The development of staphylococcal disease is related to resistance of the host to infection and to virulence of the organism (Fig. 174-1). The intact skin and mucous membranes serve as barriers to invasion by staphylococci. Defects in the mucocutaneous barriers produced by trauma, surgery, foreign surfaces (sutures, shunts, intravascular catheters), and burns increase the risk for infection.

Figure 174-1 Relationship of virulence factors and diseases associated with Staphylococcus aureus. TSST-1, toxic shock syndrome toxin-1.

Infants may acquire type-specific humoral immunity to staphylococci transplacentally. Older children and adults develop antibodies to staphylococci as a result of colonization or minor infections. Antibody to the various S. aureus toxins appears to protect against those specific toxin-mediated diseases, but humoral immunity does not necessarily protect against focal or disseminated S. aureus infection with the same organisms.

Congenital defects in chemotaxis (Job syndrome, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome) and defective phagocytosis and killing (neutropenia, chronic granulomatous disease) increase the risk for staphylococcal infections. Patients with HIV infection have neutrophils that are defective in their ability to kill S. aureus in vitro. Patients with recurrent staphylococcal infection should be evaluated for immune defects, especially those involving neutrophil dysfunction.

Clinical Manifestations

The signs and symptoms vary with the location of the infection, which is most commonly the skin but may be any tissue. Disease states of various degrees of severity are generally a result of local suppuration, systemic dissemination with metastatic infection, or systemic effects of toxin production. Although the nasopharynx and skin of many persons may be colonized with S. aureus, disease due to this organism is relatively uncommon. Skin infections due to S. aureus are considerably more prevalent among persons living in low socioeconomic circumstances and particularly among those in tropical climates.

Newborn

S. aureus is an important cause of neonatal infections (Chapter 103).

Skin

S. aureus is an important cause of pyogenic skin infections, including impetigo contagiosa, ecthyma, bullous impetigo, folliculitis, hydradenitis, furuncles, carbuncles, staphylococcal scalded skin syndrome, and staphylococcal scarlet fever. Infection may also complicate wounds or occur as superinfection of other noninfectious skin disease (eczema). Recurrent furunculosis is associated with repeated episodes of pyoderma over months to years. Recurrent skin and soft tissue infections are commonly noted with community-associated methicillin-resistant S. aureus (MRSA) and often affect the lower extremities and buttocks. S. aureus is also an important cause of wound infections and can cause deep soft tissue involvement, including cellulitis and rarely necrotizing fasciitis.

Respiratory Tract

Infections of the upper respiratory tract due to S. aureus are rare, in particular considering the frequency with which the anterior nares are colonized. In normal hosts, otitis media (Chapter 632) and sinusitis (Chapter 372) are rarely caused by S. aureus. S. aureus sinusitis is relatively common in children with cystic fibrosis or defects in leukocyte function and may be the only focus of infection in some children with toxic shock syndrome. Suppurative parotitis is a rare infection, but S. aureus is a common cause. A membranous tracheitis that complicates viral croup may be due to infection with S. aureus, but other organisms are also possible. Patients typically have high fever, leukocytosis, and evidence of severe upper airway obstruction. Direct laryngoscopy or bronchoscopy shows a normal epiglottis with subglottic narrowing and thick, purulent secretions within the trachea. Treatment requires careful airway management and appropriate antibiotic therapy.

Pneumonia (Chapter 392) due to S. aureus may be primary (hematogenous) or secondary after a viral infection such as influenza. Hematogenous pneumonia may be secondary to septic emboli from right-sided endocarditis or septic thrombophlebitis, with or without the presence of intravascular devices. Inhalation pneumonia is caused by alteration of mucociliary clearance (see cystic fibrosis, Chapter 395), leukocyte dysfunction, or bacterial adherence initiated by a viral infection. Common symptoms and signs include high fever, abdominal pain, tachypnea, dyspnea, and localized or diffuse bronchopneumonia or lobar disease. S. aureus often causes a necrotizing pneumonitis that may be associated with development of empyema, pneumatoceles, pyopneumothorax, and bronchopleural fistulas.

