Toxic shock syndrome and toxin-mediated infection

• Toxic shock syndrome is a sudden, life-threatening illness produced by bacterial toxins rather than by the bacteria directly, most often from Staphylococcus aureus or Streptococcus pyogenes.
• The two main forms are staphylococcal toxic shock syndrome (often linked to a tampon, a wound, or surgery) and streptococcal toxic shock syndrome (usually linked to a severe streptococcal soft-tissue infection).
• The defining picture is fever plus a widespread flat red rash, low blood pressure, and failure of at least two or three organ systems, and it can kill within hours.
• Clindamycin is added to standard bactericidal antibiotics specifically to stop toxin production, and removing the source (tampon, debriding tissue) is urgent.
• Scarlet fever is the milder toxin-mediated face of the same streptococcal exotoxins, with a sandpaper rash and "strawberry tongue," and responds to a 10-day course of penicillin.

By the end of this page you should be able to:

1. Explain why a bacterial toxin, not the bacteria themselves, drives the shock in toxic shock syndrome, and what a superantigen does.
2. Distinguish staphylococcal from streptococcal toxic shock syndrome by source, microbiology, and age.
3. Recognise the fever, rash, hypotension and multi-organ pattern, apply the surveillance case definitions, and separate TSS from sepsis and scarlet fever.
4. Choose and justify an empiric antibiotic regimen that includes clindamycin, state when to add Gram-negative or anaerobic cover, and explain the role of surgery.
5. Describe the evidence for intravenous immunoglobulin as an adjunct, and the honest limits of that evidence.
6. Recognise high-risk groups (menstruating women, recent surgery, varicella, older adults with diabetes) and know the preventive messages for patients and contacts.
7. Diagnose scarlet fever, state the first-line antibiotics and durations, and know its complications.

The toxins act as superantigens: instead of activating the small fraction of T-cells that recognise a specific antigen, they cross-link the major histocompatibility complex class II on antigen-presenting cells with the T-cell receptor at a site outside the normal antigen groove. The result is a massive, polyclonal activation of 5 to 30% of all T-cells, an explosive release of cytokines, capillary leak, hypotension and organ failure.^[5]

Two organisms account for almost all cases.

• Staphylococcal toxic shock syndrome is caused by toxin-producing Staphylococcus aureus. The toxin is most often toxic shock syndrome toxin-1 (TSST-1), a 194 amino-acid protein, in 89 to 95% of menstrual cases and about 50% of non-menstrual cases; the rest are caused by staphylococcal enterotoxins A, B or C.^[5] Menstrual disease (m-TSS) occurs in young menstruating women and is exclusively toxin-mediated; non-menstrual disease (nm-TSS) follows an actual staphylococcal infection and is both septic and toxin-mediated.^[5]
• Streptococcal toxic shock syndrome (STSS) is caused by Streptococcus pyogenes (group A streptococcus). The responsible toxins are the streptococcal pyrogenic exotoxins A, B and C and streptococcal superantigen A.^[5] STSS is a complication of an invasive group A streptococcal infection, most often in skin or soft tissue.

A third, much milder, toxin-mediated condition is scarlet fever, an exotoxin-producing streptococcal pharyngitis or skin infection with a characteristic rash.^[2]

TSS is not the same as sepsis. In septicaemia the illness is driven by the organism and its endotoxins; TSS can occur with negative blood cultures, especially menstrual staphylococcal disease, because it is driven by the exotoxin. In practice the two overlap and initial treatment looks similar. ^[5]

Staphylococcal TSS is rare, with a stable annual incidence of 0.03 to 0.07 cases per 100,000 population.^[5] A peak of 13.7 per 100,000 in the 1980s in the United States was linked to highly absorbent tampons and fell once tampon manufacture changed.^[5] Menstrual disease now represents a minority of cases and is most common in women aged 13 to 24 years; the incidence of menstrual disease in the UK is estimated at 0.09 per 100,000 and of non-menstrual disease at 0.04 per 100,000.^[5] Non-menstrual staphylococcal cases grew to outnumber menstrual ones after the tampon changes: in one UK series 59.4% of 180 cases were non-menstrual.^[5]

