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Introduction

Background
Bacteria of the genus Staphylococcus are gram-positive cocci that are microscopically observed as individual organisms, in pairs, and in irregular, grapelike clusters. The term Staphylococcus is derived from the Greek term staphyle, meaning "a bunch of grapes." Staphylococci are nonmotile, nonspore-forming, and catalase-positive bacteria. The cell wall contains peptidoglycan and teichoic acid. The organisms are resistant to temperatures as high as 50C, to high salt concentrations, and to drying. Colonies are usually large (6-8 mm in diameter), smooth, and translucent. The colonies of most strains are pigmented, ranging from cream-yellow to orange. The ability to clot plasma continues to be the most widely used and generally accepted criterion for the identification of Staphylococcus aureus. One such factor, bound coagulase, also known as clumping factor, reacts with fibrinogen to cause organisms to aggregate. Another factor, extracellular staphylocoagulase, reacts with prothrombin to form staphylothrombin, which can convert fibrinogen to fibrin. Approximately 97% of human S aureus isolates possess both of these forms of coagulase. S aureus is ubiquitous and may be a part of human flora found in the axillae, the inguinal and perineal areas, and the anterior nares. In 2001, von Eiff et al described 3 patterns of carriage: those who always carry a strain, those who carry the organism intermittently with changing strains, and a minority of people who never carry S aureus.1 Persistent carriage is more common in children than in adults. Wenzel and Perl (1995) found that, among healthy adults, carrier rates of 11-32% were detected in the general population, and a prevalence of 25% was detected in hospital personnel.2 Using pulsed-field gel electrophoresis (PFGE) for molecular typing, von Eiff et al (2001) found that, in most patients with S aureus bacteremia, the isolate from the patient's blood is identical to that found in the anterior nares.1 Curiously, community-associated methicillin-resistant S aureus (CAMRSA) is rarely found in the anterior nares; rather, it colonizes the skin, particularly in the perineal area. It may also colonize the pharynx, gut, and vagina.

Pathophysiology
The organism may cause disease through tissue invasion and toxin production. The toxins liberated by the organism may have effects at sites distant from the focus of infection or colonization. Tissue invasion The postulated sequence of events that leads to infection is initiated with carriage of the organism. The organism is then disseminated via hand carriage to body sites where infection may occur (either through overt breaks in dermal surfaces, such as vascular catheterization or operative incisions, or through less evident breakdown in barrier function, such as eczema or shavingassociated microtrauma). The hallmark of staphylococcal infection is the abscess, which consists of a fibrin wall surrounded by inflamed tissues enclosing a central core of pus containing organisms and leukocytes. From this focus of infection, the organisms may be disseminated hematogenously, even from the smallest abscess. The ability to elaborate proteolytic enzymes facilitates the process. This may result in pneumonia, bone and joint infection, and infection of the heart valves. In immunocompromised hosts (eg, patients with cancer who are neutropenic and have a central

venous line), 20-30% develop serious complications or fatal sepsis following catheter-related S aureus bacteremia. Persistent deep-seated infections have now been linked to small-colony variants of the organism. This population is more resistant to antibiotics and grows slowly. These organisms have been described in patients with cystic fibrosis and may contribute to the persistence of S aureus in these patients. Toxin-mediated disease The organism may also elaborate toxins that can cause specific diseases or syndromes. Enterotoxin-producing strains of S aureus cause one of the most common food-borne illnesses. The most common presentation is acute onset of vomiting and watery diarrhea 2-6 hours after ingestion. The symptoms are usually self-limited. The cause is the proliferation of toxin-producing organisms in uncooked or partially cooked food that an individual carrying the staphylococci has contaminated. A rare but well-described disorder in neonates and young children is staphylococcal scalded skin syndrome (Ritter disease). The organism produces an exfoliative toxin produced by strains belonging to phage group II. Initial features include fever, erythema, and blisters, which eventually rupture and leave a red base. Gentle shearing forces on intact skin cause the upper epidermis to slip at a plane of cleavage in the skin, which is known as the Nikolsky sign. How the exfoliative toxins produce epidermal splitting has not been fully elucidated. The most feared manifestation of S aureus toxin production is toxic shock syndrome (TSS). Although first described in children, it was most frequently associated with women using tampons during menstruation. Since the early 1990s, at least half of the cases have not been associated with menstruation. The syndrome is associated with strains that produce the exotoxin TSST-1, but strains that produce enterotoxins B and C may cause 50% of cases of nonmenstrual TSS. These toxins are superantigens, T-cell mitogens that bind directly to invariant regions of major histocompatibility complex class II molecules, causing an expansion of clonal T cells, followed by a massive release of cytokines. This cytokine release mediates the TSS; the resultant pathophysiology mimics that of endotoxic shock. In a recent worldwide trend, the proportion of infections caused by CA-MRSA has increased. Initially noted in tertiary care centers, these infections are now increasingly common in the community. Resistance to methicillin confers resistance to all penicillinase-resistant penicillins and cephalosporins. This high level of resistance requires the mec gene that encodes penicillin-binding protein 2a. This protein has decreased binding affinity for most penicillins and cephalosporins. Methicillin resistance has a wide variety of phenotypic expression. Heterogeneous resistance, recognized in the first clinical isolates described, is the typical phenotype. In this case, all cells carry the genetic markers of resistance but only a small fraction of them express the phenotype. Less frequent is homogenous resistance, with a single population of cells that are inhibited only through high concentrations of antibiotics. Methicillin-resistant S aureus (MRSA) was initially described in hospitalized populations. University affiliation and greater number of beds were institutional risk factors. In pediatric centers, number of beds, region, and metropolitan population correlated with increased risk. Since 1996, more patients with CA-MRSA have been described. The strains isolated from these patients are different from typical nosocomial organisms in their susceptibility patterns and in their PFGE characteristics. A clonal population, designated USA-300, has become the predominant circulating organism in most communities. Many of these strains produce the Panton-Valentine leukocidin, which is

