Idsa Guidelines

IDSA GUIDELINES
Practice Guidelines for the Diagnosis and

Management of Skin and Soft-Tissue Infections
Dennis L. Stevens,1,3 Alan L. Bisno,5 Henry F. Chambers,6,7 E. Dale Everett,13 Patchen Dellinger,2
Ellie J. C. Goldstein,8,9 Sherwood L. Gorbach,14 Jan V. Hirschmann,3,4 Edward L. Kaplan,15,16 Jose G. Montoya,10,11,12
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and James C. Wade17
1
Infectious Diseases Section, Veterans Affairs Medical Center, Boise, Idaho; 2Department of Surgery, 3University of Washington School
of Medicine, and 4Seattle Veterans Affairs Medical Center, Seattle, Washington; 5University of Miami Miller School of Medicine, Miami, Florida;
6
Infectious Diseases, San Francisco General Hospital, and 7University of California–San Francisco, San Francisco, 8R. M. Alden Research
Laboratory, Santa Monica, 9University of California, Los Angeles School of Medicine, Los Angeles, and 10Department of Medicine and 11Division
of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, and 12Research Institute, Palo Alto Medical Foundation,
Palo Alto, California; 13University of Missouri Health Science Center, University of Missouri, Columbia; 14Tufts University School of Medicine,
Boston, Massachusetts; 15University of Minnesota Medical School and 16Division of Epidemiology, University of Minnesota School of Public
Health, Minneapolis, Minnesota; and 17Division of Neoplastic Diseases and Related Disorders, Medical College of Wisconsin,
Milwaukee, Wisconsin
EXECUTIVE SUMMARY ters: results of blood culture and drug susceptibility

tests, complete blood cell count with differential, and
Soft-tissue infections are common, generally of mild to
creatinine, bicarbonate, creatine phosphokinase, and C-
modest severity, and are easily treated with a variety of
reactive protein levels. In patients with hypotension
agents. An etiologic diagnosis of simple cellulitis is fre-
and/or an elevated creatinine level, low serum bicar-
quently difficult and generally unnecessary for patients
bonate level, elevated creatine phosphokinase level (2–
with mild signs and symptoms of illness. Clinical as-
3 times the upper limit of normal), marked left shift,
sessment of the severity of infection is crucial, and sev-
or a C-reactive protein level 113 mg/L, hospitalization
eral classification schemes and algorithms have been
should be considered and a definitive etiologic diag-
proposed to guide the clinician [1]. However, most
nosis pursued aggressively by means of procedures such
clinical assessments have been developed from either
as Gram stain and culture of needle aspiration or punch
retrospective studies or from an author’s own “clinical
biopsy specimens, as well as requests for a surgical con-
experience,” illustrating the need for prospective studies
sultation for inspection, exploration, and/or drainage.
with defined measurements of severity coupled to man-
Other clues to potentially severe deep soft-tissue infec-
agement issues and outcomes.
tion include the following: (1) pain disproportionate
Until then, it is the recommendation of this com-
to the physical findings, (2) violaceous bullae, (3) cu-
mittee that patients with soft-tissue infection accom-
taneous hemorrhage, (4) skin sloughing, (5) skin an-
panied by signs and symptoms of systemic toxicity (e.g.,
fever or hypothermia, tachycardia [heart rate, 1100 esthesia, (6) rapid progression, and (7) gas in the tissue.
beats/min], and hypotension [systolic blood pressure, Unfortunately, these signs and symptoms often appear
!90 mm Hg or 20 mm Hg below baseline]) have blood
later in the course of necrotizing infections. In these
drawn to determine the following laboratory parame- cases, emergent surgical evaluation is of paramount im-
portance for both diagnostic and therapeutic reasons.
Emerging antibiotic resistance among Staphylococcus
Received 13 July 2005; accepted 14 July 2005; electronically published 14
aureus (methicillin resistance) and Streptococcus pyoge-
October 2005. nes (erythromycin resistance) are problematic, because
These guidelines were developed and issued on behalf of the Infectious
Diseases Society of America.
both of these organisms are common causes of a variety
Reprints or correspondence: Dr. Dennis L. Stevens, Infectious Disease Section, of skin and soft-tissue infections and because empirical
VAMC, 500 West Fort St. (Bldg. 45), Boise, ID 83702 (dlsteven@mindspring.com).
choices of antimicrobials must include agents with ac-
Clinical Infectious Diseases 2005; 41:1373–406
2005 by the Infectious Diseases Society of America. All rights reserved.
tivity against resistant strains. Minor skin and soft-tis-
1058-4838/2005/4110-0001$15.00 sue infections may be empirically treated with semi-
Guidelines for Skin and Soft-Tissue Infections • CID 2005:41 (15 November) • 1373
synthetic penicillin, first-generation or second-generation oral decision of how to treat impetigo depends on the number of
cephalosporins, macrolides, or clindamycin (A-I); however, lesions, their location (face, eyelid, or mouth), and the need
50% of methicillin-resistant S. aureus (MRSA) strains have in- to limit spread of infection to others. The best topical agent is
ducible or constitutive clindamycin resistance [2] (table 1). mupirocin (A-I), although resistance has been described [5];
Most community-acquired MRSA strains remain susceptible to other agents, such as bacitracin and neomycin, are considerably
trimethoprim-sulfamethoxazole and tetracycline, though treat- less effective treatments. Patients who have numerous lesions
ment failure rates of 21% have been reported in some series or who are not responding to topical agents should receive oral
with doxycycline or minocycline [3]. Therefore, if patients are antimicrobials effective against both S. aureus and S. pyogenes
sent home receiving these regimens, it is prudent to reevaluate (A-I) (table 2). Although rare in developed countries (!1 case/
them in 24–48 h to verify a clinical response. Progression de- 1,000,000 population per year), glomerulonephritis following
spite receipt of antibiotics could be due to infection with re- streptococcal infection may be a complication of impetigo
sistant microbes or because a deeper, more serious infection caused by certain strains of S. pyogenes, but no data demonstrate

exists than was previously realized. that treatment of impetigo prevents this sequela.
Patients who present to the hospital with severe infection or Classically, erysipelas, is a fiery red, tender, painful plaque
whose infection is progressing despite empirical antibiotic ther- with well-demarcated edges and is commonly caused by strep-
apy should be treated more aggressively, and the treatment tococcal species, usually S. pyogenes.
strategy should be based upon results of appropriate Gram Cellulitis may be caused by numerous organisms that are
stain, culture, and drug susceptibility analysis. In the case of S. indigenous to the skin or to particular environmental niches.
aureus, the clinician should assume that the organism is resis- Cellulitis associated with furuncles, carbuncles, or abscesses is
tant, because of the high prevalence of community-associated usually caused by S. aureus. In contrast, cellulitis that is diffuse
MRSA strains, and agents effective against MRSA (i.e., van- or unassociated with a defined portal is most commonly caused
comycin, linezolid, or daptomycin) should be used (A-I). Step- by streptococcal species. Important clinical clues to other causes
down to treatment with other agents, such as tetracycline or include physical activities, trauma, water contact, and animal,
trimethoprim-sulfamethoxazole, for MRSA infection may be insect, or human bites. In these circumstances appropriate cul-
possible, based on results of susceptibility tests and after an ture material should be obtained, as they should be in patients
initial clinical response. In the United States, not all laboratories who do not respond to initial empirical therapy directed against
perform susceptibility testing on S. pyogenes. However, the Cen- S. aureus and S. pyogenes and in immunocompromised hosts.
ters for Disease Control and Prevention has provided national Unfortunately, aspiration of skin is not helpful in 75%–80%
surveillance data that suggest a gradual trend of increasing mac- of cases of cellulitis, and results of blood cultures are rarely
rolide resistance of S. pyogenes from 4%–5% in 1996–1998 to positive (!5% of cases).
8%–9% in 1999–2001 [4]. Of interest, 99.5% of strains remain Penicillin, given either parenterally or orally depending on
susceptible to clindamycin, and 100% are susceptible to clinical severity, is the treatment of choice for erysipelas (A-I).
penicillin. For cellulitis, a penicillinase-resistant semisynthetic penicillin
Impetigo, erysipelas, and cellulitis. Impetigo may be or a first-generation cephalosporin should be selected (A-I),
caused by infection with S. aureus and/or S. pyogenes. The unless streptococci or staphylococci resistant to these agents
Table 1. Infectious Diseases Society of America–US Public Health Service Grading System for ranking recommendations
in clinical guidelines.
Category, grade Definition

Strength of recommendation
A Good evidence to support a recommendation for use; should always be offered
B Moderate evidence to support a recommendation for use; should generally be offered
C Poor evidence to support a recommendation; optional
D Moderate evidence to support a recommendation against use; should generally not be offered
E Good evidence to support a recommendation against use; should never be offered
Quality of evidence
I Evidence from ⭓1 properly randomized, controlled trial
II Evidence from ⭓1 well-designed clinical trial, without randomization; from cohort or case-con-
trolled analytic studies (preferably from 11 center); from multiple timeseries; or from dra-
matic results from uncontrolled experiments
III Evidence from opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert committees
1374 • CID 2005:41 (15 November) • Stevens et al.

are common in the community. For penicillin-allergic patients, the bite occurred. Patients not allergic to penicillin should re-
choices include clindamycin or vancomycin. ceive treatment with oral amoxicillin-clavulanate or with in-
Lack of clinical response could be due to unusual organisms, travenous ampicillin-sulbactam or ertapenem (B-II), because
resistant strains of staphylococcus or streptococcus, or deeper agents such as dicloxacillin, cephalexin, erythromycin, and clin-
processes, such as necrotizing fasciitis or myonecrosis. In pa- damycin have poor activity against Pasteurella multocida. Al-
tients who become increasingly ill or experience increasing tox- though cefuroxime, cefotaxime, and ceftriaxone are effective
icity, necrotizing fasciitis, myonecrosis, or toxic shock syn- against P. multocida, they do not have good anaerobic spectra.
drome should be considered, an aggressive evaluation initiated, Thus, cefoxitin or carbapenem antibiotics could be used par-
and antibiotic treatment modified, on the basis of Gram stain enterally in patients with mild penicillin allergies. Patients with
results, culture results, and antimicrobial susceptibilities of or- previous severe reactions can receive oral or intravenous doxy-
ganisms obtained from surgical specimens. cycline, trimethoprim-sulfamethoxazole, or a fluoroquinolone
Necrotizing infections. Necrotizing fasciitis may be mon- plus clindamycin.

omicrobial and caused by S. pyogenes, Vibrio vulnificus, or Aero- Human bites may occur from accidental injuries, purposeful
monas hydrophila. Recently, necrotizing fasciitis was described biting, or closed fist injuries. The bacteriologic characteristics
in a patient with MRSA infection [7]. Polymicrobial necrotizing of these wounds are complex but include infection with aerobic
fasciitis may occur following surgery or in patients with pe- bacteria, such as streptococci, S. aureus, and Eikenella corrodens,
ripheral vascular disease, diabetes mellitus, decubitus ulcers, as well as with multiple anaerobic organisms, including Fuso-
and spontaneous mucosal tears of the gastrointestinal or gas- bacterium, Peptostreptococcus, Prevotella, and Porphyromonas
trourinary tract (i.e., Fournier gangrene). As with clostridial species. E. corrodens is resistant to first-generation cephalospo-
myonecrosis, gas in the deep tissues is frequently found in these rins, macrolides, clindamycin, and aminoglycosides. Thus, in-
mixed infections. travenous treatment with ampicillin-sulbactam or cefoxitin is
Gas gangrene is a rapidly progressive infection caused by the best choice (B-III).
Clostridium perfringens, Clostridium septicum, Clostridium his- Infections associated with animal contact. Infections as-
tolyticum, or Clostridium novyi. Severe penetrating trauma or sociated with animal contact, although uncommon, are fre-
crush injuries associated with interruption of the blood supply quently severe, sometimes lethal, and diagnostically challenging.
are the usual predisposing factors. C. perfringens and C. novyi The potential use of Bacillus anthracis, Francisella tularensis,
infections have recently been described among heroin abusers and Yersinia pestis for bioterrorism has generated great interest
following intracutaneous injection of black tar heroin. C. sep- in rapid diagnostic techniques, because early recognition and
ticum, a more aerotolerant Clostridium species, may cause treatment are essential. Doxycycline or ciprofloxacin therapy is
spontaneous gas gangrene in patients with colonic lesions (such recommended in standard doses for nonpregnant adults and
as those due to diverticular disease), adenocarcinoma, or children 18 years of age, pending identification of the offending
neutropenia. agent (B-III).
Necrotizing fasciitis and gas gangrene may cause necrosis of Adults and children who receive a diagnosis of tularemia
skin, subcutaneous tissue, and muscle. Cutaneous findings of should receive an aminoglycoside, preferably streptomycin or
purple bullae, sloughing of skin, marked edema, and systemic gentamicin, for 7–10 days. In mild cases, doxycycline or tet-
toxicity mandate prompt surgical intervention. For severe racycline for 14 days is recommended (B-III) (comments re-
group A streptococcal and clostridial necrotizing infections, garding treatment of children !8 years of age are specified in
parenteral clindamycin and penicillin treatment is recom- table 3). Patients with bubonic plague should receive strepto-
mended (A-II). A variety of antimicrobials directed against aer- mycin, tetracycline, or chloramphenicol for 10–14 days and
obic gram-positive and gram-negative bacteria, as well as should be placed in isolation for 48 h after initiation of treat-
against anaerobes, may be used in mixed necrotizing infections ment, because some patients may develop secondary pneu-
(B-II). monic plague (B-III).
Infections following animal or human bites. Animal bites Data regarding antibiotic efficacy for treatment of cat-scratch
account for 1% of all emergency department visits, and dog disease are inconclusive, although 1 small study demonstrated
bites are responsible for 80% of such cases. Although Pasteurella more-rapid lymph node regression in patients receiving azith-
species are the most common isolates, cat and dog bites contain romycin, compared with patients receiving no treatment. Cu-
an average of 5 different aerobic and anaerobic bacteria per taneous bacillary angiomatosis has not been systematically stud-
wound, often including S. aureus, Bacteroides tectum, and Fu- ied, but treatment with erythromycin or doxycycline in
sobacterium, Capnocytophaga, and Porphyromonas species. The standard doses for 4 weeks has been effective in very small
decision to administer oral or parenteral antibiotics depends series (B-III).
on the depth and severity of the wound and on the time since On the basis of very incomplete data, erysipeloid is best
Table 2. Antimicrobial therapy for impetigo and for skin and soft-tissue infections.
Dosage
Antibiotic therapy,
a
by disease Adults Children Comment
b
Impetigo
Dicloxacillin 250 mg 4 times per day po 12 mg/kg/day in 4 divided doses po …
Cephalexin 250 mg 4 times per day po 25 mg/kg/day in 4 divided doses po …
c
Erythromycin 250 mg 4 times per day po 40 mg/kg/day in 4 divided doses po Some strains of Staphylococcus aureus
and Streptococcus pyogenes may be
resistant
Clindamycin 300–400 mg 3 times per day po 10–20 mg/kg/day in 3 divided doses po …
Amoxicillin/clavulanate 875/125 mg twice per day po 25 mg/kg/day of the amoxicillin compo- …
nent in 2 divided doses po

