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REVIEW

Cellulitis: Denition, Etiology, and Clinical Features


Craig G. Gunderson, MD
Department of Internal Medicine, Yale University School of Medicine, Veterans Administration Health Care System, West Haven, Conn.

ABSTRACT Cellulitis is a common condition seen by physicians. Over the past decade, skin and soft tissue infections from community-associated methicillin-resistant Staphylococcus aureus have become increasingly common. In this article, the denition, etiology, and clinical features of cellulitis are reviewed, and the importance of differentiating cellulitis from necrotizing soft tissue infections is emphasized. Empiric antimicrobial recommendations are suggested, including the most recent recommendations from the Infectious Disease Society of America. Published by Elsevier Inc. The American Journal of Medicine (2011) 124, 1113-1122 KEYWORDS: Cellulitis; Community-associated methicillin-resistant Staphylococcus aureus; Necrotizing fasciitis;
Soft tissue infections

Cellulitis is a common form of skin and soft tissue infection resulting in more than 600,000 hospitalizations per year,1 and along with cutaneous abscess, more than 9 million ofce visits.2 Traditionally, -hemolytic streptococci and Staphylococcus aureus have been considered the primary causative agents, and empiric therapy with -lactam antibiotics has been the mainstay of therapy. Over the past decade, however, numerous reports have detailed the widespread emergence of methicillin-resistant S. aureus (MRSA). Previously, MRSA infections had been limited to hospital-acquired infections or to community cases with nosocomial exposures. Over the past decade, however, an increasing proportion of outpatient S. aureus isolates has been found to be methicillinresistant. MRSA infections that occur in outpatients or within 48 hours of hospitalization and lack nosocomial exposures such as an indwelling device, recent hospitalization, surgery, dialysis, or residence in a long-term care facility, have been termed community-acquired or community-associated methicillin-resistant S. aureus (CA-

MRSA).3 Recent studies have concluded that the majority of S. aureus skin and soft tissue infections are now methicillin-resistant,4 and that CA-MRSA is the most common isolate from purulent skin and soft tissue infections in the United States.5 Although CA-MRSA has become commonly recognized as a major cause of culturable skin and soft tissue infections, its role in nonpurulent cases of cellulitis remains uncertain.6,7 Some authors have recommended that all cases of cellulitis8 be treated for MRSA, while others have recommended that therapy against CA-MRSA should be limited to cases that are severely ill or fail empiric -lactam therapy,7,9 or when local rates of MRSA are 10% of isolates.10 In February 2011, the Infectious Disease Society of America (IDSA) published its rst guideline for the treatment of MRSA,6 including in cellulitis, which, along with the IDSA guideline from 2005 for the management of skin and soft tissue infections,11 forms the basis of the treatment recommendations for this review.

Funding: None. Conict of Interest: None. Authorship: The author is solely responsible for writing this manuscript. Requests for reprints should be addressed to Craig G. Gunderson, MD, Department of Internal Medicine, Yale University School of Medicine, Veterans Administration Health Care System, 950 Campbell Avenue, West Haven, CT 06516. E-mail address: craig.gunderson@va.gov

DEFINITIONS
The terminology used to describe different types of skin and soft tissue infections is complicated because of the use of terms to describe different forms of infection (cellulitis, abscess, erysipelas), clinical scenarios (Fournier gangrene, Ludwig angina), and etiologic agents (clostridial myonecrosis, streptococcal necrotizing fasciitis).

0002-9343/$ -see front matter Published by Elsevier Inc. doi:10.1016/j.amjmed.2011.06.028

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The main types of adult skin and soft tissue infections include: 1.

2.

3.