associated with a tendency to produce abscesses, invasiveness, thrombogenesis, and morbidity and mortality. More recently, S aureus that is intermediately resistant to vancomycin has been reported in 2 hospitalized patients, which suggests that full resistance to vancomycin may eventually emerge.3 Although the possibility of interspecies transfer of vancomycin-resistance genes from vancomycinresistant Enterococcus was originally considered as the cause of this phenomenon, none of the species isolated have carried vanA, vanB, vanC1, vanC2, or vanC3 genes. Of note, the clinical isolates with intermediate resistance to vancomycin were from patients who had undergone prolonged vancomycin therapy for MRSA. Morphologically, these isolates were found to have increased extracellular material associated with the cell wall that may have been selected for during a prolonged antibiotic course.

Frequency
United States

Numbers of both community-associated and hospital-acquired infections have increased in the past 20 years. From 1990-1992, data from the National Nosocomial Infections Surveillance System for the Centers for Disease Control and Prevention (CDC) revealed that S aureus was the most common cause of nosocomial pneumonia and operative wound infections and the second most common cause of nosocomial bloodstream infections. Frequency of antibiotic resistance: In a disturbing trend, antibiotic resistance among these isolates has increased because of antibiotic pressure. Currently, less than 5% of clinical isolates remain sensitive to penicillin. Resistance to penicillin was reported as early as 1942 and is mediated by beta-lactamase, a serine protease that hydrolyzes the lactam ring. In the 1980s, MRSA emerged as a prominent hospital-based infection; consequently, the use of vancomycin increased. A CDC survey revealed that the proportion of methicillin-resistant isolates with sensitivity only to vancomycin increased from 22.8% in 1987 to 56.2% in 1997.4

Mortality/Morbidity
Morbidity and mortality from S aureus infection widely varies depending on the clinical entity. Although mortality is low in children with scalded skin syndrome, most fatalities are associated with delay in diagnosis.

Sex
The male-to-female ratio of skeletal infections is 2:1, mostly because boys are more likely to experience traumatic events.

Clinical
History

Skin and soft tissue (impetigo): Typically, this starts as a small area of erythema that progresses into bullae (filled with cloudy fluid) that rupture and heal with the formation of a honey-colored crust. Although group A Streptococcus was once considered the primary agent, Staphylococcus aureus has become the major pathogen since the 1980s. S aureus exclusively causes bullous impetigo, which is observed less frequently in the United States. This form of disease seems to arise from healthy-appearing skin. The bullae rupture, leaving a denuded area with a varnish-like coating. Scalded skin syndrome (Ritter disease): An exfoliative toxin (see Toxin-mediated disease) causes this relatively rare syndrome, which takes the form of superficial fragile blisters

that burst, leaving a tender base. The patient is often febrile and, occasionally, has mucopurulent eye discharge. This diagnosis should be made carefully, because scalded skin syndrome may be mistaken for erythema multiforme or toxic epidermal necrolysis, which can be treated with corticosteroids. Misdiagnosis delays treatment and allows exfoliation to progress, and corticosteroid therapy may potentiate bacterial superinfection. Although the mortality rate is low in children with this entity, most fatalities are associated with delay in diagnosis. Folliculitis, furuncle, and carbuncle: These are increasingly severe staphylococcal skin infections. Folliculitis is a tender pustule that involves the hair follicle. A furuncle involves both the skin and the subcutaneous tissues in areas with hair follicles, such as the neck, axillae, and buttocks. They are actually small abscesses characterized by exuding purulent material from a single opening. A carbuncle is an aggregate of connected furuncles and has several pustular openings. Skin infections may be self-limited, but they can also disseminate hematogenously and cause life-threatening septicemia. Bone infections (osteomyelitis) Children often present with sudden onset of fever and bony tenderness or a limp. The pain may be throbbing and severe; however, presentation in neonates can be subtle. Infants may appear well except for failure to move an extremity or pain on movement. Redness or swelling indicates that infection has spread into the subperiosteal space. Rupture of a focus of osteomyelitis into joint space can result in septic arthritis. This is often observed in neonates. Children with vertebral osteomyelitis present with back pain, and those younger than 3 years present with refusal to walk or with a limp. Occasionally, children with vertebral osteomyelitis present with incontinence. Children with discitis tend to present with less fever and often appear less ill than children with vertebral osteomyelitis. Septic arthritis: Typical findings include decreased range of motion, warmth, erythema, and tenderness of the joint with constitutional symptoms and fever. Infants (in whom the hip is the most commonly involved joint) are an exception, as these signs may be absent. The child typically lies with the involved joint abducted and externally rotated. Because pain fibers are located within the joint capsule, movements that compress the head of the femur into the acetabulum (eg, changing a diaper) cause pain. A portal of infection is almost never found, and the infection is nearly always unilateral. Patients with infection of the sacroiliac joint present with tenderness elicited during digital rectal examination and with pain during flexion, abduction, and external rotation of the hip. Endocarditis: The initial presentation of patients with S aureus endocarditis is fever and malaise. However, the disease has a more rapid onset than that caused by less virulent pathogens. Notably, on initial presentation, the usual physical stigmata are absent. Endocarditis may also involve healthy valves. For more detail, please see Endocarditis, Bacterial. Toxic shock syndrome (TSS) Staphylococcal TSS is a potentially life-threatening systemic bacterial intoxication. Case definition includes fever, diffuse macular erythema, and hypotension, with involvement of 3 or more of the following organ systems: GI - Emesis or diarrhea appears at the time of illness. Diarrhea is secretory and profuse, and is found in almost all patients with TSS but is uncommon in patients in septic shock. Muscular - Severe myalgia or elevated creatine kinase (CK) levels are observed. Myalgia may be one of the earliest manifestations of the disease.

