Diagnosis And Management Of Skin And Soft Tissue Infections In Children It’s a typical busy ED afternoon, and the waiting room is full. Your first patient is a two-year-old boy presenting with “bug bites.” As you greet the patient’s mother, she tells you that she never should have bought a home so close to the water, because she doesn’t remember her oldest son getting as many bug bites as the child with her today. You take the history and are surprised to learn that the bites are in the patient’s diaper area. After removing the child’s diaper, you realize that instead of bug bites he has three areas of cellulitis, one of which appears fluctuant. You begin to consider what the likelihood is that this child has contracted an infection with methicillin-resistant Staphylococcus aureus and how you should best treat it if that is what it is….

S

kin and soft tissue infections are one of the most common reasons for children to present to the emergency department (ED). In one study, the authors estimated that over 11 million ambulatory healthcare visits occur each year for skin and soft tissue infections due to Staphylococcus aureus (S. aureus) alone.1 Yet these infections have also become some of the most difficult conditions to treat. This is due to new, rapidly emerging patterns of resistance. When penicillin was first developed in 1941, all S. aureus isolates were sensitive to it.2 Today, however, S. aureus is virtually uniformly resistant to penicillin, and the majority of community-associated staphylococcal infections are becoming resistant to the semisynthetic penicillins as well. This new wave of community-acquired methicillin-resistant S. aureus (CAMRSA) is rapidly making obsolete many of the pharmacologic

AAP Sponsor Martin I. Herman, MD, FAAP, FACEP Professor of Pediatrics, UT College of Medicine, Assistant Director of Emergency Services, Lebonheur Children’s Medical Center, Memphis, TN

Editorial Board Jeffrey R. Avner, MD, FAAP Professor of Clinical Pediatrics, Co-Director of Medical Student Education in Pediatrics, Albert Einstein College of Medicine; Chief, Pediatric Emergency Medicine, Children’s Hospital at Montefiore, Bronx, NY T. Kent Denmark, MD, FAAP, FACEP Residency Director, Pediatric Emergency Medicine; Assistant Professor of Emergency Medicine and Pediatrics, Loma Linda University Medical Center and Children’s Hospital, Loma Linda, CA

Michael J. Gerardi, MD, FAAP, FACEP Clinical Assistant Professor, Medicine, University of Medicine and Dentistry of New Jersey; Director, Pediatric Emergency Medicine, Children’s Medical Center, Atlantic Health System; Department of Emergency Medicine, Morristown Memorial Hospital, Morristown, NJ Ran D. Goldman, MD Associate Professor, Department of Pediatrics, University of Toronto; Division of Pediatric Emergency Medicine and Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON Mark A. Hostetler, MD, MPH Associate Professor, Department of Pediatrics; Chief, Section of Emergency Medicine; Medical Director, Pediatric Emergency Department, The University of

Chicago, Pritzker School of Medicine, Chicago, IL Alson S. Inaba, MD, FAAP, PALS-NF Pediatric Emergency Medicine Attending Physician, Kapiolani Medical Center for Women & Children; Associate Professor of Pediatrics, University of Hawaii John A. Burns School of Medicine, Honolulu, HI; Pediatric Advanced Life Support National Faculty Representative, American Heart Association, Hawaii & Pacific Island Region Andy Jagoda, MD, FACEP Vice-Chair of Academic Affairs, Department of Emergency Medicine; Residency Program Director; Director, International Studies Program, Mount Sinai School of Medicine, New York, NY Tommy Y. Kim, MD, FAAP Attending Physician, Pediatric Emergency Department; Assistant Professor of

February 2008 Volume 5, Number 2 Authors Neil G. Uspal, MD Physician, Department of Emergency Medicine and Transport, Childrens Hospital Los Angeles, Los Angeles, CA Dewesh Agrawal, MD Assistant Professor of Pediatrics and Emergency Medicine, George Washington University School of Medicine; Director, Pediatric Residency Training Program, Children's National Medical Center, Washington, DC Peer Reviewers Denis Pauze, MD, FACEP Inova Fairfax Hospital, Falls Church, Virginia; Clinical Assistant Professor of Emergency Medicine, The George Washington University School of Medicine, Washington, DC Michael Witt, MD, MPH, FAAP Attending Physician, Division of Emergency Medicine, Children’s Hospital Boston; Instructor of Pediatrics, Harvard Medical School, Boston, MA CME Objectives Upon completing this article, you should be able to: 1. Name the primary pathogens that cause skin and soft tissue infections and identify factors which increase their pathogenicity. 2. Understand the changing epidemiology and virulence of CA-MRSA infections and discuss empiric treatment strategies for presumed CA-MRSA infections. 3. Identify the clinical manifestations of various skin and soft tissue infections in children. 4. Discuss the controversies and changing paradigms in medical treatment of skin and soft tissue infections. Date of original release: February 1, 2008 Date of most recent review: January 6, 2008 Termination date: February 1, 2011 Time to complete activity: 4 hours Medium: Print & online Method of participation: Print or online answer form and evaluation Prior to beginning this activity, see “Physician CME Information” on back page. Emergency Medicine and Pediatrics, Loma Linda Medical Center and Children’s Hospital, Loma Linda, CA Brent R. King, MD, FACEP, FAAP, FAAEM Professor of Emergency Medicine and Pediatrics; Chairman, Department of Emergency Medicine, The University of Texas Houston Medical School, Houston, TX Robert Luten, MD Professor, Pediatrics and Emergency Medicine, University of Florida, Jacksonville, FL Ghazala Q. Sharieff, MD, FAAP, FACEP, FAAEM Associate Clinical Professor, Children’s Hospital and Health Center/University of California, San Diego; Director of Pediatric Emergency Medicine, California Emergency Physicians, San Diego, CA

Gary R. Strange, MD, MA, FACEP Professor and Head, Department of Emergency Medicine, University of Illinois, Chicago, IL Adam Vella, MD, FAAP Assistant Professor of Emergency Medicine, Pediatric EM Fellowship Director, Mount Sinai School of Medicine, New York Michael Witt, MD, MPH, FAAP Attending Physician, Division of Emergency Medicine, Children’s Hospital Boston; Instructor of Pediatrics, Harvard Medical School, Boston, MA

Research Editor Christopher Strother, MD Fellow, Pediatric Emergency Medicine, Mt. Sinai School of Medicine; Chair, AAP Section on Residents, New York, NY

Accreditation: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Mount Sinai School of Medicine and Pediatric Emergency Medicine Practice. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Faculty Disclosure: Dr. Uspal, Dr. Agrawal, Dr. Pauze, and Dr. Witt report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation. Commercial Support: Pediatric Emergency Medicine does not accept any commercial support.

strategies ED physicians have been using for these infections. Additionally, other mutations in the DNA of S. aureus have made it much more virulent than before. Infections have become more aggressive, often requiring invasive treatment. The emergence of CA-MRSA has created a great deal of controversy about changing treatment paradigms. Many ED physicians now advocate never using semisynthetic penicillins in treating skin and soft tissue infections potentially caused by S. aureus, arguing that it is pointless to treat infections with an antibiotic to which many pathogens are resistant. Conversely, others argue that since there have been no changes in patient’s clinical outcomes on semisynthetic penicillins despite the emergence of CAMRSA, there is no need to change treatment regimens. Other controversies include the role of incision and drainage (I&D) and the role of hospitalization. This issue of Pediatric Emergency Medicine Practice will focus on the management of children with skin and soft tissue infections based on the newest and best available evidence from the literature. This will include a reappraisal of both the reasons these bacteria have become so difficult to treat and the most appropriate ways of treating the infections they cause. This issue will also review some of the more unusual presentations and pathogens involved in skin and soft tissue infections and the best ways to treat them.

STSS: Streptococcal Toxic Shock Syndrome TMP-SMX: Trimethoprim-Sulfamethoxazole TSS: Toxic Shock Syndrome VRE: Vancomycin-Resistant Enterococcus VRSA: Vancomycin-Resistant S. aureus

Abbreviations Used In This Article

It is difficult to pinpoint the exact number of skin and soft tissue infections occurring annually, as many patients are treated in ambulatory care settings with empiric therapy. One study, based on National Hospital Ambulatory Medical Care Survey data, estimated that there were 11.6 million visits to ambulatory care centers per year between 2001 and 2003 for skin and soft tissue infections, representing 410 visits annually per 10,000 persons.1 Compared to the period from 1992 to 1994, emergency department visits for skin and soft tissue infections were up 31%. This may be due to either more virulent infections or changing patterns of treatment for similar infections. Another study showed that annual disease incidence for skin and soft tissue infections caused by MRSA varied between 18 to 26 per 100,000 people between three sites.3 Two specific bacteria, Staphylococcus aureus and Streptococcus pyogenes (also known as group A streptococcus [GAS]), cause the vast majority of skin and soft tissue infections. This is especially true in children, in whom one or both of these two pathogens cause over 90% of these types of infections.4 They share many of the same mechanisms of pathogenicity but also have a number of mechanisms unique to each of them. They both also have the ability to constantly adapt, allowing them to evade both the

Critical Appraisal Of The Literature The literature review was performed using Ovid MEDLINE and PubMed searches for articles on skin and soft tissue infections published between 1950 and 2007, with emphases on literature published within the past five years and dealing with children. Keywords included cellulitis, skin disease, MRSA, soft tissue infection, staphylococcal infections, and streptococcal infections. Over 230 articles are referenced here, and additional articles were reviewed as well. There has been a flurry of articles over the past five to ten years on MRSA infections, as well as a healthy amount of literature published on group A streptococcus and other pathogens. These articles are typically focused on pathophysiology, although there are a number of articles on treatment as well. The literature is much less robust on decisions regarding inpatient versus outpatient treatment, and no significant, specific guidelines were found for children dealing with hospitalization decisions in the emergency department setting.

Epidemiology, Etiology, And Pathophysiology

APSGN: Acute Postreptococcal Glomerulonephritis ARF: Rheumatic Fever CA-MRSA: Community-Acquired (or CommunityAssociated) Methicillin-Resistant Staphylococcus aureus D test: Double-Disk Diffusion Test GAS: Group A Streptococcus, or Streptococcus pyogenes HA-MRSA: Hospital Acquired (or nosocomial) Methicillin-Resistant S. aureus Hib: Haemophilus influenzae type b I&D: Incision And Drainage LRINEC: Laboratory Risk Indicator For Necrotizing Fasciitis MHC: Major Histocompatibility Complex MRSA: Methicillin-Resistant S. aureus MSSA: Methicillin-Sensitive S. aureus PANDAS: Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococci PVL: Panton-Valentine Leukocidin Determinant SCCmec: Staphylococcal Cassette Chromosome mec SEs: Staphylococcal Enterotoxins SLO: Streptolysin O SLS: Streptolysin S SSSS: Staphylococcal Scalded Skin Syndrome

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body’s natural defenses as well as treatments prescribed and applied by physicians.

syndrome are principally the staphylococcal enterotoxins (SEs).16 They act as superantigens, binding to both major histocompatibility complex (MHC) class II molecules on antigen presenting cells and to T-cell receptors. Staphylococcal scalded skin syndrome (SSSS) is caused primarily by exfoliative toxins A and B (ETA and ETB), which act as serum proteases.17,18 These toxins may be expressed from any colonizing site; expressed locally they cause bullous impetigo, while acting systemically they cause SSSS. One of the great medical concerns of the past few years has been the emergence of methicillinresistant S. aureus (MRSA). In 1941, all isolated strains were susceptible to penicillin. By 1944, however, the first penicillinase-producing strains of S. aureus were described.2 The first strains of MRSA were identified in 1961, and nosocomial MRSA (also referred to as hospital acquired or HA-MRSA) infections were prevalent in large hospitals by the late 1970s.19 It was not until the late 1980s, however, that community-acquired (also referred to as community-associated) MRSA (CA-MRSA) strains were first reported.20 These infections were rare until the 1990s, when CA-MRSA began to increase exponentially in number. By 2004, one study found that CAMRSA was isolated in 59% of emergency department patients with skin and soft tissue infections.21 With the striking increase in CA-MRSA, there initially existed a concern that nosocomial MRSA had somehow escaped the hospital and become prevalent in the community. Instead, the reality is that CA-MRSA represents novel strains of MRSA different than those found in the hospital. In both nosocomial and CA-MRSA, the mecA gene encodes an altered penicillin binding protein known as PBP2a, which has decreased affinity for β-lactam antibiotics.22 This gene is encoded within a mobile genetic element know as the staphylococcal cassette chromosome (SCC) mec, containing additional regulatory and insertion genes.23 Four types of SCCmec elements have been characterized. Types II and III contain multiple determinants for resistance to other non-β-lactam antibiotics, and they are typically found in staphylococci associated with nosocomial MRSA isolates.24 Thus nosocomial MRSA strains are usually resistant to commonly used oral antibiotics in children, often requiring intravenous antibiotic therapy with vancomycin. Type IV SCCmec, on the other hand, does not contain resistance determinants for non-β-lactam antibiotics. First found in isolates of Staphylococcus epidermis in the 1970s, it was rarely described in S. aureus isolates before 1990.25 Many identical elements exist between the SCCmec type IV found in S. epidermis and S. aureus, suggesting horizontal exchange of the element between species.26 It is therefore highly likely that SCCmec type IV crossed

Staphylococcus aureus Staphylococcus aureus is a Gram-positive coccus present in air, dust, and fomites as well as colonizing humans and animals.5 It is the most common cause of skin and soft tissue infections in both adults and especially children, accounting for over 70% of all skin and soft tissue infections in the pediatric population.4,6 In humans, the primary site of colonization is the anterior nares,7 but it is also found around the eyes, perineum, wound sites, circumcision wounds, and the umbilical stump.8 Carriage rates in humans are extremely high, with 36% of children documented as carriers in at least one population and over 10% of adults being persistently colonized.9,10 This nasal carriage makes individuals more susceptible to infection.11 S. aureus has numerous mechanisms by which it causes invasive disease. While it is commensal with other skin flora in a healthy host, a break to the skin surface allows it access through this protective barrier, allowing it to cause infection. Once in the skin, S. aureus produces a host of enzymes, such as proteases, lipases, coagulases, and hyaluronidases which serve to destroy local tissue and may facilitate its spread.12 It also has numerous surface proteins, some of which act as adhesins,5 allowing for colonization and invasion of host tissue. A particular virulence factor associated with primary skin infections is the Panton-Valentine leukocidin determinant (PVL).13 While only seen in 2% of all clinical staphylococcal isolates,14 it is present in 93% of strains associated with furunculosis, 55% with cellulitis, and 50% with cutaneous abscesses.15 PVL produces two secretory proteins which are associated with the destruction of human leukocytes and erythrocytes. S. aureus also produces toxins that promote systemic disease. Those that cause toxic shock

Figure 1. Staphylococcus aureus

Reprinted from http://images.forbes.com/images/2004/05/05/staph_aureus_200x15 8.jpg. All rights reserved. All images in this article are available in color at http://ebmedicine.net/redirect/?topic=ped