4.

patients with cellulitis appear to support the primary role of streptococci.15-23 Although the reported rates of positive cultures are low, ranging from 1% to 18%, streptococcal species account for Cellulitis: any spreading infection involving the dermis and 51% of reported isolates, while S. aureus was isolated in only subcutaneous tissues.12 Purulent cellulitis is dened as celluli15%. Surprisingly, a broad range of gram-negative organisms tis with associated purulent drainaccounted for another 25%. age or exudate in the absence of a The recent guideline on the drainable abscess.6 This distincmanagement of infections by tion is signicant because purulent CLINICAL SIGNIFICANCE MRSA by the IDSA claries the cases are more likely to be due to relative contributions of strepto Cellulitis is one of the most common S. aureus.5,6,13 cocci and S. aureus by emphasinfections seen by primary care and hosErysipelas: a specic type of izing the distinction between pital-based physicians. cellulitis involving more superpurulent and nonpurulent types.6 cial dermal structures distin Cellulitis that is associated with puruCiting a large study of purulent guished clinically by raised lent drainage is most commonly due to soft tissue infections in emergency borders and clear demarcation departments across the US, which Staphylococcus aureus, including combetween involved and uninfound that 76% of cases were due munity-associated methicillin-resistant volved skin.11 The distinction to S. aureus, including 59% by S. aureus (CA-MRSA). Empiric antimicrois signicant because erysipeCA-MRSA,5 the guideline states bial therapy in these cases should be las is thought to be predothat in cases with purulence, therdirected against CA-MRSA, and modied minantly due to -hemolytic apy should be directed at CAbased on cultures. streptococci.11 MRSA. In cases of nonpurulent Abscess: any collection of pus More commonly, cellulitis is nonpurucellulitis, on the other hand, the within the dermis or subcutaguideline cites a recent study that lent. Antimicrobial therapy in such caneous tissues. 11 Clinically, assessed for evidence of streptoses should be directed at -hemolytic patients present with nodules cocci using acute and convalesstreptococci and methicillin-sensitive with surrounding erythema and cent serologies of antistreptolysin S. aureus. uctuance. The distinction beO and anti-DNase-B antibodies.7 tween abscess and cellulitis is This study found that 73% of signicant because abscesses cases of nonpurulent cellulitis had are more likely to be due to S. positive serology, supporting the traditional teaching of the 13 aureus, and are treated primarily by incision and drainage. predominant streptococcal origin for nonpurulent cellulitis. Necrotizing soft tissue infections: a necrotizing infection involving any of the soft tissue layers, including the dermis, subcutaneous tissue, supercial or deep fascia, and muscle.14 CLINICAL PRESENTATION Patients with cellulitis typically present with a brief history of pain, redness, and swelling of the involved skin.24 Commonly there is a history of a predisposing condition for cellulitis, including obesity, edema, prior saphenous vein removal, prior radiation therapy, or any skin disorder that causes a potential portal of entry, including ulcers, wounds, dry skin with ssuring, chronic skin diseases, and venous stasis.22 Toe web intertrigo also has been shown to be a risk factor for cellulitis25, especially if it is complicated by bacterial colonization with pathogenic bacteria.22,26 The history also should include assessing for risk factors associated with specic pathogens (Table 1).5,10,12,13,27-30 Risk factors for MRSA include a range of nosocomial exposures, as well as putative risk factors for CA-MRSA. Importantly, these MRSA risk factors are derived from retrospective studies, and have not been prospectively shown to be clinically useful in discriminating between MRSA and non-MRSA infections.27 The physical examination should be focused on characterizing the area of cellulitis and assessing for evidence of abscess or necrotizing infection. Most commonly, cellulitis involves the lower extremities but may involve the upper

ETIOLOGY
As noted in the 2005 guideline from the IDSA, traditional teaching is that most cases of cellulitis are due to -hemolytic streptococci, often group A, but also groups B, C, or G. S. aureus also is noted to cause cellulitis, especially when associated with furuncles, carbuncles, or abscesses.11 Nevertheless, the exact frequency of specic pathogens and the relative proportion of streptococci and S. aureus remain uncertain, largely because of the difculty in culturing most cases of cellulitis. Potential sources for culture include peripheral blood, needle aspirates, skin biopsies, and surgical specimens in cases with purulence, abscess, or necrosis. Unfortunately, cultures from blood, needle aspirate, and skin biopsy have a relatively low yield, and many cases of cellulitis are nonpurulent.7 A recent review of studies of cellulitis that used needle aspiration or punch biopsy for diagnosis questions the traditional teaching that most cases of cellulitis are due to streptococci. These authors found that S. aureus accounted for 51% of positive cultures, compared with only 27% from group A streptococcus.8 On the other hand, studies reporting the results of blood cultures in