Renal - Elevation of BUN or creatinine levels or more than 5 WBCs per high-power field in the absence of a urinary tract infection is observed. Hepatic levels of bilirubin, serum glutamic-oxaloacetic transaminase (aspartate aminotransferase), and serum glutamic-pyruvic transaminase (alanine aminotransferase) are twice the upper limit of the reference range. Hematologic The platelet count is less than 100,000/ L. Nervous system Features include disorientation and alteration in consciousness with the absence of focal neurologic signs when fever and hypotension are absent. A probable case of TSS involves 5 of the above 6 findings. A confirmed case of TSS involves all 6 findings. The most striking aspect of the disease is the rapidity with which it can progress in a previously healthy individual of any age. This is especially true in postsurgical patients, particularly following nasal surgery, because this is an area commonly colonized with S aureus. Late-onset dermatologic findings include a red and pruritic maculopapular rash, desquamation of the fingers and toes, and telogen effluvium (see Toxic Shock Syndrome). Pneumonia: Cases of rapidly progressive and fatal staphylococcal pneumonia still occur, although they were much more common in the 1950s and early 1960s, when S aureus phage type 80/81 caused frequent disease in infants. Staphylococcal pneumonia most commonly occurs in infants, young children, and patients who are debilitated. This is a rapidly progressive disease. Patients with primary staphylococcal pneumonia present with a short prodrome of fever followed by rapid onset of respiratory distress, which may include tachypnea, retractions, and cyanosis. Patients may also have prominent GI tract symptoms. Staphylococcal pneumonia may also develop after influenza infection, which seems to occur preferentially among young adults (in whom mortality reaches 50%). Typically, the child seems to recover from a febrile illness only to once again develop an increasing fever and the symptoms mentioned above. Thrombophlebitis: Usually occurring in a hospitalized patient, thrombophlebitis is characterized by fever, pain, and, occasionally, erythema at the insertion site of an intravenous catheter. Occasionally, pus is expressed. Severe suppurative thrombophlebitis may occur in burn patients, with fewer than half of diagnoses made while the patients are alive. Deep tissue abscess and infection: Muscles (myositis and pyomyositis) and organs can become infected, including the parotid gland, eyes, liver, spleen, and kidneys. These infections typically cause fever with or without localizing pain.

Physical

Skin and soft tissue (impetigo): The infection initially appears as a small area of erythema. Bullae (ie, blister-like lesions filled with cloudy fluid) appear as the disease progresses. As bullae heal, a honey-colored crust develops. Scalded skin syndrome (Ritter disease): Examination reveals superficial, fragile blisters that burst, leaving a tender base. Skin sloughs easily when touched, a condition termed the Nikolsky sign. Fever is often present, and mucopurulent eye discharge may be observed. As discussed above, the infection is often mistaken for erythema multiforme or toxic epidermal necrolysis. Misdiagnosis must be avoided. Folliculitis, furuncle, and carbuncle: Folliculitis is the appearance of a tender pustule involving a hair follicle. A furuncle is an apparent small abscess that exudes purulent

