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EDUCATIONAL OBJECTIVE: Readers will recognize and treat skin and soft-tissue infections effectively
Skin and soft-tissue infections:
Classifying and treating a spectrum
■ ABSTRACT
Skin and soft-tissue infections (SSTIs) are a common
presenting problem in both inpatients and outpatients.
SSTIs have been broadly classified as complicated or
uncomplicated, but specific disease processes and patient
characteristics are important in guiding clinical manage-
ment. Early recognition of the extent of infection, close
follow-up, and familiarity with local antibiotic susceptibil-
ity data are critical to successful treatment.
■ KEY POINTS
Categories and definitions of specific subtypes of infec-
tions are evolving and have implications for treatment.
Methicillin-resistant Staphylococcus aureus (MRSA) and
streptococci continue to be the predominant organisms in
SSTIs.
A careful history and examination along with clinical
attention are needed to elucidate atypical and severe
infections.
Laboratory data can help characterize the severity of dis-
ease and determine the probability of necrotizing fasciitis.
Although cultures are unfortunately not reliably positive,
their yield is higher in severe disease and they should be ob-
tained, given the importance of antimicrobial susceptibility.
The Infectious Diseases Society of America has recently
released guidelines on MRSA, and additional guidelines ad-
dressing the spectrum of SSTIs are expected within a year.
S
kin and soft-tissue infections (SSTIs) are a common reason for presentation to outpatient practices, emergency rooms, and hospitals.1–5^ They account for more than 14 million outpatient visits in the United States each year,^1 and visits to the emergency room and admissions to the hospital for them are increasing.2,3^ Hospital admissions for SSTIs in- creased by 29% from 2000 to 2004.^3
■ MORE MRSA NOW,
BUT STREPTOCOCCI ARE STILL COMMON
The increase in hospital admissions for SSTIs has been attributed to a rising number of infec- tions with methicillin-resistant Staphylococcus aureus (MRSA).3– In addition, strains once seen mostly in the community and other strains that were associ- ated with health care are now being seen more often in both settings. Clinical characteristics do not differ between community-acquired and health-care-associated MRSA, and there- fore the distinction between the two is becom- ing less useful in guiding empiric therapy.6, After steadily increasing for several years, the incidence of MRSA has recently stabi- lized. The US Centers for Disease Control and Prevention maintains a surveillance program and a Web site on MRSA.^8 At the same time, infections with group A, B, C, or G streptococci continue to be com- mon. The SENTRY Antimicrobial Surveil- lance Program for the United States and Can- ada collected data from medical centers in five Canadian provinces and 32 US states between 1998 and 2004. The data set represents mostly complicated infections (see below). Staphylo- coccus was the most commonly retrieved or
REVIEW
*The author has disclosed serving on advisory committees or review panels for Baxter and Astella. doi:10.3949/ccjm.79a.
CREDIT^ CME SABITHA RAJAN, MD, MSc, FHM* Division of Inpatient Medicine, Scott & White Health System, Temple, TX; Assistant Professor of Medicine, Texas A&M Health Science Center, College Station, TX; Editor, Milliman Care Guidelines
SKIN AND SOFT-TISSUE INFECTIONS
ganism ( TABLE 1 ).^9 However, streptococci were likely underrepresented, since mild or super- ficial streptococcal cellulitis may not require hospital admission, and positive cultures can be difficult to obtain in streptococcal infec- tion.
■ COMPLICATED OR UNCOMPLICATED
Complicated skin and skin structure infections is a relatively new term coined in a 1998 US Food and Drug Administration (FDA) guideline for industry on developing antimicrobial drugs.^10 Subsequent trials of antibiotics and reviews of skin infections used the guideline and its defi- nitions. However, the category of complicated skin infections contained widely disparate clinical entities ranging from deep decubitus ulcers to diabetic foot infections ( TABLE 2 ).^10 The intent of the 1998 guideline was to provide not a clinical framework but rather a guide for industry in designing trials that would include similar groups of infections and therefore be relevant when compared with each other. In 2008, the Anti-Infective Drugs Advisory Committee was convened,^11
and subsequently, in August 2010, the FDA released a revision of the guide.^12 The revised guidelines specifically exclude many diagnoses, such as bite wounds, bone and joint infections, necrotizing fasciitis, dia- betic foot infections, decubitus ulcers, cath- eter site infections, myonecrosis, and ecthyma gangrenosum. Notably, the word “bacterial” in the title excludes mycobacterial and fungal infections from consideration. The diagnoses that are included include cellulitis, erysipelas, major cutaneous abscess, and burn infections. These are further specified to include 75 cm 2 of redness, edema, or induration to standard- ize the extent of the infection—ie, the infec- tion has to be at least this large or else it is not “complicated.” The terms “complicated” and “uncompli- cated” skin and skin structure infections per- sist and can be useful adjuncts in describing SSTIs.13–16^ However, more specific descrip- tions of SSTIs based on pathogenesis are more useful to the clinician and are usually the basis for guidelines, such as for preventing surgical site infections or for reducing amputations in diabetic foot infections. This review will focus on the general cat- egories of SSTI and will not address surgical site infections, pressure ulcers, diabetic foot infections, perirectal wounds, or adjuvant therapies in severe SSTIs, such as negative pressure wound care (vacuum-assisted closure devices) and hyperbaric chambers.