Sepsis

S. aureus bacteremia and sepsis may be primary or associated with any localized infection. The onset may be acute and marked by nausea, vomiting, myalgia, fever, and chills. Organisms may localize subsequently at any site (usually a single deep focus) but are found especially in the heart valves, lungs, joints, bones, and abscesses.

In some instances, especially in young adolescent males, disseminated S. aureus disease occurs, characterized by fever, persistent bacteremia despite antibiotics, and focal involvement of 2 or more separate tissue sites (skin, bone, joint, kidney, lung, liver, heart).

In these cases, endocarditis and septic thrombophlebitis must be ruled out.

Muscle

Localized staphylococcal abscesses in muscle associated with elevation of muscle enzymes sometimes without septicemia have been called pyomyositis. This disorder has been reported most frequently from tropical areas but also occurs in the USA in otherwise healthy children. Multiple abscesses occur in 30-40% of cases. History may include prior trauma at the site of the abscess. Surgical drainage and appropriate antibiotic therapy are essential.

Bones and Joints

S. aureus is the most common cause of osteomyelitis and suppurative arthritis in children (Chapters 676 and 677).

Central Nervous System

Meningitis (Chapter 595.1) caused by S. aureus is not common; it is associated with penetrating cranial trauma and neurosurgical procedures (craniotomy, cerebrospinal fluid [CSF] shunt placement) and less frequently with endocarditis, parameningeal foci (epidural or brain abscess), diabetes mellitus, or malignancy. The CSF profile of S. aureus meningitis is indistinguishable from that in other forms of bacterial meningitis.

Heart

S. aureus is a common cause of acute endocarditis (Chapter 431) on native valves. Perforation of heart valves, myocardial abscesses, heart failure, conduction disturbances, acute hemopericardium, purulent pericarditis, and sudden death may ensue.

Kidney

S. aureus is a common cause of renal and perinephric abscess (Chapter 532), usually of hematogenous origin. Pyelonephritis and cystitis due to S. aureus are unusual.

Toxic Shock Syndrome (TSS)

S. aureus is the principal cause of TSS (Chapter 174.2), which should be suspected in anyone with fever, shock, and/or a scarlet fever-like rash.

Intestinal Tract

Staphylococcal enterocolitis rarely follows overgrowth of normal bowel flora by S. aureus, which can occur as a result of broad-spectrum oral antibiotic therapy. Diarrhea is associated with blood and mucus. Peritonitis associated with S. aureus in patients receiving long-term ambulatory peritoneal dialysis usually involves the catheter tunnel. Removal of the catheter is required to achieve a bacteriologic cure.

Food poisoning (Chapter 332) may be caused by ingestion of preformed enterotoxins produced by staphylococci in contaminated foods. Approximately 2-7 hr after ingestion of the toxin, sudden, severe vomiting begins. Watery diarrhea may develop, but fever is absent or low. Symptoms rarely persist longer than 12-24 hr. Rarely, shock and death may occur.

Diagnosis

The diagnosis of S. aureus infection depends on isolation of the organism from nonpermissive sites such as cellulitis aspirates, abscess cavities, blood, bone or joint aspirates, or other sites of infection. Swab cultures of surfaces are not as useful, as they may reflect surface contamination rather than the true cause of infection. Tissue samples or fluid aspirates in a syringe provide the best culture material. Isolation from the nose or skin does not necessarily imply causation because these sites may be normally colonized sites. Because of the high prevalence of MRSA, the increasing severity of S. aureus infections, and the fact that bacteremia is not universally present even in severe S. aureus infections, it is usually important to obtain a nonpermissive culture of any potential focus of infection as well as a blood culture prior to starting antibiotic treatment. The organism can be grown readily in liquid and on solid media. After isolation, identification is made on the basis of Gram stain and coagulase, clumping factor, and protein A reactivity. Patterns of susceptibility to antibiotics should be assessed in serious cases, as antimicrobial resistance is increasingly common.