Mupirocin ointment Apply to lesions 3 times per day Apply to lesions 3 times per day For patients with a limited number of
lesions
MSSA SSTI
Nafcillin or oxacillin 1–2 g every 4 h iv 100–150 mg/kg/day in 4 divided doses Parental drug of choice; inactive against
MRSA
Cefazolin 1 g every 8 h iv 50 mg/kg/day in 3 divided doses For penicillin-allergic patients, except
those with immediate hypersensitivity
reactions
Clindamycin 600 mg/kg every 8 h iv or 300–450 25–40 mg/kg/day in 3 divided doses iv Bacteriostatic; potential of cross-resis-
mg 3 times per day po or 10–20 mg/kg/day in 3 divided tance and emergence of resistance in
doses po erythromycin-resistant strains; inducible
resistance in MRSA
Dicloxacillin 500 mg 4 times per day po 25 mg/kg/day in 4 divided doses po Oral agent of choice for methicillin-sus-
ceptible strains
Cephalexin 500 mg 4 times per day po 25 mg/kg/day in 4 divided doses po For penicillin-allergic patients, except
those with immediate hypersensitivity
reactions
Doxycycline, minocycline 100 mg twice per day po Not recommended for persons aged Bacteriostatic; limited recent clinical
d
!8 years experience
TMP-SMZ 1 or 2 double-strength tablets twice 8–12 mg/kg (based on the trimethoprim Bactericidal; efficacy poorly documented
per day po component) in either 4 divided doses
iv or 2 divided doses po
MRSA SSTI
Vancomycin 30 mg/kg/day in 2 divided doses iv 40 mg/kg/day in 4 divided doses iv For penicillin-allergic patients; parenteral
drug of choice for treatment of infec-
tions caused by MRSA
Linezolid 600 mg every 12 h iv or 600 mg 10 mg/kg every 12 h iv or po Bacteriostatic; limited clinical experience;
twice per day po no cross-resistance with other antibi-
otic classes; expensive; may eventually
replace other second-line agents as a
preferred agent for oral therapy of
MRSA infections
Clindamycin 600 mg/kg every 8 h iv or 300–450 25–40 mg/kg/day in 3 divided doses iv Bacteriostatic; potential of cross-resis-
mg 3 times per day po or 10–20 mg/kg/day in 3 divided tance and emergence of resistance in
doses po erythromycin-resistant strains; inducible
resistance in MRSA
Daptomycin 4 mg/kg every 24 h iv Not applicable Bactericidal; possible myopathy
Doxycycline, minocycline 100 mg twice per day po Not recommended for persons aged Bacteriostatic, limited recent clinical
d
!8 years experience
TMP-SMZ 1 or 2 double-strength tablets twice 8–12 mg/kg/day (based on the trimetho- Bactericidal; limited published efficacy
per day po prim component) in either 4 divided data
doses iv or 2 divided doses po
NOTE. MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; SSTI, skin and soft-tissue infection; TMP-SMZ, trimethoprim-sulfa-
methoxazole. iv, intravenously; po, orally.
a
Doses listed are not appropriate for neonates. Refer to the report by the Committee on Infectious Diseases, American Academy of Pediatrics [6] for neonatal
doses.
b
Infection due to Staphylococcus and Streptococcus species. Duration of therapy is ∼7 days, depending on the clinical response.
c
Adult dosage of erythromycin ethylsuccinate is 400 mg 4 times per day po.
d
See [6] for alternatives in children.
Table 3. Antibiotic therapy for community-acquired and bioterrorism-related cutaneous anthrax.
Dosage
Antibiotic therapy,
a
by route of anthrax acquisition Adults Children
Community acquired
Penicillin V 200–500 mg po 4 times daily in divided doses 25–50 mg/kg/day in divided doses 2 or 4 times per day
Penicillin G 8–12 MU/day iv in divided doses every 4-6 h 100,000–150,000 U/kg/day iv in divided doses every 4-6 h
Amoxicillin 500 mg po every 8 h Persons who weigh ⭐20 kg: 500 mg po every 8 h; persons who
weigh !20 kg: 40 mg/kg po in divided doses every 8 h
Erythromycin 250 mg po every 6 h 40 mg/kg/day in divided doses every 6 h
Erythromycin lactobionate 15–20 mg/kg (4 g maximum) iv in divided 20–40 mg/kg/day iv in divided doses every 6 h
doses every 6 h
Tetracycline 250–500 mg po or iv every 6 h …
b
Doxycycline 100 mg twice per day po or iv …

b
Ciprofloxacin 500 mg twice per day or 400 mg iv every 12 h …
Bioterrorism or suspected bioterrorism
b
Doxycycline 100 mg twice per day po or iv Persons who weigh ⭐45 kg: 2.2 mg/kg every 12 h; persons
who weigh 145 kg: 100 mg twice per day po or iv
b
Ciprofloxacin 500 mg twice per day 10–15 mg/kg every 12 h po or iv (not to exceed 1 g in 24 h)
NOTE. As a rule, the use of fluoroquinolones is contraindicated by the US Food and Drug Administration for children and adolescents !18 years of age. It
should also be noted that tetracyclines are rarely used in children !8 years of age. Alternatives should be strongly considered for these 2 antibiotics [6]. iv,
intravenously; po, orally.
a
Dosages listed for children are not appropriate for neonates. Refer to the report by the Committee on Infectious Diseases, American Academy of Pediatrics
[6] for neonatal dosing regimens.
b
Doxycycline, tetracycline, and ciprofloxacin are not generally recommended during pregnancy or for children !8 years of age, except in exceptional
circumstances.
treated with oral penicillin or amoxicillin for 10 days (B-III). occur as part of a broader systemic infection; and (3) the degree
E. rhusiopathiae is resistant in vitro to vancomycin, teicoplanin, and type of immune deficiency attenuate the clinical findings.
and daptomycin (E-III). The importance of establishing a diagnosis and performing
Surgical site infections. Surgical soft-tissue infections in- susceptibility testing is crucial, because many infections are
clude those occurring postoperatively and those severe hospital acquired, and mounting resistance among both gram-
enough to require surgical intervention for diagnosis and positive and gram-negative bacteria make dogmatic empirical
treatment. The algorithm presented clearly indicates that sur- treatment regimens difficult, if not dangerous. In addition, fun-
gical site infection rarely occurs during the first 48 h after gal infections may present with cutaneous findings.
surgery, and fever during that period usually arises from non- Immunocompromised patients who are very ill or experi-
infectious or unknown causes. In contrast, after 48 h, surgical encing toxicity typically require very broad-spectrum empirical
site infection is a more common source of fever, and careful agents that include specific coverage for resistant gram-positive
inspection of the wound is indicated. For patients with a bacteria, such as MRSA (e.g., vancomycin, linezolid, dapto-
temperature !38.5C and without tachycardia, observation, mycin, or quinupristin/dalfopristin). Coverage for gram-neg-
dressing changes, or opening the incision site suffices. Patients ative bacteria may include monotherapy with a cephalosporin
with a temperature 138.5C or a heart rate 1110 beats/min possessing activity against Pseudomonas species, with carba-
generally require antibiotics as well as opening of the suture penems, or with a combination of either a fluoroquinolone or
line. Infections developing after surgical procedures involving an aminoglycoside plus either an extended-spectrum penicillin
nonsterile tissue, such as colonic, vaginal, biliary or respira- or cephalosporin.
tory mucosa, may be caused by a combination of aerobic and Infections in patients with cell-mediated immunodeficiency
anaerobic bacteria. These infections can rapidly progress and (such as that due to Hodgkin disease, lymphoma, HIV infec-
involve deeper structures than just the skin, such as fascia, tion, bone marrow transplantation, and receipt of long-term
fat, or muscle (see table 4). high-dose immunosuppressive therapy) can be caused by either
Infections in the immunocompromised host. Skin and soft common or unusual bacteria, viruses, protozoa, helminths, or
tissues are common sites of infection in compromised hosts fungi. Although infection may begin in the skin, cutaneous
and usually pose major diagnostic challenges for the following lesions can also be the result of hematogenous seeding. A well-
3 reasons: (1) infections are caused by diverse organisms, in- planned strategy for prompt diagnosis, including biopsy and
cluding organisms not ordinarily considered to be pathogens aggressive treatment protocols, is essential. Diagnostic strategies
in otherwise healthy hosts; (2) infection of the soft tissues may require laboratory support capable of rapid processing and early
detection of bacteria (including Mycobacteria and Nocardia spe- Table 4. Antibiotic choices for incisional surgical site infec-
cies), viruses, and fungi. The algorithm presented provides an tions (SSIs).
approach to diagnosis and treatment. The empirical antibiotic
Antibiotic therapy for SSIs, by site of operation
guidelines are based on results of clinical trials, national sur-
veillance antibiograms, and consensus meetings. Because an- Intestinal or genital tract
timicrobial susceptibilities vary considerably across the nation, Single agents
Cefoxitin
clinicians must base empirical treatment on the antibiograms
Ceftizoxime
in their own location.
Ampicillin/sulbactam
Microbiologic cultures are important in establishing a spe-
Ticarcillin/clavulanate
cific diagnosis, and testing the drug susceptibility of organisms Piperacillin/tazobactam
is critical for optimal antimicrobial treatment. This guideline Imipenem/cilastatin
offers recommendations for empirical treatment of specific Meropenem

community-acquired and hospital-acquired infections. None- Ertapenem
theless, therapy may fail for several reasons: (1) the initial di- Combination agents
agnosis and/or treatment chosen is incorrect, (2) the etiologic Facultative and aerobic activity
agent from a given locale is resistant to antibiotics, (3) anti- Fluoroquinolone
microbial resistance develops during treatment, and (4) the Third-generation cephalosporin
infection is deeper and more complex than originally estimated. Aztreonama
Aminoglycoside
Anaerobic activity
INTRODUCTION
Clindamycin
This practice guideline provides recommendations for diag- Metronidazolea
nosis and management of skin and soft-tissue infections in Chloramphenicol
Penicillin agent plus b-lactamase inhibitor
otherwise healthy hosts and compromised hosts of all age
Nonintestinal
groups. These infections have diverse etiologies that depend,
Trunk and extremities away from axilla or perineum
in part, on the epidemiological setting. Thus, obtaining a careful
Oxacillin
history, including information about the patient’s immune First-generation cephalosporin
status, the geographical locale, travel history, recent trauma or Axillary or perineum
surgery, previous antimicrobial therapy, lifestyle, hobbies, and Cefoxitin
animal exposure or bites is key to developing an adequate dif- Ampicillin/sulbactam
ferential diagnosis and an appropriate index of suspicion for Other single agents as described above for intestinal and
specific etiological agents. Recognizing the physical examina- genital operations
tion findings and understanding the anatomical relationships a
Do not combine aztreonam with metronidazole, because this combination
of skin and soft tissue are also crucial for establishing the correct has no activity against gram-positive cocci.
diagnosis. In some cases, this information is insufficient, and

biopsy or aspiration of tissue may be necessary. In addition, Public Health Service grading system for ranking recommen-
radiographic procedures may be useful to determine the level dations in clinical guidelines (table 1).
of infection and the presence of gas or abscess. Finally, surgical
IMPETIGO
exploration or debridement is an important diagnostic, as well
as therapeutic, procedure in immunocompromised hosts or in Impetigo, a skin infection that is common throughout the
patients with necrotizing infections or myonecrosis. world, consists of discrete purulent lesions that are nearly al-
Three contemporary problems confounding the clinical eval- ways caused by b-hemolytic streptococci and/or S. aureus. Im-
uation of patients with skin and soft-tissue infection are di- petigo occurs most frequently among economically disadvan-
agnosis, severity of infection, and pathogen-specific antibiotic taged children in tropical or subtropical regions, but it is also
resistance patterns. Dozens of microbes may cause soft-tissue prevalent in northern climates during the summer months [8].
infections, and although specific bacteria may cause a particular Its peak incidence is among children aged 2–5 years, although
type of infection, considerable overlaps in clinical presentations older children and adults may also be afflicted [9, 10]. There
exist. Clues to the diagnosis or algorithmic approaches to di- is no sex predilection, and all races are susceptible.
agnosis are covered in detail in the text to follow. Specific Prospective studies of streptococcal impetigo have demon-
recommendations for therapy are given, each with a rating that strated that the responsible microorganisms initially colonize
indicates the strength of and evidence for recommendations, the unbroken skin [8], an observation that probably explains
expressed using the Infectious Diseases Society of America–US the influence of personal hygiene on disease incidence. Skin

colonization with a given streptococcal strain precedes the de- cently, S. pyogenes, are prevalent. Topical therapy with mupi-
velopment of impetiginous lesions by a mean duration of 10 rocin is equivalent to oral systemic antimicrobials [21, 22] (A-
days. Inoculation of surface organisms into the skin by abra- I) and may be used when lesions are limited in number. It is
sions, minor trauma, or insect bites then ensues. During the expensive, however, and some strains of staphylococci are re-
course of 2– 3 weeks, streptococcal strains may be transferred sistant [5]. Suppurative complications of streptococcal impetigo
from the skin and/or impetigo lesions to the upper respiratory are uncommon, and for as yet unexplained reasons, rheumatic
tract. In contrast, in patients with staphylococcal impetigo, the fever has never occurred after streptococcal impetigo. On the
pathogens are usually present in the nose before causing cu- other hand, cutaneous infections with nephritogenic strains of
taneous disease. group A streptococci are the major antecedent of poststrep-
Impetigo usually occurs on exposed areas of the body, most tococcal glomerulonephritis in many areas of the world. No
frequently the face and extremities. The lesions remain well- conclusive data indicate that treatment of streptococcal pyo-
localized but are frequently multiple and may be either bullous derma prevents nephritis [23], but such therapy is important

or nonbullous in appearance. Bullous lesions appear initially as an epidemiologic measure in eradicating nephritogenic
as superficial vesicles that rapidly enlarge to form flaccid bullae strains from the community.
filled with clear yellow fluid, which later becomes darker, more
turbid, and sometimes purulent. The bullae may rupture, often ABSCESSES, CELLULITIS, AND ERYSIPELAS
leaving a thin brown crust resembling lacquer [11]. The lesions
Cutaneous abscesses. Cutaneous abscesses are collections of
of nonbullous impetigo begin as papules that rapidly evolve
pus within the dermis and deeper skin tissues. They are
into vesicles surrounded by an area of erythema and then be-
usually painful, tender, and fluctuant red nodules, often sur-
come pustules that gradually enlarge and break down over a
mounted by a pustule and surrounded by a rim of erythem-
period of 4–6 days to form characteristic thick crusts. The
atous swelling. Cutaneous abscesses are typically poly-
lesions heal slowly and leave depigmented areas. A deeply ul- microbial, containing bacteria that constitute the normal
cerated form of impetigo is known as ecthyma. Although re- regional skin flora, often combined with organisms from ad-
gional lymphadenitis may occur, systemic symptoms are usually jacent mucous membranes [24–30]. S. aureus is present, usu-
absent. ally as a single pathogen, in only ∼25% of cutaneous abscesses
Bullous impetigo is caused by strains of S. aureus that pro- overall. Epidermoid cysts, often erroneously labeled “seba-
duce a toxin causing cleavage in the superficial skin layer. In ceous cysts,” ordinarily contain skin flora in the cheesy ke-
the past, nonbullous lesions were usually caused by streptococci. ratinous material, even when uninflamed. Cultures of in-
Now, most cases are caused by staphylococci alone or in com- flamed cysts also yield the same organisms, suggesting that
bination with streptococci [12, 13]. Streptococci isolated from the inflammation and purulence occur as a reaction to rupture
lesions are primarily group A organisms, but occasionally, other of the cyst wall and extrusion of its contents into the dermis,
serogroups (such as C and G) are responsible. rather than as an infectious complication [31].
Assays of streptococcal antibodies are of no value in the Effective treatment of abscesses and inflamed epidermoid
diagnosis and treatment of impetigo, but they provide helpful cysts entails incision, thorough evacuation of the pus, and prob-
supporting evidence of recent streptococcal infection in patients ing the cavity to break up loculations (A-I). Simply covering
suspected of having poststreptococcal glomerulonephritis. The the surgical site with a dry dressing is usually the easiest and
anti–streptolysin O response is weak in patients with strepto- most effective treatment of the wound [32, 33], although some
coccal impetigo [14, 15], presumably because skin lipids sup- clinicians pack it with gauze or suture it closed. Gram stain,
press streptolysin O response [16], but anti–DNAse B levels are culture, and systemic antibiotics are rarely necessary (E-III).
consistently elevated [14, 15]. Unusual exceptions include the presence of multiple lesions,
In the past, therapy directed primarily at group A strepto- cutaneous gangrene, severely impaired host defenses, extensive
cocci (e.g., penicillin) was successful, both in healing the lesions surrounding cellulitis, or severe systemic manifestations of in-
and decreasing recurrences of nonbullous impetigo for at least fection, such as high fever.
several weeks [17, 18]. Because S. aureus currently accounts for Furuncles and carbuncles. Furuncles (or “boils”) are in-
most cases of bullous impetigo, as well as for a substantial fections of the hair follicle, usually caused by S. aureus, in which
portion of nonbullous infections [13, 19, 20], penicillinase- suppuration extends through the dermis into the subcutaneous
resistant penicillins or first- generation cephalosporins are pre- tissue, where a small abscess forms. They differ, therefore, from
ferred (A-I), although impetigo caused by MRSA is increasing folliculitis, in which inflammation is more superficial and pus
in frequency [13] (table 2). Erythromycin has been a mainstay is present in the epidermis. Furuncles can occur anywhere on
of pyoderma therapy, but its utility may be lessened in areas hairy skin. Each lesion consists of an inflammatory nodule and
where erythromycin-resistant strains of S. aureus, or more re- an overlying pustule through which hair emerges. When in-
fection extends to involve several adjacent follicles, producing practice, however, distinguishing between cellulitis and erysip-
a coalescent inflammatory mass with pus draining from mul- elas clinically may be difficult, and some physicians, especially
tiple follicular orifices, the lesion is called a carbuncle. Car- in northern Europe, use the term “erysipelas” to describe both
buncles tend to develop on the back of the neck and are es- infections.
pecially likely to occur in diabetic persons. Erysipelas is distinguished clinically from other forms of cu-
For small furuncles, moist heat, which seems to promote taneous infection by the following 2 features: the lesions are
drainage, is satisfactory. Larger furuncles and all carbuncles raised above the level of the surrounding skin, and there is a
require incision and drainage. Systemic antibiotics are usually clear line of demarcation between involved and uninvolved
unnecessary, unless extensive surrounding cellulitis or fever oc- tissue [41]. This disorder is more common among infants,
curs (E-III). Outbreaks of furunculosis caused by MSSA, as well young children, and older adults. It is almost always caused by
as by MRSA, may occur in families and other settings involving b-hemolytic streptococci (usually group A), but similar lesions
close personal contact (e.g., prisons), especially when skin in- can be caused by streptococci from serogroups C or G. Rarely,

