eMedicine Specialties > Dermatology > Bacterial Infections

Toxic Shock Syndrome

Steven M Manders, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania; Associate Professor, Department of Internal Medicine, Division of Dermatology, University of Medicine and Dentistry of New Jersey
Clara-Dina Cokonis, MD, Staff Physician, Department of Medicine, Division of Dermatology, Cooper Hospital University Medical Center

Updated: Jul 15, 2008

Introduction

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.

The Medscape CME course Invasive Group A Streptococcal Disease in Nursing Homes, Minnesota, 1995-2006 and the Emerging and Reemerging Infectious Diseases Resource Center. Additionally, several other eMedicine Specialty sections have articles on TSS, including Toxic Shock Syndrome from Critical Care.

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 (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, IL-1beta, and 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-1beta 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

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)

Differential Diagnoses

Acanthosis Nigricans
Kawasaki Disease
Scarlet Fever
Staphylococcal Scalded Skin Syndrome

Other Problems to Be Considered

Drug-induced hypersensitivity syndrome
Febrile drug reaction
Leptospirosis

Workup

Laboratory 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

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

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.

Antibiotics

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

Nafcillin (Nafcil, Unipen, Nallpen)

Initial therapy for suspected penicillin G-resistant streptococcal or staphylococcal infections.
Use parenteral therapy initially in severe infections. Change to oral therapy as condition warrants.
Due to thrombophlebitis, particularly in the elderly, administer parenterally only for short term (1-2 d); change to oral route as clinically indicated.

Dosing

Adult

1-2 g IV q4h

Pediatric

50-200 mg/kg/d IV divided q4-6h

Interactions

Associated with warfarin resistance when administered concurrently; effects may decrease with bacteriostatic action of tetracycline derivatives

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

To optimize therapy, determine causative organisms and susceptibility; treat for >10 d to eliminate infection and prevent sequelae (eg, endocarditis, rheumatic fever); take cultures after treatment to confirm that infection is eradicated

Clindamycin (Cleocin)

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.

Dosing

Adult

600-900 mg IV q8h

Pediatric

20-40 mg/kg/d IV divided q6-8h

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin

Contraindications

Documented hypersensitivity; regional enteritis, ulcerative colitis, antibiotic-associated colitis

Precautions

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

Cefazolin (Ancef)

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.

Dosing

Adult

0.5-1.5 g IM/IV q6-8h

Pediatric

25-100 mg/kg IM/IV qd divided q6-8h

Interactions

Probenecid may decrease excretion; may increase INR when used with warfarin

Contraindications

Documented hypersensitivity to the cephalosporin group of antibiotics

Precautions

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

Vancomycin (Vancocin)

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

Dosing

Adult

1 gram IV q12h

Pediatric

10 mg/kg IV q6h

Interactions

Cidofovir is contraindicated; clofarabine, gallium, aminoglycosides and other nephrotoxic drugs may increase nephrotoxicity

Contraindications

Documented hypersensitivity; cidofovir combined with vancomycin may increase risk of nephrotoxicity

Precautions

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

Linezolid (Zyvox)

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.

Dosing

Adult

600 mg PO/IV q12h for 10-14 d

Pediatric

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

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

Contraindications

Documented hypersensitivity

Precautions

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

Follow-up

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

Special Concerns

• Recurrence of TSS

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].

10. Larkin SM, Williams DN, Osterholm MT, Tofte RW, Posalaky Z. Toxic shock syndrome: clinical, laboratory, and pathologic findings in nine fatal cases. Ann Intern Med. Jun 1982;96(6 Pt 2):858-64. [Medline].

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].

18. Wood TF, Potter MA, Jonasson O. Streptococcal toxic shock-like syndrome. The importance of surgical intervention. Ann Surg. Feb 1993;217(2):109-14. [Medline].

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Keywords

shock, TSS, STSS, toxic strep, streptococcal toxic shock-like syndrome, streptococcal TSS, Staphylococcus aureus, S aureus

Contributor Information and Disclosures

Author

Steven M Manders, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania; Associate Professor, Department of Internal Medicine, Division of Dermatology, University of Medicine and Dentistry of New Jersey
Steven M Manders, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Clara-Dina Cokonis, MD, Staff Physician, Department of Medicine, Division of Dermatology, Cooper Hospital University Medical Center
Clara-Dina Cokonis, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine
Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont
Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

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