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Cellulitis and the role of the Clinical Microbiology Laboratory
Clinical Microbiology Newsletter Vol. 29, No. 20
www.cmnewsletter.com
October 15, 2007
Cellulitis and the Role of the Clinical Microbiology Laboratory Lawrence J. Eron, M.D., F.A.C.P., and John A. Burns, School of Medicine, University of Hawaii, Kaiser Moanalua Medical Center, Honolulu, Hawaii
Abstract We are facing twin cellulitis epidemics — necrotizing infections due to streptococci and antimicrobial resistance of Staphylococcus aureus. Streptococci have been increasingly associated with necrotizing fasciitis with or without toxic shock syndrome, and now we have a clone of S. aureus (USA 300) that can cause the same syndrome. At present, more than 60% of S. aureus isolates are resistant to methicillin. No sooner have newer antimicrobials been approved than resistance to them has started to appear. The challenge facing medicine is to improve our diagnostic capabilities so that we can detect, in real time, the type of infection, the etiologic agent, and its antimicrobial susceptibility.
Introduction Cellulitis is a major clinical problem by virtue of its incidence and severity. In the last 15 years, two developments have occurred that have transformed the landscape of cellulitis. First, increasing resistance to antibiotics, especially in Staphylococcus aureus, has greatly complicated the choice of antimicrobials in treating infections. This decision is further complicated by the difficulty in obtaining a microbiologic specimen from patients with cellulitis on which to rationally base antibiotic treatment. Secondly, there has been an increase in toxic shock syndrome and necrotizing infections associated with virulence factors carried by streptococci and S. aureus, the two most common causes of cellulitis. Because of the requisite delay of 24 to 48 hours in obtaining the results of a wound culture on a patient with cellulitis, initial therapy is necessarily empirical. The choice of an antimicrobial agent is based on the clinical pre-
Mailing address: Lawrence J. Eron, M.D., F.A.C.P., 3288 Moanalua Rd., Honolulu, HI 96734. Tel.: (808) 432-7848. Fax: (808) 432-8141. E-mail: [email protected] Clinical Microbiology Newsletter 29:20,2007
sentation, relevant epidemiological information, and the statistical likelihood of certain organisms being present. An incorrect choice of initial antimicrobial treatment could delay convalescence and lead to an increase in morbidity and mortality (1). Because resistant organisms have become increasingly widespread, there is renewed interest in developing targetoriented treatment to narrow the spectrum of the therapeutic agent in order to decrease the selective pressure for resistant bacteria, after initially using a broad-spectrum antimicrobial agent selected empirically. Guidelines, therefore, have been developed to standardize the management of cellulitis. All guidelines emphasize the importance of obtaining a culture specimen to target pathogens that may be present. An important part of the guidelines is the classification of cellulitis, which may be based on anatomical considerations (2), pathological processes (3), or practical issues, such as when to hospitalize, when to switch to oral medications, and when to discontinue treatment (4).
involving the deep dermis and subcutaneous fat (Fig. 1A). It is differentiated from more superficial infections of the skin, such as impetigo and erysipelas (Fig. 1B). The most frequently affected parts of the body are the lower extremities, followed by the upper extremities, the head, and the trunk. In the immunocompetent host, S. aureus and Streptococcus pyogenes (group A streptococci) are the main causative agents. Other streptococci, such as Streptococcus agalactiae (group B streptococci) in the diabetic patient, and occasionally groups C and G streptococci, may also cause cellulitis. While S. aureus is present in 45% of cultures of skin and soft tissue infections, beta-hemolytic streptococci are found in only 5% (5). This discrepancy is due to the fact that streptococcal infections are difficult to culture and diagnosis is usually made either serologically or, more frequently, clinically — on the basis of certain features,
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such as a raised, indurated border (Fig. 1C), a “peau d’orange” appearance of the skin (Fig. 1D), and lymphangitic spread. The onset may be rapid and, in some cases, precedes the development of erythema of the skin. The erythema may spread beyond its original borders in the first 24 hours of antimicrobial therapy (Fig. 1E). Not infrequently, vesicles or bullae develop, which are filled with seropurulent fluid, the culture of which is usually negative (Fig. 1F). Streptococcal cellulitis may be recurrent, especially where there is lymphatic or venous compromise to the drainage of an extremity. It may also recur when tinea pedis provides an entrance site for the streptococci. It is important to correct whatever predisposing factors one can, such as using compression dressings for venous insufficiency and antifungals to treat tinea pedis. In the last 10 years, streptococcal necrotizing fasciitis has increased in prevalence. The classical presentation is that of a septic patient who complains of pain out of proportion to the clinical appearance of his cellulitis. While it may begin as an apparently superficial process (Fig. 1G), it spreads rapidly along fascial planes, and may be associated with toxic shock syndrome. The skin may become gangrenous with purplish bullae or ecchymoses (Fig. 1H). The mortality rate exceeds 50% unless early surgical debridement is undertaken, which is essential for the recovery of the patient. In the operating room, copious “dishwater drainage” is encountered, with edematous, gray, subcutaneous fat, and the superficial fascial plane is easily separated from the underlying muscle by blunt dissection. Diagnostic imaging via CT or MRI scans may occasionally be useful, but in the author’s experience, it is insuffi-
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ciently specific and merely ends up wasting time and money. When the diagnosis is uncertain, a small incision can be made and the subcutaneous fat inspected. Unlike ordinary streptococcal cellulitis, streptococcal necrotizing fasciitis will be culture positive, and a Gram stain of material obtained from the wound will likely reveal grampositive cocci in chains, consistent with streptococci, leading to an early microbiological diagnosis. Clindamycin is the antimicrobial agent of choice, accompanied by a betalactam antibiotic, such as penicillin. The recommendation for clindamycin is based on in vitro studies demonstrating suppression of cytokine production. Penicillin should be added because of increasing resistance of group A streptococci to clindamycin (presently about 10% in the United States). S. aureus, Vibrio vulnificus, and a mixed infection of anaerobic and aerobic or gram-negative bacilli may also cause a necrotizing fasciitis (Fig. 1I). If mixed species of bacteria are noted on Gram stain of a necrotic wound or if an odor emanates from a wound, a diagnosis of type 1 necrotizing fasciitis should be assumed, pending culture results. In this case, broader antimicrobial coverage is advocated, such as piperacillintazobactam, to provide coverage of gram-negative bacilli, as well as anaerobic bacteria. Type 1 necrotizing fasciitis differs from that caused by streptococci (type 2 necrotizing fasciitis) in that the latter is usually more rapid in onset and progression and more frequently associated with toxic shock syndrome. Toxic shock syndrome is associated with streptococcal pyrogenic exotoxins. Adjunctive use of intravenous immunoglobulin has been recommended as a toxin neutralizer, although convincing data from clinical
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studies are lacking (6,7). Where a wound is present, tissue specimens are preferable to swabs and may grow pathogens in 20 to 40% of cases (4). However, the usual case is that there is no open wound. Punch biopsies of the skin may yield positive cultures in 20 to 30% of cases (8,9). Aspirates of the leading edge of cellulitis provide positive results in as few as 2% to as many as 40% of cases (3,10). Higher yields of aspirates may be obtained by first drawing ~1 ml of air into the barrel of the syringe and then aspirating the cellulitis with a largebore needle (≤18 gauge) for culture. The initial drawing of air into the syringe barrel is utilized to subsequently expel the small droplet of tissue fluid onto a petri dish (4,11,12). There are two situations where blood cultures are likely to be positive — in immunodeficient individuals and in those with necrotizing fasciitis, where up to 60% of blood cultures may be positive (13,14). However, absent these two situations, blood cultures of patients with cellulitis are positive in only 2% of cases (15). Because blood cultures of patients with uncomplicated cellulitis are of low yield, many experts advise against obtaining them unless there are particular risk factors. These risk factors occur in a patient with multiple co-morbidities who has had cellulitis of a proximal portion of a limb for <2 days and has not recently received antimicrobials (16). In low-risk patients, the rate of blood culture contamination often equals or exceeds that of true positives. The reporting of false-positive blood cultures often leads to extensive additional testing, extra cultures, and unnecessary procedures, such as echocardiograms. In this situation, the clinician is forced to institute unnecessary antimicrobial therapy and extend hospitalization.