■ OTHER DISEASES CAN MIMIC SSTIs
SSTIs vary broadly in their location and se- verity. Although the classic presentation of ery- thema, warmth, edema, and tenderness often signals infection, other diseases can mimic SSTIs. Common ones that should be includ- ed in the differential diagnosis include gout, thrombophlebitis, deep vein thrombosis, con- tact dermatitis, carcinoma erysipeloides, drug eruption, and a foreign body reaction.17,
■ CLUES FROM THE HISTORY
Specific exposures. A detailed history can point to possible organisms and appropriate therapy. TABLE 3 lists several risk factors or ex-
The distinction
between
community-
acquired
and health-care-
associated
MRSA
is becoming
less useful
in guiding
empiric therapy
TABLE 1
The top 10 bacteria in skin and soft-tissue
infections: North America, 1998–
RANK PATHOGEN TOTAL ISOLATES % OF ISOLATES 1 Staphylococcus aureus 2,602 44.
2 Pseudomonas aeruginosa 648 11. 3 Enterococcus species 542 9. 4 Escherichia coli 422 7.
5 Enterobacter species 282 4. 6 Klebsiella species 248 4. 7 Beta-hemolytic Streptococcus 237 4.
8 Proteus mirabilis 166 2. 9 Coagulase-negative Staphylococcus 161 2. 10 Serratia species 125 2. 3&13/5&%'30..0&5(+ +0/&43/ #&%&/#"$)%+ &5"-$0/5&.103"3:$"64&40' 4,/"/%40'55446&/'&$50/4//035)".&3$" -"5/".&3$" "/%&6301& 3&1035'30.5)&4&/53:"/5.$30#"-4637&--"/$&130(3". o %"(/.$30#0-/'&$5%4 o 85)1&3.440/'30.&-4&7*&3
SKIN AND SOFT-TISSUE INFECTIONS
■ LABORATORY STUDIES
Simple, localized SSTIs usually do not require laboratory evaluation. Jenkins et al^21 recently demonstrated that by using an algorithm for the management of hospitalized patients with cellu- litis or cutaneous abscess, they could decrease re- source utilization, including laboratory testing, without adversely affecting clinical outcome. If patients have underlying disease or more extensive infection, then baseline chemistry values, a complete blood cell count, and the C-reactive protein level should be acquired.^19 Laboratory findings that suggest more severe disease include low sodium, low bicarbonate (or an anion gap), and high creatinine levels; new anemia; a high or very low white blood cell count; and a high C-reactive protein lev- el. A high C-reactive protein level has been associated with longer hospitalization.^22
A score to estimate the risk of necrotizing fasciitis Laboratory values should be used to calculate the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score ( TABLE 4 ).20,23^ Points are allocated for high C-reactive protein, cre- atinine, glucose, and white blood cell count values and for low red blood cell counts and so- dium levels. Patients with a score of five points or less are considered at low risk, while those with six or more points are considered to be at least at intermediate risk of necrotizing fasciitis. This tool was developed retrospectively but has been validated prospectively. It has a high sensitivity and a positive predictive value of 92% in patients with a score of six points or more. Its specificity is also high, with a nega- tive predictive value of 96%.20, Necrotizing fasciitis has a mortality rate of 23.5%, but this may be reduced to 10% with
TABLE 3
Risk factors for different bacterial skin and soft-tissue infections
RISK FACTOR ASSOCIATED PATHOGEN
Diabetes mellitus Staphylococcus aureus , group B streptococci, anaerobes, gram-negative bacilli
Cirrhosis Campylobacter fetus, Klebsiella pneumoniae, Escherichia coli, Capnocytophaga canimorsus, other gram-negative bacilli, Vibrio vulnificus
Neutropenia Pseudomonas aeruginosa
Human bite wounds Oral flora ( Eikenella corrodens )
Cat bite wounds Pasteurella multocida
Dog bite wounds C canimorsus, P multocida
Rat bite wounds Streptobacillus moniliformis
Animal contact Campylobacter species
Reptile contact Salmonella species
Hot tub exposure, loofah sponge P aeruginosa
Freshwater exposure Aeromonas hydrophila
Seawater (fish tank) exposure V vulnificus, Mycobacterium marinum
Intravenous drug abuse Methicillin-resistant S aureus, P aeruginosa
Subcutaneous drug abuse Anaerobes, especially E corrodens
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RAJAN
early detection and prompt surgical interven- tion.^15 Since necrotizing fasciitis is very dif- ficult to diagnose, clinicians must maintain a high level of suspicion and use the LRINEC score to trigger early surgical evaluation. Sur- gical exploration is the only way to definitive- ly diagnose necrotizing fasciitis.
