AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Toxic shock syndrome (TSS) is a multisystem disease manifested by sudden onset of fever, chills, hypotension, and rash. Multisystem involvement may cause vomiting, diarrhea, myalgia, mucous membrane hyperemia, mental confusion, renal dysfunction, hepatic abnormalities, and thrombocytopenia. TSS is caused by toxin-producing strains of staphylococci (staphylococcal TSS) and streptococci (streptococcal TSS). Both causes are discussed in this article. Todd et al first described staphylococcal TSS in 1978.¹ The association of TSS with menstruation and tampon use was established in 1980. Cases of TSS caused by streptococci were first reported in the mid 1980s.

Pathophysiology

Staphylococcal TSS is caused by certain toxin-producing strains. TSS toxin-1 (TSST-1) is implicated in 75% of patients with TSS, enterotoxin B is implicated in 23% of patients with TSS, and enterotoxin C is implicated in 2% of patients with TSS. Evidence implicating Staphylococcus aureus in TSS is as follows:

• More than 90% of females with menses-associated TSS have vaginal colonization by S aureus, compared with a 10% carriage rate in healthy control subjects.
• Toxin-producing staphylococci can be recovered in the vast majority of patients with nonmenstrual TSS.
• TSS recurs more frequently in the absence of antistaphylococcal therapy.
• TSST-1 produced by most S aureus strains is detected in patients with TSS using titers of TSST-1 antibodies.

TSST-1 and the enterotoxins are superantigens. They result in nonspecific T-lymphocyte stimulation without normal antigenic recognition. This massive activation of lymphocytes leads to release of cytokines that contribute to the development of TSS.

Use of hyperabsorbent tampons creates conditions conducive to the production of staphylococcal TSS. Tampons increase the vaginal partial pressure of oxygen, stimulating toxin synthesis. They supply surfactants that can increase toxin production. Tampons also bind magnesium and shift the growth kinetics of S aureus to increase toxin production.

Streptococci that produce streptococcal pyrogenic exotoxin A (SPEA) (which has a 50% amino acid homology to staphylococcal enterotoxins B and C) and/or streptococcal pyrogenic exotoxin B (SPEB) cause streptococcal TSS. SPEA-producing organisms are more common in the United States, whereas SPEB-producing streptococci are recovered more frequently from patients with streptococcal TSS in Sweden and the United Kingdom. The predominant streptococcal serotype that produces TSS is M-1 (80% of strains in Sweden), although other serotypes, such as M-2, M-3, M-12, and M-28, may also produce TSS.

SPEs trigger a cascade of inflammatory cytokines, such as tumor necrosis factor-a, interleukin (IL)–2, and IL-6, leading to multiorgan injury and shock. Inflammatory cytokines may also be produced by other streptococcal components, such as peptidoglycan and lipoteichoic acid. Recently, streptococcal superantigen (SSA), a novel pyrogenic exotoxin, was isolated from an M-3 strain.

Most patients with streptococcal TSS do not have any underlying disease. Person-to-person spread of streptococcal TSS has been described.

Frequency

United States

Annual incidence of staphylococcal TSS is 1-5 cases per 100,000 menstruating women. An estimated 77-93% of cases occur in women (41% occur in females aged 13-19 y). Incidence of menstrual TSS has decreased since the discontinuation of hyperabsorbent tampon marketing. Similarly, the mortality rate has declined from 5.6% to 3.3%.

Incidence of streptococcal TSS is 5-10 cases per 100,000 population.

Mortality/Morbidity

• The mortality rate in patients with S aureus TSS is approximately 3.3%.
• The mortality rate in patients with streptococcal TSS is approximately 30%.

Sex

• Staphylococcal TSS is more common in females during menstruation. Nonmenstrual TSS is 3 times more common in females than in males.
• Streptococcal TSS affects males and females.