Streptococcal TSS is also rare but far more deadly. Overall 8 to 22% of patients with severe S. pyogenes infection go on to develop STSS, rising to 40 to 50% of those with necrotizing soft-tissue infection.^[5] Blood cultures are positive in 60 to 86% of STSS cases.^[5] The source of infection remains unknown in half of cases.^[5]

Staphylococcal strains are in the great majority methicillin-susceptible. In a French series of 102 menstrual TSS cases between 2005 and 2020 no MRSA was found, and UK surveillance (2008 to 2012) found MRSA in only 3.8% of staphylococcal TSS isolates.^[5]

Scarlet fever occurs mainly in children aged 5 to 15 years and is uncommon in children under 3 years.^[2]

Staphylococcal toxic shock syndrome. Menstrual disease arises from vaginal colonisation with a TSST-1-producing S. aureus in women who lack neutralising antibodies; the tampon creates an environment that favours bacterial growth and toxin production.^[5] Between 2003 and 2005, 22.9% of women were vaginally colonised with S. aureus and 4.2% with a TSST-1-producing strain.^[5] Non-menstrual disease can follow any staphylococcal infection, most often postoperative, or post-partum, or infection of skin lesions. Postoperative TSS appears a median of 4 days after surgery, after even trivial procedures including dermal filler or breast implant surgery.^[5]

Risk factors include surgery, skin injury, burns, varicella in children, foreign bodies (tampons, menstrual cups, intrauterine devices), and nasal carriage of S. aureus.

Streptococcal toxic shock syndrome. Risk factors are older age (most cases occur in patients aged 50 to 69 years), diabetes, malignancy, chronic liver or kidney disease, heart disease, alcohol use disorder, and use of non-steroidal anti-inflammatory drugs.^[5] The NSAID link is strong in some studies, with a 3-fold increased risk and a 22-fold rise in tissue GAS counts in an animal model, but the role remains debated and NSAIDs may simply mask the early signs.^[5] Varicella and chickenpox in children, skin trauma, minor injuries without skin breakdown, pneumonia, septic arthritis and postpartum status are also recognised sources.^[5]

Scarlet fever arises from a group A streptococcal pharyngitis or skin infection in which the organism produces a pyrogenic exotoxin. Close contact is the commonest risk factor, and crowded settings (schools, childcare, prisons, military camps) favour spread.^[2]

Both forms of TSS are driven by superantigenic exotoxins that polyclonally activate 5 to 30% of all T-cells, releasing a massive wave of pro-inflammatory cytokines with capillary leakage, vasodilation, hypotension, coagulation activation and multi-organ failure.^[5] TSST-1 and the streptococcal pyrogenic exotoxins are the main superantigens named in current reviews.^[5]

Staphylococcal menstrual disease is exclusively toxin-mediated: the organism stays in the vagina or cervix, and blood cultures are negative in all reported series.^[5] Non-menstrual staphylococcal disease is both septic and toxin-mediated, with blood cultures positive for S. aureus in about half of cases.^[5] Streptococcal TSS occurs when the organism breaches a mucosal or skin barrier, enters deep tissue or blood, and produces exotoxins; necrotizing soft-tissue infection is present in the majority.

The clinical lesson is that the toxins cause the shock, so killing the organism is not enough: toxin production must be suppressed and the source removed.

The staphylococcal form classically begins abruptly with high fever (median 39.4 degrees Celsius), a diffuse macular erythroderma (a flat, widespread red rash that often involves the palms and soles later), and hypotension.^[5] In the French series of 102 menstrual cases, tachycardia, vomiting, diarrhoea and abdominal pain were very common, and mucosal hyperaemia occurred in 50%.^[5] The rash desquamates 1 to 2 weeks later, especially on the palms and soles; desquamation is part of the surveillance case definition but appears late.^[3][5]

Multi-organ involvement is the rule and must affect at least three systems in the CDC surveillance criteria: gastrointestinal, muscular, mucous membrane, renal, hepatic, haematological or central nervous.^[3]

STSS usually follows flu-like symptoms (fever, chills, muscle pain, nausea and vomiting) and deteriorates into sepsis with hypotension, tachycardia and tachypnoea within 24 to 48 hours of first symptoms.^[1] Many patients have a severe group A streptococcal infection of the skin, soft tissue, vagina, pharynx or lungs as the portal. A generalised erythematous macular rash that may desquamate can occur, but is more often a soft-tissue infection with necrotizing fasciitis or myositis.^[4]