jury is common, such as sports teams or outdoor recreation group B streptococci or S. aureus may be involved. In older
groups [34–36]. Inadequate personal hygiene and exposure to reports, erysipelas characteristically involved the butterfly area
others with furuncles are important predisposing factors in of the face, but at present, the lower extremities are more fre-
these settings. In some cases, fomites may harbor the organism quently affected [42, 43].
and facilitate transmission of the infection. Depending on the With early diagnosis and proper treatment, the prognosis is
individual circumstances, control of outbreaks may require excellent. Rarely, however, the infection may extend to deeper
bathing with antibacterial soaps, such as chlorhexidine; thor- levels of the skin and soft tissues. Penicillin, given either par-
ough laundering of clothing, towels, and bed wear; separate enterally or orally depending on clinical severity, is the treat-
use of towels and washcloths; and attempted eradication of ment of choice (A-III). If staphylococcal infection is suspected,
staphylococcal carriage among colonized persons [36] (B-III). a penicillinase-resistant semisynthetic penicillin or a first-gen-
Some individuals have repeated attacks of furunculosis. A eration cephalosporin should be selected [44] (A-III). In a ran-
few of these persons, particularly children, have abnormal sys- domized, prospective multicenter trial [45], the efficacy of rox-
temic host responses, but for most, the only identifiable pre- ithromycin, a macrolide antimicrobial, was equivalent to that
disposing factor is the presence of S. aureus in the anterior for penicillin. Macrolide resistance among group A strepto-
nares or, occasionally, elsewhere, such as the perineum [37]. cocci, however, is increasing in the United States [46, 47].
The prevalence of nasal staphylococcal colonization in the gen- Cellulitis is an acute spreading infection of the skin, extend-
eral population is 20%–40%, but why some carriers develop ing more deeply than erysipelas to involve the subcutaneous
recurrent skin infections and others do not is usually unclear. tissues. It therefore lacks the distinctive anatomical features
The major method of controlling recurrent furunculosis is described above for erysipelas. Although most cellulitis is
the use of antibacterial agents to eradicate staphylococcal car- caused by b-hemolytic streptococci, a number of other micro-
riage. For persons with nasal colonization, one approach is the organisms may give rise to this disorder (see below).
application of mupirocin ointment twice daily in the anterior Both erysipelas and cellulitis are manifested clinically by rap-
nares for the first 5 days each month [38] (A-I). This regimen idly spreading areas of edema, redness, and heat, sometimes
reduces recurrences by ∼50%. Few systemic antibiotics attain accompanied by lymphangitis and inflammation of the regional
adequate levels in the nasal secretions to achieve protracted lymph nodes. The skin surface may resemble an orange peel
elimination of staphylococci [39]. Clindamycin is an exception, (i.e., peau d’orange) because superficial cutaneous edema sur-
and probably the best program for recurrent furunculosis rounds the hair follicles, which causes dimpling in the skin
caused by susceptible S. aureus is a single oral daily dose of because they remain tethered to the underlying dermis. Vesicles,
150 mg of this agent for 3 months, which decreases subsequent bullae, and cutaneous hemorrhage in the form of petechiae or
infections by ∼80% [40] (A-I). ecchymoses may develop on the inflamed skin. Systemic man-
Cellulitis and erysipelas. These terms refer to diffuse, ifestations are usually mild, but fever, tachycardia, confusion,
spreading skin infections, excluding infections associated with hypotension, and leukocytosis are sometimes present and may
underlying suppurative foci, such as cutaneous abscesses, nec- even occur hours before the skin abnormalities appear. Vesicles
rotizing fasciitis, septic arthritis, and osteomyelitis. Unfortu- and bullae filled with clear fluid are common. Petechiae and
nately, physicians use the words “cellulitis” and “erysipelas” ecchymoses may develop in inflamed skin; if these are wide-
inconsistently. For some, the distinction between the 2 terms spread and associated with systemic toxicity, a deeper infection
relates to the depth of inflammation: erysipelas affects the upper such as necrotizing fasciitis should be considered.
dermis, including the superficial lymphatics, whereas cellulitis These infections arise when organisms enter through
involves the deeper dermis, as well as subcutaneous fat. In breaches in the skin. Predisposing factors for these infections

include conditions that make the skin more fragile or local host infection in persons employed in aquaculture or meatpacking,
defenses less effective, such as obesity, previous cutaneous dam- respectively. Periorbital cellulitis due to Haemophilus influenzae
age, and edema from venous insufficiency or lymphatic ob- can occur in children. Diagnostic and therapeutic consider-
struction or other causes [48]. The origin of the disrupted ations of this infection have been reported by the Committee
cutaneous barrier may be trauma, preexisting skin infections on Infectious Diseases, American Academy of Pediatrics [6].
such as impetigo or ecthyma, ulceration, fissured toe webs from In neutropenic hosts, infection may be due to Pseudomonas
maceration or fungal infection, and inflammatory dermatoses, aeruginosa or other gram-negative bacilli, and in patients in-
such as eczema. Often, however, the breaks in the skin are small fected with HIV, the responsible organism may be Helicobacter
and clinically inapparent. These infections can occur at any cinaedi [71]. Occasionally, Cryptococcus neoformans causes cel-
location but are most common on the lower legs. lulitis in patients with deficient cell-mediated immunity.
Surgical procedures that increase the risk for cellulitis, pre- Because of their very low yield, blood cultures are not fruitful
sumably due to disruption of lymphatic drainage, include sa- for the typical case of erysipelas or cellulitis, unless it is par-

phenous venectomy [49, 50], axillary node dissection for breast ticularly severe [55]. Needle aspirations and skin biopsies are
cancer [51, 52], and operations for gynecologic malignancies also unnecessary in typical cases, which should respond to an-
that involve lymph node dissection, especially when followed tibiotic therapy directed against streptococci and staphylococci.
by radiation therapy, such as radical vulvectomy and radical These procedures may be more rewarding [56] for patients with
hysterectomy [53, 54]. diabetes mellitus, malignancy, and unusual predisposing fac-
Blood culture results are positive in ⭐5% of cases [55]. Re- tors, such as immersion injury, animal bites, neutropenia, and
sults of culture of needle aspirations of the inflamed skin are immunodeficiency.
bewilderingly variable, varying from ⭐5% to ∼40% in reported Diseases sometimes confused with cellulitis include acute
series [56–63], and probably depending on the patient popu- dermatitis, such as that due to contact with an allergen; gout,
lation, the definition of cellulitis, the inclusion or exclusion of with marked cutaneous inflammation extending beyond the
cases with associated abscesses, and the determination of joint involved; and herpes zoster. Acute lipodermatosclerosis,
whether isolates are pathogens or contaminants. Culture of a panniculitis that occurs predominantly in obese women with
punch biopsy specimens yields an organism in 20%–30% of lower extremity venous insufficiency, causes painful, erythem-
cases [57, 64], but the concentration of bacteria is usually quite atous, tender, warm, indurated, and sometimes scaly areas in
low [64]. Culture of these specimens, as well as other available the medial leg that resemble cellulitis [72].
evidence, including serologic studies [42, 59, 65] and techniques Therapy for the typical case of erysipelas or cellulitis should
employing immunofluorescent antibodies to detect antigens in include an antibiotic active against streptococci. Many clini-
skin biopsy specimens [66, 67], indicate that most of the in- cians choose an agent that is also effective against S. aureus,
fections arise from streptococci, often group A, but also from although this organism rarely causes cellulitis unless associated
other groups, such as B, C, or G. The source of the pathogens with an underlying abscess or penetrating trauma. A large per-
is frequently unclear, but in many infections of the lower ex- centage of patients can receive oral medications from the start
tremities, the responsible streptococci are present in the mac- [73]. Suitable agents include dicloxacillin, cephalexin, clinda-
erated or fissured interdigital toe spaces [68, 69], emphasizing mycin, or erythromycin, unless streptococci or staphylococci
the importance of detecting and treating tinea pedis and other resistant to these agents are common in the community (A-I).
causes of toe web abnormalities in these patients. Occasionally, Macrolide resistance among group A streptococci has in-
the reservoir of streptococci is the anal canal [70] or the vagina, creased regionally in the United States. For parenteral therapy,
especially for group B streptococci causing cellulitis in patients which is indicated for severely ill patients or for those unable
with previous gynecologic cancer treated with surgery and ra- to tolerate oral medications, reasonable choices include a pen-
diation therapy. S. aureus less frequently causes cellulitis, often icillinase-resistant penicillin such as nafcillin, a first-generation
associated with previous penetrating trauma, including injec- cephalosporin such as cefazolin, or, for patients with life-threat-
tion sites of illicit drug use. ening penicillin allergies, clindamycin or vancomycin (A-I). In
Many other infectious agents can produce cellulitis, but usu- cases of uncomplicated cellulitis, 5 days of antibiotic treatment
ally only in special circumstances. With cat or dog bites, for is as effective as a 10-day course [74].
example, the organism responsible is typically Pasteurella spe- Antibiotic treatment alone is effective in most patients with
cies, especially P. multocida, or Capnocytophaga canimorsus. A. cellulitis. However, patients who are slow to respond may have
hydrophila may cause cellulitis following immersion in fresh a deeper infection or underlying conditions, such as diabetes,
water, whereas infection after saltwater exposure can arise from chronic venous insufficiency, or lymphedema. In some patients,
Vibrio species, particularly V. vulnificus in warm climates. In cutaneous inflammation sometimes worsens after initiating
rare cases, Streptococcus iniae or E. rhusiopathiae may cause therapy, probably because the sudden destruction of pathogens
releases potent enzymes that increase local inflammation. In a soft-tissue infections caused by community-acquired MRSA.
single randomized, double-blind, placebo-controlled trial, sys- Traditionally regarded as a nosocomial pathogen, MRSA isolates
temic corticosteroids attenuated this reaction and hastened res- causing community-onset disease differ from their hospital
olution [75]. Specifically, 108 patients with a diagnosis of un- counterparts in several ways [82–84]. Community strains cause
complicated erysipelas were randomized to receive antibiotics infections in patients lacking typical risk factors, such as hos-
(90% received benzyl penicillin) plus either an 8-day tapering pital admission or residence in a long-term care facility; they
oral course of corticosteroid therapy beginning with 30 mg of are often susceptible to non–b-lactam antibiotics, including
prednisolone or a placebo. Subjects !18 years of age, diabetic doxycycline, clindamycin, trimethoprim-sulfamethoxazole,
patients, and pregnant women were excluded. One-third of fluoroquinolones, or rifampin; genotypically, they appear not
enrolled subjects had a previous episode of erysipelas at the to be related to local hospital strains and to contain type IV
current site of infection. Median healing time, median treat- SCCmec cassette not typical of hospital isolates [85, 86]. Finally,
ment time with intravenous antibiotics, and median duration community isolates have frequently contained genes for Pan-

of hospital stay were all shortened by 1 day in the prednisolone- ton-Valentine leukocidin [87], which has been associated with
treated group [75]. Long-term follow-up of these patients mild to severe skin and soft-tissue infections [7]. Outbreaks
showed no difference in relapse or recurrence [76]. Further caused by community-acquired MRSA isolates have occurred
studies are warranted, but in the meantime, clinicians may wish among prison and jail inmates, injection drug users, Native
to consider systemic corticosteroids as an optional adjunct for American populations, gay men, participants in contact sports,
treatment of uncomplicated cellulitis and erysipelas in selected and children [88, 89]. Thus, recurrent or persistent furuncles
adult patients. and impetigo, particularly in these high-risk groups, that do
Elevation of the affected area, an important and often ne- not respond to oral b-lactam antibiotic therapy are increasingly
glected aspect of treatment, quickens improvement by pro- likely to be caused by MRSA. Such lesions should be cultured
moting gravity drainage of the edema and inflammatory sub- and antibiotic susceptibilities determined. Fluctuant lesions
stances. Patients should also receive appropriate therapy for should be drained. An oral agent to which the isolate is sus-
any underlying condition that may have predisposed to the ceptible should be used as initial therapy (table 2). Most com-
infection, such as tinea pedis, venous eczema (“stasis derma- munity-acquired strains are susceptible to doxycycline or min-
titis”), or trauma. ocycline, but these should be avoided in children ⭐8 years old
Each attack of cellulitis causes lymphatic inflammation and and during pregnancy. Clindamycin has excellent antistaphy-
possibly some permanent damage. Severe or repeated episodes lococcal activity, but there is the potential for emergence of
resistance with high-inoculum infections caused by strains in-
of cellulitis may lead to lymphedema, sometimes substantial
ducibly resistant to erythromycin. Linezolid, daptomycin, and
enough to cause elephantiasis. Measures to reduce recurrences
vancomycin have excellent efficacy in skin and soft-tissue in-
of cellulitis include treating interdigital maceration, keeping
fections in general and against those due to MRSA specifically
the skin well hydrated with emollients to avoid dryness and
[90, 91] (A-I). However, these agents should be reserved for
cracking, and reducing any underlying edema by such meth-
patients who have severe infections requiring hospitalization or
ods as elevation of the extremity, compressive stockings or
who have not responded to attempts to eradicate the infection.
pneumatic pressure pumps, and, if appropriate, diuretic ther-
Trimethoprim-sulfamethoxazole has been used to treat serious
apy. If frequent infections occur despite such measures, pro-
staphylococcal infections, including those due to MRSA. In one
phylactic antibiotics appear reasonable; however, published
double-blind, randomized trial in which 47% of the isolates
results demonstrating efficacy have been mixed [77–80]. Be-
were MRSA, cures were documented in 37 of the 43 patients
cause streptococci cause most recurrent cellulitis, options in-
receiving trimethoprim-sulfamethoxazole, compared with 57 of
clude monthly intramuscular benzathine penicillin injections
58 patients in the vancomycin group; trimethoprim-sulfa-
of 1.2 MU in adults or oral therapy with twice-daily doses of
methoxazole failures occurred mostly in patients with MSSA
either 250 mg of erythromycin or 1 g of penicillin V (B-II).
infections [92]. If a fluoroquinolone is chosen, one with en-
An alternative, but untested, option for reliable patients with
hanced activity against gram-positive bacteria should be used
recurrent cellulitis is to try to shorten each episode by pro-
(e.g., levofloxacin, gatifloxacin, or moxifloxacin), but still there
viding oral antibiotics for them to initiate therapy as soon as
is the possibility of emergence of resistance.
symptoms of infection begins. One trial of oral selenium dem-
onstrated a reduced recurrence rate of erysipelas in secondary
NECROTIZING SKIN AND SOFT-TISSUE
lymphedema by 80% [81]. This report requires independent
INFECTIONS
confirmation.
Soft-tissue infections and the evaluation of MRSA infection. Necrotizing skin and soft-tissue infections differ from the
An emerging problem is the increasing prevalence of skin and milder, superficial infections by clinical presentation, coexisting

systemic manifestations, and treatment strategies [93, 94]. They presentation is that of cellulitis, which can advance rapidly or
are often deep and devastating. They are deep because they slowly. As it progresses, there is systemic toxicity with high
may involve the fascial and/or muscle compartments; they are temperatures. The patient may be disoriented and lethargic.
devastating because they cause major destruction of tissue and The local site shows the following features: cellulitis (90% of
can lead to a fatal outcome. These conditions are usually “sec- cases), edema (80%), skin discoloration or gangrene (70%),
ondary” infections, in that they develop from an initial break and anesthesia of involved skin (frequent, but the true incidence
in the skin related to trauma or surgery. They can be mon- is unknown).
omicrobial (usually involving streptococci or, rarely, staphy- A distinguishing clinical feature is the wooden-hard feel of
lococci) or polymicrobial (involving a mixed aerobe-anaerobe the subcutaneous tissues. In cellulitis or erysipelas the subcu-
bacterial flora). Although many specific variations of necrotiz- taneous tissues can be palpated and are yielding. But in fasciitis,
ing soft-tissue infections have been described on the basis of the underlying tissues are firm, and the fascial planes and mus-
etiology, microbiology, and specific anatomic location of the cle groups cannot be discerned by palpation. It is often possible