Age

• Staphylococcal TSS is common in people aged 15-35 years. More than 90% of cases in women occur in those aged 15-19 years.
• Streptococcal TSS is seen in all age groups; however, most cases occur in people aged 20-50 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Staphylococcal toxic shock syndrome

Staphylococcal toxic shock syndrome (TSS) is frequently seen in women during menstruation. More recently, with the decline in use of hyperabsorbent tampons, recognition of nonmenstrual TSS has been increasing. Various wounds, many appearing relatively benign, may harbor toxin-producing staphylococci. Thus, herniorrhaphy, mammoplasty, arthroscopy, and other surgical wound infections may be complicated by the development of TSS. Manifestations of TSS usually begin 2 days after surgery.

Onset of staphylococcal TSS is usually abrupt. Symptoms include fever, chills, myalgia, malaise, headache, sore throat, muscle tenderness, fatigue, vomiting, watery diarrhea, and abdominal discomfort. In a review of staphylococcal TSS by Davis and colleagues (1982), clinical findings included the following:²

• Fever - 100%
• Erythroderma - 100%
• Diarrhea - 98%
• Myalgia - 96%
• Vomiting - 92%
• Temperature higher than 40°C - 87%
• Headache - 77%
• Sore throat - 75%
• Conjunctival hyperemia - 57%
• Decreased sensorium - 40%
• Vaginal hyperemia - 33%
• Vaginal discharge - 28%
• Rigors - 25%

Criteria for the diagnosis of staphylococcal TSS include the following:

• Temperature higher than 38.9°C
• Systolic blood pressure lower than 90 mm Hg
• Rash with subsequent desquamation, especially on the palms and soles
• Involvement of 3 or more of the following organ systems:
• • GI tract - Vomiting and profuse diarrhea
  • Muscles - Severe myalgia or a greater than 5-fold increase in creatine kinase levels
  • Mucous membranes (vagina, conjunctivae, pharynx) - Frank hyperemia
  • Renal system - BUN or creatinine levels at least twice the upper reference range limit or pyuria in the absence of urinary tract infection
  • Hepatic system - Bilirubin, serum aspartate aminotransferase (AST), or serum alanine aminotransferase (ALT) levels at least twice the upper reference range limit
  • Blood - Thrombocytopenia (platelet count <100,000/mL)
  • CNS - Disorientation without focal neurologic signs
• Negative results of the serologic tests for Rocky Mountain spotted fever, leptospirosis, and measles when appropriate

Staphylococcal TSS associated with menstruation occurs more frequently in communities without a history of prior antibiotic exposure and is caused primarily by TSST-1–producing organisms. By contrast, nonmenstrual staphylococcal TSS is more common in hospitalized patients who have received prior antibiotic therapy. TSST-1 production is noted in only 50% of the patients. Enterotoxin B and C production is associated with the remainder of nonmenstrual staphylococcal TSS cases.

Streptococcal toxic shock syndrome

Onset is abrupt in patients with streptococcal TSS. An influenzalike syndrome, consisting of fever, chills, myalgia, nausea, vomiting, and diarrhea, may be noted in 20% of patients. Streptococcal TSS is defined by the following criteria:

• A: Isolation of group A streptococci
• 1. From a sterile site, such as blood, cerebrospinal fluid (CSF), pleural fluid, peritoneal fluid, or a tissue biopsy specimen
  2. From a nonsterile body site, such as the throat, vagina, sputum, or superficial skin lesions
• B: Clinical signs of severity
• 1. Hypotension - In adults, systolic blood pressure lower than or equal to 90 mm Hg; in children, systolic blood pressure lower than the fifth percentile for age
  2. Clinical and abnormal laboratory test results (requires 2 or more of the following criteria)
  3. • Renal impairment - Creatinine levels higher than or equal to 177 mol/L (>2 mg/dL) for adults or 2 or more times the upper reference range value for age; in patients with renal disease, a 2-fold or higher elevation over the baseline level
     • Coagulopathy - Platelet count less than 100 X 10⁹/L (<100,000/μL) or disseminated intravascular coagulation
     • Liver abnormalities - AST, ALT, or total bilirubin levels 2 or more times the upper reference range value for age; in patients with liver disease, a 2-fold or higher elevation over the baseline level
     • Acute respiratory distress syndrome (ARDS) - Defined by (1) acute onset of diffuse pulmonary infiltrates and hypoxemia in the absence of cardiac failure, (2) evidence of diffuse capillary leaking manifested by acute onset of generalized edema, or (3) pleural or peritoneal effusions with hypoalbuminemia
     • Soft tissue necrosis, such as necrotizing fasciitis,³ myositis, or gangrene
     • A generalized erythematous macular rash that may desquamate

The diagnosis of streptococcal TSS is definite when criteria A1, B1, and B2 are met.