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Cellulitis
Table 1 Risk Factors for Associated Pathogens in Cellulitis5,10,13

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Reported risk factors for MRSA Previous history of hospitalization or surgery within the past year Residence in a long term care facility within the past year Hemodialysis Previous MRSA infection or colonization Recent antibiotic use Contact sports Patient report of spider bite Purulent soft tissue infections Crowded living environments, including homeless shelters, prisons, soldiers Intravenous drug users Men who have sex with men Household contacts with MRSA infection Risk factors associated with other pathogens12,13,27-30 Diabetic foot infections Often polymicrobial, including gram-positive and gramnegative aerobes and anaerobes Neutropenia Gram-positive, gram-negative including Pseudomonas aeruginosa Cirrhosis Gram-negatives, also Campylobacter fetus, Vibrio vulnicus, Capnocytophaga canimorsus Intravenous drug use Staphylococcus aureus, P. aeruginosa Human bites Polymicrobial mixture of oral anaerobes and aerobes (Streptococci, S. aureus, Eikenella corrodens) Dog and cat bites Polymicrobial mixture of pathogens derived from the animal (mixed aerobic and anaerobic bacteria, including Pasteurella species) and host skin ora, including staphylococci and streptococci. Capnocytophaga canimorsus potential severe pathogen for hosts with asplenia or cirrhosis. Fresh water lacerations Aeromonas hydrophila Salt water lacerations Vibrio vulnicus Fish n or bone injuries Vibrio vulnicus, streptococci, S. aureus, gram-negatives.
MRSA methicillin-resistant Staphylococcus aureus.

extremities, trunk, perineum, or head and neck.20,24 The rash is almost universally found to be warm, red, tender, and swollen,24,31 and there may be associated lymphangitis or lymphadenopathy.24 In erysipelas, the rash is well demarcated, whereas in cellulitis the borders are less well dened. There may be associated vesicles and bullae, although if present, bullae generally are lled with clear uid as opposed to the hemorrhagic or violaceous uid found in necrotizing infections.11 Fever and constitutional symptoms are often mild or absent in uncomplicated cellulitis. In published series, fever is reported in only 26%-67% of cases.15,16,24,32 Hypotension is rare, reported in one series of hospitalized patients as present in 2.7%.32 Leukocytosis and elevated sedimentation rate are present in approximately one half of cases.16

DIFFERENTIAL DIAGNOSIS
A broad range of conditions may masquerade as cellulitis, including infections such as necrotizing fasciitis, varicella

zoster, herpetic whitlow, and erythema migrans; inammatory conditions such as acute arthritis, gout, or bursitis; or dermatologic conditions such as contact dermatitis, hypersensitivity reaction, xed drug reaction, and venous stasis disease33 (Table 2). As previously described, cutaneous abscesses are important to distinguish from cellulitis because of the necessity of drainage. One common practice for patients with lower-extremity cellulitis is to rule out deep venous thrombosis with duplex ultrasound. Data on this practice are mixed, however. Glover and Bendick34 reviewed 241 patients with a clinical diagnosis of cellulitis who were referred for ultrasound, and found no cases of proximal deep venous thrombosis (2 cases had isolated calf thrombosis). On the other hand, Rabuka et al35 retrospectively reviewed all duplex scans ordered in the emergency department with the question of cellulitis versus deep venous thrombosis. In this study, 17% had a deep venous thrombosis.35 Based on these studies, it seems that the yield for routine lower extremity ultrasound in patients with readily apparent cellulitis is very low, but for patients