infection, the initial approach to the diagnosis, antimicrobial to observe a broad erythematous tract in the skin along the
treatment, and decision to use operative management are sim- route of the infection as it advances cephalad in an extremity.
ilar for all forms and are more important than determining the If there is an open wound, probing the edges with a blunt
specific variant. instrument permits ready dissection of the superficial fascial
In the initial phases, distinguishing between a cellulitis that
planes well beyond the wound margins.
should respond to antimicrobial treatment alone and a nec-
Bacteriologic characteristics. In the monomicrobial form,
rotizing infection that requires operative intervention may be
the pathogens are S. pyogenes, S. aureus, V. vulnificus, A. hy-
difficult. Several clinical features suggest the presence of a nec-
drophila, and anaerobic streptococci (i.e., Peptostreptococcus
rotizing infection of the skin and its deeper structures: (1)
species). Staphylococci and hemolytic streptococci can occur
severe, constant pain; (2) bullae, related to occlusion of deep
simultaneously. Most infections are community acquired and
blood vessels that traverse the fascia or muscle compartments;
present in the limbs, with approximately two-thirds of cases in
(3) skin necrosis or ecchymosis (bruising) that precedes skin
the lower extremities. There is often an underlying cause, such
necrosis; (4) gas in the soft tissues, detected by palpation or
as diabetes, arteriosclerotic vascular disease, or venous insuf-
imaging; (5) edema that extends beyond the margin of ery-
ficiency with edema. Sometimes, a chronic vascular ulcer
thema; (6) cutaneous anesthesia; (7) systemic toxicity, mani-
changes into a more acute process. Cases of necrotizing fasciitis
fested by fever, leukocytosis, delirium, and renal failure; and
that arise after varicella or trivial injuries, such as minor
(8) rapid spread, especially during antibiotic therapy. Bullae
alone are not diagnostic of deep infections, because they also scratches and insect bites, are almost always due to S. pyogenes.
occur with erysipelas, cellulitis, scalded skin syndrome, dissem- The mortality in this group is high, approaching 50%–70% in
inated intravascular coagulation, purpura fulminans, some tox- patients with hypotension and organ failure [97, 98].
ins (e.g., those associated with bite from a brown-recluse spi- In the polymicrobial form, up to 15 different anaerobic and
der), and primary dermatologic conditions. aerobic organisms can be cultured from the involved fascial
plane, with an average of 5 pathogens in each wound. Most of
Necrotizing Fasciitis the organisms originate from the bowel flora (e.g., coliforms
Necrotizing fasciitis is a relatively rare subcutaneous infection and anaerobic bacteria).
that tracks along fascial planes and extends well beyond the The polymicrobial necrotizing infection is associated with 4
superficial signs of infection, such as erythema and other skin clinical settings: (1) surgical procedures involving the bowel or
changes [95, 96]. The term fasciitis sometimes leads to the penetrating abdominal trauma, (2) decubitus ulcer or a perianal
mistaken impression that the muscular fascia or aponeurosis abscess, (3) at the site of injection in injection drug users, and
is involved. The fascia most commonly referred to is the su- (4) spread from a Bartholin abscess or a minor vulvovaginal
perficial fascia, which is comprised of all of the tissue between infection. Although mixed infections are usually noted in this
the skin and underlying muscles (i.e., subcutaneous tissue). latter setting, some cases are caused by a single pathogen, par-
Clinical features. Extension from a skin lesion is seen in ticularly anaerobic Streptococcus species.
80% of cases. The initial lesion, such as a minor abrasion, insect Diagnosis. It may not be possible to diagnose fasciitis upon
bite, injection site (in the case of drug addicts), or boil, often first seeing the patient. Overlying cellulitis is a frequent accom-
is trivial. Rare cases have arisen in Bartholin gland abscess or paniment. That the process involves the deeper tissue planes
perianal abscess, from which the infection spreads via fascial is suggested by the following features: (1) failure to respond to
planes of the perineum, thigh, groin, and abdomen. The re- initial antibiotic therapy; (2) the hard, wooden feel of the sub-
maining 20% of patients have no visible skin lesion. The initial cutaneous tissue, extending beyond the area of apparent skin
involvement; (3) systemic toxicity, often with altered mental toxicity, fever, hypotension, or advancement of the skin and
status; (4) bullous lesions; and (5) skin necrosis or ecchymoses. soft-tissue infection during antibiotic therapy is an indication
CT scan or MRI may show edema extending along the fascial for surgical intervention. Third, when the local wound shows
plane. In practice, clinical judgment is the most important any skin necrosis with easy dissection along the fascia by a
element in diagnosis. Data regarding the sensitivity and spec- blunt instrument, more complete incision and drainage are
ificity of CT or MRI are unavailable, and requesting such studies required. Fourth, any soft-tissue infection accompanied by gas
may delay definitive diagnosis and treatment. The most im- in the affected tissue suggests necrotic tissue and requires op-
portant diagnostic feature of necrotizing fasciitis is the ap- erative drainage and/or debridement.
pearance of the subcutaneous tissues or fascial planes at op- Most patients with necrotizing fasciitis should return to the
eration. Upon direct inspection, the fascia is swollen and dull operating room 24–36 h after the first debridement and daily
gray in appearance, with stringy areas of necrosis. A thin, thereafter until the surgical team finds no further need for
brownish exudate emerges from the wound. Even during deep debridement. Although discrete pus is usually absent, these

dissection, there is typically no true pus. Extensive undermining wounds can discharge copious amounts of tissue fluid; ag-
of surrounding tissues is present, and the tissue planes can be gressive administration of fluid is a necessary adjunct.
dissected with a gloved finger or a blunt instrument. A Gram Antimicrobial therapy must be directed at the pathogens and
stain of the exudate demonstrates the presence of the pathogens used in appropriate doses (table 5) until repeated operative
and provides an early clue to therapy. Gram-positive cocci in procedures are no longer needed, the patient has demonstrated
chains suggest Streptococcus organisms (either group A or an- obvious clinical improvement, and fever has been absent for
aerobic). Large gram-positive cocci in clumps suggest S. aureus, 48–72 h. Treatment of polymicrobial necrotizing fasciitis must
but this is an unusual primary organism in these spreading include agents effective against both aerobes and anaerobes
infections. Samples for culture are best obtained from the deep (table 5). In general, ampicillin is useful for coverage of sus-
tissues. If the infection originated from a contaminated skin ceptible enteric aerobic organisms, such as E. coli, as well as
wound, such as a vascular ulcer, the bacteriologic characteristics for gram-positive organisms, such as Peptostreptococcus species,
of the superficial wound are not necessarily indicative of deep- group B, C, or G streptococci, and some anaerobes (A-III).
tissue infection. Direct needle aspiration of the advancing edge Clindamycin is useful for coverage of anaerobes and aerobic
as a means of obtaining material for culture can be helpful if gram-positive cocci, including most S. aureus serogroups. Me-
fluid is obtained. A definitive bacteriologic diagnosis is best tronidazole has the greatest anaerobic spectrum against the
established by culture of tissue specimens obtained during op- enteric gram-negative anaerobes, but it is less effective against
eration or by positive blood culture results. In doubtful cases, the gram-positive anaerobic cocci. Gentamicin or a fluorinated
the surgical procedure may provide both diagnosis and treat- quinolone, ticarcillin-clavulanate, or piperacillin-sulbactam is
ment. If necrotizing infection is suspected but not confirmed, useful for coverage against resistant gram-negative rods. Thus,
a small, exploratory incision should be made in the area of the best choice of antibiotics for community-acquired mixed
maximum suspicion. If a necrotizing infection is present, it will infections is a combination of ampicillin-sulbactam plus clin-
be obvious from the findings described above. If there is no damycin plus ciprofloxacin (A-III).
necrosis on exploratory incision, the procedure can be termi- Necrotizing fasciitis and/or streptococcal toxic shock syn-
nated with very little risk or morbidity to the patient. Some drome caused by group A streptococci should be treated with
have suggested biopsy for frozen section analysis to make the clindamycin and penicillin (A-II). The rationale for clinda-
diagnosis. However, if enough suspicion exists to do a biopsy, mycin is based on in vitro studies demonstrating both toxin
the diagnosis is usually evident to gross inspection without suppression and modulation of cytokine (i.e., TNF) production,
histological slides. on animal studies demonstrating superior efficacy versus that
Treatment. Surgical intervention is the major therapeutic of penicillin, and on 2 observational studies demonstrating
modality in cases of necrotizing fasciitis (A-III). Many cases of greater efficacy for clindamycin than for b-lactam antibiotics
necrotizing fasciitis, however, probably begin as cellulitis, and [99, 100]. Penicillin should be added because of the increasing
if necrotizing fasciitis is recognized early and treated aggres- resistance of group A streptococci to macrolides, although in
sively, some patients may avoid potentially mutilating surgical the United States, only 0.5% of macrolide-resistant group A
procedures. The decision to undertake aggressive surgery streptococci are also clindamycin resistant.
should be based on several considerations. First, no response A recommendation to use intravenous g-globulin (IVIG) to
to antibiotics after a reasonable trial is the most common index. treat streptococcal toxic shock syndrome cannot be made with
A response to antibiotics should be judged by reduction in certainty (B-II). Although there is ample evidence for the role
fever and toxicity and lack of advancement. Second, profound of extracellular streptococcal toxins in shock, organ failure, and

Table 5. Treatment of necrotizing infections of the skin, fascia, and muscle.
First-line Antimicrobial agent(s)

antimicrobial agent, for patients with severe
by infection type Adult dosage penicillin hypersensitivity
Mixed infection
Ampicillin-sulbactam 1.5–3.0 g every 6–8 h iv Clindamycin or metronidazolea with an amino-
or glycoside or fluoroquinolone
piperacillin-tazobactam 3.37 g every 6–8 h iv
plus
clindamycin 600–900 mg/kg every 8 h iv
plus
ciprofloxacin 400 mg every 12 h iv
Imipenem/cilastatin 1 g every 6–8 h iv …
Meropenem 1 g every 8 h iv …

Ertapenem 1 g every day iv …
Cefotaxime 2 g every 6 h iv …
plus
metronidazole 500 mg every 6 h iv
or
Streptococcus infection
Penicillin 2–4 MU every 4–6 h iv (adults) Vancomycin, linezolid, quinupristin/dalfopristin,
plus or daptomycin
S. aureus infection
Nafcillin 1–2 g every 4 h iv Vancomycin, linezolid, quinupristin/dalfopristin,
daptomycin
Oxacillin 1–2 g every 4 h iv …
Cefazolin 1 g every 8 h iv …
Vancomycin (for resistant strains) 30 mg/kg/day in 2 divided doses iv …
Clindamycin 600–900 mg/kg every 8 h iv Bacteriostatic; potential of cross-resistance
and emergence of resistance in erythromy-
cin-resistant strains; inducible resistance in
methicillin-resistant S. aureus
Clostridium infection
Clindamycin 600–900 mg/kg every 8 h iv …
Penicillin 2–4 MU every 4–6 h iv …
a
If Staphylococcus infection is present or suspected, add an appropriate agent. iv, intravenously.
tissue destruction, different batches of IVIG contain variable Anaerobic Streptococcal Myositis
quantities of neutralizing antibodies to some of these toxins, Anaerobic streptococci cause a more indolent infection than
and definitive clinical data are lacking [101]. One observational other streptococci. Unlike other necrotizing infections, infec-
study demonstrated better outcomes in patients receiving IVIG, tion of the muscle and fascial planes by anaerobic streptococci
but these patients were more likely to have had surgery and to usually is associated with trauma or a surgical procedure.
have received clindamycin than were historical control subjects Incision and drainage are critical. Necrotic tissue and debris
[102]. A second study, which was a double-blind, placebo- are resected but the inflamed, viable muscle should not be
controlled trial from northern Europe, showed no statistically removed, because it can heal and regain function. The incision
significant improvement in survival, and, specific to this sec- should be packed with moist dressings. Antibiotic treatment is
tion, no reduction in the time to no further progression of
highly effective. These organisms are all susceptible to penicillin
necrotizing fasciitis (69 h for the IVIG group, compared with
or ampicillin, which should be administered in high doses.
36 h for the placebo group) [103]. Results of these studies
provide some promise. However, this committee believes that
additional studies of the efficacy of IVIG are necessary before Pyomyositis
a recommendation can be made regarding use of IVIG for Pyomyositis, which is caused mainly by S. aureus, is the pres-
treatment of streptococcal toxic shock syndrome. ence of pus within individual muscle groups. Occasionally, S.
pneumoniae or a gram-negative enteric bacillus is responsible. usually in mixed culture, but occasionally, S. aureus is the only
Blood culture results are positive in 5%–30% of cases. Because pathogen. Pseudomonas is another common organism in the
of its geographical distribution, this condition is often called mixed culture. As with other necrotizing infections, prompt
“tropical pyomyositis,” but cases are increasingly recognized in and aggressive surgical exploration and appropriate debride-
temperate climates, especially in patients with HIV infection ment is necessary to remove all necrotic tissue, sparing the
or diabetes [104]. Presenting findings are localized pain in a deeper structures when possible (A-III).
single muscle group, muscle spasm, and fever. The disease oc-
curs most often in an extremity, but any muscle group can be Clostridial Myonecrosis
involved, including the psoas or trunk muscles. Initially, it may Clostridial gas gangrene (i.e., myonecrosis) is most commonly
not be possible to palpate a discrete abscess because the infec- caused by C. perfringens, C. novyi, C. histolyticum, and C. sep-
tion is localized deep within the muscle, but the area has a ticum. C. perfringens is the most frequent cause of trauma-
firm, wooden feel associated with pain and tenderness. In the associated gas gangrene. Increasingly severe pain beginning at

early stages, ultrasonography or CT scan may be performed to the injury site ⭐24 h after infection is the first reliable symptom.
differentiate this entity from a deep venous thrombosis. In more Skin may initially be pale, but it quickly changes to bronze and
advanced cases, a bulging abscess is usually clinically apparent. then to a purplish red. The infected region becomes tense and
Appropriate antibiotics plus extensive surgical incision and tender, and bullae filled with reddish-blue fluid appear. Gas in
drainage are required for appropriate management. the tissue, detected as crepitus or on the basis of imaging stud-
ies, is universally present by this late stage. Signs of systemic
Synergistic Necrotizing Cellulitis toxicity, including tachycardia, fever, and diaphoresis, develop
This is simply a necrotizing soft-tissue infection that involves rapidly, followed by shock and multiple organ failure.
muscle groups in addition to superficial tissues and fascia. The In contrast to traumatic gas gangrene, spontaneous gangrene
level of involvement depends on the depth and the tissue planes is principally associated with the more aerotolerant C. septicum
affected by the original operation or pathological process that and occurs predominantly in patients with neutropenia and
precedes the infection. Major predisposing causes are perirectal gastrointestinal malignancy. It develops in normal skin in the
and ischiorectal abscesses. Recognition and treatment are sim- absence of trauma as a result of hematogenous spread from a
ilar to necrotizing fasciitis, but operative exploration reveals its colonic lesion, usually cancer. A rather innocuous early lesion
deeper location. may evolve to all of the above signs over the course of 24 h.
Frequently, the diagnosis is unsuspected until gas is detected
Fournier Gangrene in tissue or systemic signs of toxicity appear. Early surgical
This variant of necrotizing soft-tissue infection involves the inspection and debridement are necessary, and Gram stain of
removed tissue shows large, spore-forming gram-positive
scrotum and penis or vulva and can have an insidious or ex-
bacilli.
plosive onset [105, 106]. The mean age of onset is 50 years.
Both traumatic and spontaneous clostridial gas gangrene are
Most patients have significant underlying disease, particularly
fulminant infections requiring meticulous intensive care, sup-
diabetes, but 20% will have no discernible cause. Most patients
portive measures, aggressive surgical debridement, and appro-
initially have a perianal or retroperitoneal infection that has
priate antibiotics. The role of hyperbaric oxygen treatment re-
spread along fascial planes to the genitalia; a urinary tract in-
mains unclear. Altemeier and Fullen [107] reported a significant
fection, most commonly secondary to a urethral stricture, that
reduction in mortality among patients with gas gangrene using
involves the periurethral glands and extends into the penis and
penicillin and tetracycline plus aggressive surgery in the absence
scrotum; or previous trauma to the genital area, providing ac-
of hyperbaric oxygen. Treatment of experimental gas gangrene
cess of organisms to the subcutaneous tissues.
has demonstrated that tetracycline, clindamycin, and chloram-
The infection can begin insidiously with a discrete area of
phenicol were more effective than penicillin [108, 109] or hy-
necrosis in the perineum that progresses rapidly over 1–2 days
perbaric oxygen treatment [110]. Because 5% of strains of C.
with advancing skin necrosis. At the outset, it tends to cause
perfringens are clindamycin resistant, the recommended anti-
superficial gangrene, limited to skin and subcutaneous tissue,
biotic treatment is penicillin plus clindamycin (B-III).
and extending to the base of the scrotum. The testes, glans
penis, and spermatic cord usually are spared, because they have
ANIMAL BITES
a separate blood supply. The infection may extend to the per-
ineum and the anterior abdominal wall through the fascial One-half of all Americans are bitten during their lifetime, usu-
planes. ally by a dog. Fortunately, 80% of the wounds are minor, but
Most cases are caused by mixed aerobic and anaerobic flora. the remaining 20% that require medical care will account for
Staphylococci and Pseudomonas species are frequently present, 1% of all emergency department visits and for 10,000 inpatient

admissions yearly. Most bites are due to dogs or cats, but bites such as cefuroxime, ceftriaxone, and cefotaxime, may be used
from exotic pets and from feral animals also occur. The pre- but may require the addition of an antianaerobic agent.
dominant pathogens in these wounds are the normal oral flora Penicillin-allergic pregnant women constitute a special pop-
of the biting animal, along with human skin organisms and ulation, because tetracyclines, sulfa compounds (during late
occasional secondary invaders (e.g., S. aureus and S. pyogenes) pregnancy), and metronidazole are contraindicated. Similarly,
[111, 112]. There are no published large case series on the the selection of an antimicrobial for penicillin-allergic children
therapy of bite wounds, but there are many smaller series and is problematic when tetracyclines and fluoroquinolones are
anecdotal reports especially focusing on complications. contraindicated. In these situations, macrolides (e.g., azithro-
Bacteriologic characteristics. Patients who present !8 h af- mycin 250–500 mg every day or telithromycin 400 mg, 2 tablets
ter injury seek either wound care or tetanus toxoid, and some by mouth every day) are occasionally used. However, these
are concerned about rabies. Patients who seek medical care patients should be observed closely and the potential increased
after 8–12 h of injury typically have established infection. The risk of failure noted.