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into S. aureus and became prevalent in the community independent of nosocomial MRSA. Multiple studies show that these CA-MRSA strains with SCCmec type IV grow faster and achieve higher infection burdens than nosocomial MRSA.27 This gives CA-MRSA a selective advantage, allowing it to thrive in the community where nosocomial MRSA cannot. The pan-resistance profile that nosocomial MRSA has creates too great a metabolic burden to thrive in the community at large. CA-MRSA is very different from the nosocomial MRSA that many feared would cross into the general public. CA-MRSA is a distinct strain of MRSA presumably selected because of antibiotic use in the community. As will be discussed later in this article, non-life-threatening CA-MRSA may be safely and successfully treated with non-beta-lactam antibiotics without fear of the pan-resistance found in nosocomial MRSA isolates. Not only does CA-MRSA have increased antibiotic resistance versus methicillin sensitive S. aureus (MSSA), it also tends to be more virulent. In one study looking at bacterial isolates from soft tissue infections at eleven emergency departments, MRSA isolates also carried the PVL gene 98% of the time, while MSSA isolates carried the PVL gene only 42% of the time.21 Therefore, CA-MRSA is much more likely to cause aggressive disease than MSSA. This is evident in the fact that a greater percentage of skin infections presenting to medical attention contain CA-MRSA21 than is seen in asymptomatic carriers.9

leading cause of skin and soft tissue infections in children, accounting for 30% of these type of infections in one study.4 Toxins elaborated by GAS cause a range of systemic illnesses, from simple scarlet fever to life threatening toxic shock syndromes. It is also associated with a number of serious immunologically mediated sequelae, including rheumatic fever (ARF), acute postreptococcal glomerulonephritis (APSGN), and the controversial pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Traditionally, streptococci have been subgrouped by their M protein, and the M protein is one of the primary means by which GAS combats host immunity. It is a transcellular peptide with two hypervariable regions, both extracellular.30 Based on this hypervariability, there are at least 124 M genotypes, with more being described.31 The Lancefield serological classification system is based on M-typing.30 M proteins function primarily by helping GAS avoid opsonization by the alternative complement system, thereby preventing phagocytosis.32-34 M proteins have also been shown to have a role in GAS adherence35 to and colonization of36 mucosal tissue. It has been noted in the past that specific Mtypes of GAS have strong correlations with specific types of infection and levels of virulence, such as the association between M-types 1, 3, 12, and 28 and toxic shock syndrome.37-41 This does not always hold, however, as pathogenic M-types can often be found in the throats of asymptomatic individuals.42 Virulence of specific M-types can be altered by the presence of prophages, which carry virulence factors horizontally between specific strains of GAS.43 Additionally, sporadic mutations also alter the M proteins.43 These factors cause the intra-Mtype variability found in specific strains of GAS. Therefore, while M-type may have an association with a specific disease pattern, it is not the only factor in GAS virulence. Other factors serve to increase GAS infectivity as well. The GAS capsule is associated with resistance to phagocytosis.30 Levels of encapsulation vary between strains of GAS, with those with greater encapsulation having greater virulence. In one study, while only 3% of GAS strains causing uncomplicated pharyngitis were capsule-producing mucoid strains, 21% of the strains that caused serious infection and 42% of the strains that caused rheumatic fever were.44 Streptolysin O (SLO) is a protein that is lytic to numerous cell types, including polymorphonuclear leukocytes. It is produced by almost all GAS strains,30 and immunity developed against it is the basis for the use of anti-streptolysin O titers to determine the past presence of GAS infection. Streptolysin S (SLS) is similar to SLO and is one of the most potent cytotoxins

Streptococcus pyogenes Streptococcus pyogenes, otherwise known as group A streptococcus (GAS), is a Gram-positive cocci arranged in pairs and chains.28 It is found on human skin and mucosal surfaces, is rarely found in animals, and does not survive outside the human host.29 In children, it is most commonly associated with pharyngitis but is also responsible for a wide range of illnesses, from simple impetigo to rapidly progressive necrotizing infections. It is the second

Figure 2. Streptococcus pyogenes

Reprinted from http://www.mgm.ufl.edu/~gulig/mmid/mmid-lab/labimage/spy1.jpg. All rights reserved.

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known.45 It acts via direct contact of tissues with GAS and is an important virulence factor in necrotizing soft tissue infections.46 GAS also secretes streptokinase which then cleaves plasminogen into its fibrinolytic plasmin form. Plasmin subsequently breaks up the localized thrombi which the body utilizes to contain infection.47 In this manner GAS is allowed improved access to the vascular system to promote systemic infection. The ability of GAS to cause systemic inflammatory responses, as in scarlet fever and streptococcal toxic shock syndrome (STSS), is mediated by a number of bacterial superantigens. Finally, much like streptococcal pharyngitis, streptococcal soft tissue infections can lead to postinfectious sequelae, such as rheumatic fever and post-streptococcal glomerulonephritis. Most believe that these disorders are caused by the molecular mimicry of specific GAS proteins to host-specific proteins, although the specific mechanism of this is unknown. Different strains of GAS vary in their rheumatogenic potential,48 explaining outbreaks of these diseases after specific outbreaks of GAS infections in a community. APSGN appears to be caused by a few select strains of GAS,30 while ARF seems to be caused by GAS whose M protein molecules share a specific surface exposed antigenic sequence.49

oral flora. Occasionally, oral trauma may allow Actinomyces to invade soft tissue and cause infection. Pulmonary and abdominal injury have also allowed for actinomycotic infection. Disease progresses from an acute, painful cellulitis to a chronic, suppurative mass.53 Nocardia, like Actinomyces, is a member of the order Actinomycetales; it is a common opportunistic infection of those with weakened immune systems. It can cause cutaneous infection via traumatic entry of foreign bodies into the skin, usually soil or decaying vegetation. Infection is typically associated with farm labor.54 Although it is usually seen in the tropics, it can be found in the southern United States.53 Clinical manifestations vary widely between patients and may include acute cellulitis, keloid-like lesions, or pustular lesions. Lesions may exhibit periods of dormancy or may chronically progress, causing tumor-like masses known as actinomycetomas.55 Sporotrichosis is a fungal skin infection also initiated by traumatic inoculation through thorns and other vegetative matter. Infection begins with formation of an ulcer or nodule at the site of inoculation, with satellite nodules forming along the path of regional lymphatics.56 The infection may progress slowly over months, often with significant delays in diagnosis and treatment. While S. aureus and GAS cause most wound infections, atypical pathogens may cause wound infections as well. Bite wounds present a distinct set of flora from those found in typical cellulitis. Human bite infections are composed of a wide variety of bacterial flora, from Streptococcus viridans and S. aureus to a wide variety of anaerobes.57 Infections from cat bites, which may cause serious infection given the depth of cat tooth penetration, contain predominantly Pasteurella multocida.58 While dog bites are much more common than cat bites, they tend to cause infection at a much lower rate. They also tend to contain Pasteurella species, as well as S. aureus.59 Other gram-negative and anaerobic bacteria may cause soft tissue infection as well. These infections are often times in the perioral or perianal areas, when these bacteria can be found as part of the normal flora.60 They may also cause secondary infections when the primary condition allows entrance into the skin, as in eczema, varicella, or trauma.61 Infections caused by these bacteria may range from simple cellulitis to fulminant necrotizing fasciitis. Pseudomonas aeruginosa is often associated with ecthyma, a painful, localized, necrotic infection of the dermis. Lesions caused by P. aeruginosa are distinct, for often times they have an abscess with a greenish discharge and a distinct odor.62 In immunocompromised patients, P. aeruginosa septicemia may cause ecthyma gangrenosum, a condition where multiple ecthyma are disseminated

Other Pathogens In the current era of immunization, most simple soft tissue infections in children are caused by one of the two organisms described previously. This was not always the case, however. At one time, Haemophilus influenzae type b (Hib) was responsible for 25% of the cases of facial cellulitis in children 3-24 months of age;50 it is now rare. Nevertheless, there are certain situations where organisms beside the aforementioned two may be causative. In most instances, the possibility of the presence of these other organisms may be ascertained through a thorough history and physical examination. While S. pneumoniae is rarely a cause of primary skin and soft tissue infections, it may be spread hematogenously to these areas. There have been a total of 239 documented cases of pneumococcal cellulitis since 1966, predominantly in children less than three years old.51 These infections were mostly periorbital or buccal, with the rest associated with another localized infection. This may be the tip of the iceberg for pneumococcal periorbital cellulitis, however, as most cases of periorbital cellulitis do not yield positive blood cultures.52 With the advent of the 7-valent pneumococcal conjugate vaccine, the number of invasive pneumococcal infections resulting in cellulitis will undoubtedly diminish. Actinomyces israelii is a slow growing, anaerobic, gram-positive bacteria which is found in the normal

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throughout the dermis. In an immunocompromised patient, mortality is high, between 38% and 77%.63,64 Although typically found in patients known to be immunocompromised, ecthyma gangrenosum may be the initial presentation of an underlying immunocompromised state.65 P. aeruginosa can also cause localized soft tissue infection in other circumstances, including exposure to fresh water or hot tubs, exposure of ear cartilage, or secondary to a puncture wound through a sneaker.66 Aquatic environments contain bacterial flora distinct from those found in terrestrial areas, which can cause significant infection. These wounds are still primarily infected with S. aureus and GAS, but they can have other pathogens as well. Salt water wounds may become infected with Vibrio species, which are facultative anaerobic gram negative rods.67 Vibrio causes highly aggressive, necrotizing soft tissue infections that often require surgical debridement.68 After Hurricane Katrina, at least seven cases of Vibrio vulnificus infection were reported, and four of those seven patients died from their infection.69 Aeromonas hydrophila is another facultative anaerobic gram-negative rod found in freshwater sources that causes aggressive infections.67 Finally, mycobacteria may be responsible for wound infections not responsive to conventional antibiotic therapy. Mycobacterium marinum is often responsible for a slowly progressive, granulomatous infection in those exposed to aquatic environments; the infection itself is often referred to as “swimming pool” or “fish tank” granuloma.70 Other non-tuberculous mycobacteria may also cause infection at contaminated wound sites several weeks after trauma.71

epidermolytic toxin into the local tissues.74 The lesions are superficial, thin walled, fluid filled, and range in size from 0.5 to 3 cm. They may be found anywhere on the body. The bullae may rupture, draining fluid ranging from serous to purulent.75 Fluid aspirated from the lesions may grow S. aureus.76

Folliculitis, Furuncles, And Carbuncles Folliculitis represents acute infection of hair follicles, usually after some sort of chemical or physical trauma. It is usually caused by S. aureus.77 The lesion evolves from a superficial erythematous nodule into a central, thin walled pustule with a surrounding red rim.62 The lesions often appear in clusters and can occur at any age.78 Furuncles, otherwise known as boils, are infections deeper within the hair follicle. They are painful, erythematous lesions with a central collection of purulent material within the hair follicle.12 They are also usually caused by S. aureus, and their incidence increases with patient age. As the infection matures, it eventually makes its way to the surface of the skin, and often drains spontaneously.62 Adjoining furuncles may coalesce to form a carbuncle, a loculated collection of purulent material that often has multiple points of drainage. With the increased prevalence of CA-MRSA in the community, there has been a recent increase in skin and soft tissue abscesses, particularly in young children. As in our opening vignette, the mechanism of infection is often claimed to be a “bug bite,” although the actual bite is not often witnessed.79 In fact, many clinicians will erroneously make a diagnosis of “spider bite” instead of bacterial infection.80 Although these abscesses do not originate at the hair follicle, they too can evolve into either simple or loculated collections of purulent material.

Differential Diagnosis Non-Bullous Impetigo Impetigo, or pyoderma, is a superficial, localized infection of the skin that is most prevalent in warm and humid climates. It is extremely common, with peak incidence between two and six years of age.72 It was believed for many years that GAS was the primary cause of impetigo; however, numerous studies have subsequently shown that S. aureus is isolated in the majority of cases, with GAS present only in about one-third of cases, usually in association with S. aureus.73 The lesions usually begin as vesicles that progress to pustules and then to the characteristic “honey crusted” lesions after rupturing.30 Systemic symptoms are infrequent.

Figure 3. Impetigo

Bullous Impetigo Bullous impetigo is a disease entity caused exclusively by S. aureus, where the bacteria releases Pediatric Emergency Medicine Practice©

Reprinted from http://www.fda.gov/consumer/updates/pics/impetigo_face.jpg.

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Cellulitis

empyema, and brain abscess if not treated promptly and aggressively.87 Unlike periorbital cellulitis, it is almost always a secondary complication of sinusitis, with bacteria crossing the thin lamina papyracea to infect the orbit. In one series of 41 pediatric patients, all 41 cases of orbital sinusitis were associated with sinusitis.88 The causative bacterial flora is therefore the same as that in sinusitis; namely S. pneumoniae, GAS, S. aureus, non-typeable H. influenzae, M. catarrhalis, and anaerobic bacteria of the upper respiratory tract.88,89 Clinically, orbital cellulitis presents with the symptoms of periorbital cellulitis but also presents with fever in addition to orbital manifestations including proptosis, chemosis (edema of the bulbar conjunctiva), ophthalmoplegia, pain with extraocular movement, and decreased visual acuity.90 Diagnosis is often confirmed with contrast-enhanced orbital computed tomography. While orbital cellulitis is now occasionally managed medically,91 early surgical consultation is critical to possibly prevent the previously mentioned complications.

Cellulitis is an acute, spreading infection of the dermis of the skin, with minimal involvement of the epidermis. It typically presents as a painful area of erythema, swelling, and tenderness. The borders of the infection site are often not distinct. It most commonly affects the legs and the digits but can also affect the face, feet, hands, torso, neck, and buttocks.12 It is typically initiated by some sort of minor trauma or bite to the skin, which gives bacteria a passageway to invade the soft tissues. Initiating factors in adults, as found in a multivariate analysis, include obesity, local wounds, and edema.81 No similar studies exist in children. The causative pathogen is typically S. aureus but in certain circumstances can also be GAS, Pasteurella spp., Aeromonas hydrophila, and Vibrio spp, amongst others. Systemic symptoms, including fever, may also be present. Cellulitis at specific sites has different etiologic and clinical characteristics and deserves special mention. Perianal cellulitis appears as a tender, bright red area circumscribing the anus. It was initially thought to be principally caused by GAS, based on anal skin cultures.82 More recent research, performed by needle aspiration, has shown a variety of flora, including Escherichia coli, Peptostreptococcus species, S. aureus, and Bacteroides fragilis.83 It is important to be able to distinguish perianal cellulitis from sexual abuse. Odontogenic infections often cause a profound ascending cellulitis. GAS is the most common cause of these infections, followed by Neisseria and diphtheroids.84,85 Patients have typically had chronic dental caries prior to the onset of acute infection. These infections are typically treated both with antibiotics and with dental extraction, though extraction may be deferred until after the infection has been treated.86

Erysipelas Erysipelas is a soft tissue infection distinct in character from typical cellulitis. It is an infection of layers of skin and cutaneous lymphatics that are superficial to the typical area of cellulitis infection. The area of infection is raised compared to the surrounding skin, and there is a distinct margin between affected and non-affected areas.30 The skin itself is fiery red and has what is often described as a “peau d’orange” appearance.28 Contrary to conventional wisdom, over 85% of cases of erysipelas occur in the arms and legs and not in the face.92 It is caused almost universally by streptococcal species, usually GAS.