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Table 2

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Differential Diagnosis of Cellulitis12,13,33 Characteristics Infectious Necrotizing fasciitis Triad of severe pain, swelling, and fever. Pain out of proportion, severe toxicity, hemorrhagic or bluish bullae, gas or crepitus, skin necrosis or extensive ecchymosis, rapid progression. A form of cellulitis with well demarcated borders. Early abscess may appear similar to cellulitis. Eventually distinguishable by appearance of a nodule with uctuance and drainage. Vesicular. Characteristic location on ngers. Often not painful, not typically located on lower extremities, ovoid appearance. Tick exposure. Essential feature is involvement of joint, with disproportionate pain with joint movement. Characteristic locations such as over the patella or olecranon, often with palpable uid collection. Distinguishable from cellulitis by lack of fever, less pain, heme deposition, and circumferential pattern. Pruritis instead of pain, absence of fever. Typically occurring soon after drug ingestion, usually not painful unless erosions occur, characteristic locations on genitalia, face, trunk; less commonly, lower extremities. Typically not associated with skin redness or fever. Patients may get erysipelas-like erythema during episodes. Distinguished from true erysipelas by recurrent nature, positive family history, and occurrence in Sephardic Jews and persons from the Middle East. Often on the anterior shin, ragged ulcers with undermined borders. Often in patients with inammatory bowel disease. Occasionally mistaken for cellulitis. Typical lesions are papules that coalesce into plaques. Commonly on upper extremities and face. Treated by corticosteroids.

Erysipelas Cutaneous abscess

Herpetic whitlow Erythema migrans Inammatory Acute arthritis (gout, septic) Acute bursitis Dermatologic Stasis dermatitis Hypersensitivity reaction Fixed drug reaction

Miscellaneous Deep venous thrombosis Rare Familial Mediterranean fever

Pyoderma gangrenosa Sweets syndrome

for whom the diagnosis is in doubt, ultrasound may be useful.

RULING OUT NECROTIZING SOFT TISSUE INFECTION


Although uncommon, necrotizing soft tissue infections are important to diagnose, given their high mortality without surgery, and are usually either streptococcal or polymicrobial in origin.14 Most patients with necrotizing soft tissue infections present with the clinical triad of severe pain, swelling, and fever.36 Possible physical examination ndings include severe toxicity, hemorrhagic or bluish bullae, skin necrosis or ecchymosis, gas or crepitus, cutaneous anesthesia, edema that extends beyond the margin of erythema, and rapid progression. Unfortunately, these so-called hard signs of necrotizing soft tissue infection often are absent at presentation.37

Laboratory tests may be useful for assessing the risk of necrotizing soft tissue infections. Wall et al37 found that the combination of a white blood cell count of 15,500 cells/ mm3 and a serum sodium concentration of 134 mmol/L effectively ruled out necrotizing soft tissue infection, although their presence was not effective at ruling in the diagnosis. Similarly, Wong et al32 described a risk score based on admission laboratory values to predict the likelihood of necrotizing soft tissue infection,32 wherein a low risk score had a 96% negative predictive value and moderate to high risk scores had a 92% positive predictive value. Both authors then outlined approaches to necrotizing soft tissue infection using their algorithms (Figure 1). Diagnostic imaging also may be useful in assessing possible necrotizing soft tissue infections. Plain lms may show subcutaneous gas, a relatively specic but insensitive nding of necrotizing infection. Computed tomography is

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Figure 1 Proposed approach to evaluating patients for necrotizing soft tissue infections (modied from Wall et al37 and Wong et al32).

more sensitive at showing soft tissue gas, and may additionally show deep fascial thickening or associated deep tissue abscesses.38 Magnetic resonance imaging has been touted as the imaging study of choice for differentiating necrotizing infections from cellulitis.39-41 Reported ndings include deep fascial involvement with thickening and inammation, and the absence of gadolinium contrast enhancement on T1-weighted images, which may reect tissue necrosis.42 Because studies of diagnostic imaging for necrotizing fasciitis have generally been retrospective case series that have lacked meaningful comparison groups,14 data on sensitivity and specicity are unknown.11 Ultimately, the only way to denitively diagnose necrotizing soft tissue infections is by surgical exploration, which is recommended urgently for any case with substantial concern. Operative ndings diagnostic of necrotizing soft tissue infection include the presence of necrotic fascia, lack of resistance of normally adherent muscular fascia to blunt

dissection (positive nger test), lack of bleeding of fascia during dissection, and the presence of foul-smelling dish water pus.36