Scarlet fever begins with pharyngitis, fever and often a white-coated tongue that peels to leave a "strawberry tongue." The rash starts on the trunk, spreads, is erythematous and blanches, has a sandpaper feel, shows Pastia lines in flexor creases, and usually spares the palms and soles. Circumoral pallor, flushing and a 2 to 5 day incubation are typical. The rash lasts about a week, after which desquamation may follow.^[2]

STSS is often misdiagnosed as staphylococcal TSS or another infection early on; the two share fever and shock, and the streptococcal portal may be minor or hidden.^[1]

Age, a recent surgical wound, tampon use, varicella, or a known streptococcal skin infection all tilt the diagnosis toward TSS.

• Blood cultures are essential. They are negative in all menstrual TSS cases, positive for S. aureus in about half of non-menstrual cases, and positive in 60 to 86% of STSS cases.^[5]
• Cultures and tests at the source: vaginal or cervical swab in suspected menstrual disease; wound, throat, sputum and deep-tissue cultures (not just superficial swabs) in STSS and suspected necrotizing soft-tissue infection.
• Full blood count and coagulation: thrombocytopenia is a diagnostic criterion; disseminated intravascular coagulation in severe streptococcal disease.
• Renal and hepatic panels, creatine kinase, bilirubin to count the affected organs.
• Imaging and surgical exploration when soft-tissue infection is suspected: magnetic resonance imaging or computed tomography to define depth; urgent surgical inspection for necrotizing infection.
• Rapid streptococcal testing (rapid antigen detection test, nucleic acid amplification test or throat culture) confirms scarlet fever or pharyngitis.^[2]

There is no bedside test for the toxins themselves, so diagnosis rests on clinical criteria plus microbiology.

The case definitions below are surveillance tools, not diagnostic formulas for the bedside, and both require desquamation or chronic criteria that appear late. They are used to standardise reporting and as a teaching scaffold.

Clinical criteria (all five for a confirmed case):

1. Fever: temperature 38.9 degrees Celsius or higher.
2. Rash: diffuse macular erythroderma.
3. Desquamation: 1 to 2 weeks after onset of rash.
4. Hypotension: systolic blood pressure 90 mm Hg or less in adults, or under the fifth percentile for age in children under 16.
5. Multi-system involvement, three or more of: gastrointestinal (vomiting or diarrhoea at onset); muscular (severe myalgia or creatine kinase above double the laboratory's upper reference value); mucous membranes (vaginal, oropharyngeal or conjunctival hyperaemia); renal (urea nitrogen or creatinine at least twice normal, or sterile pyuria); hepatic (bilirubin or transaminases at least twice normal); haematological (platelets under 100,000 per cubic millimetre); central nervous (disorientation or altered consciousness without focal signs when fever and hypotension are absent). ^[3]

Laboratory criteria: negative blood and cerebrospinal fluid cultures (a blood culture may be positive for S. aureus), and negative serology for Rocky Mountain spotted fever, leptospirosis and measles.

Case classification: probable if 4 of 5 clinical criteria plus laboratory criteria, confirmed if all 5 (including desquamation) plus laboratory criteria, unless the patient dies before desquamation.^[3] In practice many real cases never meet the confirmed criteria; desquamation appears 8 to 21 days into the illness and a French series found none of 102 menstrual cases met the confirmed criteria and only half met the probable criteria.^[5]

Clinical description: a severe illness with invasive or non-invasive group A streptococcal infection, signs of toxicity and a rapidly progressive course; the case fatality rate may exceed 50%. ^[4]

Clinical criteria:

1. Hypotension: systolic blood pressure 90 mm Hg or less in adults, or under the fifth percentile by age in children under 16.
2. Two or more of: renal impairment (creatinine 2 mg per dL or more in adults, or above double the age-specific upper reference value); coagulopathy (platelets 100,000 per cubic millimetre or less, or disseminated intravascular coagulation); hepatic involvement (aminotransferases or bilirubin at least twice normal); acute respiratory distress syndrome; a generalized erythematous macular rash that may desquamate; soft-tissue necrosis, necrotizing fasciitis or myositis, or gangrene. ^[3][4]