Diagnosis of S. aureus food poisoning is made on the basis of epidemiologic and clinical findings. Food suspected of contamination should be cultured and can be tested for enterotoxin.

Differential Diagnosis

Skin lesions due to S. aureus may be indistinguishable from those due to group A streptococci; the former usually expand slowly, while the latter are more prone to spread rapidly. S. aureus pneumonia can be suspected on the basis of chest roentgenograms that reveal pneumatoceles, pyopneumothorax, or lung abscess (Fig. 174-2). Fluctuant skin and soft tissue lesions also can be caused by other organisms, including Mycobacterium tuberculosis, atypical mycobacteria, Bartonella henselae (cat-scratch disease), Francisella tularensis, and various fungi, among others.

Figure 174-2 Pneumatocele formation. A, A 5 yr old child with Staphylococcus aureus pneumonia initially demonstrated consolidation of the right middle and lower zones. B, Seven days later, multiple lucent areas are noted as pneumatoceles develop. C, Two wk later, significant resolution is evident, with a rather thick-walled pneumatocele persisting in the right midzone associated with significant residual pleural thickening.

(From Kuhn JP, Slovis TL, Haller JO: Caffey’s pediatric diagnostic imaging, vol 1, ed 10, Philadelphia, 2004, Mosby, pp 1003–1004.)

Treatment

Antibiotic therapy alone is rarely effective in individuals with undrained abscesses or with infected foreign bodies. Loculated collections of purulent material should be relieved by incision and drainage. Foreign bodies should be removed, if possible. Therapy always should be initiated with an antibiotic consistent with the local staphylococcal susceptibility patterns as well as the severity of infection. Penicillin and amoxicillin are not appropriate, because more than 90% of all staphylococci isolated, regardless of source, are resistant to these agents. For serious infections, parenteral treatment is indicated, at least at the outset, until symptoms are controlled. Serious S. aureus infections, with or without abscesses, tend to persist and recur, necessitating prolonged therapy.

The antibiotic used as well as the dose, route, and duration of treatment depend on the site of infection, the response of the patient to treatment, and the susceptibility of the organisms recovered from blood or from local sites of infection. For most patients with serious S. aureus infection, intravenous treatment is recommended until the patient has become afebrile and other signs of infection have improved. Oral therapy is often continued for a period of time, especially in patients with chronic infection or underlying host defense problems. Treatment of S. aureus osteomyelitis (Chapter 676), meningitis (Chapter 595.1), and endocarditis (Chapter 431) are discussed in their respective chapters.

Initial treatment for serious infections thought to be due to methicillin-susceptible S. aureus (MSSA) should include semisynthetic penicillin (e.g., nafcillin, oxacillin) or less often a 1st generation cephalosporin (e.g., cefazolin). MRSA is both an important hospital and community-acquired pathogen. Community-associated MRSA infections are common throughout the USA, even in children without pre-existing risk factors. Resistance to semisynthetic penicillins and cephalosporins is related to a novel penicillin-binding protein (PB2A) that is relatively insensitive to antibiotics containing a β-lactam ring. MRSA strains appear to be at least as virulent as their methicillin-sensitive counterparts. Vancomycin (40-60 mg/kg/24 hr divided every 6 hr IV) can be used as the initial treatment for penicillin-allergic individuals and those with suspected serious S. aureus infections that might be due to MRSA. Serum levels of vancomycin should be monitored, with trough concentrations of 10-20 µg/mL, depending on the case. MRSA is also resistant to cephalosporins and carbapenems and is unreliably susceptible to the quinolones. Linezolid, daptomycin, quinupristin-dalfopristin, vancomycin with linezolid and gentamicin, and vancomycin with trimethoprim-sulfamethoxazole may be useful for serious S. aureus infections highly resistant to other antibiotics (Table 174-1).