material from a single opening. A carbuncle is an aggregate of furuncles with several openings. Bone infections (osteomyelitis): Fever, bony tenderness, or a limp indicate bone infections. Infants may appear well except for failure to move an extremity or pain on movement. Children with vertebral osteomyelitis present with back pain, and those younger than 3 years present with refusal to walk or with a limp. Occasionally, children with vertebral osteomyelitis have incontinence as a presenting symptom. Children with discitis tend to present with less fever and often appear less ill than children with vertebral osteomyelitis. Septic arthritis: Examination reveals warmth, erythema, and tenderness of the joint. Constitutional symptoms and fever are frequently observed. These findings may be absent in an infant. Children with infection of the sacroiliac joint present with tenderness elicited during digital rectal examination. Endocarditis: The clinical syndrome widely varies and may involve multiple organs. S aureus infection usually results in an acute course but may involve subacute disease. Most patients present with high fever. Chills and sweats and a new or worsened murmur may occur. Peripheral emboli such as Osler nodes, subungual hemorrhages, Janeway lesions, and Roth spots may be present. Other embolic phenomena may occur. TSS: TSS involves a fever of 38.9C or higher. Hypotension occurs, either with blood pressure below the fifth percentile for age or with an orthostatic (lying to sitting) drop in diastolic blood pressure greater than or equal to 15 mm Hg. A diffuse, erythroderma-like rash is present. Conjunctival or vaginal hyperemia may be present. Patients may have altered sensorium, even when normotensive, or may be delirious, disoriented, or agitated without focal signs. Reddened lips and tongue may be observed. Later, on recovery, desquamation of hands and feet may occur; occasionally, alopecia occurs later. Pneumonia: Fever is present. Findings of respiratory distress include tachypnea, cyanosis, grunting, and retractions. Vomiting and abdominal distension occur. Clinical deterioration is rapid. Thrombophlebitis: Patients usually have a fever and, occasionally, have cutaneous involvement such as erythema, induration, or tenderness. Occasionally, pus is expressed at the insertion site of the catheter. The exit site often does not show signs of infection. Establishing infection of an intravascular device as the cause of fever in a hospitalized patient is a diagnosis of exclusion. Deep tissue abscess and infection: Localizing tenderness may be present, as may signs of inflammation.

Causes

Skin and soft tissue (impetigo): Often occurring in young children, impetigo is spread within families and through close physical contact. Impetigo is more prevalent in warm, humid climates because of more opportunities for insect bites and cutaneous trauma. Impetigo may also be a complication of varicella. Diagnosis is usually made based on the characteristic appearance of the lesions. Bullous impetigo may also occur in endemic and epidemic patterns. Nursery outbreaks have been described, and some cases in infants have progressed to scalded skin syndrome or Ritter disease (described in History). Folliculitis, furuncle, and carbuncle: Recurrent staphylococcal skin infections develop in certain patients, such as those with impaired neutrophil function (eg, those with chronic granulomatous disease), patients with atopy and chronic eczema, and those with impaired circulation and diabetes mellitus. However, most patients with recurrent furunculosis are colonized with CA-MRSA but are otherwise healthy. Thus, an evaluation of the immune system in these individuals is seldom useful.

Bone and joint infections (osteomyelitis): Osteomyelitis typically occurs in children prior to the age of epiphyseal closure. Osteomyelitis typically originates in the metaphysis of long bones in the region of most rapid growth. Osteomyelitis usually involves (in order of frequency) the lower end of the femur, the upper end of the tibia and humerus, and the radius. Most bone and joint infections result from hematogenous spread, but significant blunt trauma is a preceding event in approximately one third of cases. In addition, penetrating wounds, compound fractures, and orthopedic appliances may introduce microbial infection directly into bone. Notably, the male-to-female ratio of skeletal infections is 2:1, mostly because boys are more likely to experience traumatic events. Septic arthritis: Staphylococci are frequent etiologic agents of septic arthritis and, since the era of successful vaccination for Haemophilus influenzae, are now more predominant in younger age groups . Bacteria can enter the joint space through hematogenous spread, direct inoculation, or contiguous spread of infection. Because the synovial membrane has a high effective blood flow, a large number of bacteria may be delivered to the joint during a period of bacteremia. Inoculation can occur when a joint is punctured with a contaminated object, and many clinical studies reveal that the knee is more likely to be punctured. In the postantibiotic era, contiguous spread has been rare, with the exception of neonatal osteomyelitis. Endocarditis: Fortunately, S aureus endocarditis is rare in pediatric patients. It often involves adolescent intravenous drug users who do not have antecedent valvular disease. These patients usually present with right-sided disease with evidence of pulmonary disease, such as pulmonary abscesses or shifting infiltrates. In children with preexisting heart disease, endocarditis is often temporally related to cardiac surgery or catheterization. Children with prosthetic valves are particularly vulnerable because of the organisms propensity to adhere to foreign materials. In addition, patients with indwelling vascular access devices are at risk, because infections from the skin can seed the catheter. TSS o Infection with toxin-producing S aureus in the absence of protective antibody is an antecedent. Younger patients may be at increased risk because they lack the protective antibodies to the enterotoxins and other exotoxins responsible for producing this clinical syndrome. However, other factors may be involved; Jacobsen et al (1989) demonstrated in a small study that not all patients without antibody develop true TSS when infected with a toxin-producing strain of the organism.5 Approximately 25% of all S aureus strains are toxigenic, and, at any time, roughly

4-10% of healthy individuals are colonized with these strains. In the 1980s, the disease was associated with the use of highly absorbent tampons in women during menstruation. Currently, many cases observed are nonmenstrual (eg, localized infections, surgery, infected varicella lesions, insect bites), and these now account for one third of all cases. These patients carry a higher mortality rate than those with menstrual TSS. Pneumonia: The primary form occurs without an extrapulmonary focus, presumably through direct inoculation to the lungs, and the secondary form results from hematogenous seeding of the lungs during endocarditis or bacteremia. Predisposing factors include infancy, chronic illness, and viral respiratory disease such as influenza. Patients with head injury and trauma who have nasopharyngeal carriage of S aureus are at increased risk of S aureus pneumonia. Thrombophlebitis: The causes are associated with infusion, including infected intravenous catheters and needles. The common point of entry for infection related to intravascular devices is the insertion site along the outside of the device.