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Cellulitis: sharp border
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Figure 1. Photographs illustrating certain features of cellulitis. (A) Streptococcal cellulitis with sharp but non-indurated borders. (B through D) Erysipelas with its “peau d’orange” appearance. Note in panel D that there is also a raised, indurated border. (E) Streptococcal cellulitis with spread beyond its original borders following 24 h of antibiotics. (F) Bulla formation due to streptococcal cellulitis. (G) Type 2 early necrotizing fasciitis caused by group A streptococci. (H) Type 2 necrotizing fasciitis with purplish bullae. (Reprinted with permission from HMP Communications. (I) Type 3 necrotizing fasciitis caused by Clostridium perfringens. (J) Type 1 necrotizing fasciitis due to mixed aerobic and anaerobic organisms in a diabetic patient. (Reprinted with permission from HMP Communications.)
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Nonetheless, clinicians feel obligated to obtain them in febrile patients with cellulitis in view of the increasing rates of antimicrobial resistance among staphylococci, as well as gram-negative bacilli. Another problem with blood cultures is the requisite 24- to 48-hour delay in obtaining antibiotic susceptibility reports. In the future, this delay may be circumvented through the use of DNA amplification assays, which will provide real-time reporting of blood culture and antibiotic susceptibility results. The availability of a culture result at the inception of therapy will allow rational antibiotic choices based on the patient’s own isolate rather than on previous epidemiological experience and predictions. Serological tests show evidence of group A streptococci in 83% of cases of cellulitis where no drainage is culturable (17). Antibodies to streptolysin O (ASO titer) and to streptococcal deoxyribonuclease B (anti-DNase B) are detectable not only in patients with cellulitis due to group A streptococci, but also in some with group G streptococcal infection, as well (18). The streptococcal anti-DNase B level is considered more sensitive than the ASO titer for the detection of streptococcal pyoderma (19,20).
Recurrent Cellulitis Streptococcal cellulitis is subject to recurrences. This may be due to persistence of tinea pedis or edema of the extremity. It may also be due to damage to the lymphatics, which may predispose the infected limb to further infection (3). If a patient suffers recurrent infection, long-term prophylaxis with an antibiotic, such as an oral penicillin (or for compliance purposes intramuscular bicillin), is recommended (21).
Cellulitis Due to S. aureus Cellulitis due to S. aureus may initially look quite similar to streptococcal cellulitis. As it evolves, it often proceeds to abscess formation, the drainage of which can be cultured following surgical incision. More than for streptococcal infections, culturing staphylococcal skin and soft tissue infections is very important for the detection of methicillinresistant S. aureus (MRSA), which has become increasingly prevalent in institutional settings (nosocomial MRSA), as well as in outpatient settings, where 154
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it is referred to as community-associated MRSA (CA-MRSA). MRSA infections carry a huge financial and personal price tag. It infects 126,000 hospitalized persons annually, and 5,000 patients die as a result of these infections. The excess costs attributable to nosocomial MRSA exceed $2.5 billion annually. The prevalence of CA-MRSA infections has increased to the point where 60 to 70% of all community-acquired S. aureus infections are now MRSA (22). This increase has been largely attributable to a single clone, USA 300, which is responsible for up to 99% of skin and soft tissue infections in many settings (23). CA-MRSA differs in several important ways from nosocomial MRSA infections. CA-MRSA is seen most frequently in those exposed to needles (drug addicts, hemodialysis patients, and insulin-dependent diabetics), in those who have been hospitalized or exposed to antibiotics in the previous 3 months, and in prison inmates, gay men, athletes in contact sports, and those of Polynesian and Native American ethnicity. However, due to its increased prevalence in the community, it is frequently seen in entirely healthy individuals without any of these risk factors. CA-MRSA infections present a considerable challenge in recognition and treatment. CA-MRSA carries the type IV SCCmecA cassette, which is quite a bit smaller than that carried by the nosocomial varieties (types I, II, and III), which carry antimicrobial resistance genes. While the nosocomial variety is resistant to trimethoprimsulfamethoxazole, minocycline, and fluoroquinolones, CA-MRSA is usually susceptible to these antimicrobials. There have been few robust studies of the effectiveness of these antimicrobials in treating moderate to severe MRSA infections. Since the majority of cellulitis is caused by streptococci without wound drainage that can be easily cultured, and because these antibiotics are not top choices to treat streptococcal infections, empirical treatment with these antibiotics may be less than optimal (24). Clindamycin, until recently, had been an excellent option to treat either streptococcal or staphylococcal cellulitis. However, inducible resistance to clindamycin by MRSA strains has © 2007 Elsevier
become increasingly prevalent (25), rendering the empirical choice of clindamycin a crap shoot in non-culturable cellulitis. For moderate to severe cellulitis caused by MRSA, it is recommended to use intravenously administered antibiotics, such as vancomycin, daptomycin, linezolid, or tigecycline. Vancomycin’s use has fallen under scrutiny recently because of MRSA’s rising MICs to vancomycin and the drug’s decreased bactericidal activity against MRSA. Additionally, the drug has been demonstrated to be less effective in the treatment of infections with MRSA strains with MICs in the range of 1 to 2 µg/ml (well within the range of susceptibility) than if the MIC is <1 µg/ml (26). CA-MRSA carries genes for multiple virulence factors, including the PantonValentin leukocidin, which have been associated with severe necrotizing skin and soft tissue infections, as well as pneumonia. The exact role of these toxins in toxic shock syndrome and necrotizing fasciitis is unclear, however. In addition to necrotizing fasciitis, these organisms cause severe necrotizing pneumonia, septic thombophlebitis, septic arthritis, and osteomyelitis of the hip and pelvic bones in children and young adults. Central to the treatment of these infections is the notion that binding and inactivation of the toxins may be helpful. Clindamycin and linezolid may be able to accomplish this (24). Intravenous immune globulin contains antibodies to Panton-Valentine leukocidin and may also be useful in this context, although the data are conflicting (6,7,27). Because of the increasing prevalence and serious nature of these infections, a great deal of effort has been expended in understanding the epidemiology of MRSA to limit its spread. By far, the principal mode of spread is via the contaminated hands of health care providers. Recommendations include cohorting MRSA-infected, as well as colonized, patients; contact precautions (including hand hygiene and decontamination of the environment and equipment); limitation of the use of fluoroquinolones and third-generation cephalosporins; and “bundles” (guidelines) for the placement and maintenance of central venous lines. Active surveillance, accompanied by Clinical Microbiology Newsletter 29:20,2007
attempts at decolonization, termed “search and destroy” (28,29), has been demonstrated to dramatically reduce the number of MRSA infections (30,31).
Toxic Shock Syndrome Toxic shock syndrome due to S. aureus wound colonization may occur without signs of infection. Staphylococcal toxic shock syndrome differs from streptococcal in several ways. While the usual signs of sepsis syndrome may accompany both, diarrhea and an erythroderma rash may be early findings in the former case. In streptococcal toxic shock syndrome, a rash usually is not present. When it is present, it is a generalized maculopapular eruption.
The MRSA Carrier State Cutaneous abscesses, either small furuncles or larger carbuncles due to S. aureus, may occur as outbreaks involving families, sports teams, or large communities. These individuals are usually healthy without any obvious immune defects. They may, however, be colonized in the nose or perineum by S. aureus, which has been identified in 30% or more of healthy individuals (32,33). The occurrence of these infections in clusters has been blamed on poor personal hygiene and close contact but is undoubtedly the result of asymptomatic carriage. Nasal colonization commonly precedes serious infection with methicillinsusceptible S. aureus (MSSA), but the situation is less clear for MRSA. CAMRSA is less frequently a colonizer than MSSA. However, MRSA tends to be much more invasive than MSSA. In a study of 812 military recruits whose nares were initially cultured, 253 (31%) were positive for S. aureus. Of these 253 soldiers, 229 (28%) were positive for MSSA, while 24 (3%) were positive for MRSA. However, only 8 of the 229 (3%) colonized with MSSA developed an invasive infection, while 9 of 24 (38%) colonized with MRSA developed invasive infections (34). Nearly one-third of patients colonized with a nosocomial strain of MRSA in an ICU developed invasive disease within 18 months (31). The situation, however, is further complicated by carriage being persistent in some persons and transient in others. Additionally, the nares are not the only site where colonization occurs. The rectum may also be an important Clinical Microbiology Newsletter 29:20,2007
reservoir among those with CA-MRSA infections (35). Topical antibacterial agents and microbicides are the preferred method of MRSA eradication. Mupirocin ointment administered twice daily in the anterior nares for 1 week has been reported to be 95% to 100% effective in the treatment of MRSA outbreaks in patients undergoing hemodialysis (36) but only 61% effective in controlling outbreaks in a nursing home (37). However, its use has been associated with the development of resistance to this agent in 19% of patients. The gene encoding high-level mupirocin resistance, mupA, has been found on a plasmid in USA300 MRSA clones (38). When in combination with mupirocin, chlorhexidine washes have been shown to increase the efficacy of decolonization. Whether resistance to chlorhexidine will develop is unknown (39). Mupirocin ointment in combination with chlorhexidine washes may temporarily achieve decolonization, but the relapse rate is high. Eradication of MRSA carriage is not permanent and may last for as little as 90 days (28). Recolonization rates at 12 months are 50% for health care workers (40) and 75% for peritoneal dialysis patients (41). The recolonization rate for hemodialysis patients is 56% at 4 months (36). For HIV-infected patients, the recolonization rate is 71% at 2.5 months (42). Relapses are often treated with rifampin in combination with another oral antimicrobial active against MRSA. Widespread use of systemic antimicrobials, however, has been associated with the development of drug resistance and the loss of valuable therapeutic agents for the treatment of infection. Finally, MRSA decolonization does not necessarily guarantee a reduction of subsequent infection.