wounds may be nonpurulent (30% of dog bites and 42% of The duration of therapy varies by the severity of the injury/
cat bites), purulent (58% of dog bites and 39% of cat bites), infection. Cellulitis and abscess often respond to 5–10 days of
or abscesses (12% of dog bites and 19% of cat bites). The therapy. The therapy for early presenting, noninfected wounds
average wound yields 5 types of bacterial isolates (range, 0–16 remains controversial. Wounds that are moderate to severe,
types of bacterial isolates), with ∼60% yielding mixed aerobic have associated crush injury, have associated edema (either pre-
and anaerobic bacteria. Pasteurella species are isolated from existing or subsequent), that are on the hands or in proximity
50% of dog bite wounds and 75% of cat bite wounds. Staph- to a bone or a joint, or that are in compromised hosts should
ylococci and streptococci are found in ∼40% of bites from both receive 3–5 days of “prophylactic” antimicrobial therapy. These
types of animals. Capnocytophaga canimorsus (formerly known wounds are often colonized with potential pathogens (85% of
as DF-2), a fastidious gram-negative rod, can cause bacteremia cases), and it is difficult to determine whether the wound will
and fatal sepsis after animal bites, especially in patients with become infected.
asplenia or underlying hepatic disease. Facultative gram-neg- Complications. Infectious complications of bite wounds
ative rods are uncommon. Bacteroides species, fusobacteria, include septic arthritis, osteomyelitis, subcutaneous abscess for-
Porphyromonas species, Prevotella heparinolytica, proprionibac- mation, tendonitis, and, rarely, bacteremia. Pain dispropor-
teria, and peptostreptococci are common anaerobes isolated tionate to the severity of injury but located near a bone or joint
from both dog bite wounds and cat bite wounds [113]. should suggest periosteal penetration. Hand wounds are often
Antimicrobial therapy. Empirical treatment of dog and cat more serious than wounds to fleshy parts of the body. These
bites is similar (table 6). Although cat bite wounds have little wound complications will necessitate prolonged therapy, such
crush injury and less wound trauma than do dog bites, they as 4–6-week courses for osteomyelitis and 3–4 -week courses
are often more severe and have a higher proportion of oste- for synovitis. Noninfectious complications include nerve or
omyelitis and septic arthritis. Cat bites have a greater prevalence tendon injury or severance, compartment syndromes, postin-
of anaerobes (65% vs. 50%) and P. multocida (75% vs. 50%) fectious and traumatic arthritis, fracture, and bleeding.
than do dog bites. For oral, outpatient therapy, amoxicillin- Adjunctive therapeutic measures are often as important as
clavulanate has been studied in a small series [114] and is antimicrobial therapy. Wounds should be cleansed with sterile
recommended (B-II). Alternative oral agents include doxycy- normal saline (no need for iodine- or antibiotic-containing
cline, as well as penicillin VK plus dicloxacillin. Other options, solutions) and superficial debris removed. Deeper debridement
including fluoroquinolones (ciprofloxacin, levofloxacin, mox- is usually unnecessary, but, if performed, should be done very
ifloxacin, and gatifloxacin), trimethoprim-sulfamethoxazole, cautiously to avoid enlarging the wound and impairing skin
and cefuroxime, may require an additional agent active against closure. Infected wounds should not be closed. Suturing
anaerobes, such as metronidazole or clindamycin. First-gen- wounds early (!8 h after injury) is controversial, and there are
eration cephalosporins, such as cephalexin, penicillinase-resis- no studies to delineate guidelines; however, approximation of
tant penicillins (e.g., dicloxacillin), macrolides (e.g., erythro- the margins by Steri-Strips (3M Health Care) and subsequent
mycin), and clindamycin, all have poor in vitro activity against closure by either delayed primary or secondary intent seem
P. multocida and should be avoided (D-III). prudent. Wounds on the face seem to be an exception and can
Intravenous options include the b-lactam/b-lactamase com- be closed primarily if seen by a plastic surgeon, provided there
binations (such as ampicillin sulbactam), piperacillin/tazobac- has been meticulous wound care, copious irrigation, and ad-
tam, second-generation cephalosporins (such as cefoxitin), and ministration of prophylactic antibiotics. During the first few
carbapenems (such as ertapenem, imipenem, and meropenem) days after injury, elevation of the injured body part, especially
(B-II). Second-generation and third-generation cephalosporins, if swollen, accelerates healing. This should be accomplished
using a passive method (a sling for outpatients or a tubular wounds, although often quite small, may extend deeply into
stockinet and an intravenous pole for inpatients). the hand tissues, and relaxation of the fist may carry organisms
Outpatients should be followed up within 24 h either by into the deep compartments and potential spaces of the hand.
phone or during an office visit. If infection progresses despite Exploration under tourniquet control may be necessary.
good antimicrobial and ancillary therapy, hospitalization Clenched-fist injuries often require hospitalization and intra-
should be considered. On occasion, a single initial dose of a venous antimicrobial therapy with agents such as cefoxitin (1
parenteral antimicrobial may be administered before starting g intravenously every 6–8 h), ampicillin-sulbactam (1.5–3 g
oral therapy. Clinicians should insure that tetanus prophylaxis intravenously every 6 h), ertapenem (1 g intravenously every
status is current. If it is outdated or if the status is unknown, 24 h), or some combination that covers S. aureus, Haemophilus
then a dose of tetanus toxoid (0.5 mL intramuscularly) should species, E. corrodens, and b-lactamase–producing anaerobes (B-
be administered. Rabies prophylaxis should be considered for III). E. corrodens is usually resistant to first-generation cepha-
all feral and wild animal bites and in geographic areas where losporins (e.g., cefazolin and cephalexin), macrolides (e.g.,

there is a high prevalence of rabies. The local department of erythromycin), clindamycin, and aminoglycosides, and these
health should be consulted about the risks and benefits of rabies agents should be avoided as monotherapy. In the type 1 b-
prophylaxis (administration on day 0 of rabies immunoglob- lactam–allergic patient, fluoroquinolones (e.g., moxifloxacin
ulin, followed by rabies human diploid cell vaccination at a and gatifloxacin) plus clindamycin, or trimethoprim-sulfa-
different site). Only anecdotal literature exists regarding the methoxazole plus metronidazole may be useful. Ancillary mea-
bacteriologic characteristics and therapy of exotic or wild an- sures include administration of tetanus toxoid as indicated. The
imal bites, but the same general principles should apply. duration of therapy is typically 4 weeks for septic arthritis and
6 weeks for osteomyelitis.
HUMAN BITES Complications. Complications are frequent and include
tendon and nerve damage, fractures, septic arthritis, and os-
Human bite wounds often result from aggressive behavior and
teomyelitis. Splinting of the hand in a position of function is
are frequently more serious than animal bites. Wounds may be
often required, as is subsequent physical therapy. Residual joint
either occlusive injuries, in which the teeth actually bite the
stiffness is common after clenched fist injury and may affect
body part, or clenched-fist injuries, which occur when the fist
function.
of one person strikes the teeth of another. Between 10% and
20% of occlusive wounds occur during sexual interactions. Bite
SOFT-TISSUE INFECTIONS FOLLOWING
wounds in children may be associated with sports-related ac-
ANIMAL CONTACT
tivity (look for imbedded teeth) but should also alert the cli-
nician to possible child abuse. Anthrax. One of several clinical manifestations of anthrax is
Bacteriologic characteristics. The bacteriologic character- a cutaneous lesion. After an incubation period of 1–12 days,
istics of these wounds reflect the normal oral flora of the biter, pruritus begins at the entry site, followed by a papule, devel-
with streptococci (especially viridans streptococci) in 80% of opment of vesicles on top of the papule, and, finally, a painless
wounds, as well as staphylococci, Haemophilus species, and ulcer with a black scab. This eschar generally separates and
Eikenella corrodens as prominent aerobic pathogens [112, 115]. sloughs after 12–14 days. Swelling surrounding the lesion can
Other gram-negative rods are infrequent. Anaerobes, including be minor or severe (i.e., malignant edema). Mild-to-moderate
Fusobacterium nucleatum and other Fusobacterium species, pep- fever, headaches, and malaise often accompany the illness. Re-
tostreptococci, Prevotella species, and Porphyromonas species, gional lymphadenopathy is common, but pus in the lesion is
are present in 160% of cases, but usually in mixed culture. absent unless a secondary infection occurs. WBC counts are
Bacteroides fragilis is rarely present. Many of the anaerobes generally normal, but mild leukocytosis can occur. Blood cul-
produce b-lactamases, making them resistant to penicillin and ture results are almost always negative. Cultures of untreated
first-generation cephalosporins. Human bites also have the po- lesions, depending on the stage of evolution, have positive re-
tential to transmit various viral diseases, such as herpes, hep- sults 180% of the time. Methods of specimen collection for
atitis B and C, and HIV infection [116–120]. culture depend on the type of lesion. With vesicles, the blister
Therapy. Evaluation and treatment should follow the gen- should be unroofed and 2 dry swabs soaked in the fluid. At a
eral principles outlined for animal bites, with irrigation and later stage, 2 moist swabs should be rotated in the ulcer base
topical wound cleansing, except that prophylactic antimicro- or beneath the eschar’s edge. Patients who have previously
bials should be given as early as possible to all patients regardless received antimicrobials or who have negative results of tests
of the appearance of the wound (table 6). An expert in hand but still have suspected cutaneous anthrax should have a punch
care should evaluate clenched-fist injuries for penetration into biopsy specimen obtained that can be submitted for special
the synovium, joint capsule, and the bone (B-III). These studies, such as immunohistochemical staining and/or PCR.

When obtaining specimens, lesions should not be squeezed to though mainly a research tool, is also a diagnostic option. Rou-
produce material for culture. Additional diagnostic methods tine histologic examination of a node, coupled with the clinical
include serologic and skin tests. findings, may strongly suggest the diagnosis. Histologic ex-
No randomized, controlled trials of therapy of cutaneous amination in conjunction with a Wharthin-Starry silver stain
anthrax exist. Most published data indicate that penicillin is is helpful but does not differentiate the species of Bartonella.
effective therapy (B-III) (table 3) and will “sterilize” most le- Aspiration of fluctuant nodes may exclude other causes of pu-
sions between a few hours to 3 days but does not accelerate rulent lymphadenopathy and sometimes is appropriate to re-
healing. Its value seems to be primarily in reducing mortality lieve pain.
from as high as 20% to 0%. On the basis of even less evidence, Treatment of cat-scratch disease with antimicrobial agents
tetracyclines, chloramphenicol, and erythromycin also appear has had variable, but rarely dramatic, results. A single, double-
to be effective. blind, placebo-controlled study involved 29 patients, 14 of
Suggested antimicrobials and dosages derive from 3 whom received azithromycin [124]. The lymph node size had

publications (table 3) [121–123]. The optimal duration of treat- regressed 30 days after treatment more often in the azithro-
ment is uncertain, but 5–9 days appears to be adequate. Sixty mycin-treated patients (P p .02 ). If antimicrobial therapy is
days of treatment is recommended when infection is associated used, patients weighing 145.5 kg (1100 lbs) should receive
with bioterrorism, because concomitant inhalation may have 500 mg of azithromycin orally on day 1, followed by 250 mg
occurred. Until results of susceptibility tests are available, cip- once daily for 4 additional days (A-I). Those weighing less
rofloxacin is rational empirical therapy (B-III), especially with than the weight listed above should receive 10 mg/kg orally
the possibility of genetically altered B. anthracis. Other fluor- on day 1, followed by 5 mg/kg on days 2–5 [124]. Cutaneous
oquinolones, such as levofloxacin, gatifloxacin, or moxifloxa- bacillary angiomatosis therapy has not been systematically
cin, are also likely to be effective. Initiation of intravenous examined. On the basis of results of case reports and small
versus oral therapy depends on the severity of the illness, par- series, either erythromycin (500 mg 4 times per day) or doxy-
ticularly the degree of edema. cycline (100 mg twice per day) appear to be effective (B-III).
Some have suggested systemic corticosteroid therapy for pa- The duration of initial therapy, although not standardized,
tients who develop malignant edema, especially of the head and should be at least 4 weeks. With relapses, retreatment with
neck, but studies supporting this recommendation are lacking. prolonged therapy (lasting several months) should be enter-
Airway compromise requiring intubation or trachostomy may tained until immunocompetence returns. Other antimicro-
occur with malignant edema. bials with some efficacy are rifampin, trimethoprim-sulfa-
Cat-scratch disease and bacillary angiomatosis. Bartonella methoxazole, and ciprofloxacin [125].
henselae causes most cases of cat-scratch disease in immuno- Erysipeloid. Erysipeloid is a cutaneous infection caused by
competent hosts. Bacillary angiomatosis, seen in immunocom- the thin, pleomorphic, non–spore-forming gram-positive rod
promised patients, especially with AIDS, can occur from either E. rhusiopathiae. It is a zoonosis seen in persons who handle
B. henselae or Bartonella quintana. In classic cat-scratch disease, fish, marine animals, swine, or poultry. Between 1 and 7 days
a papule or pustule develops 3–30 days after a scratch or a bite. after exposure, a red maculopapular lesion develops, usually on
Regional adenopathy occurs ∼3 weeks after inoculation in the fingers or hands. Erythema spreads centrifugally with cen-
nodes that drain the infected area. Extranodal disease (such as tral clearing. A blue ring with a peripheral red halo may appear,
that found in the CNS, liver, spleen, bone, and lung) develops giving the lesion a target appearance. Regional lymphangitis
in ⭐2% of cases. In ∼10% of cases, the nodes suppurate. The and/or lymphadenopathy occurs in about one-third of cases.
disease course varies, but lymphadenopathy generally resolves A severe, generalized cutaneous infection also occurs. However,
within 1–6 months. systemic symptoms and leukocytosis are unusual. Culture of a
Cutaneous bacillary angiomatosis has 2 clinical appearances. lesion aspirate and/or biopsy specimen establishes the diagnosis,
The dermal form is a red papule that varies in size from 1 but the results of blood cultures are rarely positive. Untreated
millimeter to several centimeters, and the number of lesions erysipeloid resolves during a period of 3–4 weeks, but treatment
may vary from 1 to 11000. The second form is a painful sub- probably hastens healing and perhaps reduces systemic com-
cutaneous nodule with overlying skin having a normal or dusky plications. Most of the literature concerning therapy relates to
hue. endocarditis, in which high-dose penicillin is generally used.
Definitive confirmation of Bartonella infections may be dif- On the basis of in vitro susceptibilities and anecdotal state-
ficult, because these fastidious organisms infrequently grow ments, penicillin is appropriate (B-III), although the optimum
from pus or nodal tissue. Serologic testing supports the diag- duration of therapy is unknown. For cutaneous infection, pen-
nosis. However, cross-reactivity occurs between B. henselae and icillin (500 mg orally 4 times per day) or amoxicillin (500 mg
B. quintana, as well as with a few other organisms. PCR, al- 3 times per day) for 7–10 days seems to be rational. For patients
Table 6. Recommended therapy for infections following animal or human bites.
Route of drug administration

Antimicrobial agent,
by type of bite Oral Intravenous Comment
Animal bite
Amoxicillin/clavulanate 500/875 mg twice per daya … Some gram-negative rods are
resistant; misses MRSA
Ampicillin-sulbactam … 1.5–3.0 g every 6–8 h Some gram-negative rods are
Piperacillin/tazobactam … 3.37 g every 6–8 h
Carbapenem Misses MRSA
Ertapenem … 1 g every day
Imipenem … 1 g every 6–8 h

