AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Toxic shock syndrome (TSS) is an acute febrile illness characterized by a generalized erythematous eruption accompanied by systemic involvement. It is due to toxin-producing strains of Staphylococcus aureus, both methicillin-sensitive S aureus (MSSA) and methicillin-resistant S aureus (MRSA). Originally described in 1978 and soon thereafter associated with tampon use,¹ TSS is now recognized to occur in both menstrual and nonmenstrual forms. In the late 1980s, a disease similar in appearance to TSS, but caused by invasive streptococci, was recognized. Also known as toxic strep or streptococcal toxic shocklike syndrome, streptococcal TSS (STSS) was found to share many clinical features with TSS.

Pathophysiology

Massive cytokine release as a result of toxin/superantigen activity is postulated to be the mediator of the clinical signs of TSS.² Both menstrual and nonmenstrual forms of TSS have been linked to toxin-producing strains of S aureus. More than 90% of menstrual TSS is mediated by TSS toxin-1 (TSST-1) production, which is associated with massive release of tumor necrosis factor-alpha (TNF-a) and interleukin-1 (IL-1). These cytokines have been demonstrated to produce fever, rash, hypotension, tissue injury, and shock.

The absence of an antibody to TSST-1 has been shown to be a major risk factor for acquisition of TSS; failure to generate anti-TSST-1 antibody after an episode of TSS predisposes patients to recurrent episodes. Isolates of S aureus from nonmenstrual TSS produce TSST-1 in approximately 50% of cases, whereas the remainder produces staphylococcal enterotoxin B (SEB) and staphylococcal enterotoxin C (SEC). Staphylococcal enterotoxins have been shown to be potent mediators of cytokine production and release in a similar fashion to TSST-1, thereby producing clinically similar diseases.

In most cases of STSS, toxin-producing group A streptococci have been isolated, with streptococcal pyrogenic exotoxin-A (SPE-A) production being most closely linked with invasive disease. However, group A streptococci producing streptococcal pyrogenic exotoxin-B (SPE-B), streptococcal pyrogenic exotoxin-C (SPE-C), streptococcal superantigen and mitogenic factor, as well as non–group-A streptococci, have been found to be causative in individual cases of STSS.

In a similar manner to classic TSS, it is postulated that massive cytokine release (primarily TNF-a, interleukin 1-beta [IL-1b], and interleukin 6 [IL-6]), as a result of toxin/superantigen activity, mediates the clinical signs of STSS. In addition, streptolysin O, produced by 100% of streptococcal strains associated with STSS, has also been shown to cause TNF-a, and IL-1b production and has been demonstrated to act synergistically with SPE-A. An absence of protective immunity is postulated as a potential risk factor in this population as well.

Frequency

United States

Both TSS and STSS are relatively rare; the incidence of nonmenstrual TSS exceeds that of menstrual TSS.

Mortality/Morbidity

• TSS: The mortality rate is approximately 5-15%, and recurrences have been reported in as many as 30-40% of cases.
• STSS: Mortality rates are more than 5 times higher than in TSS.

Sex

Young adult women are affected more often than men.

Age

The majority of cases of TSS and STSS have occurred in young, otherwise healthy persons aged 20-50 years, despite the fact that very young, elderly, diabetic, or immunocompromised persons are more susceptible to the acquisition of invasive staphylococcal and streptococcal infections.

CLINICAL

Section 3 of 10  

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

History

Clinically, menstrual TSS, nonmenstrual TSS, and STSS have similar features. Fever, rash, hypotension, and multiple organ involvement are the hallmarks of TSS. Desquamation of the palms and soles, as seen in many bacterial toxin-mediated disorders, usually follows the onset of the illness by 1-2 weeks.