Cellulitis Due to Gramnegative Bacilli According to the SENTRY Antimicrobial Surveillance Program (43), the following isolates have been detected in skin and soft tissue infections in hospitalized patients: S. aureus (45.9%), Pseudomonas aeruginosa (10.8%), Enterococcus species (8.2%), Escherichia coli (7%), Enterobacter species (5.8%), and Klebsiella species (5.1%). Gram-negative bacilli may cause cel© 2007 Elsevier
lulitis, especially in lower limb infections of diabetics, patients with endstage renal disease, or other co-morbidities involving immunodeficiencies. P. aeruginosa is especially associated with water habitats, such as “hot tub dermatitis” and “swimmer’s ear,” and its more malignant form of otitis externa seen in diabetics. Plantar puncture wounds in patients wearing sneakers or shoes may cause cellulitis or osteochondritis due to the fact that Pseudomonas colonizes sweaty feet. In immunosuppressed patients, Pseudomonas can cause cellulitis and bacteremia with sepsis syndrome. It may produce necrotic ulcerated lesions of the skin, called ecthyma gangrenosum. Aeromonas may cause cellulitis in persons with traumatic injuries in fresh water. V. vulnificus may cause cellulitis and sepsis in patients who are exposed to contaminated sea water. The septicemic variety is especially virulent in patients with cirrhosis. Haemophilus influenzae, previously a common cause of cellulitis in children and characterized by a purplish hue, has disappeared from the pediatric population since the vaccine became available. However, it may cause periorbital cellulitis in adults, especially due to ethmoid sinusitis or dacryocystitis.
Cellulitis Involving Traumatic and Surgical Wounds Infections of surgical sites (SSI) account for 38% of nosocomial infections in surgical patients (44). They are divided into categories of superficial incisional SSI, deep incisional SSI, and organ/space SSI. Only the first two are pertinent to this discussion. These infections may not appear until 5 to 20 days post-operatively. If the surgery was a clean procedure, infection by S . aureus is common. If surgery was performed on the intestinal tract or the female genital tract, a mixed infection of grampositive, gram-negative, and anaerobic organisms is likely. The treatment of SSI usually requires opening the infected wound to allow drainage. If there is <5 cm of erythema and induration surrounding the wound and if the patient has minimal signs of infection (fever of <38.5°C and a pulse of <100 beats/min), antibiotics may not be required. If the patient is febrile or if the erythema and induration are >5 cm, 0196-4399/00 (see frontmatter)
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a short course of 1 to 2 days of antibiotics, along with drainage, is recommended (3). Trauma, especially due to bullet and shrapnel wounds, may develop infection by P. aeruginosa and other gramnegative bacilli. Acinetobacter has been especially troublesome in Iraqi war casualties. Those who develop cellulitis following cat or dog bites are usually infected by Pasteurella multocida. Infection following human bites usually involves a mixture of bacteria found in the mouth, including streptococci, Eikenella corrodens, and anaerobic organisms.
Cellulitis of the Foot in Diabetics Limb infections in diabetics are a cause of substantial morbidity and may lead to limb amputation. They are frequently associated with plantar ulcers due to the peripheral neuropathy of diabetes (Fig.1J). Diabetic limb infections may be further complicated by peripheral vascular disease and various immunological impairments associated with diabetes. Infections may involve multiple organisms, including S. aureus (including MRSA), streptococci (especially group B streptococcus), anaerobic organisms, and gram-negative bacilli. Management of diabetic foot infections is well described in guidelines (45). Tissue specimens obtained by biopsy, ulcer curettage, or aspiration are preferable to wound swabs. Antibiotic therapy is only a small part of the treatment of diabetic limb infections. Vascular evaluation, surgical consultation for debridement when necrotic tissue or osteomyelitis is present, blood sugar control, and off-weighting of the foot are all important facets of the complete treatment of diabetic limb infections. The use of granulocyte colony-stimulating factors (45) and hyperbaric oxygen therapy may be helpful adjunctive measures, although convincing trial data are lacking (46,47).
Cellulitis in the Immunocompromised Patient Immunocompromised patients are at increased risk of skin and soft tissue infections. When infection occurs, it is critical to establish a specific etiologic diagnosis, because a wide variety of pathogens could be involved, depending on the type of immunodeficiency. Diagnosis may be further complicated 156
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by a reduced inflammatory response, making these types of infections less clinically obvious. Neutropenia, hypogammaglobulinemia, and cell-mediated deficiencies are each associated with specific types of infections. Neutropenic patients may, in the early course of their neutropenia, develop pyogenic infection and/or ecthyma lesions due to gram-positive cocci (including both MSSA and MRSA, viridans streptococci, and vancomycin-resistant enterococci), as well as gram-negative bacilli, such as P. aeruginosa. Later in their neutropenic course, they are prone to develop fungal infections due to Aspergillus and Candida species. Management of these types of infections is well described in guidelines (48,45). Hypogammaglobulinemic patients are susceptible to skin and soft tissue infection caused by S. aureus. Supplementation with intravenous gammaglobulin, incision and drainage of soft tissue abscesses, and antibiotic therapy may all be required for their management. Patients with deficiencies of cellmediated immunity, such as transplant recipients may develop fungal skin infections, due to Aspergillus and Rhizopus species and molds. Cutaneous infection due to Nocardia species and non-tuberculous mycobacterial infections may also occur. HIV-positive patients may develop disseminated cryptococcosis, histoplasmosis, and fusariosis with papular or nodular skin lesions. Diagnosis of fungal infections is aided by antigen tests for Cryptococcus and Aspergillus. Biopsy is often required to definitively diagnose these infections in order to direct pathogen-specific antimicrobial therapy.