The diagnosis of streptococcal TSS is probable when criteria A2, B1, and B2 are met.

Physical

• Staphylococcal TSS: Patients with staphylococcal TSS develop rash, hypotension, and hyperemic conjunctival, pharyngeal, and vaginal mucosae. Diffuse erythroderma, cyanosis, and edema of extremities may be noted. Desquamation, especially of the palms and soles, may follow. Alteration in mental status may result in somnolence, agitation, disorientation, and obtundation.
• Streptococcal TSS: In patients with streptococcal TSS, fever is the most common early sign, although hypothermia may be present in patients with shock. Almost 50% of patients may have normal blood pressure (systolic pressure >110 mm Hg) upon admission but develop hypotension within the subsequent 4 hours. In virtually all patients, shock is apparent at the time of admission or within 4-8 hours. A diffuse scarlatina-like erythema occurs in only 10% of patients.
• • Soft tissue infection occurs in 80% of patients and may progress from localized swelling and erythema to necrotizing fasciitis or myositis in 70% of these patients. Pain is abrupt at onset and is usually preceded by tenderness or other localized physical findings.
  • Non–soft tissue infections occur in 20% of patients and may include endophthalmitis, myositis, perihepatitis, peritonitis, and myocarditis. Confusion (55% of patients), coma, or combativeness may be noted.
• Features of Staphylococcal and Streptococcal Toxic Shock Syndrome
  

  Findings	Staphylococcal TSS	Streptococcal TSS
  Age	15-35 y	20-50 y
  Sex	More common in females	Males and females
  Local invasive disease	Absent	Present
  Generalized erythroderma	Present	Absent
  Nausea, vomiting, or diarrhea	>90% of patients	Uncommon
  Bacteremia	Uncommon	60% of patients
  Toxins implicated	TSST-1; enterotoxins B and C	Streptococcal pyrogenic exotoxins A and B
  Mortality rate	3.3%	30%

Causes

Staphylococcal toxic shock syndrome

Staphylococcal TSS is caused by certain toxin-producing strains. TSST-1 is implicated in 75% of patients with staphylococcal TSS, enterotoxin B is implicated in 23% of patients, and enterotoxin C is implicated in 2% of patients with staphylococcal TSS. Staphylococcal TSS has been associated with the following conditions:

• Menstruation
• Nonmenstrual conditions
• • Vaginal - Postpartum or following abortion
  • Surgical wounds, such as hernia repair, mammoplasty, and arthroscopy
  • Respiratory infections
  • Varicella infection⁴
  • Nasal packing

Streptococcal toxic shock syndrome

Streptococcal TSS is caused by one or both of the following toxins:

• Pyrogenic exotoxin A (common in the United States and has a 50% amino acid homology to staphylococcal enterotoxins B and C)
• Pyrogenic exotoxin B (common in Sweden and the United Kingdom)

The predominant streptococcal serotype producing TSS is M-1 (80% of strains in Sweden), although other serotypes, such as M-2, M-3, M-12, and M-28, may also produce TSS. Streptococcal TSS has been associated with the following conditions:

• Skin infections
• Surgical wounds
• Pharyngitis⁵
• Varicella infection
• Influenza virus infection
• Nonsteroidal anti-inflammatory agents: The use of nonsteroidal anti-inflammatory agents has been associated with streptococcal TSS, which is presumably caused by suppressing the early signs of streptococcal infection, thus delaying more specific antibacterial therapy.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Adenovirus infection
Drug eruption
Erythema multiforme
Toxic epidermal necrolysis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

Microbiologic studies should be performed to recover the organisms from appropriate samples, such as blood, surgical wounds, vagina, throat, or soft tissue aspirates.