Necrotizing Fasciitis

Periorbital And Orbital Cellulitis

Necrotizing fasciitis, while rare, is the most aggressive manifestation of skin and soft tissue infections

Periorbital, or preseptal cellulitis, is a superficial infection of the soft tissues anterior to the orbital septum. It presents with tenderness, swelling, and induration of the peri-orbital tissues but does not involve the globe or retro-orbital structures. It can arise either from the ascension of soft tissue infection inferior to the eye, direct inoculation, or hematogenously. Less commonly, periorbital cellulitis may result as a complication of sinusitis. Over 75% of reported cases of pneumococcal cellulitis in children are periorbital.51 It may be treated medically with antibiotics. Periorbital cellulits must be distinguished from orbital cellulitis, which involves infection of the soft tissues posterior to the orbital septum. Orbital cellulitis is an emergency, as it can cause blindness, cavernous sinus thrombosis, meningitis, subdural

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Figure 4. Periorbital Cellulitis

Reprinted from http://www.icoph.org/med/medimages/H43.jpg. All rights reserved.

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and can cause significant morbidity and mortality. It is an infection of the superficial fascia, often initiated by trauma to the integumentary system, such as a laceration, insect bite, needle puncture, or surgical wound.93 In children, risk factors for necrotizing fasciitis include malnutrition and varicella infection,61 although it also occurs in young people with no risk factors.94 A wide variety of bacteria can cause necrotizing fasciitis, with multiple organisms typically found at the infection site. GAS is the most common organism found in necrotizing fasciitis in both children61 and adults,95 with enterococcus, enterobacteriaceae, and anaerobic species common as well. Recently, S. aureus, particularly CA-MRSA, has been causing an increasing number of cases of necrotizing fasciitis as well.96 While late manifestations of necrotizing fasciitis are clinically obvious, early disease is difficult to distinguish from more typical cellulitis. In some instances a rash may not be present at all.97 Unlike patients with simple cellulitis, however, patients with necrotizing fasciitis tend to have pain that is out of proportion to their other clinical symptoms. Patients often reportedly complain of aches, chills, and feverishness.97 Additionally, many adult patients have abnormal vital signs at presentation. In one series of 15 mostly adult patients whose necrotizing fasciitis was missed at initial presentation, 73% were tachycardic (HR > 90) and 18% were hypotensive (SBP < 90).97 Laboratory values are often abnormal, and normal laboratory values may be used to rule out necrotizing fasciitis. In the adult population, a tool called the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score has been developed. It looks at variables such as CRP, WBC count, hemoglobin, creatinine, and glucose in order to not miss patients at risk for having necrotizing fasciitis early in their disease course.98 In subsequent studies using the LRINEC, it had a positive

predictive value of 40% and, more importantly, a negative predictive value of 95%.99 Once necrotizing fasciitis reaches an advanced stage, the diagnosis becomes more apparent. Within 48-72 hours of the onset of symptoms, the overlying skin develops either serous discharge or hemorrhagic blistering.61 Soon after, necrosis develops; by the fifth or sixth day of disease, a necrotic plaque develops over the affected area.100 Localized anesthesia due to nerve damage may be present as well. Patients can become septic during this time, often with high fevers, mental status changes, and multiple organ failure.61 Mortality rates are highly variable, with reports in children ranging from 18% to 45%.61,101

Toxin-Mediated Diseases While not skin infections per se, superantigen mediated diseases often are secondary to localized skin infections and merit mention. Staphylococcal scalded skin syndrome (SSSS) is a blistering skin disorder caused by exfoliating toxins produced by S. aureus.102 Individuals with antibodies to these toxins have merely the localized reaction of bullous impetigo. Individuals without these antibodies, however, have release of these toxins into the blood stream, causing systemic disease. Affected individuals are usually children under five years of age.75 Clinical manifestations include fever and erythema that evolves into easily ruptured blisters, leaving denuded skin.12 This denuded skin surface may serve as a pathway for secondary infection. Toxic shock syndrome (TSS) is a superantigen mediated disease causing fever, rash, hypotension, and potentially multi-organ failure. It may be caused either by S. aureus or GAS. While outbreaks of staphylococcal TSS were initially associated with super-absorbent tampon uses, staphylococcal TSS is now more typically associated with skin infection, post-partum trauma, and pneumonia.103 The annual incidence of staphylococcal TSS is now only 0.5

Figure 5. Orbital Cellulitis

Figure 6. Necrotizing Fasciitis

(a) proptosis, (b) soft tissue inflammation, (c) choroidal detachment, (d) retrobulbar inflammation, and (e) optic nerve sheath enhancement. Reprinted from http://www.nature.com/eye/journal/v21/n7/images/6702815f1.jpg. All rights reserved.

Pediatric Emergency Medicine Practice©

Reprinted from http://www.jyi.org/articleimages/463/originals/img0.jpg. All rights reserved.

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Children who have had extensive hospitalizations may be colonized with nosocomial MRSA,109 and this may affect empiric antibiotic choice and effectiveness. Another critical question to ask is whether or not a patient has a history of trauma at the site of infection. Bites, be they animal or human, introduce unique pathogens into soft tissues, which may cause infection. If a hand infection is being treated, it is important to ascertain a history of physical altercation and trauma caused by clenched-fist injuries57 especially in male adolescents, as lacerations resulting from contact with teeth must be treated similar to bite wounds. Wounds which are deeper than subcutaneous tissue, have jagged edges, are visibly contaminated, or contain foreign bodies have all been shown to have significantly increased rates of infection.110 Dirty wounds may lead to infection with gram negative bacteria, anaerobes, or mycobacteria, especially if a significant amount of time since the trauma has elapsed before presentation,71 complicating antimicrobial treatment. Wounds obtained in aquatic environments are especially worrisome for unique pathogens, so a history of trauma in this kind of environment should be determined. On physical examination, the general appearance of the patient should first be noted. Ill appearing children, especially infants, necessitate a more complete workup and more aggressive therapy. Mental status changes especially may be the result of toxic shock or septic shock. The appearance of a generalized rash may indicate a toxin-mediated illness or could point to the primary cause of a secondary bacterial infection, as in varicella and eczema. Vital signs should be observed for fever, tachycardia, and changes in blood pressure. The site of the infection should be examined, with careful attention paid to the characteristics and size of the lesion. In the adult population, an area of erythema greater than 0.1 m2 (1000 cm2) has been associated with increased length of hospital stay.111 The area of infection should be palpated, taking note of any fluctuance indicating the need for incision and drainage of the infection site. Additionally, pain out of proportion with the clinical finding is concerning for necrotizing fasciitis.

cases per 100,000.104 In staphylococcal TSS, patients develop acute onset of fever, chills, malaise, muscle tenderness, hypotension, and a diffuse macular rash.105 Disseminated intravascular coagulation (DIC) and end organ failure may develop, as well as anemia, thrombocytopenia, and leukocytosis. Skin desquamation occurs 7-14 days after disease onset.105 Mortality ranges from 3% to 5%.105 Streptococcal TSS has a few key features that distinguish it from staphylococcal TSS. Most patients are previously healthy but present with a deepseated GAS infection. About 50% of adult patients have necrotizing fasciitis at presentation,106 but children tend to present with different infections, such as bacteremia without focus, osteomyelitis, or a CNS infection.107 Patients with streptococcal TSS, unlike those with staphylococcal TSS, often present with severe, localized pain that often precedes localized evidence of infection.103 Patients also present with high fevers, confusion, and striking vital sign changes, with hypotension and tachycardia common.37,108 Bacteremia is much more common in children with streptococcal TSS, around 60%, and mortality is also higher in children with streptococcal than in staphylococcal TSS, with rates ranging from 5% to 10%.105

Prehospital Care Most children with skin and soft tissue infections will walk into the emergency department; however, this does not preclude the possibility of a critically ill child with the skin and soft tissue as the primary source of his or her infection. First, as always, a quick evaluation of airway, breathing, and circulation should be undertaken. Children with septic shock, toxic shock, or with rapidly progressive, necrotizing infections require rapid resuscitation. In these patients, fluid management is the most important initial management step, especially in the field. The use of pressors is also indicated if multiple boluses of crystalloid or colloid fail to stabilize the patient’s blood pressure. If a child is critically ill, transport to a pediatric facility with the appropriate critical care facilities is essential.

ED Evaluation As with most conditions, a through history and physical examination are the most important aspects of diagnosis. A generalized medical history is important in order to ascertain whether or not a patient has any medical problems that may affect disease progression, such as HIV and other sources of immunocompromised status, including malignancies, sickle cell anemia, diabetes mellitus, asplenia, and iatrogenic immunosuppression. One of the most critical questions that can be asked is whether or not a patient has had a recent hospitalization.

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Diagnostic Studies Laboratory and diagnostic tests will vary based on the severity of the infection. For simple skin infections without systemic symptoms, such as impetigo, no laboratory workup will be needed in most children. Simple cellulitis may be treated without significant laboratory work-up up as well. Multiple studies have evaluated the utility of blood cultures in cellulitis. In general, blood cultures are rarely, if

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ever, useful in cellulitis cases. Cultures were positive in only 2-8.3% of immunocompetent adults with cellulitis, with none documented as leading to changes in antibiotic therapy as a result of positive blood cultures.112-117 In children, one study showed similar results, with only 2% of blood cultures being positive, while 5.4% contained contaminants. Only one positive culture out of 243 total, in a patient who also had a septic hip and psoas abscess, resulted in a change to the antibiotic regimen.118 Fine needle aspiration of cellulitis sites for culture does have a higher yield than blood cultures, yet results are still only positive 28.5-51.7% of the time.119-121 In children, aspiration yields have been shown to be greatest at the point of maximal inflammation of the cellulitis and not at the leading edge of infection as previously thought.121 In adults, the yield of fine-needle aspiration has been shown to be greatest in patients with concurrent medical conditions that lead to cellulitis;122 however, these conditions are uncommon in children. Results of positive cultures were usually either S. aureus or GAS, with the lone exception in a pediatric study being H. influenzae121 in a sample obtained prior to the use of the Hib vaccine. For more concerning infections, blood tests may be warranted. In a study in the adult population, length of hospital stay independently increased with absolute neutrophil count greater than 10,000/mm3.111 In one study, children with necrotizing fasciitis tended to be anemic (mean hematocrit of 29%), have elevated WBC counts (mean WBC of 16,552/mm3), and have a bandemia (mean percentage bands of 4%).61 In adults, abnormalities in laboratory values in patients with necrotizing fasciitis are even more striking, with significant abnormalities in WBC count (24.5 ± 16.0 x 109/L), sodium (133 ± 5 mmol/L), and BUN (22 ± 16 mg/dL).123 Toxic shock syndrome can also manifest in highly abnormal laboratory values. While in TSS the total WBC count may be normal, there may exist a striking bandemia, with immature forms exceeding 50%.108 Additionally, particularly in late disease, end organ hypoperfusion may manifest in elevated creatinine levels37,108 and other markers of multiorgan failure. Radiology may have a small but significant role in the evaluation of soft tissue infections. Plain roentgenograms have been shown to reveal subcutaneous emphysema in 39% of patients with necrotizing fasciitis;123 however, the low sensitivity of this test makes it of low utility. Plain films may also be useful when trying to distinguish between a chronic cellulitis and an osteomyelitis and to look for retained, radio-opaque foreign bodies in trauma. Computerized tomography has been demonstrated to have a higher yield than plain films in identifying subcutaneous gas in necrotizing fasciitis.124 CT is also the modality of choice to distinguish periorbital Pediatric Emergency Medicine Practice©

from orbital cellulitis.125 MRI is excellent in distinguishing necrotizing fasciitis from cellulitis. In one study, it had 100% sensitivity and 86% specificity.126 However, its frequent lack of immediate availability and the need for sedation in children make it impractical when rapid surgical intervention may be needed. Ultrasound has also been advocated for diagnostic purposes. Chao et al demonstrated that ultrasound findings of tissue distortion with or without pus accumulation in children with cellulitis correlated with longer duration of symptoms and the presence of higher fever, WBC counts, and Creactive protein level.127 The study did not show how these findings affected clinical decision making, however. The study also found that patients who underwent either ultrasound-guided or surgical drainage of abscesses had shorter hospital stays and fever duration then those who were just treated medically with antibiotics.127 Tayal et al showed how ultrasound of patients with clinical cellulitis in the emergency department could change patient management. In this study of adult patients, 56% (71/126) had their pretest management plan altered after ultrasound of the cellulitic area, with some patients receiving previously unplanned drainage, some having drainage deferred, and some receiving further diagnostics or consultation. The pretest probability of the presence of fluid before drainage increased from 10% to 90% after ultrasound.128 As more pediatric emergency room physicians become acquainted with bedside ultrasound, the use of this technology will undoubtedly increase.