Deep tissue abscess and infection: These typically result from hematogenous seeding, although myositis or pyomyositis can result from contiguous spread of infection and endophthalmitis can follow trauma (injury or iatrogenic), for example.

The differential diagnoses of staphylococcal infections include the following:

Impetigo - None Bullous impetigo o Pemphigus o Pemphigoid o Burn o Stevens-Johnson syndrome o Dermatitis herpetiformis Scalded skin syndrome (Ritter disease) o Nonaccidental injury o Scalding o Abrasion trauma o Sunburn o Erythema multiforme o Toxic epidermal necrolysis Bone and joint infections o Bone infarction (in patients with sickle cell disease) o Toxic synovitis o Leukemia Septic arthritis o Trauma o Deep cellulitis o Henoch-Schnlein purpura o Slipped capital femoral epiphysis o Legg-Calve-Perthes disease o Leukemia o Toxic synovitis o Metabolic diseases affecting joints (Ochronosis) Endocarditis - Bacteremia TSS o Staphylococcal scalded skin syndrome o Meningococcemia o Rubeola o Adenoviral infections o Dengue fever o Severe allergic drug reactions

Differential Diagnoses
Bacteremia Burns, Chemical Endocarditis, Bacterial Enteroviral Infections Impetigo Irritable Bowel Syndrome Leptospirosis Osteomyelitis Parvovirus B19 Infection Rheumatic Fever Rocky Mountain Spotted Fever Serum Sickness

Juvenile Rheumatoid Arthritis Streptococcal Infection, Group A Kawasaki Disease Toxic Shock Syndrome

Workup
Laboratory Studies
An erythromycin-induction test, or D-test, should always be performed with staphylococcal sensitivities to reveal inducible clindamycin resistance among community-associated methicillinresistant Staphylococcus aureus (CA-MRSA).

Folliculitis, furuncle, and carbuncle: Make the diagnosis based on clinical appearance and, occasionally, on results of aspiration or incision and culture of purulent material from the lesion. Osteomyelitis: Blood culture results are positive in only 30-50% of pediatric patients. Therefore, cultures of bone aspirate are useful in obtaining the organism and planning for long-term therapy. In addition, C-reactive protein levels and erythrocyte sedimentation rate are generally elevated in acute disease. Septic arthritis: Examination of joint fluid, when obtained, is the primary means of diagnosis; the fluid should be sent to the laboratory for Gram stain and culture. In addition, the number and type of leukocytes should be determined. Median cell count in bacterial arthritis is 60.5 X 109 cells with a neutrophil predominance of greater than 75%. Often, synovial fluid glucose levels are low. Yield of culture may be improved by directly inoculating synovial fluid into blood culture bottles. Endocarditis: The most important diagnostic procedure is the blood culture. Blood should be injected into hypertonic media if the patient has been exposed to antibiotics. Obtaining 3-5 sets of large-volume blood cultures within the first 24 hours is recommended. Pneumonia: Blood culture findings for S aureus are more likely to be positive in secondary disease than in primary disease (90% vs 20%). Because blood culture results are often negative, an adequate respiratory tract specimen should be obtained prior to initiating therapy; specimens may include endotracheal sampling, pleural fluid, or lung tap. Sputum is not considered adequate because the organism is frequently present in the upper respiratory secretions of healthy individuals. Thrombophlebitis: Although treatment is occasionally controversial, obtaining a blood culture through the intravenous line and a peripheral blood culture is usually recommended.

Imaging Studies

Osteomyelitis: On plain film radiographs, destructive bone changes are usually observed 2 weeks after infection. This is because a 30-50% reduction in bone calcium content is required before an osteolytic lesion is visible. The clinical diagnosis of osteomyelitis is most often supported by findings on bone scan with technetium Tc99mlabeled diphosphonate. Increased tracer uptake reflects the inflammatory process in the bone lesion. However, this modality is not as useful in neonates or after trauma or surgery. MRI is the best imaging modality for defining purulent collections and for planning surgery. Septic arthritis: Plain radiographs show capsular swelling. They are most useful in revealing other causes of hip pain, such as Legg-Calve-Perthes disease. Radiographs should be obtained with the child in the frog leg position as well as with the legs extended and slightly internally rotated. Displacement of gluteal fat lines because of the swelling of the joint capsule is an early radiologic sign of septic arthritis. If a bone scan is performed,

increased uptake on either side of the joint is visible. As pyogenic sacroiliitis is difficult to diagnose, the radiologic method of choice is MRI or CT scanning. Endocarditis: Echocardiography is a valuable adjunct. Two-dimensional echocardiography is more sensitive than the M-mode technique, and it has been used to reveal vegetations in patients with negative culture results. However, because of variable sensitivity, a negative finding does not exclude endocarditis. Transesophageal echocardiography is more sensitive than transthoracic echocardiography in the detection of intracardiac vegetations. Pneumonia: No radiologic features are highly specific, but the chest radiograph may provide information, especially in demonstrating its progression. Radiographs of patients with primary staphylococcal pneumonia may reveal unilateral consolidation, while patients with secondary staphylococcal pneumonia are more likely to demonstrate bilateral infiltrates on radiographs. Early in the disease course, the chest radiograph may reveal minimal infiltrates, but, within hours, they rapidly progress. Pleural effusion, pneumatoceles, and pneumothorax are also common.