DIAGNOSTIC STUDIES
Most cases of cellulitis are managed empirically. According to the IDSA guideline, cultures of blood, needle aspirates, and skin biopsies are optional. Given the relatively low yield in culturing cellulitis and risk of contaminants, cultures are generally not pursued other than the common practice of obtaining blood cultures for admitted patients. Purulent infections, on the other hand, should be debrided and cultured. The IDSA does recommend that needle aspiration or skin biopsies should be considered in patients who are immunocompromised or have an abnormal exposure history, such as bite wounds. These tests also should be considered in pa-

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The American Journal of Medicine, Vol 124, No 12, December 2011 with therapy directed at MRSA. A recent study from Denver, for example, reported that 85% of hospitalized patients with cellulitis were treated with vancomycin or other antiMRSA therapy, whereas only 20% were treated with cefazolin and 8% with nafcillin. At discharge, 48% were discharged on trimethoprim-sulfamethoxazole, compared with only 6% on cephalexin and 3% on dicloxacillin.48 The recent guideline from the IDSA on the treatment of MRSA substantially changes prior recommendations about the treatment of cellulitis. For outpatients with purulent cellulitis, empiric therapy for CA-MRSA is now recommended, pending culture results. Empiric therapy for -hemolytic streptococci is considered unnecessary (class A-II recommendation). Listed options include clindamycin, trimethoprim-sulfamethoxazole (TMP-SMZ), a tetracycline such as doxycycline or minocycline, or linezolid (Table 4). For outpatients with nonpurulent cellulitis, on the other hand, empirical therapy for infection due to -hemolytic streptococci and methicillin-sensitive S. aureus is still recommended (A-II), whereas therapy for CA-MRSA is reserved for patients who fail -lactam therapy or who are severely ill. Listed options include cephalexin, dicloxacillin, and clindamycin. If therapy for both CA-MRSA and -hemolytic streptococci is desired, options include a -lactam

tients who fail to improve with empiric antibiotics.11 Various methods have been described for needle aspiration,43-45 but the most common is using a 22-gauge needle to aspirate uid from the advancing edge of the cellulitis after the area is cleaned with povidone-iodine solution. The average microbiologic yield reported in studies using needle aspiration or skin biopsy for culture is 24%,8 although rates have varied from 0-40%. An alternative to needle aspirate is using a punch biopsy for culture, although it is unclear whether this increases diagnostic yield.46 Studies of patients with cellulitis with associated open wounds or ulcers that have used swabs for culture have reported high yields of potential pathogens, but distinguishing between causative agents and contaminants may be difcult.47 A summary of possible diagnostic tests to consider in patients with cellulitis is found in Table 3.

TREATMENT
Traditionally, cellulitis has been managed empirically with antibiotics chosen to cover -hemolytic streptococci and methicillin-sensitive S. aureus. Over the past decade, with the widespread emergence of CA-MRSA as a potential pathogen, many clinicians have chosen to treat cellulitis
Table 3 Tests to Consider in Patients with Cellulitis

Laboratory tests: CBC, chemistries, ESR, CRP CK

Generally nonspecic. Can be used for LRINEC score and Wall criteria if necrotizing infection is suspected. May be useful to screen for muscle involvement of infection, which can be seen in necrotizing infections and bacterial myositis. Presence of gas strongly suggests necrotizing soft tissue infection. Specic but insensitive sign. Test of choice if suspect underlying abscess. Possible role for evaluating for necrotizing soft tissue infections. Reported signs include soft tissue gas, deep fascial thickening, and associated deep tissue abscess. Possible role for evaluating for necrotizing soft tissue infections or osteomyelitis. Deep fascial involvement evidenced by fascial thickening and enhancement, gas, and uid collections. Generally low yield, commonly obtained for hospitalized patients. High yield, uncertain pathogenic signicant unless done from debribed base. Obtain specimens by biopsy or curettage, or potentially needle aspiration. Avoid swabbing undebrided ulcers or wound drainage. Generally modest yield, consider in immunocompromised patients or patients who fail empiric treatment. Not clearly superior to above, potentially scarring. Possibly high yield, easy to do. Possibly high yield but swabs risk contamination. If purulent wound should generally be debrided before culturing.