• In a review of staphylococcal toxic shock syndrome (TSS) by Davis and colleagues, the frequencies of abnormal laboratory results were as follows:²
• • Elevated serum creatinine levels - 69%
  • Thrombocytopenia - 59%
  • Hypocalcemia - 58%
  • Azotemia - 57%
  • Hyperbilirubinemia - 54%
  • Elevated levels of hepatic enzymes - 50%
  • Leukocytosis - 48%
  • Abnormal urinary sediment - 46%
  • Elevated creatine kinase levels - 41%
  • Immature leukocytes - 36%
• Laboratory findings in patients with streptococcal TSS include the following:
• • Elevated serum creatinine levels
  • Hemoglobinuria
  • Hypoalbuminemia
  • Hypocalcemia
  • Elevated creatine kinase levels (suggesting necrotizing fasciitis or myositis)
  • Leukocytosis (with increased band forms)
  • Blood cultures (positive results in 60% of patients)
• Coagulation studies should be obtained, including prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen split products, and D-dimer.
• If CNS infection is possible, the CSF should be analyzed and cultured.
• Appropriate serologic analysis may be necessary to evaluate other possible differential diagnoses.

Imaging Studies

• Soft tissue radiography, CT scanning, or MRI may help delineate the deeper tissue involvement in patients with necrotizing fasciitis and streptococcal TSS.

Procedures

• If meningitis is possible, lumbar puncture should be performed to sample CSF for appropriate studies.

Histologic Findings

Histopathologic findings in patients with staphylococcal TSS include desquamation of vaginal and cervical mucosa, periportal hepatic inflammation, acute tubular necrosis, and the abnormal pulmonary findings of ARDS.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Seriously ill patients may require care in the ICU, including dialysis for renal failure, ventilatory support for ARDS, and correction of coagulopathy using plasma and blood products as necessary. Treatment regimens for toxic shock syndrome (TSS) include the following:

• Staphylococcal TSS
• • Aggressive fluid support with normal saline or colloids
  • Vasopressor/inotrope infusion as necessary
  • Antistaphylococcal antibiotics (nafcillin and clindamycin or vancomycin and clindamycin in patients with penicillin allergy)
  • Removal of tampons, nasal packing, and other foreign objects
  • Intravenous immunoglobulin (IVIG) therapy (sporadically reported to have salutary effects; controlled trials are incomplete)
  • Aggressive supportive care in an ICU
• Streptococcal TSS
• • Normal saline or colloids may be used. Intractable hypotension that results from diffuse capillary leaking may require large amounts of these fluids. Albumin replacement may be necessary in patients in whom albumin levels drop lower than 2 g/dL.
  • Perform vasopressor/inotrope infusion as necessary.
  • Surgical debridement is mandatory in the presence of tissue necrosis.
  • Use penicillin plus clindamycin for antibiotic treatment. Clindamycin therapy for streptococcal TSS produces better results than penicillin alone for the following reasons:
  • • Clindamycin is affected less by the growth stage of an organism than penicillin, which acts only on organisms in the growth phase and not on those in the stationary phase.
    • Clindamycin suppresses toxin production by the organism.
    • Clindamycin suppresses cytokine production by monocytes.
    • Clindamycin inhibits the synthesis of penicillin-binding proteins.
    • Clindamycin has a longer postantibiotic effect than do beta-lactam antibiotics.
  • Studies have suggested a salutary effect of IVIG therapy. In one such comparative observational study of patients treated with IVIG, the mortality rate decreased to 34%, compared with a mortality rate of 67% in historical control subjects.⁶ In the future, double-blind trials may further clarify the role of IVIG in streptococcal TSS.⁷
  • Aggressive supportive care in an ICU is needed.
  • The role of hyperbaric oxygen in streptococcal TSS remains uncertain in the absence of any comparative clinical trials.

Surgical Care

• Perform debridement of any necrotizing skin lesion, such as may be seen in patients with streptococcal TSS.
• Remove tampons, if present, in patients with staphylococcal TSS.
• Surgical debridement of necrotic tissue should be performed promptly in patients with necrotizing fasciitis and streptococcal TSS.