Treatment Impetigo A wide variety of treatments have been suggested for simple, non-bullous impetigo, ranging from observation to systemic antibiotics. A Cochrane systematic literature review was recently performed on the treatment for impetigo.129 It showed that topical mupirocin and fusidic acid (which is not commercially available in the United States) are either as effective as or more effective than systemic antibiotics with less side effects. Interestingly, bacitracin seems to be inferior to mupirocin and fusidic acid. No evidence exists to support the use of disinfectants, such as chlorhexidine, in the treatment of impetigo.130,131

Simple Abscesses And Cellulitis A mainstay of therapy in the treatment of soft tissue abscesses is incision and drainage (I&D) of the fluid collection. Controversy has existed for some time as to the efficacy of I&D alone in the treatment of 10

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simple soft tissue abscesses. In the pre-MRSA era, a number of trials demonstrated that I&D by itself was equivalent to I&D plus oral antibiotics in the management of soft-tissue infections.132-134 However, there have been no comparable studies in the CA-MRSA era. With the associated increase in virulence often seen in strains of MRSA, many are hesitant to treat abscesses that may be infected with MRSA solely with I&D for fear of inadequately treating a highly virulent pathogen. A number of studies, however, have illustrated that many physicians are treating skin abscesses which eventually grow MRSA with first and second generation cephalosporins.3,135,136 In these cases, no adverse outcomes have been reported despite the pathogen’s resistance to the prescribed antibiotics. Some have therefore proposed that this is adequate evidence that small (< 5 cm) abscesses without surrounding cellulitis in immunocompetent children may be treated with I&D alone and without antibiotics.135 The lack of a definitive study confirming this hypothesis, however, means that adequate patient follow-up must be assured prior to discharging patients after draining abscesses without antibiotic prescription. Controversy also continues to exist regarding antibiotic choice in the treatment of skin and soft tissue infections. Rates of MRSA have grown exponentially over the past 10 years. Despite this, many practitioners have continued to treat patients with cephalosporins, which should in theory not adequately treat these infections. Yet there has not been a documented concomitant increase in complications from skin and soft tissue infections. In one study comparing cefdinir versus cephalexin, (two cephalosporins to which CA-MRSA should be resistant) in a variety of skin and soft tissue infections in immunocompetent patients, clinical cure rates were 93% and 91% for the two antibiotics when treating MSSA, but also 91% and 90% when treating CAMRSA.137 Even in infections that were treated without incision and drainage, there existed in another study no significant difference in need for follow up visits, subsequent incision and drainage, or antibiotic change in patients prescribed either active or inactive therapy.3 It is unclear whether or not this is due to the self-limited nature of most simple skin and soft tissue infections or some partial in vivo efficacy of cephalosporins in treating CA-MRSA despite its resistance pattern in vitro. Without the existence of studies treating cellulitis with observation only, cellulitis of any significance still merits systemic antibiotic therapy. Phillips et al recently did a cost analysis of empiric antimicrobial strategies for cellulitis in adults in the MRSA era based on medication costs, MRSA prevalence, and probabilities for treatment failure.138 The authors concluded that for what they considered the base EBMedicine.net • February 2008

prevalence for MRSA (27%), cephalexin was the most cost-effective antimicrobial therapy. The major flaw with this study, however, is that it underestimates the ever increasing prevalence of MRSA in the community. While some authors are still reporting recent base prevalences of MRSA at around 20%,3 many others are reporting rates up to 37%,139 51%,140 and 74%.21 In the ED-based study by Moran et al, 9 of 11 communities have MRSA base prevalence rates of 50% or greater.21 Additionally, the Phillips et al study used only a 37% likelihood that cellulitis is caused by S. aureus.138 While this figure may be appropriate in adults, it is not applicable in children, where the likelihood of S. aureus being the etiologic agent in skin infections is much higher (> 70%)4,6 than 37%. After adjusting the likelihood of S. aureus to 70%, as appropriate for children, and the base prevalence of MRSA to a more realistic 50%, the model employed by Phillips et al would make empiric treatment with clindamycin more cost effective than cephalexin for cellulitis. That, along with the intrinsic sense it makes to use an antibiotic that MRSA is sensitive to in vitro to treat cellulitis, makes a non-beta-lactam antibiotic the preferable therapy for skin and soft tissue infections in children. Of the non-beta-lactam antibiotics available, clindamycin has many advantages for empiric treatment. It is active against both aerobic gram-positive (including GAS and S. aureus) and anaerobic bacteria.19 Clindamycin is highly active against CAMRSA, with susceptibilities ranging from 83% to 97%.3,136,141-143 It does have a few down sides, though. Dosing is every six to eight hours, and the liquid formulation has a poor taste that may affect compliance in children. Additionally, a proportion of CA-MRSA that are resistant to erythromycin have inducible clindamycin resistance. In these bacteria, the mutation that causes erythromycin resistance may evolve to also cause clindamycin resistance during clindamycin therapy.144 To exclude inducible clindamycin resistance, the double-disk diffusion test (D test) should be performed on all clindamycin isolates that are resistant to erythromycin to exclude this inducible resistance.145 There exists a wide variation in reported rates of inducible resistance to clindamycin in erythromycin-resistant MRSA, with some studies having rates below 10%,141,142,146 while others had rates that were significantly higher.147-149 Trimethoprim-sulfamethoxazole (TMP-SMX) also has high activity against CA-MRSA, with susceptibilities between 83% and 99% at different sites.3,136,141-143 TMP-SMX, unlike clindamycin, is not active against GAS. Therefore, it should not be used as monotherapy when GAS infection is in the differential diagnosis. Rifampin is another antibiotic to which CA-MRSA is highly susceptible.3,142,143 11

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It is potentially hepatotoxic,19 however, and may induce resistance if used as monotherapy.150 CAMRSA is also usually susceptible to tetracycline and doxycycline, with susceptibilities in CA-MRSA ranging from 55% to 92%.3,136,143 However, tetracycline antibiotics are contraindicated in pediatric patients under eight years of age, due to concerns for tooth staining and decreased bone growth. CAMRSA is highly resistant to erythromycin,3,141-143 and it should not be used in the treatment of skin and soft tissue infections. Likewise, rising GAS resistance to erythromycin has been reported.151

observed for disease improvement. Intravenous clindamycin is often given empirically in this setting not only for its excellent coverage of GAS and CAMRSA infection, but also for its ability to inhibit protein toxin production. Those patients who do appear septic, however, should be treated with antibiotics to which grampositive bacteria are highly susceptible. Intravenous vancomycin has traditionally been the mainstay of therapy for empiric treatment of serious life- or limb-threatening skin and soft tissue infections. Concern continues to grow, however, about the development of vancomycin-resistant S. aureus (VRSA). At least three cases of VRSA have been reported in the literature in the United States so far.154-156 Additionally, vancomycin has been shown to be less effective than beta-lactams in the treatment of MSSA endocarditis.157 Therefore, the addition of rifampin or gentamicin should be considered for synergistic effect in treating serious infections thought to be secondary to S. aureus.19 Linezolid is another option in the treatment of serious skin and soft tissue infections. It has activity against MRSA, GAS, S. pneumoniae, vancomycinresistant enterococcus (VRE), anaerobic bacteria, and some activity against rapidly growing mycobacteria.12 Linezolid comes in both oral and parenteral forms. There exists mixed evidence on the comparative effectiveness of vancomycin and linezolid in the treatment of serious soft tissue infections. Two studies showed linezolid to be significantly superior to vancomycin in seven day cure rates of surgical site infections158 and complicated skin and soft tissue infections159 in adults. Other studies, however, have shown no significant difference between linezolid and vancomycin in the treatment of soft tissue infections in children160 or adults.161 Some theorize that there exists intermediate resistance to vancomycin in some MRSA isolates, and this explains the apparent superior efficacy of linezolid in the treatment of MRSA infections in some studies.162 Other antibiotics have been used in the treatment of serious MRSA infections as well. Quinupristin-dalfopristin is bacteriocidal against gram-positive bacteria, including MRSA and VRE. It is approved for treatment of complicated skin and soft tissue infections and right-sided bacterial endocarditis in adults.163 Its use in children, however, has been highly limited.164 Another potentially useful antibiotic is tigecycline. It is also active against gram-positive bacteria, including MRSA and VRE, as well as gram-negative, anaerobic, and atypical bacteria. There is currently no data supporting its use in children under 18 years of age.19 No matter what therapy is chosen, it is important to obtain emergent infectious disease consultation prior to initiating any of these therapies in severe infections.

Orbital And Periorbital Cellulitis Treatment of periorbital cellulitis may vary depending on the source and severity of infection. Most cases of periorbital cellulitis can be safely managed in the outpatient setting with oral antibiotics such as amoxicillin-clavulanate, cephalosporins, or clindamycin. If the source of the cellulitis is clearly local trauma, then the antibiotic regimen should cover gram-positive organisms.90 If the patient is systemically ill, however, the causative organism is very likely Streptococcus, and both GAS and Streptococcus pneumoniae should be empirically covered in the inpatient setting with intravenous antibiotics such as ceftriaxone, ampicillin-sulbactam, or clindamycin.152 Orbital cellulitis, on the other hand, is a much more serious condition and requires more aggressive inpatient treatment. Orbital cellulitis originates almost uniformly from sinusitis; for this reason, antibiotics that cover S. pneumoniae and other organisms found in the sinuses are indicated. Typical choices for empiric intravenous therapy include ampicillin-sulbactam or ceftriaxone, either alone or with the addition of clindamycin. Since orbital cellulitis often requires surgical intervention, immediate consultation with pediatric ophthalmology and otolaryngology should be sought.153 While the therapeutic approach to orbital cellulitis in the past had been mostly surgical, conservative medical management with broad spectrum antibiotic therapy is being increasingly used with good success,91 with one small study showing successful outcomes in 9 of 10 patients treated with medical therapy alone.

Severe Skin And Soft Tissue Infections Patients with vital sign abnormalities, mental status changes, lethargy, rapidly progressing disease, fever, chills, or any other concerning symptoms should be treated aggressively with parenteral antibiotics.50 Also, children with significant comorbidities, such as asplenia or immunocompromised status, should be treated with IV antibiotics as well. Patients who have concerning infections but otherwise do not appear septic may be treated with IV antibiotics and Pediatric Emergency Medicine Practice©

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Clinical Pathway: Management Of Children With Skin And Soft Tissue Infections In The CA-MRSA Era

Concern for necrotizing fasciitis?

Emergent surgical consultation. (Class I)

YES

NO Toxic appearance OR Immunocompromised OR Limb-threatening infection?

• Hospitalize. • Fluid and/or vasopressor support as needed. (Class I) • Empiric IV vancomycin. (Class II) • Infectious disease consult. (Class III)

YES

NO • Incision & drainage (as indicated). (Class I) • Obtain specimen for culture and susceptibility testing. (Class III)

Simple impetigo?

YES

Discharge on topical mupirocin. (Class I)

YES

Febrile or ill appearing?

NO Bite wound?

YES

NO If no surrounding cellulitis, I&D alone may be adequate treatment. (Class III)

YES

Afebrile, previously healthy patient and lesion of reasonable size?

NO • Oral antibiotic Rx. (Class II) TMP/SMX + amoxicillin Or Clindamycin Or Doxycycline ( ≥ 8 years of age) • Close follow-up

Admit on empiric ampicillinsulbactam OR ticarcillinclavulanate. (Class II)

NO Discharge on amoxicillinclavulanic acid. (Class II)

• IV clindamycin or IV vancomycin. (Class II) • Consider admission to observation unit or inpatient floor. (Class II) • Infectious disease consult if no improvement in 24 hours. (Class III)

The evidence for recommendations is graded using the following scale. For complete definitions, see back page. Class I: Definitely recommended. Definitive, excellent evidence provides support. Class II: Acceptable and useful. Good evidence provides support. Class III: May be acceptable, possibly useful. Fair-to-good evidence provides support. Indeterminate: Continuing area of research. This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care. Copyright © 2008 EB Practice, LLC. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Practice, LLC.

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Necrotizing Fasciitis

In toxic shock syndrome (TSS), the first priority of therapy is establishing hemodynamic stability in patients. Patients are often in profound shock secondary to capillary leakage and require multiple boluses of crystalloid or colloid.103 Vasopressors may also be indicated. Possible sources of infection must be investigated and addressed. A vaginal examination should be performed on all female patients to ensure a foreign body is not the nidus of infection. Areas of necrotizing fasciitis or abscess should be urgently debrided or incised and drained.105 Clindamycin is a mainstay of therapy for TSS whether caused by GAS or staphylococcus. Since clindamycin works by reducing protein synthesis, it acts to halt toxin production, thereby limiting disease.176 If GAS is known to be the cause of TSS in a patient, clindamycin may be used along with parenteral penicillin in treatment. In patients in whom S. aureus-associated TSS is suspected, vancomycin should be added to clindamycin in areas where MRSA infections are common;177 otherwise, a beta-lactamase resistant anti-staphylococcal antibiotic may be used.

Patients with necrotizing fasciitis often deteriorate extremely rapidly. Morbidity and mortality rates in necrotizing fasciitis remain extremely high, with one recent study reporting a 17% mortality rate, with limb loss occurring in an additional 26% of adult patients.165 A recent pediatric series reported similar data, with mortality at 18%.61 Immediate stabilization begins with circulatory support with vasopressors in addition to crystalloid infusions if the patient presents in shock.166 Once hemodynamically stabilized, the patient should be taken to the operating room as soon as possible for surgical debridement of affected tissue. One study demonstrated a doubling of adult patient mortality when surgical debridement was delayed for more than 24 hours.167 Antibiotics have little effect prior to surgical debridement, secondary to the poor vascular supply reaching necrotic tissue.168 If antibiotics are initiated in the emergency department, however, they should cover gram-positive organisms and gram-negative aerobes and anaerobes. For many years, a broad spectrum beta-lactam antibiotic along with clindamycin was thought to be adequate therapy; however, with the reported emergence of MRSA as a causative pathogen of necrotizing fasciitis,96 it is no longer so. A regimen consisting of vancomycin, clindamycin, and a broad spectrum antibiotic covering gram-negative and anaerobic organisms would be appropriate therapy. Clindamycin is added for “the Eagle effect:” its ability to control toxin production in slowly metabolizing bacteria.169 Hyperbaric oxygen therapy has also been used to treat necrotizing fasciitis, but its efficacy is controversial.170

Atypical Pathogens The vast majority of these pathogens will be difficult to identify in a busy emergency department. Consultation with an infectious disease specialist is recommended prior to initiating treatment. Nevertheless, knowledge of the treatments of these pathogens may be helpful both in initiating new therapy and treating patients who have already begun therapy but have returned to the emergency department for further treatment. Actinomyces causes the chronic presence of “wooden” appearing, suppurative nodules in skin and soft tissues. It may be identified by either the “sulfur granule” like material that it drains or by culture.178 Treatment is high dose intravenous penicillin for two to six weeks, followed by oral penicillin for an additional 6-12 months.53 Similarly, Nocardia can cause a chronic, suppurative cellulitis or pyoderma that may be cultured on simple media. Treatment is with sulfonamides, such as TMP-SMX, for one to three months.53 Subcutaneous infection from Sporothrix schenckii causes sporotrichosis, characterized by either a solitary nodule or group of nodules along the local lymphatic track. It may be treated with either itraconazole or saturated solution of potassium iodide, with treatment lasting three to six months.179 Anaerobic infections are often associated with abscesses or necrotizing fasciitis, so drainage or surgical debridement of affected areas is essential. For many years, penicillins were the treatment of choice for anaerobic infections, but resistance to these antibiotics is increasing.60 Treatment for most

Toxin-Mediated Disease The primary treatment for staphylococcal scalded skin syndrome (SSSS) is medical pharmacotherapy. Most children without extensive skin involvement can be managed with outpatient oral antibiotics. While multi-drug resistance is rare in the staphylococcal strains causing SSSS,171 there have been multiple reports of MRSA causing SSSS.172-174 Therefore, if a cephalosporin or anti-staphylococcal penicillin is used to treat SSSS, careful follow-up must be assured. New lesions may appear 24-48 hours after the initiation of therapy, but should not be observed thereafter.102 Blisters from the rash should be kept intact; areas where blisters have erupted may be dressed with petroleumimpregnated gauze.171 More severely affected patients may need to be admitted for parenteral antibiotics as well as pain, temperature, fluid, electrolyte, and nutritional management. Very badly affected patients may require admission to a burn unit for further management.175 Pediatric Emergency Medicine Practice©