Imaging: Plain lms Ultrasound CT

MRI

Bacterial cultures: Blood cultures Associated wounds or ulcers

Needle aspiration Culture from punch biopsy Culture from uid-lled bullae Culture of drainage

CBC complete blood count; CK creatine kinase; CRP C-reactive protein; CT computed tomography; ESR erythrocyte sedimentation rate; LRINEC Laboratory Risk Indicator for Necrotizing Fasciitis; MRI magnetic resonance imaging.

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Table 4

Cellulitis
Recommended Antimicrobial Therapy for Patients with Cellulitis6,11 A-I* A-II

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Erysipelas Penicillin Outpatient purulent cellulitis Clindamycin

Drug of choice for erysipelas. 100% sensitivity of Streptococcus pyogenes. Bacteriostatic. Highly effective against Streptococci. Good efcacy data in SSTI; 3%-24% CA-MRSA resistance.49 Also, potential for inducible resistance in susceptible strains during treatment if erythromycinresistant. Bactericidal. Limited published data on SSTI. Uncertain efcacy against S. pyogenes.10 CA-MRSA rarely resistant.49 Bacteriostatic. Little recent efcacy data;10 5% CA-MRSA resistance.49 Bacteriostatic, expensive, numerous potential side effects (myelosuppression, peripheral neuropathy, optic neuritis, nausea, vomiting, diarrhea, lactic acidosis). Weekly CBC for monitoring. Highly effective against HS, CA-MRSA. Bactericidal, highly effective against HS, MSSA. See above. Highly effective against both HS and CA-MRSA. Recommended for patients who fail -lactam therapy and may be considered in all with systemic toxicity. See above. Recommended for patients who fail -lactam therapy and may be considered in all with systemic toxicity. Traditional parenteral therapy for MRSA infections. Concerns over its slow bactericidal activity. Less effective against Staphylococcus aureus than -lactams for susceptible strains.6 See above. Bactericidal, expensive. Risk of myopathy and rhabdomyolysis. Weekly CK for monitoring. Avoid administering with HMG-CoA reductase inhibitors. Bactericidal. Nephrotoxicity, monitor creatinine levels. See above; A-III recommendation for hospitalized patients. Bactericidal. Inactive against MRSA. A-II recommendation for hospitalized patients with nonpurulent cellulitis. Bactericidal. Inactive against MRSA. A-II recommendation for hospitalized patients with nonpurulent cellulitis.

TMP-SMZ Doxycycline Linezolid

A-II A-II A-II

Outpatient nonpurulent cellulitis -lactam (cephalexin or dicloxacillin) Clindamycin -lactam plus TMP-SMZ or a tetracycline Linezolid Hospitalized patients with cellulitis Vancomycin

A-II A-II A-II

A-II

A-I

Linezolid Daptomycin

A-I A-I

Telavancin Clindamycin Nafcillin or oxacillin Cefazolin Necrotizing soft tissue infections Type 1, polymicrobial Ampicillin-sulbactam/piperacillintazobactam clindamycin ciprooxacin Type 2, monomicrobial (S. pyogenes, MRSA, V. Vulnicus, others) Clindamycin plus penicillin for S. pyogenes

A-I A-III A-II A-II

A-III

Preferred per IDSA

Pathogen directed. A-II Clindamycin appears to be superior to penicillin as monotherapy, but rarely, S. pyogenes may be resistant, hence addition of penicillin.