Consultations

• Infectious diseases specialist
• Surgeon, if debridement is considered
• Other specialists and subspecialists, as the clinical situation dictates

Diet

No special diet is necessary.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goal of medical therapy is to eradicate infection and to prevent complications.

Drug Category: Antibiotics

Antibiotics are used to kill the infective organisms in patients with toxic shock syndrome (TSS). Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotic therapy should be used for 10-14 days.

Drug Category: Immunoglobulin

This agent is a purified preparation of gamma globulin. It is derived from large pools of human plasma and comprises 4 subclasses of antibodies, approximating the distribution in human serum. Immunoglobulin therapy is intended to neutralize the toxins that cause TSS.

Drug Category: Vasopressors

Vasopressors are used to correct hypotension. These agents augment both coronary and cerebral blood flow.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Transfer patients to the ICU for closer observation and aggressive therapy for hypotension and other complications.
• Patients with ARDS may require ventilatory support.
• Dialysis may be necessary in patients with severe renal failure.

Further Outpatient Care

• Female patients with staphylococcal infection should be warned against the use of tampons.

Deterrence/Prevention

• Antistaphylococcal therapy for staphylococcal toxic shock syndrome (TSS) decreases recurrence.
• Patients with staphylococcal TSS should avoid tampon use.
• Use of other intravaginal devices should be avoided in patients with TSS.
• Scrupulous wound care and appropriate early treatment of wounds should minimize TSS as a complication of these infections.

Complications

• Complications of staphylococcal TSS include the following:
• • Renal failure
  • Gangrenous/cyanotic extremities
  • Neuropsychiatric manifestations, such as memory loss and lack of concentration
• Complications of streptococcal TSS include the following:
• • Renal dysfunction progressing or persisting in all patients for 48-72 hours despite treatment (patients may require dialysis)
  • ARDS in 55% of patients
  • Death in 30% of patients
• Rarely, other complications may be noted, such as myocardial failure and pulmonary edema.

Prognosis

• Staphylococcal TSS
• • The vast majority of patients with staphylococcal TSS recover uneventfully. The mortality rate is 3.3%.
  • Staphylococcal TSS can recur, particularly in the absence of antistaphylococcal therapy and with continued use of tampons.
  • Neuropsychiatric manifestations, such as memory loss and lack of concentration, may persist in some patients.
• Streptococcal TSS: Prognosis is worse than in staphylococcal TSS and the mortality rate is 30%.

Patient Education

• Female patients with staphylococcal TSS should be warned against the use of tampons.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education article Toxic Shock Syndrome.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to promptly debride necrotic tissue in patients with necrotizing fasciitis and streptococcal toxic shock syndrome (TSS) may lead to poor outcome.
• Staphylococcal TSS may recur in the absence of effective antistaphylococcal therapy.
• Staphylococcal TSS may recur if female patients are not warned against the use of tampons.
• Failure to diagnose a mild case may result in legal liability.
• Failure to remove tampons or other implicated foreign materials in the body may cause legal liability.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Desquamative erythroderma. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
	View Full Size Image
Media type:  Photo

Media file 2:  Necrotizing fasciitis. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
	View Full Size Image
Media type:  Photo