Adjunctive Measures No discussion of cellulitis is complete without mention of certain therapeutic measures that must be undertaken to treat it effectively. If the patient with cellulitis of the lower limb suffers from chronic venous insufficiency or edema from other causes, a compression dressing is very useful in accelerating the response of a streptococcal infection to antimicrobial therapy. In diabetics, control of blood sugar, vascular remediation, debridement of necrotic tissue, and offweighting of the infected extremity are all necessary for successful treatment. © 2007 Elsevier
In a patient neutropenic from chemotherapy, it is helpful to treat with filgastrim to normalize the white blood cell count as quickly as possible. Probably the most important advance in the care of infected wounds has been the use of negative-pressure wound therapy. The theory behind this technique is that wound exudates are replete with proteases and other substances that retard wound healing and their removal accelerates healing. Multiple studies confirm its usefulness (49) in treating large wounds with exudates. Hyperbaric oxygen is a somewhat controversial measure for the treatment of anaerobic or diabetic limb infections. Arguments in favor (46) and against (47) its use both point out the excessive cost of a treatment course (approximately $20,000). The Centers for Medicare and Medicaid Services have approved it for diabetic foot ulcers that have failed standard wound care treatment for 30 days and where the ulcer penetrates to tendon, bone, or joint or is associated with deep abscess, osteomyelitis, or gangrene. An important consideration in the treatment of cellulitis is to achieve a more rapid response by modulation downward of the inflammatory response. It is not infrequent for the erythematous border of an area of cellulitis to expand during the first 24 hours of appropriate antimicrobial treatment. Fever may continue for 2, 3, or even 4 days of treatment. This is not due to insufficient antimicrobial potency but rather a slow diminution of the inflammatory response. A more rapid resolution of the clinical signs of cellulitis has been reported to occur by using either prednisone (50,51) or non-steroidal anti-inflammatory drugs (52) in combination with antimicrobial agents. In spite of these reports, combination treatment of cellulitis with anti-inflammatory agents and antimicrobial agents has yet to become the standard of care (53). References 1. Ruhe, J.J. et al. 2007. Community-onset methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: Impact of antimicrobial therapy on outcome. Clin. Infect. Dis. 44:777-784. 2. Swartz, M.N. 2007. Cellulitis. N. Engl. J. Med. 350:904-912. 3. Stevens, D.L. et al. 2005. Practice guidelines for the diagnosis and man-
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4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
agement of skin and soft-tissue infections. Clin. Infect. Dis. 41:373-406. Eron, L.J. et al. 2003. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J. Antimicrob. Chemother. 52(Suppl. S1):i3-i17. Doern, G.V. et al. 1997. Bacterial pathogens isolated from patients with skin and soft tissue infections: frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997). Diagn. Microbiol. Infect. Dis. 34:65-72. Kaul, R. et al. 1999. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome: a comparative observational study. Clin. Infect. Dis. 28:800-807. Darenberg, J. 2003. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. 37:333-340. Duvanel, T. et al. 1989. Quantitative cultures of biopsy specimens from cutaneous cellulitis. Arch. Intern. Med. 149:293-296. Hook, E.W. et al. 1986. Microbiologic evaluation of cutaneous cellulitis in adults. Arch. Intern. Med. 146:295-297. Bowler, P.G., B.I. Duerden, and D.G. Armstrong. 2001. Wound microbiology and associated approaches to wound management. Clin. Microbiol. Rev. 14:244-269. Lee, P.C., J. Turnidge, and P.J. McDonald. 1985. Fine-needle aspiration biopsy in diagnosis of soft tissue infections. J. Clin. Microbiol. 22:80-83. Eron, L.J. and B.A. Lipsky. 2006. Use of cultures in cellulitis: when, how, and why? Eur. J. Clin. Microbiol. Infect. Dis. 25:615-617. Zahar, J.R. et al. 2005. Severe soft tissue infections of the extremities in patients admitted to an intensive care unit. Clin. Microbiol. Infect. 11:79-82. Sharkawy, A. et al. 2002. Severe group A streptococcal soft-tissue infections in Ontario, 1992-1996. Clin. Infect. Dis. 23:454-460. Perl, B. et al. 1999. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin. Infect. Dis. 29:1483-1488. Peralta, G. et al. 2006. Risk factors for bacteremia in patients with limb cellulitis. Eur. J. Clin. Microbiol. Infect. Dis. 25:619-626. Jeng, A.C. and R.V. Nathan. 2005. The role of beta-hemolytic streptococci
Clinical Microbiology Newsletter 29:20,2007
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
versus Staphylococcus aureus in causing non-culturable skin and soft tissue infection, p. 96. In Abst. 43rd Ann. Meet. Infect. Dis. Soc. Am., Alexandria, VA. Eriksson, B. et al. 1996. Erysipelas: clinical and bacteriologic spectrum and serological aspects. Clin. Infect. Dis. 23:1091-1098. Bison, A.L. et al. 1973. Factors influencing serum antibody response to streptococcal pyoderma. J. Lab. Clin. Med. 81:410-420. Kaplan, K.L. et al. 1970. The influence of the site of infection on the immune response to group A streptococci. J. Clin. Investig. 49:1405-1414. Kremer, M. et al. 1991. Long-term antimicrobial therapy in the prevention of recurrent soft-tissue infections. J. Infect. 22:37-40. Kaplan, S.L. et al. 2005. Three-year surveillance of community-acquired Staphylococcus aureus infections in children. Clin. Infect. Dis. 40:17851791. King, M.D. et al. 2006. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA300 clone as the predominant cause of skin and soft-tissue infections. Ann. Intern. Med. 144:309-317. Moellering, R.C. 2006. The growing menace of community-acquired methicillin-resistant Staphylococcus aureus. Ann. Intern. Med. 144:368-70. Siberry, G.K. et al. 2003. Failure of clindamycin treatment of methicillinresistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin. Infect. Dis. 37:1257-1260. Sakoulas, G., R.C. Moellering, and G.M. Eliopoulos. 2006. Adaptation of methicillin-resistant Staphylococcus aureus in the face of vancomycin therapy. Clin. Infect. Dis. 42:S40-S50. Gauduchon, V. et al. 2004. Neutralization of Staphylococcus aureus Panton Valentine leukocidin by intravenous immunoglobulin in vitro. J. Infect. Dis. 189:346-353. Bradley, S.F. 2007. Eradication or decolonization of methicillin-resistant Staphylococcus aureus carriage: what are we doing and why are we doing it? Clin. Infect. Dis. 44:186-189. Simor, A.E. et al. 2007. Randomized controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus colonization. Clin. Infect. Dis. 44:178-
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185. Thompson, R.L., I. Cabezudo, and R.P. Wenzel. 1982. Epidemiology of nosocomial infections caused by methicillinresistant Staphylococcus aureus. Ann. Intern. Med. 97:309-317. Huang, S.S. et al. 2006. Impact of MRSA surveillance on bacteremia. Clin. Infect. Dis. 43:971-978. Graham, P.L., S.X. Lin, and E.L. Larson. 2006. A U.S. population-based survey of Staphylococcus aureus colonization. Ann. Intern. Med. 144:318-325. Rybak, M.J. and K.L. LaPlante. 2005. Community-associated methicillinresistant Staphylococcus aureus: a review. Pharmacotherapy 25:74-85. Ellis, M.W. et al. 2004. Natural history of community-acquired methicillinresistant Staphylococcus aureus colonization and infection in soldiers. Clin. Infect. Dis. 39:971-979. Eveillard, M. et al. 2006. Evaluation of a strategy of screening multiple anatomical sites for methicillin-resistant Staphylococcus aureus at admission to a teaching hospital. Infect. Control Hosp. Epidemiol. 27:181-184. Bommer, J. et al. 1995. Elimination of Staphylococcus aureus in hemodialysis patients. ASAIO J. 41:127-131. Mody, L. et al. 2003. Mupirocin decolonization of Staphylococcus aureus carriers in two long-term care facilities: a randomized, double-blinded, placebocontrolled trial. Clin. Infect. Dis. 37:1467-1474. Diep, B.A. et al. 2006. Complete genome sequence of USA300, an epidemic clone of community-acquired methicillin-resistant Staphylococcus aureus. Lancet 367:731-739. Weber, D.J. and W.A. Rutala. 2006. Use of germicides in the home and the healthcare setting: is there a relationship between germicide use and antibiotic resistance? Infect. Control Hosp. Epidemiol. 27:107-119. Loeb, M. et al. 2003. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization. Cochran Database Syst. 4:CD003340. Perez-Fontan, M. et al. 1993. Treatment of Staphylococcus aureus nasal carriers in continuous ambulatory peritoneal dialysis with mupirocin: long-term results. Am. J. Kidney Dis. 22:708-712. Martin, J.J. et al. 1999. A randomized clinical trial of mupirocin in the eradication of Staphylococcus aureus nasal carriage in human immunodeficiency virus disease. J. Infect. Dis. 180:896-899. Rennie, R.P. et al. 2003. Occurrence
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and antimicrobial susceptibility patterns of pathogens isolated from skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 2000). Diagn. Microbiol. Infect. Dis. 45:287-293. 44. Mangram, A.J. et al. 1999. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect. Control Hosp. Epidemiol. 20:250-278. 45. Lipsky, B.A. et al. 2004. Diagnosis and treatment of diabetic foot infections. Clin. Infect. Dis. 39:885-910. 46. Barnes, R.C. 2006. Point: hyperbaric oxygen is beneficial for diabetic foot
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wounds. Clin. Infect. Dis. 43:811-192. 47. Berendt, A.R. 2006. Counterpoint: hyperbaric oxygen for diabetic foot wounds is not effective. Clin. Infect. Dis. 43:193-198. 48. Huges, W.T. et al. 2002. Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin. Infect. Dis. 34:730-751. 49. Armstrong, D.G., L.A. Lavery, and the Diabetic Foot Study Consortium. 2005. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomized controlled trial. Lancet 366:1704-1710. 50. Bergkvist, P.I. and K. Sjobeck. 1997.
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Antibiotic and prednisolone therapy of erysipelas: a randomized, double blind, placebo-controlled study. Scand. J. Infect. Dis. 29:377-382. 51. Bergkvist, P.I. and K. Sjobeck. 1998. Relapse of erysipelas following treatment with prednisolone or placebo in addition to antibiotics: a 1-year followup. Scand. J. Infect. Dis. 30:206-207. 52. Dall, L. et al. 2005. Rapid resolution of cellulitis in patients managed with combination antibiotic and anti-inflammatory therapy. Cutis 15:177-180. 53. Eron, L.J. 2005. Infection and the inflammatory response: two sides of the same coin. Contagion 2:324-326.