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anaerobic skin and soft tissue infections should also cover aerobic gram-positive bacteria, since they are often concomitant pathogens. Simple infections may be treated with clindamycin, with optional addition of a second or third generation cephalosporin for additional gram-negative coverage. Ertapenem is a newer class I carbapenem with good coverage against both aerobic and anaerobic organisms180 and may be used as well. Other options include penicillin-beta-lactamase-inhibitor combinations (such as ampicillin-sulbactam, piperacillin-tazobactam, or ticarcillin-clavulanate) and linezolid for severe infections.66 Pseudomonas infections require treatment with antibiotics with anti-pseudomonal activity. Ill children with ecthyma gangrenosum should be recognized immediately as having a potentially lifethreatening condition and should be treated aggressively,181 particularly in immunocompromised children. For severe or systemic infections, an aminoglycoside, such as tobramycin, amikacin, or gentamicin, plus an anti-pseudomonal cephalosporin, such as ceftazidime or cefepime, as indicated.182 For more localized infections, topical antibiotics or hot compresses with 2% acetic acid may be used.183 In patients age 18 or over, ciprofloxacin is a useful antibiotic as well, as it is available in both oral and intravenous formulations. Salt water wounds infected with Vibrio species must be treated aggressively because even superficial wounds can progress to necrotizing soft-tissue infections.68 Wounds exposed to seawater demonstrating a rapidly progressing cellulitis should be treated as Vibrio infectious until proven otherwise.67 Immediate surgical debridement should be undertaken, and patients should be treated with parenteral antibiotics. In children eight years of age or greater, the recommended antibiotic regimen is a tetracycline, typically doxycycline, and ceftazidime.67 In children under this age, treatment decisions are more difficult. While Vibrio is sensitive to all third-generation cephalosporins,184 the severity of patient illness may dictate using a tetracycline as well. In at least one case report, doxycycline was used in this manner.185 Aeromonas hydrophila infected wounds can also develop rapidly progressive cellulitis or myonecrosis.28 Rapidly progressing wounds exposed to freshwater in children should be treated with a third or fourth generation cephalosporin that also covers Pseudomonas.186 Treatment for atypical mycobacterial infections varies based on the species identified. No specific treatment regimen has been established for Mycobacterium marinum infections. Examples of regimens that have been used in clinical practice include tetracyclines, TMP-SMX, and rifampin plus ethambutol.70 Other non-pulmonary mycobacterial infections are treated on the basis on antimicrobial EBMedicine.net • February 2008

susceptibility testing, but regimens often include amikacin and clarithromycin.187

Special Circumstances Bites (Human And Animal) Human bites are occasionally a cause of infection in the pediatric emergency department, either via clenched-fist injury or occlusive bite. In children, a recent study showed about 50% of bites occurring during play and 41% occurring during altercations, with the latter increasing with increasing age.188 Several studies have been performed on the bacteriology of human bite infections. Talan et al analyzed the results of infected human bite wounds in 50 patients.57 They found that the median number of isolates per wound was four, with both aerobes and anaerobes typically isolated. Typical species included Streptococcus anginosus, Staphylococcus aureus, and Eikenella corrodens as well as other anaerobes. Similar results have been found in other studies as well.189 While significant resistance was encountered to penicillin and other antibiotics, virtually all species tested were sensitive to beta-lactamase-resistant penicillins, making them the recommended treatment for infected human bites. We recommend empiric treatment with amoxicillinclavulanate for oral therapy, and empiric treatment with either ampicillin-sulbactam, ticarcillin-clavulanate, or cefoxitin for intravenous therapy. Dogs are responsible for the vast majority of animal bites presenting to emergency departments. Cat bites, on the other hand, are less common but are more likely to be infected. Like human bite infections, bacterial isolates from infected dog and cat bites are polymicrobial. One multicenter study showed common pathogens in infected dog and cat bites to be Pasteurella, Streptococcus, Staphylococcus, Fusobacterium, and Bacteroides.190 The drug of choice

Figure 7. Clenched Fist Fighting Injury from Contact with Human Tooth

Reprinted from http://www.aafp.org/afp/20031201/2167.html. All rights reserved.

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Risk Management Pitfalls For Skin And Soft Tissue Infections even previously healthy patients should be presumed to have MRSA and should be treated accordingly pending pathogen culture and sensitivity results.

1. “The patient looked well, so I didn’t think the abscess needed to be drained.” Incision and drainage of abscesses is a mainstay of therapy in the treatment of soft tissue infections. In fact, many of these infections will improve with simple I&D alone. Failure to drain an abscess may result in treatment failure and complications for patients.

6. “I went ahead and treated the infected cat bite as I would any infected wound.” Clindamycin is not recommended therapy for Pasteurella infections. Instead, these patients should be treated with either amoxicillin-clavulanate or ampicillin-sulbactam.

2. “There was no crepitus, so I didn’t consider necrotizing fasciitis in my differential diagnosis.”

7. “I forgot to ask the patient about exposure to fresh or saltwater.”

Necrosis and crepitus are late findings in patients with necrotizing fasciitis. Morbidity and mortality increase with delay in diagnosis of necrotizing fasciitis. Therefore, if any patient presents with concerning symptoms, such as pain disproportionate to the size of the lesion, prompt surgical consultation should be obtained.

Vibrio vulnificus and Aeromonas hydrophila are bacteria found in salt and freshwater, respectively. They can rapidly progress to necrotizing soft tissue infections. Infections originating from wounds obtained in these environments merit careful observation and follow-up.

3. “I thought the patient might have necrotizing fasciitis, but I decided to start antibiotics and wait for the final read on the imaging before consulting surgery.”

8. “I decided to treat empirically without obtaining a wound culture.” Culture results may lead empiric treatment regimens to be either narrowed or altered. Bacteria may be resistant to appropriate empiric regimens. Cultures should be obtained on all wound cultures prior to treatment.

Antibiotics have little effect prior to surgical debridement, secondary to the poor vascular supply reaching necrotic tissue. Therefore, the only definitive treatment for necrotizing fasciitis is surgery. These infections progress rapidly, so delays in treatment increase the probability of patient morbidity and mortality. Any patient who is suspected to have necrotizing fasciitis should have an emergent surgery consult.

9. “I treated his cellulitis with clindamycin without ordering a double disk diffusion test.” CA-MRSA that are initially resistant to erythromycin and sensitive to clindamycin may subsequently develop inducible clindamycin resistance upon treatment. Therefore, it is necessary to test for this inducible clindamycin resistance with the double-disk diffusion test (D test). If this resistance is present, clindamycin should not be used.

4. “I didn’t think that CA-MRSA had reached my area of the country yet.” High rates of CA-MRSA infections have been documented in places as diverse as Los Angeles, Baltimore, Atlanta, Minnesota, and Texas. Unless you know the resistance pattern of bacteria in your community, presume a high burden of CAMRSA in your patients, and treat them accordingly.

10. “The neonate clearly had simple cellulitis, so I discharged him on oral clindamycin.” Skin and soft tissue infections in neonates can be caused by gram-negative pathogens, such as E. coli and Klebsiella. For this reason, clindamycin may be inadequate coverage for these neonatal infections as it has poor gram-negative coverage. Additionally, neonates may appear relatively well, yet have a severe, systemic infection. Neonates with all but the most trivial skin infections should have a full sepsis workup and should be hospitalized on IV antibiotics.

5. “My patient had no risk factors for MRSA, so I treated him with amoxicillin.” Amoxicillin is never appropriate therapy for S. aureus infection. S. aureus is virtually uniformly resistant to penicillin and amoxicillin therapy. In addition, studies have shown that the prevalence of CA-MRSA is high even in patients with no ‘risk factors’ for MRSA infection. Therefore, Pediatric Emergency Medicine Practice©

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for the treatment of isolated Pasteurella infection is penicillin. However, given the existence of beta-lactamase-producing Pasteurella191 as well as the betalactamase activity of anaerobic pathogens also associated with mammalian bite infections,192 betalactamase resistant penicillins are the best choice for treatment of these infections. As with human bites, we recommend empiric treatment with amoxicillinclavulanate for oral therapy, and empiric treatment with either ampicillin-sulbactam or ticarcillin-clavulanate for intravenous therapy. Clindamycin should not be used for Pasteurella infections. For both human and animal bites, penicillin allergic adolescents may be treated with quinolones, which have efficacies similar to amoxicillin-clavulanate. Younger children with a penicillin allergy may be treated with a combination of TMP-SMX and clindamycin.193 Monotherapy with azithromycin may also be used,194 although these infections will need closer followup as macrolides are not as effective in vitro against bite pathogens when compared to amoxicillin-clavulanate.195

necrotizing fasciitis in these adult diabetic patients.198 Nevertheless, there is no evidence that children with diabetes mellitus are at greater risk for skin infections or their complications. Therefore, pediatric patients with diabetes mellitus who are reasonably well controlled and have had no endstage complications from their disease may be treated like their non-diabetic counterparts. Children with neoplasms are at risk of both skin infections caused by unique pathogens as well as aggressive infection caused by typical pathogens due to their level of immunocompromise. Adults with Hodgkin’s disease may present with pruritis, new onset eczema, or secondary S. aureus infections.199 As stated previously, children with immunodeficiencies are at risk for ecthyma gangrenosum, a cutaneous manifestation of systemic sepsis. It is typically caused by Pseudomonas aeruginosa but may also be caused by Aeromonas hydrophila, S. aureus, Serratia marcescens, Aspergillus spp. and Mucor spp.200 Ecthyma gangrenosum rarely may represent the first manifestation of malignancy.201 Neutropenic patients are also at greater risk for primary fungal infections, but these remain uncommon and usually present in a similar manner to those found in healthy individuals.202 Children with malignancies who present with fever and soft tissue infections, particularly those who present with neutropenia, need to be treated aggressively, with prompt, broad spectrum parenteral antibiotics such as ceftazidime or piperacillintazobactam either alone or with vancomycin.203

Immunocompromised Patients A number of pre-existing conditions may complicate the disease course and therefore treatment of soft tissue infections. In the adult community, patients with diabetes mellitus are at greater risk for both skin infections196 and S. aureus bacteremia developing from those skin infections197 than their non-diabetic counterparts. There also exists a greater risk of

Cost-Effective Strategies 3. Use antibiotics appropriate for CA-MRSA infections. In the new era of CA-MRSA, clindamycin and trimethoprim-sulfamethoxazole are more efficacious and less expensive than third-generation cephalosporins. By using non-beta-lactam antibiotics, you may decrease medication costs and prescribe a more efficacious treatment regimen.

1. Avoid unnecessary laboratory tests. Multiple studies have demonstrated the lack of utility of blood cultures in treating simple cellulitis. Fine needle aspiration of areas of cellulitis also have a low yield. If a patient is without fever and is clinically well, cellulitis and other skin infections may be treated empirically without any laboratory tests. 2. Consider incision and drainage without antibiotics in simple skin abscesses without surrounding cellulitis. I&D without antibiotic treatment was demonstrated to be equivalent to I&D plus oral antibiotics in the management of soft-tissue infections in the pre-MRSA era. While no studies have been completed on this strategy more recently, the high cure rates seen in MRSA infections when treated with first generation cephalosporins suggest that I&D alone remains an effective therapeutic strategy. EBMedicine.net • February 2008

4. Utilize the availability of observation units. Observation units are an excellent way to ensure therapeutic efficacy without the cost of an inpatient admission. The vast majority of patients admitted to observation units with skin infections have been shown to be able to be discharged within 24 hours.

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Patients without fever but with soft tissue infection should be treated aggressively as well, as even seemingly insignificant infection may rapidly worsen. At least one study has also demonstrated an increased risk of skin infections in individuals with hemoglobinopathies, such as sickle cell anemia.204 Patients with skin infections and fever, however, should be treated as any patient with sickle cell anemia and fever: with empiric broad spectrum antibiotics while blood cultures are pending.205 While pediatric patients with HIV are also at greater risk for serious skin and soft tissue infection, they tend to have similar infections to healthy children.206 This is unlike adults, who tend to also develop opportunistic infections.207 Patients with bacterial soft tissue infections generally can be treated as their healthy counterparts would be, often with oral antibiotics.208 In addition to bacterial infections, patients with HIV often have serious fungal skin infections. Patients often develop significant cutaneous candidal infections, frequently with widespread papules and pustules as well as significant dermatophytoses.208

communities and hospitals as well.210,211 Neonates with histories of prematurity, low birth weight, chronic underlying diseases, prolonged hospitalization, invasive or surgical procedures, indwelling catheters, or prolonged use of antimicrobial agents are at particular risk of infection with S. aureus.211 Toxin-mediated diseases, such as staphylococcal scalded skin syndrome, are common in neonates and have often been seen as early as within the first week of life.212,213 Epidemics of neonatal SSSS can occur and have been traced to an individual healthcare worker in at least one instance.214 Unlike older children, neonates with nosocomial skin and soft tissue infections often have infections caused by gram-negative bacteria. These pathogens are often transferred from the mother either in utero or during passage through the birth canal. In a study of 49 mostly preterm neonates with bacteremia, 22% had subcutaneous abscesses as the source of their infection.215 Of the 10 neonates with abscesses, nine had gram-negative pathogens grow from their abscess cultures. In neonates, the umbilical stump can be the initial source of bacterial skin infections. Major risk factors for omphalitis include inadequate umbilical stump care and low birth weight, and it is much more common in the developing than the developed world.216 Common causative pathogens include S. aureus, Staphylococcus epidermidis, groups A and B Streptococcus, Escherichia coli, Klebsiella, Pseudomonas, and Clostridium difficile.217 It may be characterized by the extent of infection, ranging from simple purulent discharge to extension into the deep fascia. The presence of cord vessels makes systemic spread and septicemia of particular concern.217

Neonatal Infection Neonates are also at risk for MRSA infection. Fortunov et al demonstrated this in a series of 89 cases of neonatal S. aureus infection at Texas Children’s Hospital between August 2001 and March 2005. Of the 89 documented cases, 61 were of MRSA, most clinically diagnosed as having either pustulosis or cellulitis/abscess.209 Outbreaks of CA-MRSA infections in neonates have been noted in a number of

Key Points For Skin And Soft Tissue Infections soft tissue infections to determine if they have either a complicating past medical history or a history of present illness which would suggest an atypical pathogen. • Have a high clinical suspicion for necrotizing fasciitis since findings classically associated with it are often only present late in the disease course. • Incision and drainage is an essential part of any therapeutic strategy for skin and soft tissue infections associated with focal collections of purulent material. • Treat simple skin and soft tissue infections with clindamycin pending wound cultures and sensitivities; alternatively, use a combination of trimethoprim-sulfamethoxazole and amoxicillin. • Impetigo may be treated without systemic antibiotics; topical mupirocin is usually sufficient. Simple cellulitis and cellulitis surrounding an abscess warrant systemic antimicrobial therapy.