Table 174-1 PARENTERAL ANTIMICROBIAL AGENT(S) FOR TREATMENT OF BACTEREMIA AND OTHER SERIOUS STAPHYLOCOCCUS AUREUS INFECTIONS

SUSCEPTIBILITY	ANTIMICROBIAL AGENTS	COMMENTS
I. INITIAL EMPIRIC THERAPY (ORGANISM OF UNKNOWN SUSCEPTIBILITY)
Drugs of choice:	Vancomycin ± gentamicin or rifampin	For life-threatening infections (i.e., septicemia, endocarditis, CNS infection); linezolid could be substituted if the patient has received several recent courses of vancomycin
	Nafcillin or oxacillin*	For non–life-threatening infection without signs of sepsis (e.g., skin infection, cellulitis, osteomyelitis, pyarthrosis) when rates of MRSA colonization and infection in the community are low
	Clindamycin	For non–life-threatening infection without signs of sepsis when rates of MRSA colonization and infection in the community are substantial and prevalence of clindamycin resistance is low
	Vancomycin	For non–life-threatening, hospital-acquired infections
II. METHICILLIN-SUSCEPTIBLE, PENICILLIN-RESISTANT S. AUREUS (MSSA)
Drugs of choice:	Nafcillin or oxacillin*^,†
Alternatives (depending on susceptibility results):	Cefazolin*
	Clindamycin
	Vancomycin	Only for penicillin- and cephalosporin-allergic patients
	Ampicillin + sulbactam
III. MRSA
A. Health Care–Associated (Multidrug-Resistant)
Drugs of choice:	Vancomycin ± gentamicin or ± rifampin^†
Alternatives: susceptibility testing results available before alternative drugs are used
	Trimethoprim-sulfamethoxazole
	Linezolid^‡
	Quinupristin-dalfopristin^‡
	Fluoroquinolones	Not recommended for people younger than 18 yr of age or as monotherapy
B. Community (Not Multidrug-Resistant)
Drugs of choice:	Vancomycin^†	For life-threatening infections
	Vancomycin ± gentamicin (or ± rifampin^†)	For pneumonia, septic arthritis, osteomyelitis, skin or soft tissue infections
	Vancomycin ± gentamicin (or ± rifampin^†)	For skin or soft tissue infections
Alternatives:	Clindamycin (if strain susceptible by “D test)
Alternatives:	Trimethoprim-sulfamethoxazole
IV. VANCOMYCIN INTERMEDIATELY SUSCEPTIBLE OR VANCOMYCIN-RESISTANT S. AUREUS^†
Drugs of choice:	Optimal therapy is not known	Dependent on in vitro susceptibility test results
	Linezolid^‡
	Daptomycin^§
	Quinupristin-dalfopristin^‡
Alternatives:	Vancomycin + linezolid ± gentamicin
Alternatives:	Vancomycin + trimethoprim-sulfamethoxazole^†

CNS, central nervous system; MRSA, methicillin-resistant S. aureus.

* Penicillin- and cephalosporin-allergic patients should receive vancomycin as initial therapy for serious infections.

^† One of the adjunctive agents, gentamicin or rifampin, should be added to the therapeutic regimen for life-threatening infections such as endocarditis or CNS infection or infections with a vancomycin-intermediate or vancomycin-resistant S. aureus strain. Consultation with an infectious diseases specialist should be considered to determine which agent to use and duration of use.

^‡ Linezolid and quinupristin-dalfopristin are 2 agents with activity in vitro and efficacy in adults with multidrug-resistant, gram-positive organisms, including S. aureus. Because experience with these agents in children is limited, consultation with an infectious diseases specialist should be considered before use.

^§ Daptomycin is active in vitro against multidrug-resistant, gram-positive organisms, including S. aureus, but has not been used often in children. Daptomycin is approved by the U.S. Food and Drug Administration only for the treatment of complicated skin and skin structure infections in patients 18 yr of age and older.

From the American Academy of Pediatrics: Red book: 2009 report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, pp 610–611.

Rare vancomycin intermediate and vancomycin-resistant strains have also been reported, mostly in patients being treated with vancomycin, emphasizing the need for restricting the prescription of unnecessary antibiotics and the importance of isolation of the causative organism and susceptibility testing in serious infections.