Media file 3:  Strawberry tongue. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Todd J, Fishaut M, Kapral F, Welch T. Toxic-shock syndrome associated with phage-group-I Staphylococci. Lancet. Nov 25 1978;2(8100):1116-8. [Medline].
2. Davis JP, Osterholm MT, Helms CM, et al. Tri-state toxic-shock syndrome study. II. Clinical and laboratory findings. J Infect Dis. Apr 1982;145(4):441-8. [Medline].
3. Brogan TV, Nizet V, Waldhausen JH, et al. Group A streptococcal necrotizing fasciitis complicating primary varicella: a series of fourteen patients. Pediatr Infect Dis J. Jul 1995;14(7):588-94. [Medline].
4. Bradley JS, Schlievert PM, Sample TG. Streptococcal toxic shock-like syndrome as a complication of varicella. Pediatr Infect Dis J. Jan 1991;10(1):77-9. [Medline].
5. Chapnick EK, Gradon JD, Lutwick LI, et al. Streptococcal toxic shock syndrome due to noninvasive pharyngitis. Clin Infect Dis. May 1992;14(5):1074-7. [Medline].
6. Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome--a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis. Apr 1999;28(4):800-7. [Medline].
7. Baxter F, McChesney J. Severe group A streptococcal infection and streptococcal toxic shock syndrome. Can J Anaesth. Nov 2000;47(11):1129-40. [Medline].
8. Adams D, Fenton SJ, Nichol PF. Streptococcal pancreatitis and toxic shock syndrome in a 2-month-old infant. J Pediatr Surg. Jan 2007;42(1):261-3. [Medline].
9. Bader MS, Hamodat M, Hutchinson J. A fatal case of Staphylococcus aureus: associated toxic shock syndrome following nipple piercing. Scand J Infect Dis. 2007;39(8):741-3. [Medline].
10. Bartter T, Dascal A, Carroll K, Curley FJ. 'Toxic strep syndrome'. A manifestation of group A streptococcal infection. Arch Intern Med. Jun 1988;148(6):1421-4. [Medline].
11. Branco RG, Garcia PC, Piva JP, et al. Glucose level and risk of mortality in pediatric septic shock. Pediatr Crit Care Med. Jul 2005;6(4):470-2. [Medline].
12. Burnett AM, Domachowske JB. Therapeutic considerations for children with invasive group a streptococcal infections: a case series report and review of the literature. Clin Pediatr (Phila). Jul 2007;46(6):550-5. [Medline].
13. Byer RL, Bachur RG. Clinical deterioration among patients with fever and erythroderma. Pediatrics. Dec 2006;118(6):2450-60. [Medline].
14. Chuang YY, Huang YC, Lin TY. Toxic shock syndrome in children: epidemiology, pathogenesis, and management. Paediatr Drugs. 2005;7(1):11-25. [Medline].
15. Cockerill FR, MacDonald KL, Thompson RL, et al. An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. JAMA. Jan 1 1997;277(1):38-43. [Medline].
16. Cone LA, Stone RA, Schlievert PM, et al. An early favorable outcome of streptococcal toxic shock syndrome may require a combination of antimicrobial and intravenous gamma globulin therapy together with activated protein C. Scand J Infect Dis. 2006;38(11-12):960-3. [Medline].
17. Cone LA, Woodard DR, Byrd RG, et al. A recalcitrant, erythematous, desquamating disorder associated with toxin-producing staphylococci in patients with AIDS. J Infect Dis. Apr 1992;165(4):638-43. [Medline].
18. Daghistani HI, Issa AA, Shehabi AA. Frequency of nasal and wound isolates of Staphylococcus aureus associated with TSST-1 production in Jordanian population. FEMS Immunol Med Microbiol. Feb 2000;27(2):95-8. [Medline].
19. Davis JP, Chesney PJ, Wand PJ, LaVenture M. Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med. Dec 18 1980;303(25):1429-35. [Medline].
20. DiPersio JR, File TM, Stevens DL, et al. Spread of serious disease-producing M3 clones of group A streptococcus among family members and health care workers. Clin Infect Dis. Mar 1996;22(3):490-5. [Medline].