Histologic Findings

For scalded skin syndrome (Ritter disease), histologic examination of a skin biopsy specimen is the most helpful, because demonstration of midepidermal separation at the zona granulosa is diagnostic of this entity and excludes erythema multiforme in which dermoepidermal cleavage occurs.

Treatment
Medical Care
Because community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) causes more than one half of all staphylococcal infections in most communities, empiric therapy with penicillins or cephalosporins is inadequate. Some experts recommend combination therapy with a penicillinase-resistant penicillin or cephalosporin (in case the organism is methicillin-sensitive S aureus [MSSA]) and clindamycin or a quinolone. Others suggest use of clindamycin, trimethoprimsulfamethoxazole (TMP-SMX), rifampin, or a quinolone. Finally, because of concerns about induction of resistance, some recommend using TMP-SMX and rifampin in combination, rather than singly.

Impetigo, folliculitis, furuncle, carbuncle: Impetigo and other minor skin infections (ie, superficial or localized infections) may be treated with a topical agent such as mupirocin or retapamulin. However, most CA-MRSA strains are or readily become resistant to mupirocin. More extensive or serious skin disease and bullous impetigo are treated with oral antistaphylococcal agents, as noted above. Scalded skin syndrome (Ritter disease): As with any S aureus toxinmediated disease, treatment should aim to eradicate the focus of infection and end toxin production. Administer large doses of intravenous antistaphylococcal agents, such as oxacillin (150 mg/kg/d), or a first-generation cephalosporin, such as cefazolin (100 mg/kg/d). In vitro, clindamycin has been shown to inhibit the synthesis of TSST-1 and is extremely effective in combination with one of the agents mentioned above. Children with denuded skin should be touched as little as possible. Topical antimicrobial agents have little use, because skin damage is self-limited once systemic antibiotics are administered. Osteomyelitis: Empirically, initiating a semisynthetic penicillin (eg, oxacillin [150 mg/kg/d]) and clindamycin (30-40 mg/kg/d) is a good choice for most cases of community-acquired osteomyelitis. In patients with allergy to penicillin, a first-generation cephalosporin and

clindamycin (30-40 mg/kg/d) are an excellent alternative. Use vancomycin or linezolid when the other drugs mentioned are absolutely not tolerated or when resistance or the clinical course dictates. The duration of therapy is a controversial topic in the literature, but the consensus among multiple authors is that the minimum effective treatment time is 4-6 weeks. A switch to oral therapy is acceptable if the child is able to take oral antibiotics, is afebrile, and if he or she has demonstrated a good clinical response to parenteral antibiotics. Septic arthritis: As in osteomyelitis, initiate an appropriate antistaphylococcal drug (eg, oxacillin, which is penicillinase resistant; clindamycin; cefazolin) parenterally. These antibiotics readily reach joint fluid, and the concentration in the joint fluid is 30% of the serum value. Therapy usually continues for at least 4 weeks. Duration of parenteral therapy is often debated. Some authors have demonstrated efficacy with 1 week of parenteral therapy followed with 3 weeks of oral therapy. Consider a switch to oral therapy based on the considerations mentioned above. Joint fluid that reaccumulates should be removed, and a sample should be cultured to assess the efficacy of therapy and to make the patient more comfortable. Endocarditis Duration of therapy for endocarditis, which is a life-threatening infection, is at least 4 weeks. The combination of a beta-lactam and an aminoglycoside is advocated, because it increases bacterial killing in vitro and in animal models of endocarditis. In patients with MRSA, combinations of vancomycin with aminoglycosides should be used. Rifampin, because of its lipid solubility, is another potent agent when used in combination with nafcillin and gentamicin or vancomycin and gentamicin, especially in patients with prosthetic valve endocarditis. Rifampin should never be used alone because resistance can develop. The response to therapy is usually slow, and patients may continue to have bacteremia, fever, and leukocytosis for at least a week after therapy is initiated. Some authors recommend obtaining blood cultures after the end of therapy. Treatment with antibiotics is specific to the etiologic agent and its characteristics. For more information, see Endocarditis, Bacterial.

Surgical Care

Osteomyelitis: Surgery is usually indicated to drain purulent material from the subperiosteal space or if infected foreign material is present. Septic arthritis: In an infant, septic arthritis of the hip and shoulder is a surgical emergency; these joints should be drained as soon as possible to prevent bony destruction. In addition, if a large amount of fibrin, tissue debris, or loculation is present, preventing adequate drainage with needle aspiration, the joint should be surgically drained. Endocarditis: If endocarditis occurs in the presence of an intracardiac foreign body, it may require removal. Toxic shock syndrome (TSS): All potential foci of infection should be explored and surgically drained. Thrombophlebitis: Remove the infected intravenous line in patients who are immunocompromised or severely ill or when infection is impossible to eradicate medically.

Medication

The major antibiotics active against the staphylococcal organism are presented here.