Serious S. aureus infections (septicemia, endocarditis, central nervous system infections, TSS) should be treated initially with intravenous vancomycin or methicillin, nafcillin, or oxacillin depending on the local staphylococcal resistance pattern until the causative organism is isolated and its susceptibility determined. Rifampin or gentamicin may be added for synergy in serious infections (endocarditis).

In many of these infections, oral antimicrobials may be substituted to complete the course of treatment after an initial period of parenteral therapy and determination of antimicrobial susceptibilities. Despite in vitro susceptibility of S. aureus to ciprofloxacin and other quinolone antibiotics, these agents should not be used in serious staphylococcal infections, because their use has been associated with rapid development of resistance. Trimethoprim-sulfamethoxazole may be an effective oral antibiotic for many strains of both methicillin-susceptible S. aureus (MSSA) and MRSA.

Dicloxacillin (50-100 mg/kg/24 hr divided 4 times per day PO) and cephalexin (25-100 mg/kg/24 hr divided 3 to 4 times per day PO) are absorbed well orally and are effective for MSSA. Amoxicillin-clavulanate (40-80 mg amoxicillin/kg/24 hr divided 3 times per day PO) is also effective. Clindamycin (30-40 mg/kg/24 hr divided 3 to 4 times per day PO) has proved effective for the treatment of skin, soft tissue, bone, and joint infections due to susceptible S. aureus strains confirmed by a clinical microbiology laboratory using the “D-test.” Clindamycin is bacteriostatic and should not be used to treat endocarditis, brain abscess, or meningitis due to S. aureus. Given that the mechanism of action of clindamycin involves inhibition or protein synthesis, many experts use clindamycin to treat S. aureus toxin–mediated illnesses (TSS) to inhibit toxin production. The duration of oral therapy depends on the response as determined by the clinical response and roentgenographic and laboratory findings.

Skin and soft tissue infection and respiratory tract infection may often be managed by oral therapy or by an initial brief course of parenteral antibiotics followed by oral medication. Ceftaroline (IV) is approved for MRSA skin infections in adults.

Prognosis

Untreated S. aureus septicemia is associated with a high fatality rate, which have been reduced significantly by appropriate antibiotic treatment. S. aureus pneumonia can be fatal at any age but is more likely to be associated with high morbidity and mortality in young infants or in patients whose therapy has been delayed. Prognosis also may be influenced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. In most cases with abscess formation, surgical drainage is necessary.

Prevention

S. aureus infection is transmitted primarily by direct contact. Strict attention to handwashing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another (Chapter 166). Use of a hand wash containing chlorhexidine or alcohol is recommended. In hospitals or other institutional settings, all persons with acute S. aureus infections should be isolated until they have been treated adequately. There should be constant surveillance for nosocomial S. aureus infections within hospitals. When MRSA is recovered, strict isolation of affected patients has been shown to be the most effective method for preventing nosocomial spread of infection. Thereafter, control measures should be directed toward identification of new isolates and strict isolation of newly colonized or infected patients. Clusters of cases may be defined by molecular typing. If associated with a singular molecular strain, it may also be necessary to identify colonized hospital personnel and eradicate carriage in affected individuals.

Patients with recurrent S. aureus skin infection may be treated with hypochlorite baths (1 teaspoon common bleach solution per gallon of water), an appropriate oral antibiotic, and nasal mupirocin in an attempt to prevent recurrences.

Food poisoning (Chapter 332) may be prevented by excluding individuals with S. aureus infections of the skin from the preparation and handling of food. Prepared foods should be eaten immediately or refrigerated appropriately to prevent multiplication of S. aureus with which the food may have been contaminated.

Bibliography

Appelbaum PC. Microbiology of antibiotic resistance in Staphylococcus aureus. Clin Infect Dis. 2007;45:S165-S170.

Baranwal AK, Singhi SC, Jayashree M. A 5-year PICU experience of disseminated staphylococcal disease, part 2: management, critical care needs and outcome. J Trop Pediatr. 2007;53:252-258.

Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus skin infections from and elephant calf—San Diego, California, 2008. MMWR Morb Mortal Wkly Rep. 2009;58:194-198.

Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus among players on a high school football team—New York City, 2007. MMWR Morb Mortal Wkly Rep. 2009;58:52-55.

Climo MW, Sepkowitz KA, Zuccotti G, et al. The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial. Crit Care Med. 2009;37:1858-1865.

Creech CB, Beekmann SE, Chen Y, et al. Variability among pediatric infectious diseases specialists in the treatment and prevention of methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J. 2008;27:270-272.

Day MD, Gauvreau K, Shulman S, et al. Characteristics of children hospitalized with infective endocarditis. Circulation. 2009;119:865-870.

DeLeo FR, Otto M, Kreiswirth B, et al. Community-associated methicillin-resistant Staphylococcus aureus. Lancet. 2010;375:1557-1566.

Duong M, Markwell S, Peter J, et al. Randomized, controlled trial of antibiotics on the management of community-acquired skin abscesses in the pediatric patient. Ann Emerg Med. 2010;55:401-407.

Fisher RG, Chain RL, Hair PS, et al. Hypochlorite killing of community-associated methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2008;27:934-935.

Fontanilla JM, Kirkland KB, Talbot EA, et al. Outbreak of skin infections in college football team members due to an unusual strain of community-acquired methicillin-susceptible Staphylococcus aureus. J Clin Microbiol. 2010;48:609-611.

Fortunov RM, Hulten KG, Hammerman WA, et al. Community-acquired Staphylococcus aureus infections in term and near-term previously healthy neonates. Pediatrics. 2006;118:874-881.

Frederiksen MS, Espersen F, Frimodt-Moller N, et al. Changing epidemiology of pediatric Staphylococcus aureus bacteremia in Denmark from 1971 through 2000. Pediatr Infect Dis J. 2007;26:398-405.

Frymoyer A, Hersh AL, Benet LZ, et al. Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009;28:398-402.

Gerber JS, Coffin SE, Smathers SA, et al. Trends in the incidence of methicillin-resistant Staphylococcus aureus infection in children’s hospitals in the United States. Clin Infect Dis. 2009;49:65-71.

Gonzalez BE, Teruya J, Mahoney DHJr, et al. Venous thrombosis associated with staphylococcal osteomyelitis in children. Pediatrics. 2006;117:1673-1679.

Hanses F, Spaeth C, Ehrenstein BP, et al. Risk factors associated with long-term prognosis of patients with Staphylococcus aureus bacteremia. Infection. 2010;38:465-470.

Haque NZ, Zuniga LC, Peyrani P, et al. Relationship of vancomycin minimum inhibitory concentrations to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest. 2010;138(6):1356-1362.

Hulten KG, Kaplan SL, Gonzalez BE, et al. Three-year surveillance of community onset health care-associated Staphylococcus aureus infections in children. Pediatr Infect Dis J. 2006;25:349-353.

Hyun DY, Mason EO, Forbes A, et al. Trimethoprim-sulfamethozazole or clindamycin for treatment of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J. 2009;28:57-58.

Jacqueline C, Amador G, Caillon J, et al. Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis. J Antimicrob Chemother. 2010;65:1749-1752.

Jang HC, Kim SH, Kim KH, et al. Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem. Clin Infect Dis. 2009;49:395-401.

Jung YJ, Koh Y, Hong SB, et al. Effect of vancomycin plus rifampicin in the treatment of nosocomial methicillin-resistant Staphylococcus aureus pneumonia. Crit Care Med. 2010;38:175-180.

Liu C. The bundled approach to MRSA surgical site infection prevention. Arch Intern Med. 2011;171(1):73-74.

Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guideline by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285-292.

Lo WT, Lin WJ, Tseng MH, et al. Risk factors and molecular analysis of panton-valentine leukocidin-positive methicillin-resistant Staphylococcus aureus colonization in healthy children. Pediatr Infect Dis J. 2008;27:713-718.