Meropenem … 1 g every 8 h
Doxycycline 100 mg twice per day … Excellent activity against Pas-
teurella multocida; some strepto-
cocci are resistant
Penicillin 500 mg 4 times per day …
plus
dicloxacillin 500 mg 4 times per day
TMP-SMZ 160–800 mg twice per day … Good activity against aerobes; poor
activity against anaerobes
Metronidazole 250–500 mg 4 times per day … Good activity against anaerobes; no
activity against aerobes
Clindamycin 300 mg 3 times per day … Good activity against staphylococci,
streptococci and anaerobes; misses
P. multocida
First-generation cephalosporin Good activity against staphylococci
and streptococci; misses P. multo-
cida and anaerobes
Cephalexin 500 mg 3 times per day …
Cefazolin … 1 g every 8 h
Second-generation cephalosporin Good activity against P. multocida;
misses anaerobes
Cefuroxime 500 mg twice per day 1 g every day
Cefoxitin … 1 g every 6–8 h
Third-generation cephalosporin
Ceftriaxone … 1 g every 12 h
Cefotaxime … 2 g every 6 h
Fluoroquinolones Good activity against P. multocida;
misses MRSA and some anaerobes
Ciprofloxacin 500–750 mg twice per day 400 mg every 12 h
Gatifloxacin 400 mg every day …
Moxifloxacin 400 mg every day 400 mg every day
Human bite
Amoxicillin/clavulanate 500 mg every 8 ha … Some gram-negative rods are
Ampicillin/sulbactam … 1.5– 3.0 g every 6 h Some gram-negative rods are
Carbapenem Misses MRSA
Ertapenem … 1 g every day
Imipenem … 1 g every day
Meropenem … 1 g every day
Doxycycline 100 mg twice per day … Good activity against Eikenella spe-
cies, staphylococci, and
anaerobes; some streptococci are
resistant
(continued)
Table 6. (Continued.)
Route of drug administration

Antimicrobial agent,
by type of bite Oral Intravenous Comment
TMP-SMZ 160–800 mg twice per day … Good activity against aerobes; poor
activity against anaerobes
Metronidazole 250–500 mg 4 times per day … Good activity against anaerobes; poor
activity against aerobes
Clindamycin 300 mg 3 times per day … Good activity against staphylococci,
streptococci, and anaerobes;
misses Eikenella corrodens
Cephalosporin Good activity against staphylococci
and streptococci; misses E. corro-
dens and gram-negative anaerobes

Cephalexin 500 mg 4 times per day …
Cefazolin … 1 g every 8 h
Fluoroquinolone Good activity against E. corrodens;
misses MRSA and some anaerobes
Ciprofloxacin 500–750 mg twice per day 400 mg every 12 h
Gatifloxacin 400 mg every day 400 mg every day
Moxifloxacin 400 mg every day 400 mg every day
NOTE. As a rule, the use of fluoroquinolones is contraindicated by the US Food and Drug Administration for children and adolescents !18 years of age. It
should also be noted that tetracyclines are rarely used in children younger than 8 years of age. Alternatives should be strongly considered for these two antibiotics
[6]. MRSA, methicillin-resistant Staphylococcus aureus. TMP-SMZ, trimethoprim-sulfamethoxazole.
a
Should be given with food.
who are intolerant of penicillins, treatment with cephalospo- bonic plague may develop septicemia and secondary plague
rins, clindamycin, or fluoroquinolones should be effective. E. pneumonia, the latter permitting person-to-person transmis-
rhusiopathiae is resistant to vancomycin, teicoplanin, and dap- sion. Diagnosis can be made by blood cultures and by aspirating
tomycin [125, 126]. lymph nodes for staining and culture. PCR and other more
Glanders. Glanders, caused by the aerobic gram-negative sophisticated tests are generally available only at reference lab-
rod Burkholderia mallei, is mainly a disease of solipeds (e.g., oratories. Results of serologic tests may provide retrospective
horses and mules). Humans become accidental hosts either by confirmation.
inhalation or skin contact. Although other organs may be in- No controlled comparative trials of therapy for plague exist.
volved, pustular skin lesions and lymphadenopathy with sup- Streptomycin has been the drug of choice (B-III), although
purative nodes can be a prominent feature. Almost all glanders tetracycline and chloramphenicol are also considered to be ap-
infections preceded the antibiotic era. Results of in vitro sus- propriate therapy (table 7). Although there have been no recent
ceptibility tests suggest that ceftazidime, gentamicin, imipenem, reports of treatment of any sizable numbers of cases of plague,
doxycycline, and ciprofloxacin should be effective. A recent studies from the Vietnam War period showed that most patients
laboratory-acquired case was successfully treated with imipe- actually received streptomycin plus either tetracycline or chlor-
nem and doxycycline for 2 weeks, followed by azithromycin amphenicol. Some patients have been successfully treated with
and doxycycline for an additional 6 months [127]. kanamycin. Gentamicin has been suggested as a substitute for
Bubonic plague. Plague results from infection with Y. pes- streptomycin, but its use in humans has been limited. On the
tis, a facultative, anaerobic gram-negative coccobacillus. It pri- basis of in vitro susceptibilities and murine models, fluoro-
marily affects rodents, being maintained in nature by several quinolones are another option. A multidrug-resistant strain of
species of fleas that feed on them. Three plague syndromes Y. pestis has been isolated in Madagascar, and it is suspected
occur in humans: septicemic, pneumonic, and bubonic. Bu- that an antimicrobial-resistant strain of the plague bacillus has
bonic plague, the most common and classic form, develops been developed for biologic warfare. Unless introduced into
when humans are bitten by infected fleas or have a breach in the rodent population, however, Y. pestis as a biowarfare agent
the skin when handling infected animals. Domestic cat scratches is much more likely to be used as an aerosol, thus producing
or bites may also transmit bubonic plague. Patients usually pneumonic plague rather than bubonic plague. Ciprofloxacin
develop fever, headache, chills, and tender regional lymphade- has been suggested as a drug for both treatment and prevention
nopathy 2–6 days after contact with the organism. A skin lesion of plague due to biowarfare agents, despite a lack of docu-
at the portal of entry is sometimes present. Patients with bu- mented efficacy in humans. The optimal duration for treating
Table 7. Therapy for bubonic plague.
Dosage
Adults (including
Drug pregnant women) Childrena
b
Streptomycin 1 g im twice per day 30 mg/kg im daily in 2 divided doses
Gentamicinb 2 mg/kg loading dose, followed by 1.7 mg/kg/day in 3 2 mg/kg every 8 h iv
divided doses iv
c
Tetracycline 500 mg po every 6 h …
Chloramphenicol 25 mg/kg iv every 6 h (not to exceed 6 g total dose daily) 25 mg/kg iv every 6 h (not to exceed 6 g total dose daily)
Doxycyclinec 100 mg iv or po twice daily Persons who weigh 145 kg: 100 mg iv or po twice daily;
persons who weigh ⭐45 kg: 2.2 mg/kg iv or po twice
daily
Ciprofloxacinc 500 mg po twice daily or 400 mg iv twice daily 20 mg/kg po twice daily or 15 mg/kg iv twice daily

NOTE. Agents of bioterrorism may be genetically altered for antimicrobial resistance. im, intramuscularly; iv, intravenously; po, orally.
a
Not appropriate for neonates.
b
Aminoglycoside dosages need adjustment according to renal function.
c
Doxycycline, tetracycline, and ciprofloxacin should be used only under exceptional circumstances in children !8 years of age or during pregnancy.
bubonic plague is unknown, but 10–14 days is probably ade- choice for tularemia for several decades (B-III). A 1994 review
quate. In view of the forgoing, the recommendations in reviews found 294 cases treated with streptomycin but only 20, 43, and
by Perry and Fetherston [128] and by Inglesby et al. [129] seem 36 patients treated with tetracycline, chloramphenicol, and gen-
to be rational (table 7). Patients with bubonic plague should tamicin, respectively [130]. Since then, a few patients have been
be placed in respiratory isolation until completion of 48 h of received fluoroquinolones. Francisella species are resistant to
effective drug therapy, because some develop secondary pneu- most b-lactam antibiotics. Even with favorable in vitro sus-
monic plague. ceptibilities, failure rates with ceftriaxone have been high. One
Tularemia—ulceroglandular or glandular. F. tularensis, al- patient has responded to imipenem, and 2 patients have re-
though hardy and persistent in nature, is a fastidious, aerobic, sponded to erythromycin. When static drugs such as tetra-
gram-negative coccobacillus. Illness can often be categorized cyclines or chloramphenicol are used, relapses may be more
into several fairly distinct syndromes—ulceroglandular, glan- common, but often the patients have received brief therapy
dular, typhoidal, pneumonic, oculoglandular, or oropharyngeal. (duration, !7 to 10 days).
The glandular varieties are generally acquired by handling in-
Acutely ill adults or children should receive an aminogly-
fected animals, by tick bites, and sometimes by animal bites,
coside, preferably streptomycin or possibly gentamicin. For
especially from cats. Biting flies occasionally transmit the illness
adults, the regimen for streptomycin is 30 mg/kg per day in 2
in the United States, whereas mosquitoes are common vectors
divided doses (!2 g daily) or gentamicin 3–5 mg/kg per day
in Europe. After an incubation period of 3–10 days, the patient
in 3 divided doses. For children, streptomycin should be ad-
typically develops a skin lesion (an ulcer or an eschar) at the
ministered at 30 mg/kg per day in 2 divided doses and gen-
entry site of the organism, along with tender regional adeno-
tamicin at 6 mg/kg per day in 3 divided doses [130]. Treatment
pathy in the lymph nodes—thus the term “ulceroglandular.”
duration of 7–10 days is appropriate, with dosages of amino-
In some patients, the skin lesion is inconspicuous or healed by
glycosides adjusted according to renal function. Although no
the time that they seek medical care, resulting in “glandular”
tularemia. The illness is often associated with substantial fever, data exist, treatment with a parenteral agent until the acute
chills, headache, and malaise. illness is controlled, followed by an oral agent, seems to be
Confirmation of the diagnosis is usually accomplished by rational.
means of serologic testing. Results of routine cultures are often In mild-to-moderate disease, oral tetracycline (500 mg 4
negative unless cysteine-supplemented media are used. Unsus- times per day) or doxycycline (100 mg twice per day) is ap-
pected growth of Francisella species can cause laboratory-ac- propriate. Chloramphenicol (2–3 g daily in 4 divided doses)
quired disease. PCR shows considerable promise for diagnosis. has been used in adults. Oral chloramphenicol is no longer
No prospective controlled or randomized trials of therapy distributed in the United States, and the rare, but serious ad-
for tularemia have been performed, nor has the optimal du- verse effect—bone marrow aplasia—makes it an undesirable
ration of treatment been established, but many patients will agent. A few cases have been treated with fluoroquinolones,
require initiation of treatment before confirmation of the di- with mixed results [131–133]. Oral levofloxacin (500 mg daily)
agnosis. Streptomycin has been considered to be the drug of or ciprofloxacin (750 mg twice per day) in adults may be rea-

sonable for mild to moderate illness. With oral regimens, pa- erythematous changes can occur around or near a surgical
tients should receive at least 14 days of therapy. incision during the first week without swelling or wound drain-
age. Most resolve without any treatment, including antibiotics.
SURGICAL SITE INFECTIONS (SSIs) The cause is unknown but may relate to tape sensitivity or to
other local tissue insult not involving bacteria. Numerous ex-
Infections of surgical wounds are the most common adverse
perimental studies and clinical trials examining the prevention
events affecting hospitalized patients who have undergone
of SSIs demonstrate that antibiotic therapy that is begun im-
surgery [134]. Data from the National Nosocomial Infection
mediately after surgery or that is continued for long periods
Surveillance System show an average SSI incidence of 2.6%,
after the procedure does not prevent or cure this inflammation
accounting for 38% of nosocomial infections in surgical pa-
tients [135]. The frequency of SSI is clearly related to the or infection [138–143]. Therefore, the suspicion of possible SSI
category of operation, with clean and low-risk operations (as does not justify use of antibiotics without a definitive diagnosis
defined by the National Nosocomial Infection Surveillance and the initiation of other therapeutic measures, such as open-

System classification) having the lowest rate of infection and ing the wound (B-III) (figure 1).
contaminated and high-risk operations having greater infec- Most SSIs have no clinical manifestations for at least 5 days
tion rates [136]. Very few sources of objective evidence com- after the operation, and many may not become apparent for
pare treatments for SSI. up to 2 weeks. Later infections are less likely, but surveillance
SSIs are divided into the categories of superficial incisional standards mandate a follow-up duration of 30 days. Rarely does
SSI, deep incisional SSI, and organ/space SSI [135]. Superficial any bacterial pathogen cause fever and clinical evidence of soft-
incisional SSIs involve only the subcutaneous space, between tissue infection within the first 48 h after an operation or injury.
the skin and underlying muscular fascia, occur within 30 days Infections that do occur in this time frame are almost always
of the index operation, and are documented with at least 1 of due to S. pyogenes or Clostridium species. Accordingly, fever or
the following findings: (1) purulent incisional drainage; (2) systemic signs during the first several days after surgery should
positive results of culture of aseptically obtained fluid or tissue be followed by direct examination of the wound to rule out
from the superficial wound; (3) local signs and symptoms of signs suggestive of streptococcal or clostridial infection but
pain or tenderness, swelling, and erythema, with the incision should not otherwise cause further manipulation of the wound.
opened by the surgeon (unless culture results are negative); or Patients with an early infection due to streptococci or clostridia
(4) diagnosis of SSI by the attending surgeon or physician. have wound drainage with the responsible organisms present
A deep incisional infection involves the deep layers of soft on Gram stain. WBCs may not be evident in most clostridial
tissue (e.g., fascia and muscle) in the incision and occurs within and some early streptococcal infections. Another rare cause of
30 days after the operation or within 1 year after the operation early fever and systemic signs after operation is toxic shock
if a prosthesis was inserted and has the same findings as de- syndrome due to staphylococcal wound infection [144, 145].
scribed for a superficial incisional SSI.
In these cases, the wound is often deceptively benign in ap-
An organ/space SSI has the same time constraints and evi-
pearance. Erythroderma occurs early but not immediately, and
dence for infection as a deep incisional SSI and involves any
desquamation occurs late. Fever, hypotension, abnormal he-
part of the anatomy (organs or spaces) other than the incision
patic and renal blood findings, and diarrhea may be early find-
opened during the operation [135]. Superficial and deep in-
ings. Treatment is to open the incision, obtain and culture a
cisional SSIs are skin and soft-tissue infections and will be
wound specimen, and begin antistaphylococcal treatment.
discussed in this guideline. Organ/space SSIs are usually dealt
The primary, and most important, therapy for SSI is to open
with separately as infections related to the relevant organ and
space. Any deep SSI that does not resolve in the expected man- the incision, evacuate the infected material, and continue dress-
ner after treatment should be investigated as a possible super- ing changes until the wound heals by secondary intention.
ficial manifestation of a deeper organ/space infection. Although patients commonly receive antibiotics when SSI is
In diagnosing SSIs, the physical appearance of the incision first diagnosed, there is little or no evidence supporting this
probably provides the most reliable information. Local signs of practice. Studies of subcutaneous abscesses found no benefit
pain, swelling, erythema, and purulent drainage are usually for antibiotic therapy when combined with drainage [24, 33].
present. In morbidly obese patients or in patients with deep, The single published trial of antibiotic administration for SSIs
multilayer wounds (such as wounds following thoracotomy), found no clinical benefit associated with this treatment [146].
the external signs of SSIs may be very late but always appear. Most textbooks of surgery, infectious diseases, or even surgical
Although many patients with SSIs will have fever, it usually infectious diseases extensively discuss the epidemiologic char-
does not occur immediately after operation, and in fact, most acteristics, prevention, and surveillance of SSIs but not their
postoperative fevers are not associated with SSI [137]. Flat, treatment [147–153]. Two articles contain simple, unrefer-
Figure 1. Algorithm for the management and treatment of surgical site infections. *For patients with type 1 (anaphylaxis or hives) allergy to b-
lactam antibiotics. Where the rate of infection with methicillin-resistant Staphylococcus aureus infection is high, consider vancomycin, daptomycin,
or linezolid, pending results of culture and susceptibility tests. Adapted and modified with permission from [154]. GI, gastrointestinal.
enced, recommendations to open an infected wound without mon organisms. Because incisions in the axilla have a significant
using antibiotics [154, 155]. recovery of gram-negative organisms and incisions in the per-
A common practice, endorsed by expert opinion, is to open ineum have a higher incidence of gram-negative organisms and
all infected wounds (B-III). If there is minimal surrounding anaerobes [24, 26, 157], antibiotic choices should be made
evidence of invasive infection (!5 cm of erythema and indu- accordingly (table 4). Figure 1 presents a schematic algorithm
ration), and if the patient has minimal systemic signs of in- to approach patients with suspected SSI [154] and includes
fection (a temperature of !38.5C and a pulse rate of !100 specific antibiotic recommendations [158].
beats/min), antibiotics are unnecessary. Because incision and
drainage of superficial abscesses rarely causes bacteremia [156], INFECTIONS IN THE IMMUNE COMPROMISED
antibiotics are not needed. For patients with a temperature of HOST
138.5C or a pulse rate of 1100 beats/min, a short course of
antibiotics, usually for a duration of 24–48 h, may be indicated. Immunocompromised patients, by definition, are at increased
The antibiotic choice is usually empirical but can be supported risk of infection and have a decreased ability to control local
by findings of Gram stain and results of culture of the wound infection [159–161]. Skin and soft-tissue infections are com-
contents. SSIs that occur after an operation on the intestinal mon, and because they are caused by a wide range of pathogens
tract or female genitalia have a high probability of having a and are often part of a widely disseminated infection, they
mixed gram-positive and gram-negative flora with both fac- frequently pose a difficult clinical problem [162, 163]. Infection
ultative and anaerobic organisms. If such an infection is being prevention in immunocompromised patients is important and
treated with empirical antibiotics, any antibiotic considered to demands careful attention to measures that protect the skin
be appropriate for treatment of intra-abdominal infection is from unnecessary trauma, maceration, or alterations in the
reasonable (table 4). If the operation was a clean procedure normal microbial flora. When infections do develop, it is critical
that did not enter the intestinal or genital tracts, S. aureus to establish a specific etiologic diagnosis, because many are
(including MRSA) and streptococcal species are the most com- nosocomial and are caused by pathogens with increased anti-