Laboratory criterion: isolation of group A streptococcus. Probable if the case definition is met with isolation from a non-sterile site and no other aetiology; confirmed if isolation from a normally sterile site.^[4]

Unlike the staphylococcal definition, STSS is a clinical diagnosis supported by culture; a "probable" case can be treated while cultures are pending. The CDC clinical guidance for STSS is dated August 2025.^[1]

TSS is a medical emergency. First-hour care is that of septic shock: airway, high-flow oxygen, large-volume crystalloid, early vasopressors, intensive care, and antibiotics given immediately rather than after imaging.^[5]

Empiric treatment targets Gram-positive cocci and includes a protein-synthesis-inhibiting (antitoxic) agent. CDC guidance for STSS lists penicillin and clindamycin in conjunction as first-line antibiotics.^[1] IDSA 2014 guidance states that necrotizing fasciitis or STSS caused by group A streptococci should be treated with both clindamycin and penicillin, because clindamycin suppresses streptococcal toxin and cytokine production.^[6]

• Clindamycin (or linezolid) is added for toxin suppression; evidence from in-vitro work and observational studies in severe group A streptococcal infection supports the combination, although there has been no randomised trial of the combination specifically in TSS.^[5]
• Clindamycin resistance is variable worldwide and can be common in some regions, so sensitivities must guide de-escalation.^[5] Macrolide resistance among group A streptococci is under 5% in the United States but higher in parts of Europe.^[6]
• MRSA must be covered empirically when the local rate is high, in patients with known carriage, household contact, a recent hospital stay or antibiotics, or a recent stay in a high-resistance area.^[5]
• In suspected polymicrobial necrotizing soft-tissue infection, broad Gram-positive, Gram-negative and anaerobic cover is started immediately without waiting for surgical exploration.^[5]
• Parenteral bactericidal antibiotics are started within the first hour, and de-escalation follows susceptibility testing.^[5]
• In the specific case of a menstrual staphylococcal TSS, a source-controlled S. aureus in a previously healthy woman usually responds to an anti-staphylococcal beta-lactam plus a toxin-suppressing agent.

Without removing the source, antibiotics alone cannot clear the toxin. Menstrual TSS requires removal of tampons, cups or intrauterine devices plus a vaginal or cervical sample. Suspected non-menstrual TSS and STSS require urgent surgery: exploration of the wound, deep cultures, radical debridement of necrotic tissue, drainage of abscesses. In STSS the portal can be subtle, so any cellulitis, minor wound or pain out of proportion warrants surgical inspection.^[5]

Intravenous immunoglobulin can neutralise superantigen activity in the laboratory and has been studied in severe streptococcal infection, but the clinical evidence is incomplete and conflicting:

• IDSA states that the efficacy of IVIG in STSS has not been definitively established, citing batch-to-batch variation in neutralising antibody content, observational data confounded by surgery and clindamycin use, and a Northern European double-blind placebo-controlled trial in which mortality improvement did not reach statistical significance.^[6]
• CDC lists IVIG as something that can be considered for severely ill patients early in the clinical course, although efficacy has not been proven.^[1]
• The 2024 literature review concludes that the value of polyclonal IVIG as an adjunct in TSS still requires further evaluation.^[5]
• The randomised Northern European trial mentioned above reported mortality of 10% in the IVIG group versus 36% in controls, a difference that did not reach statistical significance, with a better SOFA score at days 2 and 3.^[5]
• A systematic review found benefit in clindamycin-treated STSS; other meta-analyses found none.^[5]

Practical position: use IVIG early for severely ill STSS (or staphylococcal TSS with profound shock) where locally available, but be explicit with the team and the family about the strength of the evidence. Staphylococcal TSS may be less responsive to IVIG than streptococcal TSS.

• Fluids, vasopressors and organ support as for any septic shock.
• The optimal duration of antibiotics is not set by trials. Many teams continue for 10 to 14 days or for 48 to 72 hours after the last definitive source-control procedure in a patient who is recovering, but evidence for this specific duration is limited.^[5]
• There is no role for hyperbaric oxygen based on available evidence.
• Probiotics or vaccination (a TSST-1 variant vaccine in early phase trials) are research possibilities, not current management.