The Medical Letter. Ceftaroline fosamil (Teflaro)—a new IV cephalosporin. Med Lett Drugs Ther. 2011;53(1356):5-6.

Morales G, Picazo JJ, Baos E, et al. Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus aureus. Clin Infect Dis. 2010;50:821-825.

Naseri I, Jerris RC, Sobol SE. Nationwide trends in pediatric Staphylococcus aureus head and neck infections. Arch Otolaryngol Head Neck Surg. 2009;135:14-16.

Pannaraj PS, Hulten KG, Gonzalez BE, et al. Infective pyomyositis and myositis in children in the era of community-acquired, methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis. 2006;43:953-960.

Reed C, Kallen AJ, Patton M, et al. Infection with community-onset Staphylococcus aureus and influenza virus in hospitalized children. Pediatr Infect Dis J. 2009;28:572-576.

Ross AC, Toltzis P, O’Riordan MA, et al. Frequency and risk factors for deep focus of infection in children with Staphylococcus aureus bacteremia. Pediatr Infect Dis J. 2008;27:396-399.

Tebruegge M, Pantazidou A, Thorburn K, et al. Bacterial tracheitis: a multi-centre perspective. Scand J Infect Dis. 2009:1-10.

Valente AM, Jain R, Scheurer M, et al. Frequency of infective endocarditis among infants and children with Staphylococcus aureus bacteremia. Pediatrics. 2005;115:e15-19.

Varshney AK, Martinez LR, Hamilton SM, et al. Augmented production of Panton-Valentine leukocidin toxin in methicillin-resistant and methicillin-susceptible Staphylococcus aureus is associated with worse outcome in a murine skin infection model. J Infect Dis. 2010;201:92-96.

Wolkewitz M, Frank U, Philips G, et al. Mortality associated with in-hospital bacteremia caused by Staphylococcus aureus: a multistate analysis with follow-up beyond hospital discharge. J Antimicrob Chemother. 2011;66:381-386.

Yoshinaga M, Niwa K, Niwa A, et al. Risk factors for in-hospital mortality during infective endocarditis in patients with congenital heart disease. Am J Cardiol. 2008;101:114-118.

174.2 Toxic Shock Syndrome

James K. Todd

TSS is an acute multisystem disease characterized by fever, hypotension, an erythematous rash with subsequent desquamation on the hands and feet, and multisystem involvement including vomiting, diarrhea, myalgias, nonfocal neurologic abnormalities, conjunctival hyperemia, and strawberry tongue.

Etiology

TSS is caused by TSST-1–producing and some enterotoxin-producing strains of S. aureus, which may colonize the vagina or cause focal sites of staphylococcal infection.

Epidemiology

Many cases occur in menstruating women 15-25 yr of age and who use tampons or other vaginal devices (diaphragm, contraceptive sponge). TSS also occurs in children, nonmenstruating women, and men usually associated with an identifiable focus of S. aureus infection. Nonmenstrual TSS has occurred with S. aureus infection of nasal packing or infections including wound infections, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary bacteremia. Without antimicrobial therapy, menstrual TSS has a 30% recurrence rate if tampons are used, with secondary cases being milder and occurring within 5 mo of the original episode. The overall mortality rate of treated patients is 3-5%. Most strains of S. aureus associated with TSS have been susceptible to the semi-synthetic β-lactam antibiotics, including 1st generation cephalosporins, but some methicillin/cephalosporin–resistant cases have been reported.