microbial resistance. Skin lesions, no matter how small or in- Initial Infection in Neutropenic Patients
nocuous in appearance, should be carefully evaluated, and the Historically, the primary gram-negative pathogens have been
clinician must remember that their gross appearance is fre- E. coli, Klebsiella species, and P. aeruginosa, but there is wide
quently altered by the decreased inflammatory response. Thus, variability in the pathogens isolated in different treatment cen-
the initial clinical impressions must be supplemented with a ters [159, 160, 164, 165]. The relative incidence of gram-neg-
systematic approach for diagnosis and treatment [164, 165]. ative bacilli as causes of initial infections has decreased signif-
After considering the important patient-specific factors con- icantly during the past 2 decades, but they remain important
cerning the patient’s immune compromised status (e.g., neu- pathogens for patients with profound neutropenia (!100 poly-
tropenia or neutrophil defects, cellular immune defect, and morphonuclear leukocytes/mL) with a prolonged duration (7–
iatrogenic procedures), the gross morphologic characteristics 10 days) or for patients who have not received antibacterial
of the skin lesion(s) should be characterized, the extent of the prophylaxis during their period of neutropenia [168]. Der-
infection determined (e.g., localized vs. disseminated), and ap- matologic manifestations of gram-negative skin and soft-tissue

propriate diagnostic tests undertaken to identify the infecting infections include erythematous maculopapular lesions, focal
pathogen. Finally, antimicrobial therapy should be initiated, on or progressive cellulitis, cutaneous nodules [167], and ecthyma
the basis of the important clinical parameters identified and gangrenosum. Ecthyma gangrenosum begins as painless, ery-
the most likely offending pathogens [164, 165]. Although blood thematous, macules that rapidly become painful and necrotic
cultures or tests for detection of antigen in blood or vesicular during a 12–24-h period. They may be discrete or multiple; are
fluid may be helpful, the most specific method is aspiration or found preferentially in the groin, axilla, or trunk; and can in-
biopsy of the lesion to obtain material for histological and crease in size from 1 cm to 110 cm in !24 h. Ecthyma gan-
microbiological evaluation. Analysis of lesion biopsy specimens grenosum is a cutaneous vasculitis caused by bacterial invasion
of the media and adventitia of the vessel wall. Progression of
yields positive results for only 20% of otherwise healthy patients
the lesion leads to dermal necrosis, and bacteria are often visible
with focal skin lesions [57]. Similar prospective studies in-
during microscopic analysis of biopsy specimens. Ecthyma gan-
volving immunocompromised patients have not been per-
grenosum has classically been reported to occur with P. aeru-
formed. Consequently, most clinicians who treat immunocom-
ginosa infections, but similar lesions can occur with dissemi-
promised patients combine blood cultures, tests for antigen
nated infections caused by other Pseudomonas species,
detection, and radiographic imaging with analysis of a biopsy
Aeromonas species, Serratia species, S. aureus, Stenotrophomonas
specimen obtained from the abnormal skin lesion to optimize
maltophilia, Candida species, and fungi, including Aspergillus,
recovery of the offending pathogen and to direct pathogen-
Mucor, and Fusarium species [166].
specific antimicrobial therapy and local surgical management.
The increased use of antimicrobial prophylaxis with fluor-
oquinolones or trimethoprim-sulfamethoxazole and the fre-
Predisposition to Infection: Neutropenia
quent reliance on indwelling vascular access devices have re-
Patients with neutropenia are predisposed to infection because sulted in gram-positive organisms being the most frequently
of insufficient circulating neutrophils, lack of adequate myeloid isolated pathogens in initial infections [169]. These organisms,
marrow reserve, or congenital or acquired defects in neutrophil in order of decreasing prevalence, include coagulase-negative
function [159–163, 165]. Neutropenia is frequently associated staphylococci, viridans streptococci, enterococci, S. aureus, Co-
with mucosal or integumentary barrier disruption, and the in- rynebacterium species, Clostridium species, and Bacillus species
digenous colonizing florae are responsible for most infections. and often represent part of the patient’s normal skin flora. Soft-
More than 20% of patients with chemotherapy-induced neu- tissue infections due to these pathogens usually begin as a focal
tropenia develop skin and soft-tissue infections, many of which area of erythematous cutaneous tenderness, a macular or ma-
are due to hematogenous dissemination from other sites, such culopapular eruption, or as cellulitis. The most frequent in-
as the sinuses, lungs, and the alimentary tract [162, 163, 166]. fection sites are the groin, axilla, areas of cutaneous disruption
Important pathogens for neutropenic patients can be separated (e.g., vascular catheter or bone marrow aspiration sites), or
into organisms most likely to cause an “initial infection” (char- other portions of skin that are moist and frequently abraded.
acterized by !7 days of fever and neutropenia) and those more Hematogenous dissemination of these gram-positive organisms
likely to cause a “subsequent infection” (with an onset after 7 to the skin and soft tissue is uncommon except for S. aureus
days of neutropenia) [159, 167]. Pathogens causing initial in- and some Clostridium species. A toxic shock–like syndrome has
fections are usually bacteria, including both gram-negative and been described with blood stream infections caused by toxin-
gram-positive organisms. Pathogens causing subsequent infec- producing viridans streptococci, and diffuse erythroderma can
tions are usually antibiotic-resistant bacteria, yeast, or fungi be part of the early clinical presentation [170].
(table 8). The foundation of the initial treatment of patients with neu-
Table 8. Skin and soft-tissue infections in the immune compromised host: treatment and management.
Frequency or
reason for
Predisposing factor, pathogen Type of therapy Duration of therapy surgery Adjunct
Neutropenia
Initial infection
Bacteria
Gram negative Monotherapy or antibiotic 7–14 days Rare G-CSF/GM-CSF;
combination granulocyte therapya
Gram positive Pathogen specific 7–10 days Rare No
Subsequent infection
Antibiotic-resistant Pathogen specific 7–14 days Rare G-CSF/GM-CSF;b
a
bacteria granulocyte therapy

Fungi Amphotericin B, voriconazole, or Clinical and radiologic For localized Catheter removal;
caspofungin resolution infection G-CSF/GM-CSF;b
granulocyte therapya
Cellular immune deficiency
Bacteria
Nocardia species Trimethoprim-sulfamethoxazole or 3–12 months Rare No
sulfadiazine
Atypical mycobacteria Antibiotic combination (including 3–6 weeks Yes No
a macrolide)
Fungi
Cryptococcus species Amphotericin B plus 5-fluorocyto- 8–12 weeks No No
sine or fluconazole
Histoplasma species Amphotericin B or itraconazole
Viruses
Varicella-zoster virus Acyclovir 7–10 days No No
famciclovir
valacyclovir
Herpes simplex virus Acyclovir 7 days No No
famciclovir
valacyclovir
Cytomegalovirus Ganciclovir 21 days No No
NOTE. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor.

a
Use if gram-negative bacillary infection is unresponsive to appropriate antimicrobial therapy or if the patient has invasive fungal infection.
b
Progressive infection, pneumonia, and invasive fungal infection.
tropenia is the administration of empirical, broad-spectrum regimen. This strategy, however, has no impact on the survival
antibiotics at the first clinical signs or symptoms of infection, of adult patients with neutropenia-associated bloodstream in-
including fever [159–161, 164, 165]. Antibiotic selection should fections due to gram-positive organisms [171], and because of
follow the clinical care guidelines developed by the Infectious the increasing prevalence of vancomycin-resistant organisms,
Diseases Society of America and the National Comprehensive current guidelines restrict the empirical use of this agent [164,
Cancer Network [164, 165]. Excellent results have been re- 165]. Thus, if empirical vancomycin is administered, it should
ported for gram-negative infections using broad-spectrum be discontinued if culture results remain negative after 72–96
monotherapy with carbapenems, cephalosporins that possess h [164, 165]. Decisions regarding initial empirical antibiotic
antipseudomonal activity, or piperacillin/tazobactam [164]. regimens and the subsequent antimicrobial adjustments, how-
Antibiotic combinations using an aminoglycoside plus an an- ever, must consider adequate antimicrobial coverage against the
tipseudomonal-penicillin or a extended-spectrum cephalospo- more virulent gram-positive organisms (S. aureus, viridans
rin, or the combination of an extended-spectrum penicillin and streptococci, or antibiotic-resistant pathogens, such as MRSA,
ciprofloxacin, are also frequently recommended [164, 165]. vancomycin-resistant enterococci, or penicillin-resistant S.
Treatment of neutropenia-associated infections due to gram- pneumoniae.) [170, 172–175]. Linezolid or daptomycin may be
positive organisms is now dictated by the increasing resistance acceptable alternatives to vancomycin. Linezolid is the drug of
of these pathogens, leading many clinicians to consider the choice for infections caused by vancomycin-resistant entero-
empirical use of vancomycin as part of the initial antibiotic cocci, but potential hematologic toxicity and cost should limit

its use to individuals with pathogen-directed needs [176]. Al- routine use of azole antifungal prophylaxis was reported to be
though linezolid and daptomycin have US Food and Drug as high as 12% for patients with profound and prolonged neu-
Administration approval for skin and soft-tissue infections, no tropenia or recipients of blood or bone marrow transplants
prospective, randomized studies involving compromised pa- [183]. Candida albicans (62% of candidiasis cases) and Candida
tients have been performed. tropicalis (21% of candidiasis cases) were most frequently iso-
Surgical intervention is rarely appropriate early during neu- lated. Between 6% and 13% of patients with invasive candidiasis
tropenia-associated infection but may be necessary to drain a develop single or multiple nodular skin lesions [166, 183]. Such
soft-tissue abscess after marrow recovery or for treatment of a lesions are discrete, pink-to-red subcutaneous papules or nod-
progressive polymicrobial fasciitis. Most such infections do not ules and are most commonly found on the trunk and extrem-
require adjunct colony-stimulating factor therapy or granulo- ities. The nodules are usually smaller (diameter, 0.5–0.8 cm)
cyte transfusions, but these therapies are often considered when than ecthyma gangrenosum lesions, are initially nontender, and
infection progresses despite appropriate antimicrobial treat- may evolve to develop central pallor; the nodules may become

ment [159–161, 176, 177]. hemorrhagic in thrombocytopenic patients [160, 166]. Myositis
can develop as a consequence of hematogenous infection and
Subsequent Infection in Neutropenic Patients is most common with C. tropicalis infections [185, 186]. In
Subsequent infections are the major cause of infection-asso- these cases, pain is often the chief initial complaint. Muscle
ciated morbidity and mortality for patients with prolonged and soft-tissue abscess formation is uncommon, but when re-
(duration, 7–10 days) and profound (!100 polymorphonuclear ported, it has usually followed bone marrow recovery.
leukocytes/mL) neutropenia [159–161]. Of such patients, 25%– Trichosporon beigelii. T. beigelii is an uncommon, but
50% develop a second or subsequent episode of fever and/or frequently fatal disseminated fungal infection that often in-
infection [167]. Although the skin and soft tissues are less fre- volves the skin [187]. Dermatologic manifestations vary from
quently infected (10%–15% of cases), they may represent an multiple erythematous macules to maculopapular lesions, and
early site of infection dissemination. Among subsequent infec- analysis of tissue biopsy specimens reveals a mixture of true
tions, 10%–15% are caused by antibiotic-resistant gram-neg- hyphae, pseudohyphae, budding yeast, and arthroconidia that
ative bacilli, 30%–40% are caused by antibiotic-resistant gram- can be easily mistaken for Candida species [166].
positive organisms (coagulase-negative staphylococci and Aspergillus species. Infections due to Aspergillus species
vancomycin-resistant enterococci, most commonly), and 150% occur in 2%–10% of patients with profound and prolonged
are caused by fungi [167]. Despite the incidence of subsequent neutropenia, and they may be increasing in frequency [188,
infections caused by antibiotic-resistant gram-positive patho- 189]. Mortality remains high for all of these infections [188,
gens, the empirical administration of vancomycin is unjustified 190]. Aspergillus fumigatus is the most frequently isolated spe-
for patients with neutropenia and persistent fever (!96 h after cies (50% of cases), followed by Aspergillus flavus, Aspergillus
initiation of empirical antibiotic therapy) who are clinically niger, and Aspergillus terreus [188]. Isolation of Aspergillus spe-
stable and have no identified site of infection [178]. Empirical cies from blood cultures is infrequent, but dissemination to the
antifungal therapy for patients with neutropenia and persistent brain, gastrointestinal tract, and other visceral organs is com-
fever remains a common clinical practice, as revealed by 2 monly revealed during autopsy [191]. Cutaneous infections are
clinical studies using amphotericin B that were conducted in unusual, but they may occur secondary to hematogenous dis-
the 1980s [179, 180]. Recently, 2 randomized, international, semination or locally at sites of intravenous catheter insertion
multicenter trials found that caspofungin [181] and voricon- or at nail bed and cuticle junctions on fingers and toes [192,
azole [182] were each suitable alternatives to amphotericin B 193]. Because Aspergillus organisms have a propensity for an-
in this patient population. Thus, profoundly neutropenic pa- gioinvasion, they produces painful skin nodules that may rap-
tients with persistent fever who are systemically ill despite em- idly become necrotic and resemble pyoderma gangrenosum
pirical antibiotic therapy may benefit from empirical antifungal lesions [166].
treatment (B-I). Rhizopus and Mucor species. Cutaneous infections due to
Candida species. The frequency and occurrence of can- organisms from the Rhizopus and Mucor genera are uncom-
didiasis has been well described [183, 184]. More than 80% of mon, but similar to infections due to Aspergillus species, epi-
high-risk patients who develop neutropenia are colonized with dermal and dermal necrosis may develop, because of the ten-
Candida species, and superficial mucosal and cutaneous infec- dency of these organism to invade blood vessels. Skin lesions
tions are common. These noninvasive infections can be effec- are usually erythematous, nodular, and tender. Local Mucor
tively treated with improved skin care and a topical antifungal infections have occurred as a consequence of contaminated
agent or with a short course systemic azole antibiotic (e.g., bandages or other skin trauma, but patients with pulmonary
fluconazole). The incidence of invasive candidiasis before the Mucor infection may also develop secondary cutaneous in-
volvement from presumed hematogenous dissemination [194, arise from local skin inoculation, whereas others result from
195]. Disseminated infections are almost never associated with hematogenous dissemination.
positive blood culture results, but even without a documented Bacteria. Nontuberculous mycobacteria are ubiquitous,
fungal bloodstream infection, the mortality rate for these in- and most cutaneous mycobacteria infections occur after pri-
fections remains very high [196]. mary inoculation at sites of skin disruption or trauma, but
Fusarium species. Fusarium species are now more fre- hematogenous dissemination does occur [210–215]. Dissemi-
quently identified as the infecting pathogens in patients with nated infection with Mycobacterium avium complex occurs
prolonged and profound neutropenia [196–198]. Patients com- preferentially among patients with HIV disease, whereas blood-
monly have myalgias and persistent fever despite antimicrobial stream infections with Mycobacterium fortuitum, Mycobacte-
therapy. Skin lesions occur in 60%–80% of these infections and rium chelonae, Mycobacterium abscessus, Mycobacterium ulcer-
begin as multiple erythematous macules with central pallor that ans, or Mycobacterium mucogenicum are more frequent among
quickly evolve to papules and necrotic nodules. Lesions localize compromised hosts with indwelling vascular-access devices

