race, MD, MPH, Division of Infectious Diseases, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9113.
Table 1. History of Staphylococcus aureus antibiotic resistance

Date Event

1940s Penicillin was introduced. Within 1 year, penicillin-
 resistant S. aureus (PRSA) occurred first in the hospital
 and later in the community (2).

1960s Semisynthetic penicillins were designed to overcome PRSA.
 Within 1 year, methicillin-resistant S. aureus (MRSA) was
 documented first in the hospital and later in the community

1981 Hartman described the alteration of penicillin-binding
 proteins as a major resistance mechanism of MRSA (4).
 Penicillin-binding protein 2a has decreased affinity for
 beta-lactam antibiotics.

1990s Distinct community-acquired MRSA isolates were described.

Table 2. Comparison of hospital-and community-acquired
methicillin-resistant Staphylococcus aureus (MRSA)

Type of MRSA Association with antibiotic overuse

Hospital-acquired Positive association with broad-spectrum
(HA) antibiotics (i.e., cephalosporins such as
 cefepime or quinolones, which eradicate
 susceptible gram-positive, gram-negative,
 and anaerobic flora)

Community-acquired No specific antibiotic usage pattern has been
(CA) associated with CA- MRSA (with the possible
 exception of amoxicillin use in children) (8)

Type of MRSA Resistance genes

Hospital-acquired Contains distinct SCCmec types, plasmids
(HA) encoding resistance to various antibiotics,
 as well as heavy metal resistance elements

Community-acquired Contains SCCmec type IV

Type of MRSA Toxins

Hospital-acquired Characteristically lacks the toxin genes

Community-acquired May possess staphylococcal enterotoxins B and C,
(CA) toxic shock syndrome toxin-1, and Panton-Valentine

Table 3. Functions of staphylococcal toxins

Toxin Function

Staphylococcal Potent emetic activity
(A through O)

ExfoIiative toxin Bind to keratohyalin granules. Toxin A is
A and B chromosomally encoded, while toxin B is plasmid

Toxic shock Former names: staphylococcal pyrogenic toxin C and
syndrome toxin-1 staphylococcal enterotoxin F. Involved in cytokine
 release. Unique ability to cross mucosal surfaces.

Panton-Valentine Comprises two elements that are secreted separately
leukocidin and then recombine to create an active toxin that
 induces pore formation in cell membranes of
 monocytes, macrophages, and polymorphonuclear
 neutrophils. The result is cellular cytolysis
 (leukopenia) and the release of interleukin-8 and
 leukotriene B4, as well as other cytokines (14-17).
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Title Annotation:Dermatology Report
Author:Race, Elizabeth; Berthelot, Cindy; Cather, Jennifer Clay
Publication:Baylor University Medical Center Proceedings
Article Type:Clinical report
Geographic Code:1U7TX
Date:Oct 1, 2005
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