Clinical Microbiology Newsletter 29:20,2007
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October 15, 2007
Cellulitis and the Role of the Clinical Microbiology Laboratory Lawrence J. Eron, M.D., F.A.C.P., and John A. Burns, School of Medicine, University of Hawaii, Kaiser Moanalua Medical Center, Honolulu, Hawaii
Abstract We are facing twin cellulitis epidemics — necrotizing infections due to streptococci and antimicrobial resistance of Staphylococcus aureus. Streptococci have been increasingly associated with necrotizing fasciitis with or without toxic shock syndrome, and now we have a clone of S. aureus (USA 300) that can cause the same syndrome. At present, more than 60% of S. aureus isolates are resistant to methicillin. No sooner have newer antimicrobials been approved than resistance to them has started to appear. The challenge facing medicine is to improve our diagnostic capabilities so that we can detect, in real time, the type of infection, the etiologic agent, and its antimicrobial susceptibility.
Introduction Cellulitis is a major clinical problem by virtue of its incidence and severity. In the last 15 years, two developments have occurred that have transformed the landscape of cellulitis. First, increasing resistance to antibiotics, especially in Staphylococcus aureus, has greatly complicated the choice of antimicrobials in treating infections. This decision is further complicated by the difficulty in obtaining a microbiologic specimen from patients with cellulitis on which to rationally base antibiotic treatment. Secondly, there has been an increase in toxic shock syndrome and necrotizing infections associated with virulence factors carried by streptococci and S. aureus, the two most common causes of cellulitis. Because of the requisite delay of 24 to 48 hours in obtaining the results of a wound culture on a patient with cellulitis, initial therapy is necessarily empirical. The choice of an antimicrobial agent is based on the clinical pre-
Mailing address: Lawrence J. Eron, M.D., F.A.C.P., 3288 Moanalua Rd., Honolulu, HI 96734. Tel.: (808) 432-7848. Fax: (808) 432-8141. E-mail: [email protected] Clinical Microbiology Newsletter 29:20,2007
sentation, relevant epidemiological information, and the statistical likelihood of certain organisms being present. An incorrect choice of initial antimicrobial treatment could delay convalescence and lead to an increase in morbidity and mortality (1). Because resistant organisms have become increasingly widespread, there is renewed interest in developing targetoriented treatment to narrow the spectrum of the therapeutic agent in order to decrease the selective pressure for resistant bacteria, after initially using a broad-spectrum antimicrobial agent selected empirically. Guidelines, therefore, have been developed to standardize the management of cellulitis. All guidelines emphasize the importance of obtaining a culture specimen to target pathogens that may be present. An important part of the guidelines is the classification of cellulitis, which may be based on anatomical considerations (2), pathological processes (3), or practical issues, such as when to hospitalize, when to switch to oral medications, and when to discontinue treatment (4).
involving the deep dermis and subcutaneous fat (Fig. 1A). It is differentiated from more superficial infections of the skin, such as impetigo and erysipelas (Fig. 1B). The most frequently affected parts of the body are the lower extremities, followed by the upper extremities, the head, and the trunk. In the immunocompetent host, S. aureus and Streptococcus pyogenes (group A streptococci) are the main causative agents. Other streptococci, such as Streptococcus agalactiae (group B streptococci) in the diabetic patient, and occasionally groups C and G streptococci, may also cause cellulitis. While S. aureus is present in 45% of cultures of skin and soft tissue infections, beta-hemolytic streptococci are found in only 5% (5). This discrepancy is due to the fact that streptococcal infections are difficult to culture and diagnosis is usually made either serologically or, more frequently, clinically — on the basis of certain features,
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such as a raised, indurated border (Fig. 1C), a “peau d’orange” appearance of the skin (Fig. 1D), and lymphangitic spread. The onset may be rapid and, in some cases, precedes the development of erythema of the skin. The erythema may spread beyond its original borders in the first 24 hours of antimicrobial therapy (Fig. 1E). Not infrequently, vesicles or bullae develop, which are filled with seropurulent fluid, the culture of which is usually negative (Fig. 1F). Streptococcal cellulitis may be recurrent, especially where there is lymphatic or venous compromise to the drainage of an extremity. It may also recur when tinea pedis provides an entrance site for the streptococci. It is important to correct whatever predisposing factors one can, such as using compression dressings for venous insufficiency and antifungals to treat tinea pedis. In the last 10 years, streptococcal necrotizing fasciitis has increased in prevalence. The classical presentation is that of a septic patient who complains of pain out of proportion to the clinical appearance of his cellulitis. While it may begin as an apparently superficial process (Fig. 1G), it spreads rapidly along fascial planes, and may be associated with toxic shock syndrome. The skin may become gangrenous with purplish bullae or ecchymoses (Fig. 1H). The mortality rate exceeds 50% unless early surgical debridement is undertaken, which is essential for the recovery of the patient. In the operating room, copious “dishwater drainage” is encountered, with edematous, gray, subcutaneous fat, and the superficial fascial plane is easily separated from the underlying muscle by blunt dissection. Diagnostic imaging via CT or MRI scans may occasionally be useful, but in the author’s experience, it is insuffi-
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ciently specific and merely ends up wasting time and money. When the diagnosis is uncertain, a small incision can be made and the subcutaneous fat inspected. Unlike ordinary streptococcal cellulitis, streptococcal necrotizing fasciitis will be culture positive, and a Gram stain of material obtained from the wound will likely reveal grampositive cocci in chains, consistent with streptococci, leading to an early microbiological diagnosis. Clindamycin is the antimicrobial agent of choice, accompanied by a betalactam antibiotic, such as penicillin. The recommendation for clindamycin is based on in vitro studies demonstrating suppression of cytokine production. Penicillin should be added because of increasing resistance of group A streptococci to clindamycin (presently about 10% in the United States). S. aureus, Vibrio vulnificus, and a mixed infection of anaerobic and aerobic or gram-negative bacilli may also cause a necrotizing fasciitis (Fig. 1I). If mixed species of bacteria are noted on Gram stain of a necrotic wound or if an odor emanates from a wound, a diagnosis of type 1 necrotizing fasciitis should be assumed, pending culture results. In this case, broader antimicrobial coverage is advocated, such as piperacillintazobactam, to provide coverage of gram-negative bacilli, as well as anaerobic bacteria. Type 1 necrotizing fasciitis differs from that caused by streptococci (type 2 necrotizing fasciitis) in that the latter is usually more rapid in onset and progression and more frequently associated with toxic shock syndrome. Toxic shock syndrome is associated with streptococcal pyrogenic exotoxins. Adjunctive use of intravenous immunoglobulin has been recommended as a toxin neutralizer, although convincing data from clinical
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studies are lacking (6,7). Where a wound is present, tissue specimens are preferable to swabs and may grow pathogens in 20 to 40% of cases (4). However, the usual case is that there is no open wound. Punch biopsies of the skin may yield positive cultures in 20 to 30% of cases (8,9). Aspirates of the leading edge of cellulitis provide positive results in as few as 2% to as many as 40% of cases (3,10). Higher yields of aspirates may be obtained by first drawing ~1 ml of air into the barrel of the syringe and then aspirating the cellulitis with a largebore needle (≤18 gauge) for culture. The initial drawing of air into the syringe barrel is utilized to subsequently expel the small droplet of tissue fluid onto a petri dish (4,11,12). There are two situations where blood cultures are likely to be positive — in immunodeficient individuals and in those with necrotizing fasciitis, where up to 60% of blood cultures may be positive (13,14). However, absent these two situations, blood cultures of patients with cellulitis are positive in only 2% of cases (15). Because blood cultures of patients with uncomplicated cellulitis are of low yield, many experts advise against obtaining them unless there are particular risk factors. These risk factors occur in a patient with multiple co-morbidities who has had cellulitis of a proximal portion of a limb for <2 days and has not recently received antimicrobials (16). In low-risk patients, the rate of blood culture contamination often equals or exceeds that of true positives. The reporting of false-positive blood cultures often leads to extensive additional testing, extra cultures, and unnecessary procedures, such as echocardiograms. In this situation, the clinician is forced to institute unnecessary antimicrobial therapy and extend hospitalization.
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Figure 1. Photographs illustrating certain features of cellulitis. (A) Streptococcal cellulitis with sharp but non-indurated borders. (B through D) Erysipelas with its “peau d’orange” appearance. Note in panel D that there is also a raised, indurated border. (E) Streptococcal cellulitis with spread beyond its original borders following 24 h of antibiotics. (F) Bulla formation due to streptococcal cellulitis. (G) Type 2 early necrotizing fasciitis caused by group A streptococci. (H) Type 2 necrotizing fasciitis with purplish bullae. (Reprinted with permission from HMP Communications. (I) Type 3 necrotizing fasciitis caused by Clostridium perfringens. (J) Type 1 necrotizing fasciitis due to mixed aerobic and anaerobic organisms in a diabetic patient. (Reprinted with permission from HMP Communications.)