• Remember that strains of Staphylococcus aureus causing skin and soft tissue infections have become more virulent and resistant to antibiotics over the past ten years. • CA-MRSA, unlike HA-MRSA, is usually susceptible to common oral non-beta-lactam antibiotics. • Skin and soft tissue infections should be presumed to be caused by CA-MRSA and treated as such until clinical and laboratory evidence proves otherwise. • GAS represents a smaller but significant cause of skin and soft tissue infections, and infections caused by it are often indistinguishable from those caused by S. aureus. Treatment of GAS is often much easier, as GAS is universally sensitive to penicillin and amoxicillin. • Consider atypical pathogens in atypical cases of skin and soft tissue infections. • Take a thorough history of patients with skin and Pediatric Emergency Medicine Practice©

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Necrotizing fasciitis can complicate skin and soft tissue infection in neonates as well. In one metaanalysis of 66 reported cases of neonatal necrotizing fasciitis in the literature, 71% were secondary to omphalitis.218 Infections were polymicrobial in 74% of cases, with typical pathogens including S. aureus, Escherichia coli, Clostridium spp. and Bacteroides spp. Mortality occurred in 59% of cases, with death usually secondary to shock, disseminated intravascular coagulation, or multiorgan failure. Treatment includes surgical debridement and broad spectrum antibiotics. Treatment of all skin and soft tissue infections should be aggressive, given the immature immune system of neonates. A full sepsis evaluation should be performed in neonates with all but the most simple of infections. Given the wide range of pathogens potentially affecting neonates, broad spectrum parenteral antibiotics should be used. Vancomycin should be used for empiric gram-positive coverage in significant infections, while a third-generation cephalosporin, such as cefotaxime or ceftazidime, should be used for broad gram-negative coverage.

Controversies/Cutting Edge Home IV Antibiotics A number of programs have recently been developed to provide parenteral therapeutics in the home setting rather than in the hospital.222 This type of therapy has also been utilized in adult patients with cellulitis requiring IV antibiotics. In one study, 125 patients were discharged from the emergency department with once-daily IV ceftriaxone or teicoplanin arranged for at home use. This resulted in both high cure rates (98.4%) and significant savings.223 A second study utilized primarily cefazolin twice daily in 124 patients with a reasonably good rate of cure (84.7%).224 In pediatric populations, this kind of therapy presents a number of problems. First, therapy was administered through an IV, which is impractical in active children who are highly likely to remove their IVs at home. Secondly, these studies were performed at a time when rates of CA-MRSA were lower than they are today. Home therapy would now require clindamycin, which is dosed at least three times a day. Finally, home therapy required the presence of a team of nurses on hand that can administer therapy and evaluate patients at home. This is a system that is not in place at many pediatric hospitals. Nevertheless, home therapy may be an option in select adolescent patients seen at facilities where the resources are in place to implement it.

Hand Infections Extra care must be taken when evaluating hand infections due to the possibility of extension of infection into the tendon sheaths. The soft tissue of the dorsum of the hand is generally loose, and infection generally remains dorsal to the extensor tendons.219 Prompt medical management is required however, as infection may spread to the deeper tendons. In addition to antibiotic therapy, hand infections managed medically require immobilization and elevation. Hand movement may spread infection; therefore, infected hands should be splinted in a functional position, while elevation will reduce edema.219 The splint should be removed once the acute infection is controlled, as prolonged splinting increases the risk of contracture. Antibiotic treatment of hand infections is equivalent to other skin and soft tissue infections, although consideration of mycobacterial infection should be made in cases of penetrating trauma.220 Infections of the palmar aspect of individual digits are extremely concerning, as these infections may rapidly involve the flexor tendons. Four criteria have been classically used to diagnose tenosynovitis. They are: (1) uniform, symmetric digit swelling; (2) at rest, digit is held in partial flexion; (3) excessive tenderness along the entire course of the flexor tendon sheath; and (4) pain along the tendon sheath with passive digit extension.221 Tenosynovitis is generally associated with penetrating trauma to the hand. In cases of tenosynovitis, prompt surgical consultation is warranted, with exposure and copious irrigation of the tendon sheath.220

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Treatment Of Carrier State Studies have shown that individuals with S. aureus infection often have the same strain of the bacteria in their nares,225 and persistent nasal carriage of S. aureus is associated with a higher rate of staphylococcal soft tissue infection.226 At least one study, performed in soldiers, showed a strong association between MRSA carriage and subsequent MRSA infection.227 A number of studies have been performed looking at ways to reduce staphylococcal nasal carriage in the hopes of reducing recurrent staphylococcal infections, often with discouraging results. Perl et al performed a double-blind, randomized control study on pre-operative patients, treating those with nasal carriage of S. aureus with either nasal mupirocin or placebo prior to surgery.228 There was no significant difference in the rates of post-operative wound infections between the two groups of patients. Other studies have also found a lack of significant effect.229,230 One study did show a reduction in MRSA infections during an outbreak at a child care center when children, staff, and family members were treated.231 Nevertheless, carrier state treatment as prophylaxis

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for MRSA infection cannot definitively be recommended in the ED setting at this time.

should be made as well. Patients exposed to fresh or saltwater may merit inpatient observation to rule out aggressive infections from either Vibrio species or Aeromonas hydrophila. Patients who have primary varicella and a secondary bacterial skin infection may need to be monitored closely secondary to the higher incidence of necrotizing fasciitis in this patient group.61 Finally, infections of the hand and face merit closer observation secondary to their ability to progress to more severe infection. Physical examination findings may influence admission decisions as well. Fever may serve as an indicator of systemic infection. The size of the area of infection is also often a determinant in whether to admit, although there exists no specific criteria for admission based on lesion size. The presence of extreme pain, anesthesia at the site of infection, or crepitus suggest necrotizing fasciitis, although these are all late findings. Finally, the presence of laboratory findings, such as elevated ANC, bandemia, or an elevated CRP, may all suggest more severe infection. One option for many patients with skin and soft tissue infections of unclear severity is a brief admission to an observation unit. In one study, skin and soft tissue infections were the third leading diagnosis in adult patients admitted to an observation unit, and 85% of those admitted were discharged within 24 hours.237 A similar rate of discharge (73%) was found in another study of adult patients with skin and soft tissue infections.238 Admitting patients to an observation unit allows the ED physician reassurance that the patient’s infection is improving without incurring the significant costs of inpatient hospitalization.

Vaccines Given the continued emergence of MRSA as a health threat in both children and adults, renewed attention has been focused on developing a vaccine against S. aureus. Most research has centered on developing a vaccine against the capsular polysaccharides of S. aureus, as similar techniques were used to develop pneumococcal vaccines.232 A phase III trial was performed on a staphylococcal vaccine in patients with end-stage renal disease that showed partial immunity to S. aureus at 40 weeks postimmunization but loss of that immunity at 54 weeks postimmunization.233 Additional studies on both this and other types of vaccines are continuing. A vaccine is also in development for GAS infections. A phase I study of a multivalent recombinant M protein peptide fragment vaccine has shown success in eliciting an antibody response.234 Development of this type of vaccine is complicated, however, by the large numbers of M proteins associated with GAS.29 Additional research is continuing in developing a vaccine based on conserved regions of the streptococcal M protein.

Disposition The decision to admit a patient with a skin or soft tissue infection is multifactorial, as there is no one criterion alone that determines whether or not a patient merits admission. Additionally, data on rates of and criteria for admission to the hospital from the emergency department are scant. One study of adults with MRSA infections found an admission rate of 15%.21 A Canadian study described an admission rate of only 7% of adults with cellulitis in a series of 414 patients, although patients made a median of four return visits to the ED for their illness.235 Any patient showing signs of septicemia, including vital sign instability or mental status changes, should be admitted, possibly to an intensive care unit. A patient’s medical history should influence admissions decisions. Patients with neutropenia should be admitted automatically for all but the most insignificant of infections. Other medical problems that may lead to poorer medical outcomes, such as HIV, sickle cell anemia, other immunodeficiencies, and malnutrition, should be considered as well.236 Patients with histories of prolonged hospitalizations are at risk for nosocomial MRSA and may merit hospitalization. Recent exposure to antibiotics, steroids, or other immunomodulators may also make infections more aggressive or difficult to treat. Consideration as to the nature of the infection Pediatric Emergency Medicine Practice©

Summary Skin and soft tissue infections are an extremely common reason for children to present to the pediatric emergency department. They range in severity from the innocuous impetigo to the potentially fatal necrotizing fasciitis. The continued evolution of the pathogens that cause skin and soft tissue infections has made determining the appropriate therapy for them a constant challenge. Resistance patterns of the bacteria causing these infections are continually changing. Additionally, the virulence of the infections caused by these bacteria is increasing as well. With a strong knowledge of resistance patterns and potential therapeutic pitfalls, however, these infections may be treated appropriately and safely.

References Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, 20

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randomized, and blinded trial should carry more weight than a case report. To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study, will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, will be noted by an asterisk (*) next to the number of the reference.

19. Le J, Lieberman JM. Management of community-associated methicillin-resistant Staphylococcus aureus infections in children. Pharmacotherapy. 2006;26(12):1758-1770. (Review) 20. Rathore MH, Kline MW. Community-associated methicillin-resistant Staphylococcus aureus infections in children. Pediatr Infect Dis J. 1989;8:645-647. (Case report) *21. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355(7):666-674. (Prospective; 422 patients) 22. Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev. 1997;10:781-791. (Review article) 23. Zetola N FJ, Nuermberger EL, Bishai WR. Communityacquired methicillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis. 2005;5(5):275-286. (Review article) 24. Ito T, Katayama Y, Asada K, et al. Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2001;45(5):1323-1336. (Laboratory research) 25. Wisplinghoff H, Rosato AE, Enright MC, Noto M, Craig W, GL A. Related clones containing SCCmec type IV predominate among clinically significant Staphylococcus epidermidis isolates. Antimicrob Agents Chemother. 2003;47(11):3574-3579. (Laboratory research) 26. Mongkolrattanothai K, Boyle S, Murphy TV, Daum RS. Novel non-mecA-containing staphylococcal chromosomal cassette composite island containing pbp4 and tagF genes in a commensal staphylococcal species: a possible reservoir for antibiotic resistance islands in Staphylococcus aureus. Antimicrob Agents Chemother. 2004;48(5):1823-1836. (Laboratory research) 27. Okuma K, Iwakawa K, Turnidge JD, et al. Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community. J Clin Microbiol. 2002;40(11):4289-4294. (Laboratory research) 28. Vinh DC, Embil JM. Rapidly Progressive Soft Tissue Infections. Lancet Infect Dis. 2005;5:501-513. (Review article) 29. Currie BJ. Group A streptococcal infections of the skin: molecular advances but limited therapeutic progress. Curr Opin Infect Dis. 2006;19:132-138. (Review article) 30. Bisno AL, Brito MO, Collins CM. Molecular basis of group A streptococcal virulence. Lancet Infect Dis. 2003;3:191-200. (Review article) 31. Facklam RF, Martin DR, Lovgren M, et al. Extension of the Lancefield classification for group A streptococci by addition of 22 new M protein gene sequence types from clinical isolates: emm103 to emm124. Clin Infect Dis. 2002;34:28-38. (Laboratory research) 32. Horstmann RD, Sievertsen HJ, Knobloch J, Fischetti VA. Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H. Proc Natl Acad Sci USA. 1988;85:1657-1661. (Laboratory research) 33. Johnsson E, Berggard K, Kotarsky H, et al. Role of the hypervariable region in streptococcal M proteins: binding of a human complement inhibitor. J Immunolo. 1998;161:4894-4901. (Laboratory research) 34. Berggard K, Johnsson E, Morfeldt E, Persson J, Stalhammar-Carlemalm M, Lindahl G. Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes. Mol Microbiol. 2001;42:539-551. (Laboratory research) 35. Wang JR, Stinson MW. M protein mediates streptococcal adhesion to HEp-2 cells. Infect Immun. 1994;62:442-448. (Laboratory research) 36. Caparon MG, Stephens DS, Olsen A, Scott JR. Role of M protein in adherence of group A streptococci. Infect Immun. 1991;59:1811-1817. (Laboratory research) 37. Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 1989;321:1-7. (Retrospective; 20 patients)

1. McCaig LF, McDonald LC, Mandal S, Jernigan DB. Staphylococcus aureus associated skin and soft tissue infections in ambulatory care. Emerg Inf Dis. 2006;12:17151723. (Database review; 34,000 patient visits) 2. Kirby W. Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science. 1944;99:452453. (Laboratory research) *3. Fridkin SK, Hageman JC, Morrison M, et al. Methicillinresistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436-1444. (Prospective; 1647 patients) 4. Darmstadt GL. Oral antibiotic therapy for uncomplicated bacterial skin infections in children. Pediatr Infect Dis J. 1997;16:227-240. (Review article) 5. Lowy FD. Staphylococcus aureus infections. N Engl J Med. 1998;339:520-533. (Review article) 6. Fluit AC, Schmitz FJ, Verhoef J, European SENTRY Participant Group. Frequency of isolation of pathogens from bloodstream, nosocomial pneumonia, skin and soft tissue, and urinary tract infections occurring in European patients. Eur J Clin Microbiol Infect Dis. 2001;20:188-191. (Prospective; 15,704 patients) 7. Kluytmans J, van Belkum A, Verburgh H. Nasal Carriage of Staphylococcus aureus: epidemiology, underlying mechanisms and associated risk factors. Clin Microbiol Rev. 1997;10:505-520. (Review article) 8. Ladhani S, Joannou CL, Lochrie DP, Evans RW, Poston SM. Clinical, microbial, and biochemical aspects of the exfoliative toxins causing staphylococcal scalded-skin syndrome. Clin Microbiol Rev. 1999;12(2):224-242. (Review article) 9. Huang YC, Su LH, Chen CJ, Lin TY. Nasal carriage of methicillin-resistant Staphylococcus aureus in school children without identifiable risk factors in northern Taiwan. Pediatr Infect Dis J. 2005;24(3):276-278. (Prospective; 399 patients) 10. Noble WC, Valkenburg HA, Wolters CHL. Carriage of Staphylococcus aureus in random samples of a normal population. J Hyg. 1967;65(65):567-573. (Prospective) 11. Wenzel RP, Perl TM. The significance of nasal carriage of Staphylococcus aureus and the incidence of postoperative wound infection. J Hosp Infect. 1995;31:13-24. (Review) 12. Ladhani S, Garbash M. Staphylococcal skin infections in children. Paediatr Drugs. 2005;7(2):77-102. (Review) 13. Ji G, Beavis RC, Novick RP. Bacterial interference caused by autoinducing peptide variants. Science. 1997;276:2027-2030. (Laboratory research) 14. Vandenesch F, Naimi T, Enright MC, et al. Communityacquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis. 2003;9(8):978-984. (Laboratory research) 15. Lina G, Piemont Y, Godail-Gamot F, et al. Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis. 1999;29(5):1128-1132. (Laboratory research) 16. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000;13:16-34. (Review article) 17. Manders SM. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol. 1998;39:383398. (Review article) 18. Dancer SJ, Garratt R, Saldanha J, Jhoti H, Evans R. The epidermolytic toxins are serine proteases. FEBS Lett. 1990;268:129-132. (Laboratory research)