21. Drage LA. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. Jan 1999;74(1):68-72. [Medline].
22. Dries DJ. Vasoactive drug support in septic shock. Shock. Nov 2006;26(5):529-30. [Medline].
23. Fortenberry JD, Paden ML. Extracorporeal therapies in the treatment of sepsis: experience and promise. Semin Pediatr Infect Dis. 2006;17:72-9. [Medline].
24. Garbe PL, Arko RJ, Reingold AL, et al. Staphylococcus aureus isolates from patients with nonmenstrual toxic shock syndrome. Evidence for additional toxins. JAMA. May 3 1985;253(17):2538-42. [Medline].
25. Hackett SP, Stevens DL. Superantigens associated with staphylococcal and streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor-beta synthesis. J Infect Dis. Jul 1993;168(1):232-5. [Medline].
26. Hajjeh RA, Reingold A, Weil A, Shutt K, Schuchat A, Perkins BA. Toxic shock syndrome in the United States: surveillance update, 1979 1996. Emerg Infect Dis. Nov-Dec 1999;5(6):807-10. [Medline].
27. Harkness GA, Bentley DW, Mottley M, Lee J. Streptococcus pyogenes outbreak in a long-term care facility. Am J Infect Control. Jun 1992;20(3):142-8. [Medline].
28. Hasegawa T, Hashikawa SN, Nakamura T, et al. Factors determining prognosis in streptococcal toxic shock-like syndrome: results of a nationwide investigation in Japan. Microbes Infect. Oct 2004;6(12):1073-7. [Medline].
29. Holm SE. Invasive group A streptococcal infections. N Engl J Med. Aug 22 1996;335(8):590-1. [Medline].
30. Kain KC, Schulzer M, Chow AW. Clinical spectrum of nonmenstrual toxic shock syndrome (TSS): comparison with menstrual TSS by multivariate discriminant analyses. Clin Infect Dis. Jan 1993;16(1):100-6. [Medline].
31. Kansal R, Davis C, Hansmann M, Seymour J, Parsonnet J, Modern P. Structural and functional properties of antibodies to the superantigen TSST-1 and their relationship to menstrual toxic shock syndrome. J Clin Immunol. May 2007;27(3):327-38. [Medline].
32. Kass EH, Parsonnet J. On the pathogenesis of toxic shock syndrome. Rev Infect Dis. Sep-Oct 1987;9 Suppl 5:S482-9. [Medline].
33. Khojasteh VJ, Edwards-Jones V, Childs C, Foster HA. Prevalence of toxin producing strains of Staphylococcus aureus in a pediatric burns unit. Burns. May 2007;33(3):334-40. [Medline].
34. Lin JJ, Wu CT, Hsia SH, Chiu CH. Bullous impetigo: a rare presentation in fulminant streptococcal toxic shock syndrome. Pediatr Emerg Care. May 2007;23(5):318-20. [Medline].
35. MacIsaac CM, Page MA, Biggs BA, Visvanathan K. Staphylococcal toxic shock syndrome: still a problem. Med J Aust. Jun 20 2005;182(12):651. [Medline].
36. Martin JM, Green M. Group A streptococcus. Semin Pediatr Infect Dis. Jul 2006;17(3):140-8. [Medline].
37. Mehta S, McGeer A, Low DE, et al. Morbidity and mortality of patients with invasive group A streptococcal infections admitted to the ICU. Chest. Dec 2006;130(6):1679-86. [Medline].
38. Mollick JA, Rich RR. Characterization of a superantigen from a pathogenic strain of Streptococcus pyogenes. Clin Res. 1991;39:213A.
39. O'Grady KA, Kelpie L, Andrews RM, et al. The epidemiology of invasive group A streptococcal disease in Victoria, Australia. Med J Aust. Jun 4 2007;186(11):565-9. [Medline].
40. O'Loughlin RE, Roberson A, Cieslak PR, et al. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004. Clin Infect Dis. Oct 1 2007;45(7):853-62. [Medline].
41. Omland LH, Rasmussen SW, Hvolris J, Friis-Moller A. Necrotizing fasciitis caused by TSST-1 producing penicillin-sensitive Staphylococcus aureus--a case report. Acta Orthop. Apr 2007;78(2):296-7. [Medline].
42. Osterholm MT, Davis JP, Gibson RW, et al. Tri-state toxic-state syndrome study. I. Epidemiologic findings. J Infect Dis. Apr 1982;145(4):431-40. [Medline].