Pathogenesis

The primary toxin associated with TSS is TSST-1, which acts as a superantigen causing massive loss of fluid from the intravascular space. TSST-1–negative S. aureus strains have been isolated from patients with TSS, suggesting that other toxins (primarily the enterotoxins) have a role in TSS (especially nonmenstrual). Epidemiologic and in vitro studies suggest that these toxins are selectively produced in a clinical environment consisting of a neutral pH, a high PCO₂, and an “aerobic” PO₂, which are the conditions found in the vagina with tampon use during menstruation. Approximately 90% of adults have antibody to TSST-1 without a history of clinical TSS, suggesting that most individuals are colonized at some point with a toxin-producing organism at a site (anterior nares) where low-grade or inactive toxin exposure results in an immune response without disease. The risk factors for symptomatic disease include a nonimmune host colonized with a toxin-producing organism, which is exposed to focal growth conditions (menstruation plus tampon use or abscess) that induce toxin production. It appears that some hosts may have a varied cytokine response to exposure to TSST-1, helping to explain a spectrum of severity of TSS that may include staphylococcal scarlet fever.

Clinical Manifestations

The diagnosis of TSS is based on clinical manifestations (Table 174-2). The onset is abrupt, with high fever, vomiting, and diarrhea, and is accompanied by sore throat, headache, and myalgias. A diffuse erythematous macular rash (sunburn-like or scarlatiniform) appears within 24 hr and may be associated with hyperemia of pharyngeal, conjunctival, and vaginal mucous membranes. A strawberry tongue is common. Symptoms often include alterations in the level of consciousness, oliguria, and hypotension, which in severe cases may progress to shock and disseminated intravascular coagulation. Complications, including acute respiratory distress syndrome, myocardial dysfunction, and renal failure, are commensurate with the degree of shock. Recovery occurs within 7-10 days and is associated with desquamation, particularly of palms and soles; hair and nail loss have also been observed after 1-2 mo. Many cases of apparent scarlet fever without shock may be caused by TSST-1-producing S. aureus strains.

Table 174-2 DIAGNOSTIC CRITERIA OF STAPHYLOCOCCAL TOXIC SHOCK SYNDROME

MAJOR CRITERIA (ALL REQUIRED)

Acute fever; temperature >38.8°C

Hypotension (orthostatic, shock; below age-appropriate norms)

Rash (erythroderma with convalescent desquamation)

MINOR CRITERIA (ANY 3 OR MORE)

Mucous membrane inflammation (vaginal, oropharyngeal or conjuctival hyperemia, strawberry tongue)

Vomiting, diarrhea

Liver abnormalities (bilirubin or transaminase greater than twice upper limit of normal)

Renal abnormalities (urea nitrogen or creatinine greater than twice upper limit of normal, or greater than 5 white blood cells per high power field)

Muscle abnormalities (myalgia or creatinine phosphokinase greater than twice upper limit of normal)

Central nervous system abnormalities (alteration in consciousness without focal neurological signs)

Thrombocytopenia (100,000/mm³ or less)

EXCLUSIONARY CRITERIA

Absence of another explanation

Negative blood cultures (except occasionally for Staphylococcus aureus)

From the American Academy of Pediatrics Red book: 2009 report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 602.

Diagnosis

There is no specific laboratory test; appropriate selective tests reveal involvement of multiple organ systems, including the hepatic, renal, muscular, gastrointestinal, cardiopulmonary, and central nervous systems. Bacterial cultures of the associated focus (vagina, abscess) before administration of antibiotics usually yield S. aureus, although this is not a required element of the definition.

Differential Diagnosis

Group A streptococcus can cause a similar TSS-like illness, termed streptococcal TSS (Chapter 176), which is often associated with severe streptococcal sepsis or a focal streptococcal infection such as cellulitis, necrotizing fasciitis, or pneumonia.

Kawasaki disease closely resembles TSS clinically but is usually not as severe or rapidly progressive. Both conditions are associated with fever unresponsive to antibiotics, hyperemia of mucous membranes, and an erythematous rash with subsequent desquamation. However, many of the clinical features of TSS are usually absent or rare in Kawasaki disease, including diffuse myalgia, vomiting, abdominal pain, diarrhea, azotemia, hypotension, acute respiratory distress syndrome, and shock (Chapter 160). Kawasaki disease typically occurs in children younger than 5 yr. Scarlet fever, Rocky Mountain spotted fever, leptospirosis, toxic epidermal necrolysis, sepsis, and measles must also be considered in the differential diagnosis.