Antistaphylococcal antibiotics
Serious staphylococcal infections require treatment with parenteral penicillinase-resistant penicillin (eg, nafcillin, oxacillin) or first-generation or second-generation cephalosporins (eg, cephalexin, cefuroxime) plus clindamycin. Vancomycin is reserved for staphylococcal strains that are resistant to penicillinase-resistant penicillins (ie, MRSA) and clindamycin, or for when the patient has potentially life-threatening infection or intoxication. Mupirocin or retapamulin may be used for superficial localized infections (ie, impetigo).

Dicloxacillin

Binds to one or more penicillin-binding proteins, which, in turn, inhibits synthesis of bacterial cell walls. For treatment of infections caused by penicillinase-producing staphylococci. May be used to initiate therapy when staphylococcal infection is suspected.


Adult

Dosing Interactions Contraindications Precautions

125-500 mg PO q6h
Pediatric

<40 kilograms: 12.5-50 mg/kg/d PO divided q6h; doses up to 50-100 mg/kg/d have been used for PO therapy for osteomyelitis >40 kilograms: Administer as in adults

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Oxacillin

Bactericidal antibiotic that inhibits cell wall synthesis. Used in the treatment of infections caused by penicillinase-producing staphylococci.


Adult

Dosing Interactions Contraindications Precautions

0.25-1 g IV q6h
Pediatric

150 mg/kg/d IV divided qid

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Nafcillin

Initial therapy for suspected penicillin Gresistant staphylococcal infections. Use parenteral therapy initially in severe infections. Change to PO therapy as condition warrants.


Adult

Dosing Interactions Contraindications Precautions

0.5-1 g IV/IM q4-6h


Pediatric

Neonates: <1200 grams or <7 days and 1200-2000 grams: 50 mg/kg/d IV divided q12h <7 days and >2000 grams or >7 days and 1200-2000 grams: 75 mg/kg/d IV divided q8h >7 days and >2000 grams: 100 mg/kg/d IV divided q6h Children: 100-200 mg/kg/d IV divided qid; not to exceed 12 g/d Reduce dose by 50% in renal or hepatic impairment

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Cephalexin (Keflex)

First-generation cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. Bactericidal activity against rapidly growing organisms. Primary activity against skin flora.


Adult

Dosing Interactions Contraindications Precautions

250-500 mg PO q6h; not to exceed 4 g/d


Pediatric

25-100 mg/kg/d PO divided q6h; not to exceed 4 g/d

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Cefuroxime (Ceftin oral, Kefurox injection)

Broad-spectrum cephalosporin most closely resembling the second-generation cephalosporins. Cefuroxime is stable against beta-lactamaseproducing organisms.


Adult

Dosing Interactions Contraindications Precautions

250-500 mg PO bid; alternatively, 1 g IV q8h


Pediatric

Serious infections: 150 mg/kg/d IV divided q8h Impetigo: 250-mg tab PO q12h 30 mg/kg/d PO susp divided bid; not to exceed 1 g/d

Dosing Interactions Contraindications Precautions

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Cefazolin

First-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. Primarily active against skin flora, including S aureus. Typically used alone for skin and skin structure coverage.


Adult

Dosing Interactions Contraindications Precautions

0.5-2 g IV q6-8h; not to exceed 12 g/d


Pediatric

50-100 mg/kg/d IV divided q8h; not to exceed 6 g/d

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Amoxicillin and clavulanate (Augmentin)

Drug combination treats bacteria resistant to beta-lactam antibiotics. For children >3 mo, base dosage regimen on amoxicillin content. Because of different amoxicillin/clavulanic acid ratios in 250-mg tab (ie, 250/125) versus 250-mg chewable tab (ie, 250/62.5), do not use 250-mg tab until child is >40 kg.


Adult

Dosing Interactions Contraindications Precautions

250-500 mg PO q8h; not to exceed 2 g/d

Pediatric

<3 months: 30 mg (based on amoxicillin component) per kg/d PO divided q12h Use 125 mg/5 mL PO susp >3 months and <40 kilograms: 45 mg (based on amoxicillin component) per kg/d PO divided bid/tid >40 kilograms: Administer as in adults

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Vancomycin (Lyphocin, Vancocin, Vancoled)

Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated in patients who are unable to receive or who have not responded to penicillins and cephalosporins or for infections with resistant staphylococci. Use CrCl to adjust dose in patients diagnosed with renal impairment.


Adult

Dosing Interactions Contraindications Precautions

0.5 g IV q6h or 1 g IV q24h


Pediatric

Neonates: <7 days and >2000 grams: 30 mg/kg/d IV divided q12h >7 days and >2000 grams: 45 mg/kg/d IV divided q8h <1 month and <1200 grams: 15 mg/kg/d IV q24h <1 month and 1200-2000 grams: 20-30 mg/kg/d IV divided q12-18h Infants >1 month and children: 40 mg/kg/d IV divided q8h Seriously ill cancer patients and patients with suspected CNS infection: 60 mg/kg/d IV divided q6h The necessity of monitoring drug levels is debated; to achieve an adequate therapeutic level in severe infections, the upper range of the peak (40 mcg/mL) should be reached

Dosing Interactions Contraindications Precautions Dosing Interactions

Contraindications Precautions Dosing Interactions Contraindications Precautions

Clindamycin (Cleocin)

Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, arresting RNA-dependent protein synthesis.