Physical

• Skin and mucous membrane lesions
• • The eruption of TSS is defined as diffuse macular erythroderma; however, a scarlatiniform eruption, often with flexural accentuation, frequently is present.
  • Erythema and edema of palms and soles
  • Hyperemia of conjunctiva and mucous membranes
  • Strawberry tongue
  • Delayed desquamation of palms and soles
• Multisystem organ involvement
• • Fever greater than 38.9°C (102°F)
  • Cardiovascular - Hypotension, cardiomyopathy
  • Gastrointestinal - Nausea, vomiting, diarrhea (usually secretory)
  • Muscular - Rhabdomyolysis, severe myalgias, muscle tenderness, muscle weakness
  • Renal - Azotemia, acute renal failure
  • Neurologic - Toxic encephalopathy probably related to cerebral edema
  • Pulmonary - Adult respiratory distress syndrome
  • Hepatic - Elevated serum aspartate aminotransferase and serum bilirubin levels, centrilobular hepatic necrosis
  • Hematologic - Thrombocytopenia, leukocytosis, disseminated intravascular coagulation
  • Metabolic - Hypophosphatemia, hypocalcemia, electrolyte imbalances (especially metabolic acidosis)

Causes

• TSS may occur as a complication of S aureus cellulitis. Most frequently, however, infection with the causative strains of staphylococci develop in patients with certain predisposing factors, such as the following:
• • Influenza
  • Sinusitis
  • Tracheitis
  • Intravenous drug use
  • HIV infection
  • Burn wounds
  • Allergic contact dermatitis
  • Gynecologic infection
  • Postpartum period
  • Postoperative infection: Importantly, in nonmenstrual TSS caused by a postoperative infection, the classic signs of localized infection, such as erythema, tenderness, and purulence, may be absent from the site of infection, thereby making clinical diagnosis challenging.
• The following are predisposing factors for STSS:
• • Wounds: The skin is often the portal of entry in STSS, with soft-tissue infections developing in 80% of patients. The initial presentation of STSS often is localized pain in an extremity, which rapidly progresses over 48-72 hours to manifest both local and systemic signs of STSS. Cutaneous signs may include localized edema and erythema, a bullous and hemorrhagic cellulitis, necrotizing fasciitis or myositis, or gangrene. Soft-tissue involvement of this nature is distinctly uncommon in staphylococcal TSS. STSS may uncommonly occur in the absence of cutaneous involvement; in these cases, differentiation from staphylococcal TSS becomes more difficult.
  • Varicella
  • Influenza A
  • Nonsteroidal anti-inflammatory drug use (controversial association)

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Drug-induced hypersensitivity syndrome
Febrile drug reaction
Leptospirosis

WORKUP

Section 5 of 10  

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

Lab Studies

• Blood cultures - Positive in 5-15% of TSS and approximately 50% of STSS
• CBC count - Leukocytosis and thrombocytopenia
• Chemistry profile
• • Elevated BUN and creatinine as well as abnormal LFTs
  • Occasional hypocalcemia - Unclear basis
• Urinalysis - Microscopic hematuria and occasional myoglobinuria
• Creatinine kinase - Occasionally elevated secondary to muscle injury

Histologic Findings

A clinical diagnosis is often made. The histologic findings, although nonspecific in some cases, are usually quite characteristic and consist of a superficial perivascular and interstitial mixed-cell infiltrate that contains neutrophils and sometimes eosinophils. Foci of spongiosis-containing neutrophils and scattered necrotic keratinocytes sometimes are clustered within the epidermis. When present, bullae are subepidermal in location.

TREATMENT

Section 6 of 10  

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

Medical Care

Treatment of TSS includes supportive therapy, including hydration, vasopressors, penicillinase-resistant antibiotics, and drainage of infected sites. In vitro studies have suggested that sublethal concentrations of silver sulfadiazine cream lead to increased toxin production by S aureus; therefore, mupirocin ointment or povidone iodine solution may be better choices for topical care of infected sites. Washing with chlorhexidine gluconate may be beneficial in eradicating MRSA. Drotrecogin alfa has been reported to be beneficial in treating MRSA TSS.³

Management of STSS is similar to that of TSS. Supportive therapy, vasopressors, and antibiotics are the cornerstones of treatment. The increasingly reported clinical resistance of streptococci to penicillin G, as well as the difficulty in being able to distinguish STSS from TSS in some cases, suggests the need for adequate antimicrobial coverage for both staphylococci and penicillin-resistant streptococci. Consider clindamycin, erythromycin, cephalosporins, or other agents as deemed appropriate by clinical presentation and culture results. Intravenous immunoglobulin (IVIG) has been reported to be dramatically effective in STSS but is not yet in widespread use.⁴