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84. Unkel JH, Mckibben DH, Fenton SJ, et al. Comparison of odontogenic and nonodontogenic facial cellulitis in a pediatric hospital population. Pediatr Dent. 1997;19:476-479. (Retrospective; 100 patients) 85. Tunnessen WW. Practical aspects of bacterial skin infections in children. Pediatr Dermatol. 1985;2:225. (Review article) 86. Lin YT, Lu PW. Retrospective study of pediatric facial cellulitis of odontogenic origin. Pediatr Infect Dis J. 2006;25:339-342. (Retrospective; 56 patients) 87. Jain A, Rubin PA. Orbital cellulitis in children. Int Ophthalmol Clin. 2001;41:71-86. (Review article) 88. Nageswaren S, Woods CR, Benjamin DK, Givner LB, Shetty AK. Orbital cellulitis in children. Pediatr Infect Dis J. 2006;25:695-699. (Retrospective; 41 patients) 89. Barone SR, Aiuto LT. Periorbital and orbital cellulitis in the Haemophilus influenzae vaccine era. J Pediatr Ophthalmol Strabismus. 1997;34:293-296. (Retrospective; 134 patients) 90. Giver LB. Periorbital versus orbital cellulitis. Pediatr Infect Dis J. 2002;21:1157-1158. (Review article) 91. Starkey CR, Steele RW. Medical management of orbital cellulitis. Pediatr Infect Dis J. 2001;20:1002-1005. (Case reports) 92. Chartier C, Grosshans E. Erysipelas. Int J Dermatol. 1990;29:459-467. (Review article) 93. Kihiczak GG, Schwartz RA, Kapila R. Necrotizing fasciitis: a deadly infection. J Eur Acad Dermatol Venereol. 2006;4:365369. (Review article) 94. Cox NH. Streptococcal necrotizing fasciitis and the dermatologist. Br J Dermatol. 1999;141:613-614. (Review article) 95. Elliot D, Kufera JA, Myers RA. The microbiology of necrotizing soft tissue infections. Am J Surg. 2000;179:361366. (Retrospective; 198 patients) 96. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352:1445-1453. (Retrospective; 14 patients) 97. Bisno AL, Cockerill FR 3rd, Bermudez CT. The initial outpatient-physician encounter in group A streptococcal necrotizing fasciitis. Clin Infect Dis. 2000;31:607-608. (Retrospective; 15 patients) 98. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32:1535-1541. (Retrospective; 454 patients) 99. Wong CH. Tissue oxygen saturation monitoring in diagnosing necrotizing fasciitis of the lower limb: a valuable tool but only for a select few. Ann Emerg Med. 2005;45:461-462. (Letter) 100. Dahl PR, Perniciaro C, Holmkvist KA, O’Conner MI, Gibson LE. Fulminant group A streptococcal necrotizing fasciitis: clinical and pathologic findings in 7 patients. J Am Acad Dermatol. 2002;47:489-492. (Retrospective; 7 patients) 101. Barton LL, Jeck DT, Vaidya VU. Necrotizing Fasciitis in children: Report of two cases and review of the literature. Arch Pediatr Adolesc Med. 1996;150:105-108. (Case report, review article) 102. Ladhani S. Recent developments in staphylococcal scalded skin syndrome. Clin Microbiol Infect. 2001;7:301-307. (Review article) 103. Stevens DL. The toxic shock syndromes. Infect Dis Clin North Am. 1996;10:727-746. (Review article) 104. Hajjeh RA, Reingold A, Weil A, et al. Toxic shock syndrome in the United States: surveillance update, 1979-1996. Emerg Inf Dis. 1999;5:807-810. (Retrospective; 5296) 105. Chuang YY, Huang YC, Lin TY. Toxic shock syndrome in children: epidemiology, pathogenesis, and management. Pediatr Drugs. 2005;7:11-25. (Review article) 106. Bisno Al, Stevens DL. Streptococcal infections of skin and soft tissue. N Engl J Med. 1996;334:240-245. (Review article) 107. O’Brien KL, Beall B, Barrett NL, et al. Epidemiology of invasive group a streptococcus disease in the United States, 1995-1999. Clin Infect Dis. 2002;35:268-276. (Retrospective; 2002 cases) 108. Stevens DL. Invasive group A streptococcus infections. Clin Infect Dis. 1992;14:2-11. (Review article)

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149. Chavez-Bueno S, Bozdogan B, Katz K. Inducible clindamycin resistance and molecular epidemiologic trends of pediatric community-acquired methicillin-resistant Staphylococcus aureus in Dallas, Texas. Antimicrob Agents Chemother. 2005;49:2283-2288. (Prospective; 197 patients) 150. Munckhof WJ, Kleinschmidt SL, Turnidge JD. Resistance development in community-acquired strains of methicillinresistant Staphylococcus aureus: an in vitro study. Int J Antimicrob Agents. 2004;24:605-608. (Laboratory research) 151. Green MD, Beall B, Marcon MJ, et al. Multicentre surveillance of the prevalence and molecular epidemiology of macrolide resistance among pharyngeal isolates of group A streptococci in the USA. J Antimicrob Chemother. 2006;57:1240-1243. (Laboratory research) 152. Donahue SP, Schwartz G. Preseptal and orbital cellulitis in childhood. A changing microbiologic spectrum. Ophthalmology. 1998;105:1902-1905. (Retrospective; 70 patients) 153. Howe L, Jones NS. Guidelines for the management of periorbital cellulitis/abscess Clin Otolaryngol. 2004;29:725728. (Review article) 154. Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin- United States, 2002. MMWR Morb Mortal Wkly Rep. 2002;51:565567. (Case report) 155. Whitener CJ, Park SY, Browne FA, et al. Vancomycinresistant Staphylococcus aureus in the absence of vancomycin exposure. Clin Infect Dis. 2004;38:1049-1055. (Case report) 156. Centers for Disease Control and Prevention. Vancomycinresistant Staphylococcus aureus- New York, 2004. MMWR Morb Mortal Wkly Rep. 2004;53:322-323. (Case report) 157. Fowler VG Jr, Scheld WM, Bayer AS. Endocarditis and intravascular infections. 6th ed. Philadelphia: Elsevier, Inc; 2005. (Textbook) 158. Weigelt J, Kaafarani HM, Itani KM, Swanson RN. Linezolid eradicates MRSA better than vancomycin from surgical-site infections. Am J Surg. 2004;188:760-766. (Prospective; comparative; 139 patients) 159. Itani KM, Weigelt J, Li JZ, Duttagupta S. Linezolid reduces length of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven methicillinresistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents. 2005;26:442-448. (Prospective; randomized; controlled; 1200 patients) 160. Yogev R, Patterson LE, Kaplan SL, et al. Linezolid for the treatment of complicated skin and skin structure infections in children. Pediatr Infect Dis J. 2003;22:S172-177. (Prospective; randomized; controlled; 120 patients) 161. Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis. 2002;34:1481-1490. (Prospective; randomized; controlled; 480 patients) 162. Howden BP, Charles PG, Johnson PD, Ward PB, Grayson ML. Improved outcomes with linezolid for methicillinresistant Staphylococcus aureus infections: better drug or reduced vancomycin susceptibility? Antimicrob Agents Chemother. 2005;49:4816. (Letter) 163. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-655. (Prospective; randomized; controlled; 246 patients) 164. Loeffler AM, Drew RH, Perfect JR, et al. Safety and efficacy of quinupristin/dalfopristin for treatment of invasive Gram-positive infections in pediatric patients. Pediatr Infect Dis J. 2002;21:950-956. (Retrospective; 127 patients) 165. Anaya DA, McMahon K, Nathens AB, Sullivan SR, Foy H, Bulger E. Predictors of Mortality and Limb Loss in Necrotizing Soft Tissue Infections. Arch Surg. 2005;140:151157. (Retrospective; 166 patients) 166. Kuncir EJ, Tillou A, St Hill CR, Petrone P, Kimbrell B, Asensio JA. Necrotizing soft-tissue infections. Emerg Med Clin North Am. 2003;21:1075-1087. (Review article)

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167. Frieschlag JA, Ajalat G, Busuttil RW. Treatment of necrotizing soft tissue infections: the need for a new approach. Am J Surg. 1985;149:751-755. (Retrospective; 21 patients) 168. Wilson HD, Haltalin KC. Acute necrotizing fasciitis in childhood: report of 11 cases. AJDC. 1973;125:591-595. (Retrospective; 11 patients) 169. Frank G, Mahoney HM, Eppes SC. Musculoskeletal infections in children. Pediatr Clin North Am. 2005;52:10831106. (Review article) 170. Jallali N, Whithey S, Butler PE. Hyperbaric oxygen as adjuvant therapy in the management of necrotizing fasciitis. Am J Surg. 2005;189:462-466. (Review article) 171. Patel GK, Finlay AY. Staphylococcal scalded skin syndrome: diagnosis and management. Am J Clin Dermatol. 2003;4:165-175. (Review article) 172. Ito Y, Funabashi Yoh M, Toda K, Shimazaki M, Nakamura T, Morita E. Staphylococcal scalded-skin syndrome in an adult due to methicillin-resistant Staphylococcus aureus. J Infect Chemother. 2002;8:256-261. (Case report) 173. Yamaguchi T, Yokota Y, Terajima J, et al. Clonal association of Staphylococcus aureus causing bullous impetigo and the emergence of new methicillin-resistant clonal groups in Kansai district in Japan. J Infect Dis. 2002;185:1511-1516. (Laboratory research) 174. Ackland KM, Darvay A, Griffin C, Aali SA, Russell-Jones R. Staphylococcal scalded skin syndrome in an adult associated with methicillin-resistant Staphylococcus aureus. Br J Dermatol. 1999;14:518-520. (Case report) 175. Greenwood JE, Dunn KW, Davenport PJ. Experience with severe extensive blistering skin disease in a paediatric burns unit. Burns. 2000;26:82-87. (Case report; review) 176. Stevens DL, Ma Y, Salmi DB, McIndoo E, Wallace RJ, Bryant AE. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2007;195:202-211. (Laboratory research) 177. American Academy of Pediatrics. Toxic Shock Syndrome. In:Pickering LK, Baker CJ, Overturf GD, Prober CG, eds. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006. (Book chapter) 178. Cocuroccia B, Gubinelli E, Fazio M, Girolomoni G. Primary cutaneous actinomycosis of the forehead. J Eur Acad Dermatol Venereol. 2003;17:331. (Case report) 179. Koga T, Matsuda T, Matsumoto T, Furue M. Therapeutic Approaches to Subcutaneous Mycoses. Am J Clin Dermatol. 2003;4:537-543. (Review article) 180. Goldstein EJ, Citron DM, Merriam CV, et al. Comparative in vitro activity of ertapenem and 11 other antimicrobial agents against aerobic and anaerobic pathogens isolated from skin and soft tissue animal and human bite wound infections. J Antimicrob Chemother. 2001;48:641-651. (Laboratory research) 181. Viola L, Langer A, Pulitano S, Chiaretti A, Piastra M, Polidori G. Serious Pseudomonas aeruginosa infection in healthy children: case report and review of the literature. Pediatr Int. 2006;48:330-333. (Case report; review) 182. Silvestre JF, Betlloch MI. Cutaneous manifestations due to Pseudomonas infection. Int J Dermatol. 1999;38:419-431. (Review article) 183. Sloss JM, Cumberland N, Milner SM. Acetic acid used for the elimination of Pseudomonas aeruginosa from burn and soft tissue wounds. J R Army Med Corps. 1993;139:49-51. (Prospective; 16 patients) 184. Oliver JD. Wound infections caused by Vibrio vulnificus and other marine bacteria. Epidemiol Infect. 2005;133:383391. (Review article) 185. Chiu S, Chis CH, Jaing TH, Chang KJ, Lin TY. Necrotising fasciitis caused by Vibrio vulnificus in a child without known risk factors. Eur J Pediatr. 2002;161:464-465. (Case report) 186. Reed KC, Crowell MC, Castro MD, Sloan ML. Skin and soft tissue infections after injury in the ocean: Culture methods and antibiotic therapy for marine bacteria. Mil Med. 1999;164:198-201. (Laboratory research)

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187. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association. Am J Respir Crit Care Med. 1997;156:S125. (Practice guideline) 188. Merchant RC, Fuerch J, Becker BM, Mayer KH. Comparison of the Epidemiology of Human Bites Evaluated at Three US Pediatric Emergency Departments. Pediatr Emerg Care. 2005;21:833-838. (Retrospective; 115 patients) 189. Merriam CV, Fernandez HT, Citron DM, Tyrrell KL, Warren YA, Goldstein EJ. Bacteriology of human bite wound infections. Anaerobe. 2003;9:83-86. (Retrospective; 57 patients) 190. Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJ. Bacteriologic Analysis of Infected Dog and Cat Bites. N Engl J Med. 1999;340:85-92. (Prospective; 107 patients) 191. Naas T, Benaoudia F, Lebrun L, Nordmann P. Molecular Identification of TEM-1 ß-Lactamase in a Pasteurella multocida Isolate of Human Origin. Eur J Clin Microbiol Infect Dis. 2004;20:210-213. (Laboratory research) 192. Goldstein EJ, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT. Comparative in vitro activity of faropenem and 11 other antimicrobial agents against 405 aerobic and anaerobic pathogens isolated from skin and soft tissue infections from animal and human bites. J Antimicrob Chemother. 2002;50:411-420. (Laboratory research) 193. American Academy of Pediatrics. Bite Wounds. In:Pickering LK, Baker CJ, Overturf GD, Prober CG, eds. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006. (Book chapter) 194. Bradley, JS. Bite-Wound Infections. In: Jenson HB, Baltimore RS, eds. Pediatric Infectious Disease: Principles and Practice, 2nd ed. Philadelphia, PA: W.B. Saunders Co; 2002. (Book chapter) 195. Goldstein EJ, Citron DM, Hunt GS, Hudspeth M, Merriam CV. Activities of HMR 3004 (RU 64004) and HMR 3647 (RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and eight other antimicrobial agents against unusual aerobic and anaerobic human and animal bite pathogens isolated from skin and soft tissue infections in humans. Antimicrob Agents Chemother. 1998;42:1127-32. 196. Muller LMAJ, Gorter KJ, Hak E, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41:281-288. (Prospective; controlled; 7417 patients) 197. Willcox PA, Rayner BL, Whitelaw DA. Communityacquired Staphylococcus aureus bacteraemia in patients who do not abuse intravenous drugs. QJM. 1998;91:41-47. (Prospective; 113 patients) 198. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections. Risk factors for mortality and strategies for management. Ann Surg. 1996;224:672-683. (Retrospective; 198 patients) 199. Rubenstein M, Duvic M. Cutaneous manifestations of Hodgkin’s disease. Int J Dermatol. 2006;45:251-256. (Review article) 200. Bodey GP, Bolivar R, Fainstein V, Jadeja L. Infections caused by Pseudomonas aeruginosa. Rev Infect Dis. 1983;5:279-313. (Review article) 201. Pouryousefi A, Foland J, Michie CA, Cummins M. Ecthyma gangrenosum as a very early herald of acute lymphoblastic leukaemia. J Paediatr Child Health. 1999;35:505-506. (Case report) 202. Mays S, Bogle MA, Bodey GP. Cutaneous Fungal Infections in the Oncology Patient: Recognition and Management. Am J Clin Dermatol. 2006;7:31-43. (Review article) 203. Golden E, Beach B, Hastings C. The pediatrician and medical care of the child with cancer. Pediatr Clin North Am. 2002;49:1319-1338. (Review article) 204. Al-Mahfouz MM, Hamdi KI, Baker SS. Bacterial skin infections among patients with hemoglobinopathies. Saudi Med J. 2005;26:1092-1094. (Prospective; 168 patients)