preferentially to the extremities but also occur on the face and [216]. Sporadic cases in compromised hosts are also reported
trunk. Recovery of Fusarium species from blood cultures is with Mycobacterium kansasii, Mycobacterium haemophilum, and
common (40%–50% of cases) [191]. Mortality from this in- Mycobacterium marinum. Dermatologic manifestations include
fection remains high among patients with persistent immu- a poorly resolving cellulitis, painless 1–2-cm nodules, necrotic
nodeficiency, although the new azole antifungal agents appear ulcers, and subcutaneous abscesses.
to be promising [199]. Treatment of nontuberculous mycobacterial infections of the
The clinician must remember that yeast and fungal infections skin and soft tissues requires prolonged combination therapy
remain the primary cause of infection-associated death among (duration, 6–12 weeks) that should include a macrolide anti-
patients with neutropenia or patients who undergo blood or biotic (e.g., clarithromycin). Surgical debridement is appro-
bone marrow transplantation [200, 201]. Diagnosis of these priate and often necessary to remove devitalized tissue and to
infections remains difficult, and recovery of fungi from an as- promote skin and soft-tissue healing [216].
piration or biopsy of skin or soft tissue almost always warrants Cutaneous Nocardia infections usually represent metastatic
aggressive therapy. Amphotericin B and lipid formulations of foci of infection from a primary pulmonary source. Nocardia
amphotericin B have been the gold standard of treatment, but asteroides, Nocardia farcinica, and Nocardia brasiliensis have
newer antifungal agents, such as voriconazole and caspofungin, been associated with cutaneous disease [217, 218]. The der-
appear to be at least as effective against Aspergillus species, matologic manifestations are usually limited to subcutaneous
Fusarium species, and non-albicans species of Candida [164, nodules or abscess and panniculitis. Soft-tissue abscesses are
165, 184, 202–204]. All of the new antifungal agents have less frequently painless and are cold to the touch. The incidence of
serious acute toxicity and less nephrotoxicity but are also more local and disseminated Nocardia infections has decreased with
expensive than conventional amphotericin B [203–208]. The the routine use of trimethoprim-sulfamethoxazole prophylaxis
importance of treatment with adjunct growth factor or gran- for patients who experience prolonged periods of cellular im-
ulocyte transfusion is unsubstantiated, but they are frequently mune deficiency.
considered for patients who remain profoundly neutropenic Trimethoprim-sulfamethoxazole remains the treatment of
and unresponsive to antimicrobial therapy [177]. The routine choice [218], but other sulfa antibiotics (e.g., sulfadiazine and
use of azole prophylaxis in high-risk patients has dramatically sulfasoxazole) or imipenem are effective. Prolonged therapy is
decreased the incidence of invasive C. albicans infections but important, and the duration of treatment (6–24 months)
has increased the incidence of infections due to azole-resistant should take into account the presence of disseminated disease
yeast, including C. glabrata or C. krusei [209]. and the extent of the patient’s underlying immune suppression.
Surgical debridement is recommended for necrotic nodules or
Predisposition to Infections: Cellular Immune Deficiency large subcutaneous abscesses.
Patients with Hodgkin lymphoma or non-Hodgkin lymphoma; Fungi. Cryptococcal infections originate in the lungs, often
recipients of blood, marrow, or solid organ transplants; and with early hematogenous dissemination to the meninges and
patients being treated with corticosteroids and other immune skin or soft tissues [219], but primary cutaneous cryptococcus
suppressants are predisposed to infection because of abnor- also occurs [220]. Single or multiple painless skin lesions in-
malities of their cellular (lymphocyte-mediated) immune func- volving the face and scalp develop in 5%–10% of clinically
tion. These patients are at increased risk for infections, and the infected patients, and in some patients, these lesions may pre-
infections are caused by a select group of bacteria, fungi, viruses, cede documented cryptococcal meningitis by several weeks. Cu-
protozoa, and helminthes, but only a few of these cause skin taneous cryptococcal infections may appear as papules (often
and soft-tissue infections (table 8). Some of these infections similar to moluscum contagiosum lesions), nodules, or pustules

or as chronic draining necrotic ulcers [220]. Cryptococcal cel- for at least 4–6 days, with the entire disease duration being !2
lulitis has occurred in recipients of blood, bone marrow, or weeks. In immune suppressed hosts, lesions may continue to
solid organ transplants [221], although the incidence has dra- develop over a longer period (7–14 days) and generally heal
matically decreased with the prophylactic use of the newer azole more slowly unless effective antiviral therapy is administered
agents, particularly fluconazole. Fluconazole is often used as [164, 165, 230, 231]. Without adequate treatment, some im-
initial treatment, for patients with more mild infections, or to mune suppressed patients develop chronic ulcerations with per-
complete treatment after the patient has shown clinical and sistent viral replication complicated by secondary bacterial and
microbiologic improvement with amphotericin B and 5-flu- fungal superinfection. Disseminated VZV lesions characteris-
cytosine induction therapy [222, 223]. Surgical debridement tically begin on the face and trunk and then evolve peripherally.
and/or drainage are not helpful in the management of skin or Cutaneous VZV, unlike smallpox, usually show lesions simul-
soft-tissue cryptococcal infections [223]. taneously in the varied stages of infection progression. Preven-
Cutaneous manifestations of acute progressive disseminated tion of viral reactivation with oral acyclovir, famciclovir, or

histoplasmosis are rare [224] and usually occur in patients with valacyclovir is an important component of the treatment of
severe cellular immune deficiency, where they appear as non- cutaneous VZV infection [164, 165]. Such therapy is usually
specific maculopapular eruptions that may become hemor- administered to high-risk patients during the period of max-
rhagic. Oral ulcers sometimes present, particularly in the sub- imum immunosuppression. Recipients of an allogenic blood
acute, disseminated form of the disease. Histopathologic and bone marrow transplant routinely take acyclovir (800 mg
analysis of these skin lesions reveals necrosis surrounding the twice per day) or valacyclovir (500 mg twice per day) during
superficial dermal vessels, and with special stains, both intra- the first year after transplantation [165]. High-dose intravenous
cellular and extracellular yeast may be seen. Prompt adminis- acyclovir remains the treatment of choice for VZV infections
tration of amphotericin B therapy is the recommended treat- in compromised hosts [228] (B-III). Oral acyclovir, famciclovir,
ment for patients with cellular immune deficiency and acute, and valacyclovir are beneficial for VZV infections in otherwise
life-threatening, progressive disseminated histoplasmosis [225]. healthy hosts, but oral therapy should probably be reserved for
Patients often show a rapid clinical improvement within 1–2 mild cases of VZV disease in patients with transient immune
weeks, and itraconazole can then replace amphotericin B to suppression or as treatment to complete therapy once the pa-
complete at least 6–12 months of treatment. Patients with ill- tient has shown a clinical response to intravenous acyclovir
nesses that result in profound and prolonged immune sup- [165, 230, 231].
pression should receive long-term suppressive therapy with itra- Herpes simplex virus (HSV) has a worldwide distribution,
conazole after the initial treatment course is complete. and 190% of adults have antibody to HSV-1 by the fifth decade
Viruses. Varicella zoster virus (VZV) is one of the 2 most of life [231, 232]. Antibodies against HSV-2 appear in puberty
frequent herpesviruses to cause cutaneous infection in im- and correlate with sexual activity. The seroprevalence of HSV-
munosuppressed patients [226–228]. Patients without a pre- 2 antibody among patients in the United States is now 20%–
ceding history of varicella are at significant risk of developing 25% [232, 233]. HSV infections in compromised hosts are
the disease if exposed, but herpes zoster with or without dis- almost exclusively due to viral reactivation [232]. Orofacial and
semination is a more frequent clinical concern [227, 228]. Be- genital sites are the most common cutaneous locations, but
tween 65% and 70% of adult patients are seropositive for VZV, autoinoculation can occur in almost any area. Infections of the
and this identifies those patients at risk for future reactivation fingernail bed and cuticle (herpetic whitlow) occur because of
infection. Herpes zoster occurs most frequently during the first inoculation of HSV at sites of epidermal surface breakdown.
year after treatment, or after receipt of a blood, bone marrow, Cutaneous lesions are often preceded by localized pain or a
or a solid organ transplant [226, 229]. Depending on the in- tingling sensation. Early skin lesions are usually focal, erythem-
tensity of treatment or type of transplantation, 25%–45% of atous, and maculopapular. These evolve to form thin-walled
such patients develop dermatomal zoster, with a 10%–20% risk vesicles and then pustules before becoming small ulcers. Lesions
of developing dissemination without prompt and effective an- frequently coalesce, and chronic, poorly healing ulcers are char-
tiviral therapy. A few patients present initially with disseminated acteristic of HSV infections among immunocompromised
cutaneous infection that mimics varicella. Herpes zoster (also hosts. These ulcerative lesions rarely include a vesicular com-
known as “shingles”) causes a unilateral, vesicular eruption with ponent, thus making the clinical diagnosis of a chronic HSV
dermatomal pain that often precedes the skin findings by 24– infection more difficult. Bloodborne HSV dissemination, man-
72 h (and sometimes longer). Early lesions are erythematous ifested by multiple vesicles over a widespread area of the trunk
macules that rapidly evolve to papules and then to vesicles. or extremities, is uncommon, but when seen among compro-
The vesicles frequently coalesce, form bullae, and scab before mised hosts, it is usually secondary HSV-2 infection. Acyclovir
healing. Lesions in otherwise healthy hosts continue to erupt is the treatment of choice for HSV infections, although fam-
ciclovir and valacyclovir are also highly effective [164, 165]. positive when the catheter infection is limited to the entry site
The development of acyclovir-resistant HSV isolates is well de- [164, 165, 236]. The skin manifestations of a tunnel infection
scribed and occurs more frequently among immune compro- include a painful cellulitis that may progress to necrosis or
mised patients [234]. Suppression of HSV reactivation or con- ulceration. Many early port-pocket infections are painless, hin-
tinued treatment until the ulcerated skin or mucosal lesions dering the clinician’s ability to recognize the catheter as the site
have totally healed may decrease the incidence of infections of infection. Gram-positive organisms cause two-thirds of the
caused by acyclovir-resistant HSV strains. The treatment of vascular device infections. Whereas coagulase-negative staph-
acyclovir-resistant HSV isolates is a prolonged course of intra- ylococci are the most frequent pathogens, gram-negative bacilli,
venous foscarnet [234]. Surgery should be avoided in patients fungi, and atypical mycobacteria are other causes [165, 236].
with HSV infections, unless a documented bacterial or fungal The prevalence of infection due to gram-positive pathogens
abscess is identified. justifies recommending the use of empirical intravenous van-
Cutaneous cytomegalovirus infections have a highly variable comycin for treatment of clinically serious catheter-associated

appearance, including cutaneous nodules, ulcers, indurated infections [164, 165]. Most entry-site infections can be treated
plaques, maculopapular eruptions, and hemorrhagic vesicles. effectively with appropriate antimicrobial therapy without cath-
The true prevalence of these cutaneous infection is uncertain, eter removal [164, 165, 236]. Tunnel or port-pocket infections
because many have a bland appearance, biopsies are only rarely require catheter removal and culture, with modification of the
performed, and infection sites usually do not contain cells that empirical antimicrobial therapy on the basis of culture and
demonstrate cytomegalovirus inclusions [235]. Prolonged gan- susceptibility test results [165, 236]. Catheter-site infections
ciclovir therapy is the treatment of choice [165]. caused by fungi or nontuberculosis mycobacteria routinely re-
Parasites. Rarely, the skin and soft-tissue structures of im- quire catheter removal and debridement of devitalized soft tis-
munosuppressed patients can also be affected by parasites, in- sues [211]. A recent report documented a 100% cure of tunnel
cluding but not limited to Strongyloides stercoralis, free-living infections caused by nontuberculous mycobacteria with com-
ameba (Acanthamoeba species and Balamuthia species), and bination antimicrobial therapy for 3–6 weeks plus catheter re-
Sarcoptes scabiei. moval and debridement of the infected soft tissue [211].
Infections Related to Iatrogenic Procedures

Acknowledgments
Many iatrogenic procedures disrupt the integumentary barrier
and increase the risk of infection for immunocompromised Potential conflicts of interest. D.L.S. has received research funding
from Wyeth, Lederle, Pfizer, Amgen, Roche, and Cubist and has served as
patients. Vascular-access devices are the most common iatro- a consultant for Schering Plough, Pfizer and Arpida. A.L.B. has served as
genic factor that predisposes patients to skin and soft-tissue a consultant for Merck, Cubist, Pharmacia, and Schering Plough. H.F.C.
infections, but many patients with intravenous catheters also has received grant or research support from Ortho-McNeil and Cubist,
has served as a consultant for or on the advisory board of Otho-McNeil
have additional factors (e.g., neutropenia, cellular immuno-
and Osmotics, and has received honoraria from Basilea. P.D. has received
deficiency, or humoral immunodeficiency) that increase their grants for clinical research from, served on the advisory board of, and/or
risk of infection. Intravenous vascular-access devices are almost lectured for honoraria from GlaxoSmithKline, Bayer, Eli Lily, Merck, Wy-
eth-Ayerst, Bristol-Myers Squibb, AstraZeneca, Pfizer, Aventis, Hoffman–
universal for patients, such as blood, marrow, and solid organ
La Roche, Arrow, Ortho-McNeil, Perke-Davis, Abbot, ICOS, Immunex,
transplant recipients, who are undergoing cancer therapy or in Chiron, Searle, Cubist, Virucon, InterMune, Peninsula, Johnson & Johnson,
need of intensive care. These vascular devices allow adminis- and BRAHMS. E.J.C.G. has served as a consultant for, on the speakers’
tration of multiagent therapy, blood products, prolonged an- bureaus of, and/or has received research support from Merck, Aventis,
Cubist, Bayer, Schering Plough, GlaxoSmithKline, Ortho-McNeil, and Vi-
timicrobial treatment, intravenous nutrition, and withdrawal curon and has served on the scientific advisory board of Merck, Bayer, and
of blood for monitoring and microbial evaluation. Many of Schering Plough. J.G.M. has served on the speakers’ bureaus of Merck,
these catheters remain in place for prolonged periods, and the Pfizer, Enzon, Aventis, and Schering Plough. All other authors: no conflicts.
risk of cutaneous infections varies with the device, the duration

of catheter placement, and the severity of immune suppression.
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Note added in proof. Since this article was accepted for publication, the Food and Drug Administration has approved dalbavancin
(Seltzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of
skin and soft-tissue infections. Clin Infect Dis 2003; 37:1298–303) and tigecycline (Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The
efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison
studies with vancomycin-aztreonam. Clin Infect Dis 2005; 41[Suppl 5]:S341–53) for treatment of skin and soft-tissue infections,
including those caused by methicillin-resistant Staphylococcus aureus. Dalbavancin was compared with the standard-of-care regimen,

and cure rates and adverse effects were similar between study groups. Tigecycline was compared with vancomycin-aztreonam, and
outcomes were similar between study groups. Interestingly, the incidence of nausea and vomiting was higher among patients in the
tigecycline arm, and transaminase levels were higher in the vancomycin-aztreonam arm.

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IDSA GUIDELINES

Practice Guidelines for the Diagnosis and

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EXECUTIVE SUMMARY ters: results of blood culture and drug susceptibility

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Category, grade Definition

1374 • CID 2005:41 (15 November) • Stevens et al.

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diagnosis. In some cases, this information is insufficient, and

1378 • CID 2005:41 (15 November) • Stevens et al.

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1380 • CID 2005:41 (15 November) • Stevens et al.

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1382 • CID 2005:41 (15 November) • Stevens et al.

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1384 • CID 2005:41 (15 November) • Stevens et al.

First-line Antimicrobial agent(s)

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1386 • CID 2005:41 (15 November) • Stevens et al.

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1388 • CID 2005:41 (15 November) • Stevens et al.

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Route of drug administration

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Route of drug administration

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1392 • CID 2005:41 (15 November) • Stevens et al.

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1394 • CID 2005:41 (15 November) • Stevens et al.

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NOTE. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor.

1396 • CID 2005:41 (15 November) • Stevens et al.

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1398 • CID 2005:41 (15 November) • Stevens et al.

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Infections Related to Iatrogenic Procedures

risk of cutaneous infections varies with the device, the duration

1400 • CID 2005:41 (15 November) • Stevens et al.

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1402 • CID 2005:41 (15 November) • Stevens et al.

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1404 • CID 2005:41 (15 November) • Stevens et al.

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1406 • CID 2005:41 (15 November) • Stevens et al.

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