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Nonetheless, clinicians feel obligated to obtain them in febrile patients with cellulitis in view of the increasing rates of antimicrobial resistance among staphylococci, as well as gram-negative bacilli. Another problem with blood cultures is the requisite 24- to 48-hour delay in obtaining antibiotic susceptibility reports. In the future, this delay may be circumvented through the use of DNA amplification assays, which will provide real-time reporting of blood culture and antibiotic susceptibility results. The availability of a culture result at the inception of therapy will allow rational antibiotic choices based on the patient’s own isolate rather than on previous epidemiological experience and predictions. Serological tests show evidence of group A streptococci in 83% of cases of cellulitis where no drainage is culturable (17). Antibodies to streptolysin O (ASO titer) and to streptococcal deoxyribonuclease B (anti-DNase B) are detectable not only in patients with cellulitis due to group A streptococci, but also in some with group G streptococcal infection, as well (18). The streptococcal anti-DNase B level is considered more sensitive than the ASO titer for the detection of streptococcal pyoderma (19,20).
Recurrent Cellulitis Streptococcal cellulitis is subject to recurrences. This may be due to persistence of tinea pedis or edema of the extremity. It may also be due to damage to the lymphatics, which may predispose the infected limb to further infection (3). If a patient suffers recurrent infection, long-term prophylaxis with an antibiotic, such as an oral penicillin (or for compliance purposes intramuscular bicillin), is recommended (21).
Cellulitis Due to S. aureus Cellulitis due to S. aureus may initially look quite similar to streptococcal cellulitis. As it evolves, it often proceeds to abscess formation, the drainage of which can be cultured following surgical incision. More than for streptococcal infections, culturing staphylococcal skin and soft tissue infections is very important for the detection of methicillinresistant S. aureus (MRSA), which has become increasingly prevalent in institutional settings (nosocomial MRSA), as well as in outpatient settings, where 154
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it is referred to as community-associated MRSA (CA-MRSA). MRSA infections carry a huge financial and personal price tag. It infects 126,000 hospitalized persons annually, and 5,000 patients die as a result of these infections. The excess costs attributable to nosocomial MRSA exceed $2.5 billion annually. The prevalence of CA-MRSA infections has increased to the point where 60 to 70% of all community-acquired S. aureus infections are now MRSA (22). This increase has been largely attributable to a single clone, USA 300, which is responsible for up to 99% of skin and soft tissue infections in many settings (23). CA-MRSA differs in several important ways from nosocomial MRSA infections. CA-MRSA is seen most frequently in those exposed to needles (drug addicts, hemodialysis patients, and insulin-dependent diabetics), in those who have been hospitalized or exposed to antibiotics in the previous 3 months, and in prison inmates, gay men, athletes in contact sports, and those of Polynesian and Native American ethnicity. However, due to its increased prevalence in the community, it is frequently seen in entirely healthy individuals without any of these risk factors. CA-MRSA infections present a considerable challenge in recognition and treatment. CA-MRSA carries the type IV SCCmecA cassette, which is quite a bit smaller than that carried by the nosocomial varieties (types I, II, and III), which carry antimicrobial resistance genes. While the nosocomial variety is resistant to trimethoprimsulfamethoxazole, minocycline, and fluoroquinolones, CA-MRSA is usually susceptible to these antimicrobials. There have been few robust studies of the effectiveness of these antimicrobials in treating moderate to severe MRSA infections. Since the majority of cellulitis is caused by streptococci without wound drainage that can be easily cultured, and because these antibiotics are not top choices to treat streptococcal infections, empirical treatment with these antibiotics may be less than optimal (24). Clindamycin, until recently, had been an excellent option to treat either streptococcal or staphylococcal cellulitis. However, inducible resistance to clindamycin by MRSA strains has © 2007 Elsevier
become increasingly prevalent (25), rendering the empirical choice of clindamycin a crap shoot in non-culturable cellulitis. For moderate to severe cellulitis caused by MRSA, it is recommended to use intravenously administered antibiotics, such as vancomycin, daptomycin, linezolid, or tigecycline. Vancomycin’s use has fallen under scrutiny recently because of MRSA’s rising MICs to vancomycin and the drug’s decreased bactericidal activity against MRSA. Additionally, the drug has been demonstrated to be less effective in the treatment of infections with MRSA strains with MICs in the range of 1 to 2 µg/ml (well within the range of susceptibility) than if the MIC is <1 µg/ml (26). CA-MRSA carries genes for multiple virulence factors, including the PantonValentin leukocidin, which have been associated with severe necrotizing skin and soft tissue infections, as well as pneumonia. The exact role of these toxins in toxic shock syndrome and necrotizing fasciitis is unclear, however. In addition to necrotizing fasciitis, these organisms cause severe necrotizing pneumonia, septic thombophlebitis, septic arthritis, and osteomyelitis of the hip and pelvic bones in children and young adults. Central to the treatment of these infections is the notion that binding and inactivation of the toxins may be helpful. Clindamycin and linezolid may be able to accomplish this (24). Intravenous immune globulin contains antibodies to Panton-Valentine leukocidin and may also be useful in this context, although the data are conflicting (6,7,27). Because of the increasing prevalence and serious nature of these infections, a great deal of effort has been expended in understanding the epidemiology of MRSA to limit its spread. By far, the principal mode of spread is via the contaminated hands of health care providers. Recommendations include cohorting MRSA-infected, as well as colonized, patients; contact precautions (including hand hygiene and decontamination of the environment and equipment); limitation of the use of fluoroquinolones and third-generation cephalosporins; and “bundles” (guidelines) for the placement and maintenance of central venous lines. Active surveillance, accompanied by Clinical Microbiology Newsletter 29:20,2007
attempts at decolonization, termed “search and destroy” (28,29), has been demonstrated to dramatically reduce the number of MRSA infections (30,31).
Toxic Shock Syndrome Toxic shock syndrome due to S. aureus wound colonization may occur without signs of infection. Staphylococcal toxic shock syndrome differs from streptococcal in several ways. While the usual signs of sepsis syndrome may accompany both, diarrhea and an erythroderma rash may be early findings in the former case. In streptococcal toxic shock syndrome, a rash usually is not present. When it is present, it is a generalized maculopapular eruption.
The MRSA Carrier State Cutaneous abscesses, either small furuncles or larger carbuncles due to S. aureus, may occur as outbreaks involving families, sports teams, or large communities. These individuals are usually healthy without any obvious immune defects. They may, however, be colonized in the nose or perineum by S. aureus, which has been identified in 30% or more of healthy individuals (32,33). The occurrence of these infections in clusters has been blamed on poor personal hygiene and close contact but is undoubtedly the result of asymptomatic carriage. Nasal colonization commonly precedes serious infection with methicillinsusceptible S. aureus (MSSA), but the situation is less clear for MRSA. CAMRSA is less frequently a colonizer than MSSA. However, MRSA tends to be much more invasive than MSSA. In a study of 812 military recruits whose nares were initially cultured, 253 (31%) were positive for S. aureus. Of these 253 soldiers, 229 (28%) were positive for MSSA, while 24 (3%) were positive for MRSA. However, only 8 of the 229 (3%) colonized with MSSA developed an invasive infection, while 9 of 24 (38%) colonized with MRSA developed invasive infections (34). Nearly one-third of patients colonized with a nosocomial strain of MRSA in an ICU developed invasive disease within 18 months (31). The situation, however, is further complicated by carriage being persistent in some persons and transient in others. Additionally, the nares are not the only site where colonization occurs. The rectum may also be an important Clinical Microbiology Newsletter 29:20,2007
reservoir among those with CA-MRSA infections (35). Topical antibacterial agents and microbicides are the preferred method of MRSA eradication. Mupirocin ointment administered twice daily in the anterior nares for 1 week has been reported to be 95% to 100% effective in the treatment of MRSA outbreaks in patients undergoing hemodialysis (36) but only 61% effective in controlling outbreaks in a nursing home (37). However, its use has been associated with the development of resistance to this agent in 19% of patients. The gene encoding high-level mupirocin resistance, mupA, has been found on a plasmid in USA300 MRSA clones (38). When in combination with mupirocin, chlorhexidine washes have been shown to increase the efficacy of decolonization. Whether resistance to chlorhexidine will develop is unknown (39). Mupirocin ointment in combination with chlorhexidine washes may temporarily achieve decolonization, but the relapse rate is high. Eradication of MRSA carriage is not permanent and may last for as little as 90 days (28). Recolonization rates at 12 months are 50% for health care workers (40) and 75% for peritoneal dialysis patients (41). The recolonization rate for hemodialysis patients is 56% at 4 months (36). For HIV-infected patients, the recolonization rate is 71% at 2.5 months (42). Relapses are often treated with rifampin in combination with another oral antimicrobial active against MRSA. Widespread use of systemic antimicrobials, however, has been associated with the development of drug resistance and the loss of valuable therapeutic agents for the treatment of infection. Finally, MRSA decolonization does not necessarily guarantee a reduction of subsequent infection.