• Multi-organ failure, particularly renal, hepatic, respiratory and coagulopathic.
• Soft-tissue necrosis, gangrene and loss of digits or limbs from necrotizing soft-tissue infection.
• Amputation and permanent joint stiffness after deep soft-tissue destruction.
• Deep tissue loss requiring skin grafting or reconstructive surgery in severe necrotizing infection.
• Recurrence if the source or predisposition remains (untreated tampon-related colonisation, persistent nasal carriage, uncontrolled diabetes).
• Long-term lymphoedema and scarring from deep soft-tissue infection.
• Pregnancy loss and maternal multi-organ failure in postpartum STSS.

Staphylococcal TSS carries a mortality of about 5% overall: low in menstrual disease (some series report no deaths) but 4 to 22% in non-menstrual disease, which affects older and more comorbid patients.^[5] Postoperative TSS carries a mortality of about 9.4%.^[5]

Streptococcal TSS has a mortality of 14 to 64% depending on the series and population, and a 12.7-fold increased risk of death during invasive group A streptococcal infection once STSS is present.^[5] Mortality is under 1% in postpartum STSS and substantially lower in children than in older adults.^[5][1]

Scarlet fever itself rarely causes direct death; the danger is in the non-suppurative and suppurative complications listed below.

• Menstrual hygiene: during the highest-risk years, use tampons for no more than a few hours at a time, avoid highly absorbent tampons, wash hands, alternate tampons with external products, and remove a tampon promptly if it becomes uncomfortable or if fever or rash develops. Suspected menstrual TSS is a medical emergency; any woman with sudden fever, a red rash and low blood pressure in the first few days of menstruation needs urgent assessment.
• Surgical and wound care: high index of suspicion for postoperative fever with pain, rash or disproportionate pain; NSAID use can delay recognition. Consider S. aureus nasal decolonisation in selected high-risk surgical patients (standard infection-control programme).
• Varicella: vaccinate against varicella to prevent secondary STSS in children and adults.
• Household contacts of invasive group A streptococcal infection: CDC does not routinely recommend prophylaxis or screening for contacts, although many clinicians offer a single dose of long-acting intramuscular penicillin or alternative to household contacts aged 65 years or older, or to other increased-risk contacts, during an outbreak.^[1]
• Scarlet fever in schools: children should stay home until afebrile and for at least 12 (and up to 24) hours after starting appropriate antibiotics.^[2]
• Post-exposure prophylaxis for invasive group A strep follows national guidance.

There is no specific vaccine for TSS available for routine care.

Scarlet fever should be managed as a streptococcal pharyngitis. Antibiotics are given only when a streptococcal test (rapid antigen detection test, nucleic acid amplification test or throat culture) is positive; they are not given for a non-specific rash.^[2]

First-line antibiotics (CDC 2026 guidance):^[2]

• Penicillin V by mouth: children 250 mg two or three times daily for 10 days; adolescents and adults 250 mg four times daily or 500 mg twice daily for 10 days. ^[2]
• Amoxicillin by mouth: 50 mg per kg once daily (maximum 1000 mg) for 10 days, or 25 mg per kg (maximum 500 mg) twice daily for 10 days. ^[2]
• Benzathine penicillin G intramuscularly: under 27 kg one dose of 600,000 units; 27 kg or more one dose of 1,200,000 units. ^[2]

Alternatives for patients with penicillin allergy (oral): cephalexin 20 mg per kg per dose twice daily (maximum 500 mg per dose) for 10 days, cefadroxil 30 mg per kg once daily (maximum 1 g) for 10 days, clindamycin 7 mg per kg per dose three times daily (maximum 300 mg per dose) for 10 days, azithromycin 12 mg per kg once daily (maximum 500 mg) for 5 days, or clarithromycin 7.5 mg per kg per dose twice daily (maximum 250 mg per dose) for 10 days. Cephalosporins are avoided in patients with immediate-type hypersensitivity to penicillin.^[2]

Penicillin resistance has never been reported in group A streptococcus; macrolide and clindamycin resistance varies geographically and over time.^[2]

Benefits of treatment: symptom relief, reduced transmission, and prevention of acute rheumatic fever and of suppurative complications (otitis media, peritonsillar and retropharyngeal abscesses, cervical lymphadenitis, invasive group A streptococcal disease). After 12 hours of appropriate antibiotics the patient is generally no longer infectious.^[2]

Complications of scarlet fever:^[2]

• Suppurative: cervical lymphadenitis, peritonsillar and retropharyngeal abscess, otitis media and invasive group A streptococcal disease.
• Non-suppurative: acute rheumatic fever and post-streptococcal glomerulonephritis, which appear after the infection has cleared and reflect immune mechanisms rather than live organisms.