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205. Wong WY. Prevention and management of infection in children with sickle cell anaemia. Paediatr Drugs. 2001;3:793-801. (Review article) 206. Domachowske JB. Pediatric human immunodeficiency virus infection. Clin Microbiol Rev. 1996;9:448-468. (Review article) 207. Zuckerman G, Metrou M, Berstein LJ. Neurologic disorders and dermatologic manifestations in HIV infected children. Pediatr Emerg Care. 1991;7:99-105. (Review article) 208. Stefanaki C, Stratigos AJ, Stratigos JD. Skin manifestations of HIV-1 infection in children. Clin Dermatol. 2002;20:74-86. (Review article) *209. Fortunov RM, Hulten KG, Hammerman WA, Mason Jr EO, Kaplan SL. Community-Acquired Staphylococcus aureus infections in term and near-term previously healthy neonates. Pediatrics. 2006;118:874-881. (Retrospective; 89 patients) 210. Centers for Disease Control and Prevention (CDC). Community-associated methicillin-resistant Staphylococcus aureus infection among healthy newborns—Chicago and Los Angeles County, 2004. MMWR Morb Mortal Wkly Rep. 2006;55:329-332. (Case report) 211. Bratu S, Eramo A, Kopec R, et al. Community-associated Methicillin-resistant Staphylococcus aureus in hospital nursery and maternity units. Emerg Inf Dis. 2005;11:808-813. (Case report) 212. Baartmans MGA, Maas MH, Dokter J. Neonate with staphylococcal scalded skin syndrome. Arch Dis Child Fetal Neonatal Ed. 2006;91:F25. (Case report) 213. Haveman LM, Fleer A, de Vries LS, Gerards LJ. Congenital staphylococcal scalded skin syndrome in a premature infant. Acta Paediatr. 2004;93:1661-1662. (Case report) 214. El Helali N, Carbonne A, Naas T, et al. Nosocomial outbreak of staphylococcal scalded skin syndrome in neonates: epidemiological investigation and control. J Hosp Infect. 2005;61:130-138. (Case report) 215. Mandal D, Littner Y, Mimouni FB, Dollberg S. Nosocomial cutaneous abscesses in septic infants. Arch Dis Child Fetal Neonatal Ed. 2004;89:F161. (Retrospective; 10 patients) 216. Sawardekar KP. Changing spectrum of neonatal omphalitis. Pediatr Infect Dis J. 2004;23:22-26. (Prospective; 207 patients) 217. Fraser N, Davies BW, Cusack J. Neonatal omphalitis: A review of its serious complications. Acta Paediatr. 2006;95:519-522. (Review article) 218. Hseih WS, Yang PH, Chao HC, Lai JY. Neonatal necrotizing fasciitis: A report of three cases and review of the literature. Pediatrics. 1999;103:e53. (Case report; review article) 219. Spann M, Talmor M, Nolan WB. Hand infections: basic principles and management. Surg Infect. 2004;5:210-220. (Review article) 220. Small LN, Ross JJ. Suppurative tenosynovitis and septic bursitis. Infect Dis Clin North Am. 2005;19:991-1005. (Review article) 221. Clark DC. Common acute hand infections. Am Fam Physician. 2003;68:2167-2176. (Review article) 222. Caplan GA, Ward JA, Brennan NJ, Coconis J, Board N, Brown A. Hospital in the home: a randomized controlled trial. Med J Aust. 1999;170:156-160. (Prospective; randomized; controlled; 100 patients) 223. Nathwani D. The Management of Skin and Soft Tissue Infections: Outpatient Parenteral Antibiotic Therapy in the United Kingdom. Chemotherapy. 2001;47:17-23. (Prospective; 125 patients) 224. Donald M, Marlow N, Swinburn E, Wu M. Emergency department management of home intravenous antibiotic therapy for cellulitis. Emerg Med J. 2005;22:715-717. (Retrospective; 124 patients) 225. Von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. N Engl J Med. 2001;344:11-16. (Prospective; 219 patients) 226. Wertheim HF, Melles DC, Vos MC. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005;5:751-762. (Review article)

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227. Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of community-acquired methicillinresistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis. 2004;39:971-979. (Prospective; 812 patients) 228. Perl TM, Cullen JJ, Wenzel RP, et al. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N Engl J Med. 2002;36:1871-1877. (Prospective; randomized; controlled; 4080 patients) 229. Wertheim HF, Vos MC, Ott A, et al. Mupirocin prophylaxis against nosocomial Staphylococcus aureus infections in nonsurgical patients: a randomized study. Ann Intern Med. 2004;140:419-425. (Prospective; randomized; controlled; 1602 patients) 230. Kalmeijer MD, Coertjens H, Van Nieuwland-Bollen PM, et al. Surgical site infections in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study. Clin Infect Dis. 2002;35:353-358. (Prospective; randomized; controlled; 614 patients) 231. Jensen JU, Jensen ET, Larsen AR, et al. Control of a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in a day-care institution. J Hosp Infect. 2006;63:8492. (Prospective; 38 patients) 232. John CC, Schreiber JR. Therapies and vaccines for emerging bacterial infections: Learning from methicillinresistant Staphylococcus aureus. Pediatr Clin North Am. 2006;53:699-713. (Review article) 233. Shinefield H, Black S, Fattom A, et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N Engl J Med. 2002;346:491-496. (Prospective; randomized; controlled; 1804 patients) 234. Kotloff KL, Corretti M, Palmer K, et al. Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial. JAMA. 2004;292:709-715. (Prospective; 28 patients) 235. Dong SL. ED management of cellulitis: a review of five urban centers. Am J Emerg Med. 2001;19:535-540. (Retrospective; 416 patients) 236. Eron LJ, Lipsky BA, Low DE, Nathwani D, Tice AD, Volturo GA. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother. 2003;52:i3-17. (Practice guideline) 237. R. R. Management of patients with infectious diseases in an emergency department observation unit. Emerg Med Clin North Am. 2001;19:187-207. (Review article) 238. Hostetler B, Leikin JB, Timmons JA, et al. Patterns of use of an emergency department-based observation unit. Am J Ther. 2002;9:499-502. (Retrospective; 5714 patients)

CME Questions 1. Which pathogen is associated with over 70% of skin and soft tissue infections in children? a. Streptococcus pyogenes b. Streptococcus pneumoniae c. Staphylococcus epidermis d. Staphylococcus aureus e. Pasteurella multocida 2. Which of these virulence factors is associated with GAS infection? a. Panton-Valentine leukocidin determinant (PVL) b. Streptolysin O c. Exfoliative toxins A and B (ETA and ETB) d. Penicillin binding protein 2a (PBP2a) e. Beta-lactamase production 3. Actinomyces israelii is found living with the normal flora in which area of the body? a. Lower respiratory tract b. Colon 26

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4.

5.

6.

7.

8.

9.

10.

11.

c. Oral cavity d. Anterior nares e. Skin Which of the following bacteria is most typically associated with infected cat bites? a. Streptococcus pyogenes b. Streptococcus pneumoniae c. Staphylococcus epidermis d. Staphylococcus aureus e. Pasteurella multocida Ecthyma gangrenosum is the dermatologic manifestation of systemic infection with which of the following pathogens? a. Aeromonas hydrophila b. Mycobacterium marinum c. Pasteurella multocida d. Haemophilus influenzae e. Pseudomonas aeruginosa Orbital cellulitis is predominantly a complication of what condition? a. Odontogenic infection b. Bacteremia c. Meningitis d. Sinusitis e. Cavernous sinus thrombosis Erysipelas is cause by what pathogen? a. Streptococcus pyogenes b. Streptococcus pneumoniae c. Staphylococcus epidermis d. Staphylococcus aureus e. Pasteurella multocida Which of the following is a significant risk factor for necrotizing fasciitis in children? a. Varicella infection b. Eczema c. Obesity d. Edema e. Staphylococcus aureus infection What treatment for non-bullous impetigo has been shown in systematic reviews to have a high cure rate while minimizing systemic side effects? a. Observation only b. Disinfection with chlorhexidine c. Topical bacitracin d. Topical mupirocin e. Systemic cephalexin Which of the following antibiotics is MRSA typically resistant to? a. Clindamycin b. TMP-SMX c. Erythromycin d. Vancomycin e. Linezolid What is the most effective therapy for necrotizing fasciitis? a. Intravenous clindamycin b. Oral cephalexin

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12.

13.

14.

15.

16.

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c. Intravenous vancomycin d. Intravenous rifampin and gentamycin e. Surgical debridement Which is not a classic symptom of tenosynovitis? a. Uniform, symmetric digit swelling b. Digit held in partial flexion at rest c. Prolonged capillary refill time of the affected digit d. Excessive tenderness along the entire course of the flexor tendon sheath e. Pain along the tendon sheath with passive digit extension Localized release of epidermolytic toxin causes which of the following conditions? a. Non-bullous impetigo b. Bullous impetigo c. Scalded skin syndrome d. Toxic shock syndrome e. Furunculosis “Fish tank” granuloma is the common name for one of the clinical manifestations of dermatologic infection by what slow-growing organism? a. Aeromonas hydrophila b. Mycobacterium marinum c. Vibrio vulnificus d. Haemophilus influenzae e. Pseudomonas aeruginosa What is the relationship between hospitalacquired MRSA (HA-MRSA) and communityacquired MRSA (CA-MRSA) a. CA-MRSA evolved from HA-MRSA b. HA-MRSA evolved from CA-MRSA c. CA-MRSA and HA-MRSA most likely evolved independently d. HA-MRSA and CA-MRSA are in a constant exchange of virulence and resistance factors e. HA-MRSA is more easily treated than CAMRSA The term “inducible clindamycin resistance” describes what phenomenon? a. The presence of clindamycin resistance in MRSA when found in the hospital setting b. The development of clindamycin resistance in polymicrobial infections c. The development of clindamycin resistance in previously erythromycin resistant, clindamycin sensitive S. aureus when treated with clindamycin d. The development of clindamycin resistance in GAS infections when they are not treated for a full ten days e. The presence of clindamycin resistance by S. aureus that can be overcome with the use of high-dose clindamycin therapy

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Physician CME Information

Free Report: “Evidence-Based Medicine: A Guide For Physicians”

Date of Original Release: February 1, 2008. Date of most recent review: January 6, 2008. Termination date: February 1, 2011. Accreditation: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Mount Sinai School of Medicine and Pediatric Emergency Medicine Practice. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 48 AMA PRA Category 1 Credit(s)TM per year. Physicians should only claim credit commensurate with the extent of their participation in the activity. ACEP Accreditation: Pediatric Emergency Medicine Practice is also approved by the American College of Emergency Physicians for 48 hours of ACEP Category 1 credit per annual subscription. AAP Accreditation: This continuing medical education activity has been reviewed by the American Academy of Pediatrics and is acceptable for up to 44 AAP credits. These credits can be applied toward the AAP CME/CPD Award available to Fellows and Candidate Fellows of the American Academy of Pediatrics. Needs Assessment: The need for this educational activity was determined by a survey of medical staff, including the editorial board of this publication; review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency physicians. Target Audience: This enduring material is designed for emergency medicine physicians, physician assistants, and nurse practitioners. Goals & Objectives: Upon completion of this article, you should be able to: (1) demonstrate medical decision-making based on the strongest clinical evidence; (2) cost-effectively diagnose and treat the most critical ED presentations; and (3) describe the most common medicolegal pitfalls for each topic covered. Discussion of Investigational Information: As part of the newsletter, faculty may be presenting investigational information about pharmaceutical products that is outside Food and Drug Administration approved labeling. Information presented as part of this activity is intended solely as continuing medical education and is not intended to promote off-label use of any pharmaceutical product. Disclosure of Off-Label Usage: This issue of Pediatric Emergency Medicine Practice discusses no off-label use of any pharmaceutical product. Faculty Disclosure: It is the policy of Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. In compliance with all ACCME Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to complete a full disclosure statement. The information received is as follows: Dr. Uspal, Dr. Agrawal, Dr. Pauze, and Dr. Witt report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation. Method of Participation: • Print Subscription Semester Program: Paid subscribers with current and valid licenses in the United States who read all CME articles during each Pediatric Emergency Medicine Practice six-month testing period, complete the post-test and the CME Evaluation Form distributed with the June and December issues, and return it according to the published instructions are eligible for up to 4 hours of CME credit for each issue. You must complete both the post test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates will be delivered to each participant scoring higher than 70%. • Online Single-Issue Program: Current, paid subscribers with current and valid licenses in the United States who read this Pediatric Emergency Medicine Practice CME article and complete the online post-test and CME Evaluation Form at EBMedicine.net are eligible for up to 4 hours of Category 1 credit toward the AMA Physician’s Recognition Award (PRA). You must complete both the post-test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates may be printed directly from the Web site to each participant scoring higher than 70%. Hardware/Software Requirements: You will need a Macintosh or PC with internet capabilities to access the website. Adobe Reader is required to download archived articles.

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Class Of Evidence Definitions Each action in the clinical pathways section of Pediatric Emergency Medicine Practice receives a score based on the following definitions. Class I • Always acceptable, safe • Definitely useful • Proven in both efficacy and effectiveness Level of Evidence: • One or more large prospective studies are present (with rare exceptions) • High-quality meta-analyses • Study results consistently positive and compelling Class II • Safe, acceptable • Probably useful Level of Evidence: • Generally higher levels of evidence • Non-randomized or retrospective studies: historic, cohort, or case control studies • Less robust RCTs • Results consistently positive Class III • May be acceptable • Possibly useful • Considered optional or alternative treatments

Level of Evidence: • Generally lower or intermediate levels of evidence • Case series, animal studies, consensus panels • Occasionally positive results Indeterminate • Continuing area of research • No recommendations until further research Level of Evidence: • Evidence not available • Higher studies in progress • Results inconsistent, contradictory • Results not compelling Significantly modified from: The Emergency Cardiovascular Care Committees of the American Heart Association and representatives from the resuscitation councils of ILCOR: How to Develop EvidenceBased Guidelines for Emergency Cardiac Care: Quality of Evidence and Classes of Recommendations; also: Anonymous. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Part IX. Ensuring effectiveness of community-wide emergency cardiac care. JAMA 1992;268(16):2289-2295.

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