Cellulitis Due to Gramnegative Bacilli According to the SENTRY Antimicrobial Surveillance Program (43), the following isolates have been detected in skin and soft tissue infections in hospitalized patients: S. aureus (45.9%), Pseudomonas aeruginosa (10.8%), Enterococcus species (8.2%), Escherichia coli (7%), Enterobacter species (5.8%), and Klebsiella species (5.1%). Gram-negative bacilli may cause cel© 2007 Elsevier
lulitis, especially in lower limb infections of diabetics, patients with endstage renal disease, or other co-morbidities involving immunodeficiencies. P. aeruginosa is especially associated with water habitats, such as “hot tub dermatitis” and “swimmer’s ear,” and its more malignant form of otitis externa seen in diabetics. Plantar puncture wounds in patients wearing sneakers or shoes may cause cellulitis or osteochondritis due to the fact that Pseudomonas colonizes sweaty feet. In immunosuppressed patients, Pseudomonas can cause cellulitis and bacteremia with sepsis syndrome. It may produce necrotic ulcerated lesions of the skin, called ecthyma gangrenosum. Aeromonas may cause cellulitis in persons with traumatic injuries in fresh water. V. vulnificus may cause cellulitis and sepsis in patients who are exposed to contaminated sea water. The septicemic variety is especially virulent in patients with cirrhosis. Haemophilus influenzae, previously a common cause of cellulitis in children and characterized by a purplish hue, has disappeared from the pediatric population since the vaccine became available. However, it may cause periorbital cellulitis in adults, especially due to ethmoid sinusitis or dacryocystitis.
Cellulitis Involving Traumatic and Surgical Wounds Infections of surgical sites (SSI) account for 38% of nosocomial infections in surgical patients (44). They are divided into categories of superficial incisional SSI, deep incisional SSI, and organ/space SSI. Only the first two are pertinent to this discussion. These infections may not appear until 5 to 20 days post-operatively. If the surgery was a clean procedure, infection by S . aureus is common. If surgery was performed on the intestinal tract or the female genital tract, a mixed infection of grampositive, gram-negative, and anaerobic organisms is likely. The treatment of SSI usually requires opening the infected wound to allow drainage. If there is <5 cm of erythema and induration surrounding the wound and if the patient has minimal signs of infection (fever of <38.5°C and a pulse of <100 beats/min), antibiotics may not be required. If the patient is febrile or if the erythema and induration are >5 cm, 0196-4399/00 (see frontmatter)
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a short course of 1 to 2 days of antibiotics, along with drainage, is recommended (3). Trauma, especially due to bullet and shrapnel wounds, may develop infection by P. aeruginosa and other gramnegative bacilli. Acinetobacter has been especially troublesome in Iraqi war casualties. Those who develop cellulitis following cat or dog bites are usually infected by Pasteurella multocida. Infection following human bites usually involves a mixture of bacteria found in the mouth, including streptococci, Eikenella corrodens, and anaerobic organisms.
Cellulitis of the Foot in Diabetics Limb infections in diabetics are a cause of substantial morbidity and may lead to limb amputation. They are frequently associated with plantar ulcers due to the peripheral neuropathy of diabetes (Fig.1J). Diabetic limb infections may be further complicated by peripheral vascular disease and various immunological impairments associated with diabetes. Infections may involve multiple organisms, including S. aureus (including MRSA), streptococci (especially group B streptococcus), anaerobic organisms, and gram-negative bacilli. Management of diabetic foot infections is well described in guidelines (45). Tissue specimens obtained by biopsy, ulcer curettage, or aspiration are preferable to wound swabs. Antibiotic therapy is only a small part of the treatment of diabetic limb infections. Vascular evaluation, surgical consultation for debridement when necrotic tissue or osteomyelitis is present, blood sugar control, and off-weighting of the foot are all important facets of the complete treatment of diabetic limb infections. The use of granulocyte colony-stimulating factors (45) and hyperbaric oxygen therapy may be helpful adjunctive measures, although convincing trial data are lacking (46,47).
Cellulitis in the Immunocompromised Patient Immunocompromised patients are at increased risk of skin and soft tissue infections. When infection occurs, it is critical to establish a specific etiologic diagnosis, because a wide variety of pathogens could be involved, depending on the type of immunodeficiency. Diagnosis may be further complicated 156
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by a reduced inflammatory response, making these types of infections less clinically obvious. Neutropenia, hypogammaglobulinemia, and cell-mediated deficiencies are each associated with specific types of infections. Neutropenic patients may, in the early course of their neutropenia, develop pyogenic infection and/or ecthyma lesions due to gram-positive cocci (including both MSSA and MRSA, viridans streptococci, and vancomycin-resistant enterococci), as well as gram-negative bacilli, such as P. aeruginosa. Later in their neutropenic course, they are prone to develop fungal infections due to Aspergillus and Candida species. Management of these types of infections is well described in guidelines (48,45). Hypogammaglobulinemic patients are susceptible to skin and soft tissue infection caused by S. aureus. Supplementation with intravenous gammaglobulin, incision and drainage of soft tissue abscesses, and antibiotic therapy may all be required for their management. Patients with deficiencies of cellmediated immunity, such as transplant recipients may develop fungal skin infections, due to Aspergillus and Rhizopus species and molds. Cutaneous infection due to Nocardia species and non-tuberculous mycobacterial infections may also occur. HIV-positive patients may develop disseminated cryptococcosis, histoplasmosis, and fusariosis with papular or nodular skin lesions. Diagnosis of fungal infections is aided by antigen tests for Cryptococcus and Aspergillus. Biopsy is often required to definitively diagnose these infections in order to direct pathogen-specific antimicrobial therapy.
Adjunctive Measures No discussion of cellulitis is complete without mention of certain therapeutic measures that must be undertaken to treat it effectively. If the patient with cellulitis of the lower limb suffers from chronic venous insufficiency or edema from other causes, a compression dressing is very useful in accelerating the response of a streptococcal infection to antimicrobial therapy. In diabetics, control of blood sugar, vascular remediation, debridement of necrotic tissue, and offweighting of the infected extremity are all necessary for successful treatment. © 2007 Elsevier
In a patient neutropenic from chemotherapy, it is helpful to treat with filgastrim to normalize the white blood cell count as quickly as possible. Probably the most important advance in the care of infected wounds has been the use of negative-pressure wound therapy. The theory behind this technique is that wound exudates are replete with proteases and other substances that retard wound healing and their removal accelerates healing. Multiple studies confirm its usefulness (49) in treating large wounds with exudates. Hyperbaric oxygen is a somewhat controversial measure for the treatment of anaerobic or diabetic limb infections. Arguments in favor (46) and against (47) its use both point out the excessive cost of a treatment course (approximately $20,000). The Centers for Medicare and Medicaid Services have approved it for diabetic foot ulcers that have failed standard wound care treatment for 30 days and where the ulcer penetrates to tendon, bone, or joint or is associated with deep abscess, osteomyelitis, or gangrene. An important consideration in the treatment of cellulitis is to achieve a more rapid response by modulation downward of the inflammatory response. It is not infrequent for the erythematous border of an area of cellulitis to expand during the first 24 hours of appropriate antimicrobial treatment. Fever may continue for 2, 3, or even 4 days of treatment. This is not due to insufficient antimicrobial potency but rather a slow diminution of the inflammatory response. A more rapid resolution of the clinical signs of cellulitis has been reported to occur by using either prednisone (50,51) or non-steroidal anti-inflammatory drugs (52) in combination with antimicrobial agents. In spite of these reports, combination treatment of cellulitis with anti-inflammatory agents and antimicrobial agents has yet to become the standard of care (53). References 1. Ruhe, J.J. et al. 2007. Community-onset methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: Impact of antimicrobial therapy on outcome. Clin. Infect. Dis. 44:777-784. 2. Swartz, M.N. 2007. Cellulitis. N. Engl. J. Med. 350:904-912. 3. Stevens, D.L. et al. 2005. Practice guidelines for the diagnosis and man-
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16.