Adult

Dosing Interactions Contraindications Precautions

150-450 mg PO q6h 1.2-1.8 g/d IV divided bid/qid; may increase dose, not to exceed 4.8 g/d
Pediatric

10-30 mg/kg/d PO divided q6-8h 25-40 mg/kg/d IV divided q6-8h; not to exceed 4.8 g/d

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Daptomycin (Cubicin)

First of new antibiotic class termed cyclic lipopeptides. Binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis, and, ultimately, causing cell death. Indicated to treat complicated skin and skin structure infections caused by S aureus (including methicillin-resistant strains), S pyogenes, S agalactiae, S dysgalactiae, and E faecalis (vancomycin-susceptible strains only). Indicated for skin and skin structure infections.

Dosing Interactions Contraindications Precautions

Adult

CrCl >30 mL/min: 4 mg/kg IV q24h infused over 30 min CrCl <30 mL/min: 4 mg/kg IV q48h (including hemodialysis or CAPD)
Pediatric

<18 years: Not established >18 years: Administer as in adults

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Linezolid (Zyvox)

Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against staphylococci.


Adult

Dosing Interactions Contraindications Precautions

400-600 mg PO/IV q12h


Pediatric

Preterm neonate <7 days: 10 mg/kg PO/IV q12h Term neonates-12 years: 10 mg/kg PO/IV q8h >12 years: Administer as in adults

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Rifampin (Rifadin injection/oral, Rimactane oral)

Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.


Adult

Dosing Interactions Contraindications Precautions

S aureus: 600 mg/d PO/IV with other antibiotics


Pediatric

S aureus: 15 mg/kg/d PO/IV divided q12h with other antibiotics

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Sulfamethoxazole and trimethoprim (Bactrim, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.


Adult

Dosing Interactions Contraindications Precautions

160/800 mg PO q12h
Pediatric

<2 years: Do not administer >2 years: 6-12 mg of trimethoprim/kg/d in 2 doses

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing

Interactions Contraindications Precautions

Mupirocin (Bactroban)

For elimination of S aureus. Inhibits bacterial growth by inhibiting RNA and protein synthesis.


Adult

Dosing Interactions Contraindications Precautions

Apply small amount topically to affected area 2-5 times per d for 5-14 d Apply intranasal ointment 2-4 times per d and topical cream or ointment 3-5 times per d
Pediatric

Apply as in adults

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Retapamulin (Altabax)

Topical antibiotic available as a 1% ointment. First of new antibiotic class called pleuromutilins. Inhibits protein synthesis by binding to 50S subunit on ribosome. Indicated for impetigo caused by Staphylococcus aureus or Streptococcus pyogenes.


Adult

Dosing Interactions Contraindications Precautions

Apply topically to affected site bid for 5 d


Pediatric

<9 months: Not established >9 months: Apply as in adults

Dosing Interactions Contraindications

Blood products
These agents stimulate an immune response and offer transient protection while the host immune system develops antibodies.

Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Immune globulin, intravenous (Carimune, Gamunex, Polygam S/D)

Actions include neutralizing circulating myelin antibodies through anti-idiotypic antibodies, downregulating proinflammatory cytokines (including interferon gamma), blocking Fc receptors on macrophages, suppressing inducer T and B cells, and augmenting suppressor T cells. Also blocks the complement cascade and promotes remyelination. May increase CSF IgG (10%). IVIG has been shown to have high concentration of TSST-1 and the staphylococcal enterotoxins implicated in the pathogenesis of TSS. These antibodies may interfere with the binding of toxins that cause TSS.


Adult

Dosing Interactions Contraindications Precautions

400 mg/kg IV as single dose infused over several hours


Pediatric

Administer as in adults

Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions Dosing Interactions Contraindications Precautions

Follow-up
Further Outpatient Care

Appropriately monitor renal function, CBC count, and serum hepatic transaminase levels while patients with Staphylococcus aureus infection are undergoing therapy.

Complications

S aureus infection may result in pneumonia, bone and joint infection, and infection of the heart valves. In immunocompromised hosts (eg, patients with cancer who are neutropenic and have a central venous line), 20-30% develop serious complications or fatal sepsis following catheter-related S aureus bacteremia. Community-associated methicillin-resistant S aureus (CA-MRSA) infection is more serious and is associated with thrombogenesis.

Patient Education

For excellent patient education resources, visit eMedicine's Women's Health Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Toxic Shock Syndrome and Boils.

Miscellaneous
Medicolegal Pitfalls

Scalded skin syndrome (Ritter disease) is often mistaken for erythema multiforme or toxic epidermal necrolysis, which may be treated with steroids. Misdiagnosis delays treatment and allows exfoliation to progress, and steroid therapy may potentiate bacterial superinfection. Most fatalities are associated with delay in diagnosis. Another potential medical pitfall is failure to realize that, in an infant, septic arthritis of the hip and shoulder is a surgical emergency. These joints should be drained as soon as possible to prevent bony destruction. In addition, if a large amount of fibrin, tissue debris, or loculation is present, which prevents adequate drainage with needle aspiration, the joint should be surgically drained