43. Paris AL, Herwaldt LA, Blum D, et al. Pathologic findings in twelve fatal cases of toxic shock syndrome. Ann Intern Med. Jun 1982;96(6 Pt 2):852-7. [Medline].
44. Powell C, Bubb S, Clark J. Toxic shock syndrome in a neonate. Pediatr Infect Dis J. Aug 2007;26(8):759-60. [Medline].
45. Reingold AL, Hargrett NT, Dan BB, et al. Nonmenstrual toxic shock syndrome: a review of 130 cases. Ann Intern Med. Jun 1982;96(6 Pt 2):871-4. [Medline].
46. Rosene KA, Copass MK, Kastner LS, et al. Persistent neuropsychological sequelae of toxic shock syndrome. Ann Intern Med. Jun 1982;96(6 Pt 2):865-70. [Medline].
47. Schlievert PM. Comparison of cotton and cotton/rayon tampons for effect on production of toxic shock syndrome toxin. J Infect Dis. Oct 1995;172(4):1112-4. [Medline].
48. Schlievert PM. Use of intravenous immunoglobulin in the treatment of staphylococcal and streptococcal toxic shock syndromes and related illnesses. J Allergy Clin Immunol. Oct 2001;108(4 Suppl):S107-10. [Medline].
49. Schwartz B, Elliott JA, Butler JC, et al. Clusters of invasive group A streptococcal infections in family, hospital, and nursing home settings. Clin Infect Dis. Aug 1992;15(2):277-84. [Medline].
50. Seal DV. Necrotizing fasciitis. Curr Opin Infect Dis. Apr 2001;14(2):127-32. [Medline].
51. Stegmayr B, Bjorck S, Holm S, et al. Septic shock induced by group A streptococcal infection: clinical and therapeutic aspects. Scand J Infect Dis. 1992;24(5):589-97. [Medline].
52. Stevens DL. Streptococcal toxic shock syndrome associated with necrotizing fasciitis. Annu Rev Med. 2000;51:271-88. [Medline].
53. Stevens DL, Madaras-Kelly KJ, Richards DM. In vitro antimicrobial effects of various combinations of penicillin and clindamycin against four strains of Streptococcus pyogenes. Antimicrob Agents Chemother. May 1998;42(5):1266-8. [Medline]. [Full Text].
54. 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. Jul 6 1989;321(1):1-7. [Medline].
55. Stoner MJ, Goodman DG, Cohen DM, Fernandez SA, Hall MW. Rapid fluid resuscitation in pediatrics: testing the American College of Critical Care Medicine guideline. Ann Emerg Med. Nov 2007;50(5):601-7. [Medline].
56. Subedi A, Ubeda C, Adhikari RP, Penades JR, Novick RP. Sequence analysis reveals genetic exchanges and intraspecific spread of SaPI2, a pathogenicity island involved in menstrual toxic shock. Microbiology. Oct 2007;153(Pt 10):3235-45. [Medline].
57. Taylor CM, Riordan FA, Graham C. New football boots and toxic shock syndrome. BMJ. 2006;332:1376-8. [Medline].
58. Tolan RW. Toxic shock syndrome complicating influenza A in a child: case report and review. Clin Infect Dis. Jul 1993;17(1):43-5. [Medline].
59. Ulrich RG. Evolving superantigens of Staphylococcus aureus. FEMS Immunol Med Microbiol. Jan 2000;27(1):1-7. [Medline].
60. Vayalumkal JV, Whittingham H, Vanderkooi O, Stewart TE, Low DE, Mulvey M. Necrotizing pneumonia and septic shock: suspecting CA-MRSA in patients presenting to Canadian emergency departments. CJEM. Jul 2007;9(4):300-3. [Medline].
61. Vincent JL, Sun Q, Dubois MJ. Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin Infect Dis. Apr 15 2002;34(8):1084-93. [Medline].
62. White MC, Thornton K, Young AE. Early diagnosis and treatment of toxic shock syndrome in paediatric burns. Burns. Mar 2005;31(2):193-7. [Medline].
63. Wilson AL, Kaufman MW, Thomson RB Jr, Gavin PJ. Fulminant fatal toxic shock syndrome with Staphylococcus aureus. Am J Emerg Med. Feb 2007;25(2):225-6. [Medline].
64. Young AE, Thornton KL. Toxic shock syndrome in burns: diagnosis and management. Arch Dis Child Educ Pract Ed. Aug 2007;92(4):ep97-100. [Medline].

Article Last Updated: Feb 1, 2008