17.
agement of skin and soft-tissue infections. Clin. Infect. Dis. 41:373-406. Eron, L.J. et al. 2003. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J. Antimicrob. Chemother. 52(Suppl. S1):i3-i17. Doern, G.V. et al. 1997. Bacterial pathogens isolated from patients with skin and soft tissue infections: frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997). Diagn. Microbiol. Infect. Dis. 34:65-72. Kaul, R. et al. 1999. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome: a comparative observational study. Clin. Infect. Dis. 28:800-807. Darenberg, J. 2003. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. 37:333-340. Duvanel, T. et al. 1989. Quantitative cultures of biopsy specimens from cutaneous cellulitis. Arch. Intern. Med. 149:293-296. Hook, E.W. et al. 1986. Microbiologic evaluation of cutaneous cellulitis in adults. Arch. Intern. Med. 146:295-297. Bowler, P.G., B.I. Duerden, and D.G. Armstrong. 2001. Wound microbiology and associated approaches to wound management. Clin. Microbiol. Rev. 14:244-269. Lee, P.C., J. Turnidge, and P.J. McDonald. 1985. Fine-needle aspiration biopsy in diagnosis of soft tissue infections. J. Clin. Microbiol. 22:80-83. Eron, L.J. and B.A. Lipsky. 2006. Use of cultures in cellulitis: when, how, and why? Eur. J. Clin. Microbiol. Infect. Dis. 25:615-617. Zahar, J.R. et al. 2005. Severe soft tissue infections of the extremities in patients admitted to an intensive care unit. Clin. Microbiol. Infect. 11:79-82. Sharkawy, A. et al. 2002. Severe group A streptococcal soft-tissue infections in Ontario, 1992-1996. Clin. Infect. Dis. 23:454-460. Perl, B. et al. 1999. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin. Infect. Dis. 29:1483-1488. Peralta, G. et al. 2006. Risk factors for bacteremia in patients with limb cellulitis. Eur. J. Clin. Microbiol. Infect. Dis. 25:619-626. Jeng, A.C. and R.V. Nathan. 2005. The role of beta-hemolytic streptococci
Clinical Microbiology Newsletter 29:20,2007
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
versus Staphylococcus aureus in causing non-culturable skin and soft tissue infection, p. 96. In Abst. 43rd Ann. Meet. Infect. Dis. Soc. Am., Alexandria, VA. Eriksson, B. et al. 1996. Erysipelas: clinical and bacteriologic spectrum and serological aspects. Clin. Infect. Dis. 23:1091-1098. Bison, A.L. et al. 1973. Factors influencing serum antibody response to streptococcal pyoderma. J. Lab. Clin. Med. 81:410-420. Kaplan, K.L. et al. 1970. The influence of the site of infection on the immune response to group A streptococci. J. Clin. Investig. 49:1405-1414. Kremer, M. et al. 1991. Long-term antimicrobial therapy in the prevention of recurrent soft-tissue infections. J. Infect. 22:37-40. Kaplan, S.L. et al. 2005. Three-year surveillance of community-acquired Staphylococcus aureus infections in children. Clin. Infect. Dis. 40:17851791. King, M.D. et al. 2006. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA300 clone as the predominant cause of skin and soft-tissue infections. Ann. Intern. Med. 144:309-317. Moellering, R.C. 2006. The growing menace of community-acquired methicillin-resistant Staphylococcus aureus. Ann. Intern. Med. 144:368-70. Siberry, G.K. et al. 2003. Failure of clindamycin treatment of methicillinresistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin. Infect. Dis. 37:1257-1260. Sakoulas, G., R.C. Moellering, and G.M. Eliopoulos. 2006. Adaptation of methicillin-resistant Staphylococcus aureus in the face of vancomycin therapy. Clin. Infect. Dis. 42:S40-S50. Gauduchon, V. et al. 2004. Neutralization of Staphylococcus aureus Panton Valentine leukocidin by intravenous immunoglobulin in vitro. J. Infect. Dis. 189:346-353. Bradley, S.F. 2007. Eradication or decolonization of methicillin-resistant Staphylococcus aureus carriage: what are we doing and why are we doing it? Clin. Infect. Dis. 44:186-189. Simor, A.E. et al. 2007. Randomized controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus colonization. Clin. Infect. Dis. 44:178-
© 2007 Elsevier
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
185. Thompson, R.L., I. Cabezudo, and R.P. Wenzel. 1982. Epidemiology of nosocomial infections caused by methicillinresistant Staphylococcus aureus. Ann. Intern. Med. 97:309-317. Huang, S.S. et al. 2006. Impact of MRSA surveillance on bacteremia. Clin. Infect. Dis. 43:971-978. Graham, P.L., S.X. Lin, and E.L. Larson. 2006. A U.S. population-based survey of Staphylococcus aureus colonization. Ann. Intern. Med. 144:318-325. Rybak, M.J. and K.L. LaPlante. 2005. Community-associated methicillinresistant Staphylococcus aureus: a review. Pharmacotherapy 25:74-85. Ellis, M.W. et al. 2004. Natural history of community-acquired methicillinresistant Staphylococcus aureus colonization and infection in soldiers. Clin. Infect. Dis. 39:971-979. Eveillard, M. et al. 2006. Evaluation of a strategy of screening multiple anatomical sites for methicillin-resistant Staphylococcus aureus at admission to a teaching hospital. Infect. Control Hosp. Epidemiol. 27:181-184. Bommer, J. et al. 1995. Elimination of Staphylococcus aureus in hemodialysis patients. ASAIO J. 41:127-131. Mody, L. et al. 2003. Mupirocin decolonization of Staphylococcus aureus carriers in two long-term care facilities: a randomized, double-blinded, placebocontrolled trial. Clin. Infect. Dis. 37:1467-1474. Diep, B.A. et al. 2006. Complete genome sequence of USA300, an epidemic clone of community-acquired methicillin-resistant Staphylococcus aureus. Lancet 367:731-739. Weber, D.J. and W.A. Rutala. 2006. Use of germicides in the home and the healthcare setting: is there a relationship between germicide use and antibiotic resistance? Infect. Control Hosp. Epidemiol. 27:107-119. Loeb, M. et al. 2003. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization. Cochran Database Syst. 4:CD003340. Perez-Fontan, M. et al. 1993. Treatment of Staphylococcus aureus nasal carriers in continuous ambulatory peritoneal dialysis with mupirocin: long-term results. Am. J. Kidney Dis. 22:708-712. Martin, J.J. et al. 1999. A randomized clinical trial of mupirocin in the eradication of Staphylococcus aureus nasal carriage in human immunodeficiency virus disease. J. Infect. Dis. 180:896-899. Rennie, R.P. et al. 2003. Occurrence
0196-4399/00 (see frontmatter)
157
and antimicrobial susceptibility patterns of pathogens isolated from skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 2000). Diagn. Microbiol. Infect. Dis. 45:287-293. 44. Mangram, A.J. et al. 1999. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect. Control Hosp. Epidemiol. 20:250-278. 45. Lipsky, B.A. et al. 2004. Diagnosis and treatment of diabetic foot infections. Clin. Infect. Dis. 39:885-910. 46. Barnes, R.C. 2006. Point: hyperbaric oxygen is beneficial for diabetic foot
158
0196-4399/00 (see frontmatter)
wounds. Clin. Infect. Dis. 43:811-192. 47. Berendt, A.R. 2006. Counterpoint: hyperbaric oxygen for diabetic foot wounds is not effective. Clin. Infect. Dis. 43:193-198. 48. Huges, W.T. et al. 2002. Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin. Infect. Dis. 34:730-751. 49. Armstrong, D.G., L.A. Lavery, and the Diabetic Foot Study Consortium. 2005. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomized controlled trial. Lancet 366:1704-1710. 50. Bergkvist, P.I. and K. Sjobeck. 1997.
© 2007 Elsevier
Antibiotic and prednisolone therapy of erysipelas: a randomized, double blind, placebo-controlled study. Scand. J. Infect. Dis. 29:377-382. 51. Bergkvist, P.I. and K. Sjobeck. 1998. Relapse of erysipelas following treatment with prednisolone or placebo in addition to antibiotics: a 1-year followup. Scand. J. Infect. Dis. 30:206-207. 52. Dall, L. et al. 2005. Rapid resolution of cellulitis in patients managed with combination antibiotic and anti-inflammatory therapy. Cutis 15:177-180. 53. Eron, L.J. 2005. Infection and the inflammatory response: two sides of the same coin. Contagion 2:324-326.
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