Consultations

• Infectious disease specialist - To determine appropriate antibiotic coverage
• Critical care specialist - To evaluate and treat potential complications
• Dermatologist

MEDICATION

Section 7 of 10  

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

Antibiotics are important in the treatment of TSS. Because distinguishing STSS from TSS may be difficult, adequate antibiotic coverage for both staphylococci and streptococci is suggested until a definitive bacterial pathogen is isolated. Antibiotics should include a parenteral antistaphylococcal/streptococcal semisynthetic penicillin or a first-generation cephalosporin in combination with clindamycin. When MRSA is suspected, vancomycin or linezolid and rifampin may be added to or in place of an antistaphylococcal/streptococcal penicillin or cephalosporin.

Drug Category: Antibiotics

Drug Name	Clindamycin (Cleocin)
Description	Drug of choice in STSS. 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 t-RNA from ribosomes causing RNA-dependent protein synthesis to arrest.
Adult Dose	600-900 mg IV q8h
Pediatric Dose	20-40 mg/kg/d IV divided q6-8h
Contraindications	Documented hypersensitivity; regional enteritis, ulcerative colitis, antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug Name	Cefazolin (Ancef)
Description	Semisynthetic first-generation cephalosporin that exhibits bactericidal activity by inhibiting cell wall synthesis. Active against penicillinase producing S aureus; however, MRSA and GAS are resistant.
Adult Dose	0.5-1.5 g IM/IV q6-8h
Pediatric Dose	25-100 mg/kg IM/IV qd divided q6-8h
Contraindications	Documented hypersensitivity to the cephalosporin group of antibiotics
Interactions	Probenecid may decrease excretion; may increase INR when used with warfarin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dosage in renal insufficiency or failure; seizures may occur in patients with renal impairment administered high doses; caution in patients with a penicillin or beta-lactam allergy; may cause pseudomembranous colitis; may increase prothrombin time

Drug Name	Vancomycin (Vancocin)
Description	Tricyclic glycopeptide antibiotic that exhibits bactericidal effects by inhibiting cell wall and RNA synthesis and by altering bacterial cell membrane permeability; ideally used when MRSA is suspected
Adult Dose	1 gram IV q12h
Pediatric Dose	10 mg/kg IV q6h
Contraindications	Documented hypersensitivity; cidofovir combined with vancomycin may increase risk of nephrotoxicity
Interactions	Cidofavir is contraindicated; clofarabine, gallium, aminoglycosides and other nephrotoxic drugs may increase nephrotoxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Adjust dosage in renal insufficiency or failure; may cause nephrotoxicity, ototoxicity, reversible neutropenia, and, rarely thrombocytopenia; red man syndrome erythroderma may occur; oral formulations of vancomycin are not systemically absorbed and should not be used for systemic infections

Drug Name	Linezolid (Zyvox)
Description	Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.
Adult Dose	600 mg PO/IV q12h for 10-14 d
Pediatric Dose	Preterm neonate <7 days: 10 mg/kg PO/IV q12h; in cases of suboptimal response, may use 10 mg/kg PO/IV q8h Term neonates to 12 years: 10 mg/kg PO/IV q8h for 10-14 d >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May cause hypertension when used concomitantly with adrenergic agents including pseudoephedrine, sympathomimetic agents, vasopressor or dopaminergic agents (reduce dose of dopamine or epinephrine if concurrent use required); serotonin syndrome may occur if used concomitantly with serotonergic agents including tricyclic antidepressants, meperidine, dextromethorphan, trazodone, venlafaxine, and selective serotonin reuptake inhibitors; may cause myelosuppression or pseudomembranous colitis inhibitors
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Has mild MAOI properties and has potential to have same interactions as other MAOIs; caution in uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism, and patients who are at increased risk for bleeding, have preexisting thrombocytopenia, receive concomitant medications that may decrease platelet count or function, or who may require >2 wk of therapy (monitor platelet counts); unnecessary use may lead to development of resistance to drug; may cause peripheral or optic neuropathy