HS beta-hemolytic streptococci; CA-MRSA community-acquired S. aureus; MSSA methicillin-susceptible S. aureus; MRSA methicillin-resistant S. aureus; SSTI skin and soft-tissue infection; TMP-SMZ trimethoprim-sulfamethoxazole. *All grading of recommendations per the Infectious Disease Society of America (IDSA) guidelines.6,11 Grade A Good evidence to support a recommendation for use; should always be offered. Quality of evidence I Evidence from at least one randomized, controlled trial; II Evidence from at least one well-designed nonrandomized clinical trial or cohort or case-controlled study, or multiple time-series, or from substantial results from uncontrolled experiments; III Evidence from opinions of respected authorities.

such as amoxicillin plus either TMP-SMZ or a tetracycline, or linezolid alone. Monotherapy with TMP-SMZ or a tetracycline for nonpurulent cellulitis is not recommended given limited published efcacy data and concerns about effectiveness against streptococci.49,50

Hospitalized patients with cellulitis have, by denition, complicated skin and soft tissue infection, which also includes patients with deep soft tissue infections, surgical and traumatic wound infections, major abscesses, and infected ulcers and burns.6 For these patients, the IDSA states that

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The American Journal of Medicine, Vol 124, No 12, December 2011 cellulitis are inammatory in nature. This led to at least one trial of adjuvant corticosteroids, which found that patients given 8 days of prednisolone had a signicantly shorter duration of illness and decreased length of hospitalization.51 Although not a widespread practice, the IDSA recommends that clinicians consider the addition of corticosteroids for the treatment of cellulitis.

therapy for CA-MRSA should be considered pending culture data. Listed options include vancomycin, linezolid, daptomycin, and telavancin (all A-I). Clindamycin also is listed as an option, but with a lower level of evidence (A-III). For hospitalized patients with nonpurulent cellulitis, however, the IDSA guideline states that -lactam therapy remains an acceptable option, with reservation of MRSAactive therapy for patients who fail to respond. Of note, the IDSA does not recommend different antibiotics for diabetics with cellulitis than it does for nondiabetics, except in cases of chronic diabetic foot infections.28 Antimicrobial medications based on IDSA recommendations, including for necrotizing soft tissue infections, are listed in Table 4. The overall approach to cellulitis is shown in Figure 2.

Duration of Therapy and Failure to Respond


The optimal duration of antibiotics for cellulitis is unknown. Most authorities comment that durations of 5-10 days are commonly needed,6 or longer, depending on clinical response.12 The Sanford Guide to Antimicrobial Therapy52 recommends that therapy be continued until 3 days after acute inammation disappears. This common practice of continuing antibiotics until erythema has resolved has been questioned by at least one study, which randomized a group of patients with uncomplicated cellulitis who were improving after 5 days of standard therapy to either placebo or an additional 5 days of antibiotic.53 These authors found that 98% of both groups of patients had complete clinical resolution of their cellulitis, suggesting that at least for patients with uncomplicated cellulitis who are already improving after 5 days of treatment, additional antibiotic is unnecessary.

Adjuvant Treatments for Cellulitis


Although not specically studied, treatment of patients edema when present may hasten recovery and prevent recurrent cellulitis. This may be done with compression dressings or stockings, leg elevation, and potentially, diuretics when indicated. Another potential adjuvant treatment is corticosteroids. Given the difculty culturing microbes in cellulitis, some authorities have surmised that many of the manifestations of

Figure 2 Suggested approach to cellulitis.6 MSSA methicillin-susceptible Staphylococcus aureus; CA-MRSA communityassociated methicillin-resistant S. aureus; TMP-SMZ trimethoprim-sulfamethoxazole.