Blood cultures in some cases Blood cultures have a low yield and are usually not cost-effective, but they should be obtained in patients who have lymphedema, immune deficiency, fever, pain out of proportion to the findings on examination, tachycardia, or hy- potension, as blood cultures are more likely to be positive in more serious infections and can help guide antimicrobial therapy. Blood cul- tures are also recommended in patients with infections involving specific anatomic sites, such as the mouth and eyes.^19
Aspiration, swabs, incision and drainage Fluid aspirated from abscesses and swabs of debrided ulcerated wounds should be sent for Gram stain and culture. Gram stain and culture have widely varying yields, from less than 5% to 40%, depending on the source and technique. 19 Cultures were not routinely obtained before MRSA emerged, but knowing antimicrobial susceptibility is now important to guide antibiotic therapy. Unfortunately, in cellulitis, swabs and aspi- rates of the leading edge have a low yield of around 10%. 25 One prospective study of 25 hospitalized patients did report a higher yield of positive cultures in patients with fe- ver or underlying disease, 26 so aspirates may be used in selected cases. In small studies, the yield of punch biopsies was slightly bet- ter than that of needle aspirates and was as high as 20% to 30%. 27
FIGURE 1. Depth of involvement in skin and soft-tissue infections.
.
Epidermis
Dermis
Superficial fascia
Subcutaneous tissue
Deep fascia
Muscle
Erysipelas Impetigo Folliculitis
Ecthyma Furunculosis Carbunculosis
Cellulitis
Necrotizing fasciitis
Myonecrosis (clostridial and nonclostridial)
RAJAN
for outpatient therapy include clindamycin on its own, trimethoprim-sulfamethoxazole or a tetracycline in combination with a beta-lac- tam, or linezolid on its own. Increasing rates of resistance to clindamy-
cin, tetracycline, and trimethoprim-sulfa- methoxazole in community-acquired MRSA may limit empiric treatment. In areas where resistance is prevalent, culture with antimi- crobial susceptibility testing may be required
TABLE 5
Treatment recommendations for methicillin-resistant Staphylococcus aureus
DIAGNOSIS TREATMENT COVERAGE Impetigo and other minor infections
Mupirocin 2% topical ointment (Bactroban) Methicillin-resistant Staphylococcus aureus (MRSA) Abscess, furuncle, carbuncle
Incision and drainage None
Purulent cellulitis Clindamycin (Cleocin) 300–450 mg by mouth three times a day
Beta-hemolytic Streptococcus and MRSA Trimethoprim-sulfamethoxazole (Bactrim) 1–2 double-strength tablets by mouth twice a day
MRSA
Doxycycline (Doryx) 100 mg by mouth twice a day MRSA Minocycline (Minocin) 200 mg for one dose, then 100 mg by mouth twice a day
MRSA
Linezolid (Zyvox) 600 mg by mouth twice a day MRSA Nonpurulent cellulitis A beta-lactam—eg, cephalexin (Keflex) 500 mg by mouth four times a day
Beta-hemolytic Streptococcus
Clindamycin 300–450 mg by mouth three times a day Beta-hemolytic Streptococcus and MRSA Linezolid 600 mg by mouth twice a day Beta-hemolytic Streptococcus and MRSA A beta-lactam—eg, amoxicillin 500 mg by mouth three times a day AND trimethoprim-sulfamethoxazole one or two double- strength tablets by mouth twice a day OR Doxycycline 100 mg by mouth twice a day OR Minocycline 200 mg for one dose then 100 mg by mouth twice a day
Beta-hemolytic Streptococcus and MRSA
Complicated SSTI Vancomycin 15–20 mg/kg intravenously every 8–12 hours MRSA Linezolid 600 mg by mouth or intravenously twice a day Beta-hemolytic Streptococcus and MRSA Daptomycin (Cubicin) 4 mg/kg intravenously per day MRSA Telavancin (Vibativ) 10 mg/kg intravenously per day MRSA Clindamycin 600 mg by mouth or intravenously three times a day
Beta-hemolytic Streptococcus and MRSA Complicated abscess Incision and drainage and oral or intravenous antibiotics to cover MRSA
As above
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SKIN AND SOFT-TISSUE INFECTIONS
before starting one of these antibiotics. The use of rifampin (Rifadin) as a single agent is not recommended because resistance is likely to develop. Also, rifampin is not use- ful as adjunctive therapy, as evidence does not support its efficacy.19,27,
■ ANTIMICROBIAL TREATMENT FOR SSTIs IN HOSPITALIZED PATIENTS