Clinical guidance for STSS and the 2026 scarlet fever guidance come from CDC publications updated in 2025 and 2026 respectively.^[1][2]

• Children. Staphylococcal TSS in children is less common but often associated with varicella or focal infection; STSS occurs in children (including post-varicella) and has a substantially lower mortality than in older adults. Scarlet fever is common in school-age children.^[1]
• Pregnancy. Postpartum STSS is rare but recognised and has the lowest mortality of the streptococcal forms; menstrual TSS can occur with tampon use; a tampon should always be removed if fever develops during the period. ^[1]
• Immunocompromised patients and patients on biologics are at increased risk of severe soft-tissue infection, and broad cover is chosen empirically.
• Older adults with diabetes, liver disease, malignancy or chronic kidney disease are the group in which STSS most often proves fatal.

• Diagnosis is clinical: fever, a scarlatiniform rash, hypotension and multi-organ failure in any patient with a source of infection. No bedside test for toxin is needed.
• Blood cultures, creatinine, liver function tests, platelets and coagulation can usually be sent; use them to count affected organs.
• Empiric therapy with penicillin plus clindamycin is inexpensive and addresses both organism and toxin; add metronidazole or broader Gram-negative cover only when a polymicrobial soft-tissue infection is suspected.
• Source control by surgical debridement may be the step that saves the most lives; if a surgeon is not available, early referral is critical.
• Tampon and wound-hygiene messages and varicella vaccination are cheap, high-impact preventive measures.

• Toxic shock syndrome is a toxin-mediated shock: bacterial superantigens polyclonally activate 5 to 30% of T-cells, producing a cytokine storm.
• Staphylococcal TSS (TSST-1 or enterotoxins A, B or C) is often menstrual and exclusively toxin-mediated, with negative blood cultures; non-menstrual disease is both septic and toxin-mediated.
• Streptococcal TSS (streptococcal pyrogenic exotoxins) complicates invasive group A streptococcal infection, usually of skin or soft tissue.
• The clinical picture is abrupt fever, diffuse macular erythroderma, hypotension and multi-organ involvement, often progressing to shock within 24 to 48 hours in STSS.
• Empiric therapy in the first hour is bactericidal antibiotics plus a toxin-suppressing agent, penicillin and clindamycin in streptococcal disease and an anti-staphylococcal beta-lactam plus clindamycin or linezolid in staphylococcal disease.
• Source control (removing tampons or debriding tissue) is mandatory; antibiotics alone do not clear the toxin.
• IVIG can be considered in severely ill patients, especially STSS, but its efficacy is not firmly established and major trials were inconclusive.
• Staphylococcal TSS mortality is about 5% overall, and 4 to 22% in non-menstrual disease; STSS mortality is 14 to 64%.
• Scarlet fever is the mild toxin-mediated end of group A streptococcal infection; diagnosis requires a positive streptococcal test, and first-line treatment is a 10-day course of penicillin.
• Rash desquamation (8 to 21 days) is a late feature that confirms retrospectively; early cases must be treated on suspicion, not on the case definition.
• NSAIDs may both predispose to STSS and mask its early signs, delaying care.

• Sepsis and septic shock
• Staphylococcus aureus infections
• Streptococcus pyogenes (group A streptococcus) infections
• Necrotizing fasciitis
• Scarlet fever
• Acute rheumatic fever and post-streptococcal glomerulonephritis
• Tampon-related and menstrual disorders
• Paediatric streptococcal infections

The numbers, doses, criteria and first-line statements in this topic come from the six references in the front matter, with quotes saved in sources/toxic-shock-syndrome/. The newest guideline editions used are CDC STSS clinical guidance (5 August 2025) and CDC scarlet fever clinical guidance (20 February 2026), with IDSA 2014 skin and soft-tissue guidelines and the Atchade et al. 2024 literature review for treatment evidence. Where the literature is divided, for example on IVIG efficacy, both positions are given rather than a single conclusion.