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Hydration
• Drainage of infected sites
• Vasopressors
• Oxygen
• Stress-dose steroids
• Drotrecogin alfa
• Blood products
• Mechanical ventilation
• Sedation/analgesia
• Blood glucose control
• Chlorhexidine gluconate wash
• Mupirocin
• Retapamulin

Complications

• Hypotension
• Myocardial dysfunction
• Acute renal failure
• Adult respiratory distress syndrome
• Disseminated intravascular coagulation
• Fluid and electrolyte abnormalities

Prognosis

• Although early intervention may prevent progression of the disease, both TSS and STSS carry significant morbidity and mortality.

Patient Education

• 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 10  

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

Special Concerns

• Recurrence of TSS

REFERENCES

Section 10 of 10

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

1. Shands KN, Schmid GP, Dan BB, Blum D, Guidotti RJ, Hargrett NT, et al. Toxic-shock syndrome in menstruating women: association with tampon use and Staphylococcus aureus and clinical features in 52 cases. N Engl J Med. Dec 18 1980;303(25):1436-42. [Medline].
2. Rosen H. Superantigens. Int J Dermatol. Jan 1997;36(1):14-6. [Medline].
3. Haddadin DW, Samnani IQ, Moorman JP. Drotrecogin alfa (activated) for nonmenstrual toxic shock syndrome associated with methicillin resistant Staphylococcus aureus infection. South Med J. Nov 2006;99(11):1295-6. [Medline].
4. Darenberg J, Ihendyane N, Sjölin J, Aufwerber E, Haidl S, Follin P, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. Aug 1 2003;37(3):333-40. [Medline].
5. 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].
6. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. Mar 2004;32(3):858-73. [Medline].
7. Drage LA. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. Jan 1999;74(1):68-72. [Medline].
8. Durand G, Bes M, Meugnier H, Enright MC, Forey F, Liassine N, et al. Detection of new methicillin-resistant Staphylococcus aureus clones containing the toxic shock syndrome toxin 1 gene responsible for hospital- and community-acquired infections in France. J Clin Microbiol. Mar 2006;44(3):847-53. [Medline].
9. Hoge CW, Schwartz B, Talkington DF, Breiman RF, MacNeill EM, Englender SJ. The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome. A retrospective population-based study. JAMA. Jan 20 1993;269(3):384-9. [Medline].
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11. Manders SM. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol. Sep 1998;39(3):383-98; quiz 399-400. [Medline].
12. Nelson C. Early recognition and treatment of staphylococcal and streptococcal toxic shock. J Pediatr Adolesc Gynecol. Aug 2004;17(4):289-92. [Medline].
13. Reingold AL, Hargrett NT, Shands KN, Dan BB, Schmid GP, Strickland BY. Toxic shock syndrome surveillance in the United States, 1980 to 1981. Ann Intern Med. Jun 1982;96(6 Pt 2):875-80. [Medline].
14. Stevens DL. The toxic shock syndromes. Infect Dis Clin North Am. Dec 1996;10(4):727-46. [Medline].
15. Strausbaugh LJ. Toxic shock syndrome. Are you recognizing its changing presentations?. Postgrad Med. Nov 1 1993;94(6):107-8, 111-3, 117-8. [Medline].
16. Wenisch C, Laferl H, Szell M, Smolle KH, Grisold A, Bertha G, et al. A holistic approach to MRSA eradication in critically ill patients with MRSA pneumonia. Infection. Jun 2006;34(3):148-54. [Medline].
17. Wolf JE, Rabinowitz LG. Streptococcal toxic shock-like syndrome. Arch Dermatol. Jan 1995;131(1):73-7. [Medline].
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19. Working Group on Severe Streptococcal Infections. Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. The Working Group on Severe Streptococcal Infections. JAMA. Jan 20 1993;269(3):390-1. [Medline].

Article Last Updated: Nov 8, 2007