For hospitalized patients with a complicated or severe SSTI, empiric therapy for MRSA should be started pending culture results. FDA-approved options are vancomycin, li- nezolid, daptomycin (Cubicin), tigecycline (Tygacil), and telavancin (Vibativ). Data on clindamycin are very limited in this popula- tion. A beta-lactam antibiotic such as cefazo- lin (Ancef) may be considered in hospitalized patients with nonpurulent cellulitis, and the regimen can be modified to MRSA-active therapy if there is no clinical response. Li- nezolid, daptomycin, vancomycin, and tela- vancin have adequate streptococcal coverage in addition to MRSA coverage. Clindamycin is approved by the FDA for treating serious infections due to S aureus. It has excellent tissue penetration, particularly in bone and abscesses. Clindamycin resistance in staphylococci can be either constitutive or inducible, and clinicians must be watchful for signs of resis- tance. Diarrhea is the most common adverse ef- fect and occurs in up to 20% of patients. Clostridium difficile colitis may occur more frequently with clindamycin than with other oral agents, but it has also has been reported with fluoroquinolones and can be associated with any antibiotic therapy.^30 Trimethoprim-sulfamethoxazole is not FDA-approved for treating any staphylococ- cal infection. However, because 95% to 100% of community-acquired MRSA strains are sus- ceptible to it in vitro, it has become an im- portant option in the outpatient treatment of SSTIs. Caution is advised when using it in el- derly patients, particularly those with chronic renal insufficiency, because of an increased risk of hyperkalemia. Tetracyclines. Doxycycline is FDA-ap- proved for treating SSTIs due to S aureus ,
although not specifically for MRSA. Mino- cycline may be an option even when strains are resistant to doxycycline, since it does not induce its own resistance as doxycycline does. Tigecycline is a glycylcycline (a tetra- cycline derivative) and is FDA-approved in adults for complicated SSTIs and intra-ab- dominal infections. It has a large volume of distribution and achieves high concentrations in tissues and low concentrations in serum. The FDA recently issued a warning to con- sider alternative agents in patients with seri- ous infections because of higher rates of all- cause mortality noted in phase III and phase IV clinical trials. Due to this warning and the availability of multiple alternatives active against MRSA, tigecycline was not included in the Infectious Diseases Society of America guidelines.^31 Linezolid is a synthetic oxazolidinone and is FDA-approved for treating SSTIs and nosocomial pneumonia caused by MRSA. It has 100% oral bioavailability, so parenteral therapy should only be given if there are prob- lems with gastrointestinal absorption or if the patient is unable to take oral medications. Long-term use of linezolid (> 2 weeks) is limited by hematologic toxicity, especially thrombocytopenia, which occurs more fre- quently than anemia and neutropenia. Lactic acidosis and peripheral and optic neuropathy are also limiting toxicities. Although myelo- suppression is generally reversible, peripheral and optic neuropathy may not be. Linezolid should not used in patients tak- ing selective serotonin reuptake inhibitors if they cannot stop taking these antidepressant drugs during therapy, as the combination can lead to the serotonin syndrome. Vancomycin is still the mainstay of paren- teral therapy for MRSA infections. However, its efficacy has come into question, with con- cerns over its slow bactericidal activity and the emergence of resistant strains. The rate of treatment failure is high in those with infec- tion caused by MRSA having minimum in- hibitory concentrations of 1 μg/mL or greater. Vancomycin kills staphylococci more slowly than do beta-lactams in vitro and is clearly in- ferior to beta-lactams for methicillin-sensitive S aureus bacteremia. Daptomycin is a lipopeptide antibiotic
The depth
of infection
is hard to tell
on examination
SKIN AND SOFT-TISSUE INFECTIONS
epidemiologic characteristics cannot distinguish community-asso- ciated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investiga- tion. Clin Infect Dis 2007; 44:471–482.
- Centers for Disease Control and Prevention. MRSA Infections. http:// www.cdc.gov/mrsa/statistics/MRSA-Surveillance-Summary.html. Ac- cessed December 14, 2011.
- Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Con- temporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis 2007; 57:7–13.
- US Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER). Guidance for Industry: Uncomplicated and Complicated Skin and Skin Structure Infections—Developing Antimicrobial Drugs for Treatment (draft guidance). July 1998. http://www.fda.gov/ohrms/ dockets/98fr/2566dft.pdf. Accessed September 7, 2011.
- US Food and Drug Administration. CDER 2008 Meeting Documents. Anti-Infective Drugs Advisory Committee. http://www.fda.gov/ ohrms/dockets/ac/cder08.html#AntiInfective. Accessed September 7,
- US Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER). Guidance for Industry: Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment (draft guidance). August 2010. http://www.fda.gov/downloads/Drugs/GuidanceCom- plianceRegulatoryInformation/Guidances/ucm071185.pdf. Accessed December 14, 2011.
- Cornia PB, Davidson HL, Lipsky BA. The evaluation and treatment of complicated skin and skin structure infections. Expert Opin Pharma- cother 2008; 9:717–730.
- Ki V, Rotstein C. Bacterial skin and soft tissue infections in adults: a review of their epidemiology, pathogenesis, diagnosis, treatment and site of care. Can J Infect Dis Med Microbiol 2008; 19:173–184.
- May AK, Stafford RE, Bulger EM, et al; Surgical Infection Society. Treatment of complicated skin and soft tissue infections. Surg Infect (Larchmt) 2009; 10:467–499.
- Napolitano LM. Severe soft tissue infections. Infect Dis Clin North Am 2009; 23:571–591.
- Papadavid E, Dalamaga M, Stavrianeas N, Papiris SA. Subcutaneous sarcoidosis masquerading as cellulitis. Dermatology 2008; 217:212–
- Falagas ME, Vergidis PI. Narrative review: diseases that masquerade as infectious cellulitis. Ann Intern Med 2005; 142:47–55.
- Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005; 41:1373–1406.
- Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Labora-
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- Jenkins TC, Knepper BC, Sabel AL, et al. Decreased antibiotic utiliza- tion after implementation of a guideline for inpatient cellulitis and cutaneous abscess. Arch Intern Med 2011; 171:1072–1079.
- Lazzarini L, Conti E, Tositti G, de Lalla F. Erysipelas and cellulitis: clinical and microbiological spectrum in an Italian tertiary care hospital. J Infect 2005; 51:383–389.
- Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis 2007; 44:705–710.
- Hasham S, Matteucci P, Stanley PR, Hart NB. Necrotising fasciitis. BMJ 2005; 330:830–833.
- Newell PM, Norden CW. Value of needle aspiration in bacteriologic diagnosis of cellulitis in adults. J Clin Microbiol 1988; 26:401–404.
- Sachs MK. The optimum use of needle aspiration in the bacteriolog- ic diagnosis of cellulitis in adults. Arch Intern Med 1990; 150:1907–
- Liu C, Bayer A, Cosgrove SE, et al; Infectious Diseases Society of America. Clinical practice guidelines by the Infectious Diseases soci- ety of America for the treatment of methicillin-resistant Staphylo- coccus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18–e55.
- Hammond SP, Baden LR. Clinical decisions. Management of skin and soft-tissue infection—polling results. N Engl J Med 2008; 359:e20.
- Perlroth J, Kuo M, Tan J, Bayer AS, Miller LG. Adjunctive use of ri- fampin for the treatment of Staphylococcus aureus infections: a sys- tematic review of the literature. Arch Intern Med 2008; 168:805–819.
- Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998; 40:1–15.
- US Food and Drug Administration. FDA Drug Safety Communica- tion: increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections. September 2010. http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm. Accessed September 7, 2011.
- Moellering RC Jr. A 39-year-old man with a skin infection. JAMA 2008; 299:79–87.
- Zilberberg MD, Shorr AF, Micek ST, et al. Hospitalizations with healthcare-associated complicated skin and skin structure infections: impact of inappropriate empiric therapy on outcomes. J Hosp Med 2010; 5:535–540.
- Wong CH, Chang HC, Pasupathy S, Khin LW, Tan JL, Low CO. Necro- tizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am 2003; 85:1454–1460.
- Hsiao CT, Weng HH, Yuan YD, Chen CT, Chen IC. Predictors of mor- tality in patients with necrotizing fasciitis. Am J Emerg Med 2008; 26:170–175. ADDRESS : Sabitha Rajan, MD, MSc, FHM, Division of Inpatient Medicine, Scott & White Health System, 2401 South 31st Street, Temple, TX 78608; e-mail srajan@swmail.sw.org.
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