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9. Moellering RC Jr. The growing menace of community-acquired methicillin-resistant Staphylococcus aureus. Ann Intern Med. 2006; 144(5):368-370. 10. Daum RS. Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. N Engl J Med. 2007; 357(4):380-390. 11. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373-1406. 12. Swartz MN. Clinical practice. Cellulitis. N Engl J Med. 2004;350(9): 904-912. 13. Stevens DL, Eron LL. Cellulitis and soft-tissue infections. Ann Intern Med. 2009;150(1):ITC11. 14. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis. 2007;44(5):705-710. 15. Ho PW, Pien FD, Hamburg D. Value of cultures in patients with acute cellulitis. South Med J. 1979;72(11):1402-1403. 16. Hook EW 3rd, Hooton TM, Horton CA, Coyle MB, Ramsey PG, Turck M. Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med. 1986;146(2):295-297. 17. Lutomski DM, Trott AT, Runyon JM, Miyagawa CI, Staneck JL, Rivera JO. Microbiology of adult cellulitis. J Fam Pract. 1988;26(1): 45-48. 18. Kielhofner MA, Brown B, Dall L. Inuence of underlying disease process on the utility of cellulitis needle aspirates. Arch Intern Med. 1988;148(11):2451-2452. 19. Brook I, Frazier EH. Clinical features and aerobic and anaerobic microbiological characteristics of cellulitis. Arch Surg. 1995;130(7): 786-792. 20. Kulthanan K, Rongrungruang Y, Siriporn A, et al. Clinical and microbiologic ndings in cellulitis in Thai patients. J Med Assoc Thai. 1999;82(6):587-592. 21. Perl B, Gottehrer NP, Raveh D, Schlesinger Y, Rudensky B, Yinnon AM. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis. 1999;29(6):1483-1488. 22. Bjornsdottir S, Gottfredsson M, Thorisdottir AS, et al. Risk factors for acute cellulitis of the lower limb: a prospective case-control study. Clin Infect Dis. 2005;41(10):1416-1422. 23. Peralta G, Padron E, Roiz MP, et al. Risk factors for bacteremia in patients with limb cellulitis. Eur J Clin Microbiol Infect Dis. 2006; 25(10):619-626. 24. Ginsberg MB. Cellulitis: analysis of 101 cases and review of the literature. South Med J. 1981;74(5):530-533. 25. Bristow IR, Spruce MC. Fungal foot infection, cellulitis and diabetes: a review. Diabet Med. 2009;26(5):548-551. 26. Dupuy A, Benchikhi H, Roujeau JC, et al. Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ. 1999;318(7198):15911594. 27. Miller LG, Quan C, Shay A, et al. A prospective investigation of outcomes after hospital discharge for endemic, community-acquired methicillin-resistant and -susceptible Staphylococcus aureus skin infection. Clin Infect Dis. 2007;44(4):483-492. 28. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004;39(7):885-910. 29. Horowitz Y, Sperber AD, Almog Y. Gram-negative cellulitis complicating cirrhosis. Mayo Clin Proc. 2004;79(2):247-250. 30. Imberg R, Potasman I, Weissman Y, Grupper M. Hand infections following penetrating sh ns or bones injuries (FFBI): a large, hospital based, retrospective study. Infection. 2008;36(6):565-569. 31. Newell PM, Norden CW. Value of needle aspiration in bacteriologic diagnosis of cellulitis in adults. J Clin Microbiol. 1988;26(3):401-404. 32. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32(7):1535-1541. 33. Falagas ME, Vergidis PI. Narrative review: diseases that masquerade as infectious cellulitis. Ann Intern Med. 2005;142(1):47-55.

For patients who fail to respond to empiric therapy, options include adding anti-MRSA therapy, adding gramnegative coverage, searching for a drainable focus with imaging, and needle aspiration for culture. Even with appropriate diagnosis and therapy, some patients are slow to respond.11 For hospitalized patients, the average length of stay for cellulitis in the US is 4.5 days,1 but some patients remain hospitalized for prolonged periods.54,55 One study found that independent predictors of prolonged lengths of stay included edema, prior use of diuretics, and absolute neutrophil counts 10 109/L,55 indicating that edema and possibly disease severity were the primary determinants of duration of therapy. Although unproven, this suggests that aggressive therapy for coexisting edema may be a useful adjuvant therapy.

CONCLUSIONS
Cellulitis is a common cause of infection for adult patients. Until the past decade, empiric treatment using -lactam antibiotics has been standard. Specic microbiologic diagnosis was rarely pursued or found. Over the past decade, however, community isolates of S. aureus have been found to be increasingly resistant to even extended-spectrum -lactams. Studies of skin and soft tissue infections during this time, particularly purulent infections, have found a large proportion to be due to CA-MRSA. It remains unknown, however, how much of nonpurulent cases are due to CA-MRSA. High-quality randomized, controlled trials comparing different antibiotic regimens for nonpurulent cellulitis are needed. Lastly, studies to evaluate duration of therapy and preventive strategies also are overdue.

References
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