eMedicine Specialties > Emergency Medicine > Infectious Diseases

Toxic Shock Syndrome

Vicken Y Totten, MD, MS, FACEP, FAAFP, Assistant Professor, Case Western Reserve University School of Medicine; Director of Research, Department of Emergency Medicine, University Hospitals, Case Medical Center
Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center

Updated: Aug 31, 2009

Introduction

Background

Toxic shock syndrome (TSS) is a shock syndrome caused by the inflammatory response to toxins produced by various bacteria, most commonly Streptococcus and Staphylococcus species. Staphylococcal TSS (STSS) was first described by Todd et al in 1978.¹ He described 7 children aged 8-17 years who had shock from S aureus infection, and they distinguished this syndrome from the scalded skin syndrome. Cone et al, in 1987, published observations on 2 patients with streptococcal toxic shock.²
 

Group A streptococci on Gram stain of blood isolated from a patient who developed toxic shock syndrome. Courtesy of T. Matthews.

In 1995, the Centers for Disease Control and Prevention (CDC) published a Case Definition for Streptococcal Toxic Shock Syndrome and updated it in 1996. In 1997, the CDC published a Confirmed Case Definition for Toxic Shock Syndrome (TSS), which removed the requirement for culture-positive streptococcal species and specifically permitted Staphylococcus aureus infection to be included in the definition.5 The case definition no longer requires confirmation of infection by a specific organism.  

TTS has been linked to many initiating bacterial infections, including pneumonia, osteomyelitis, sinusitis, and skin as well as gynecologic conditions and infections.

To qualify as toxic shock syndrome, a patient must have a temperature higher than 38.9°C, hypotension (septic shock), the typical diffuse erythroderma followed by desquamation (unless the patient dies before desquamation can occur) and involvement of at least 3 organ systems. Criteria for a probable case are met when a patient lacks only one of the characteristics of the confirmed case definition.⁵ Also see Toxic-Shock Syndrome Clinical Case Definition from the CDC.

Pathophysiology

Toxic shock syndrome is the result of the immune system’s reaction to one or more of a large family of true exotoxins referred to collectively as pyrogenic toxin superantigens, which are produced by certain streptococci and staphylococci. Superantigens are referred to in the pertinent literature as SAgs. Superantigens cause T-cell activation, subsequent activation of other cell types, and prodigious release of cytokines and chemokines. These superantigens bind to MHC class II molecule and T-cell receptor. This binding activates 20-30% of T cells, whereas a typical antigen activates only 0.01% of T cells. The structures of the specific toxins vary by bacterial genetic subtype. Superantigen and endotoxin are clearly both toxic with the latter responsible for septic shock in gram (-) sepsis. Both given together, however, is 50,000 times more lethal than with either toxin given by itself.⁶

Other documented virulence factors include a complement-inhibiting protein (also known as streptococcal inhibitor of compliment or sic), an exotoxin (speA), iron(III) binding factor, collagen binding factor (cpa), and fibrinogen binding factor (prt2-like).7  Not all of these factors are expressed by every bacterium that has been implicated in toxic shock syndrome (TSS).

By 1990, the superantigen exotoxin TSS toxin-1 (TSST-1) had been implicated in most cases of menstrual TSS (mTSS) and was designated SAg TSST-1.

Nonmenstrual TSS can be associated with any of the 15 other described SAgs but is most often associated with S aureus strains that make TSST-1, staphylococcal enterotoxin B (SEB), or staphylococcal enterotoxin C (SEC). Nonmenstrual TSS commonly follows bacterial superinfection of the upper respiratory tract after viral infection. Nonmenstrual TSS can be caused by TSST-1 (50%) or by SEB or SEC (together nearly 50%).

Enterotoxins A-E have all been characterized. All are relatively low molecular weight, fairly heat- and protease-stable molecules. TSST-1 is a protein with two major domains, referred to as A and B. The molecule begins with a short N-terminal alpha-helix that then leads into a claw-shaped structure in domain B that is made up of beta strands. Sequencing studies indicate that staphylococcal enterotoxins B and C and streptococcal pyrogenic exotoxin A share highly significant sequence similarity; staphylococcal enterotoxins A, D, and E share highly significant sequence similarity; while TSST-1 and streptococcal pyrogenic exotoxin B and C share little, if any, sequence similarity with any of the other toxins.⁸ Staphylococcal enterotoxins B and C were found to share nearly 50% sequence homology with streptococcal scarlet fever toxin A, although they share no homology with TSST-1.⁹  

By 1999, the M factors were elucidated. M1 is the bacterial subtype most frequently associated with invasive disease, followed by M3, M28, M12, and M4 strains. By 2002, amino-acid sequencing and genetic sequencing demonstrated that the surface-exposed group A streptococcal (GAS) protein M, of which over a hundred subtypes have been identified, was a primary determinant of virulence. Amino acid variation in the amino-terminal portion of the protein serves as the basis for the determination of the M type.

The emm gene codes for the M protein, and although Tyrrell et al have shown that the M1 type can be characterized based on variation seen within the sic gene, investigators have reported emm gene sequencing is a better method of typing GAS. (Incomplete international collections of M antisera limit the ability to serologically characterize all of the new emm types, and these are therefore currently referred to as emm types rather than M types.)¹⁰

Endotoxin mechanism of action

These endotoxins are called superantigens because they do not require processing by antigen-presenting cells but instead interact directly with the invariant region of the class II major histocompatibility complex (MHC) molecule of the human T cells.

In typical T-cell recognition, an antigen is taken up by an antigen-presenting cell, processed, expressed on the cell surface in complex with class II MHC in a groove formed by the alpha and beta chains of class II MHC, and recognized by an antigen-specific T-cell receptor.11  

The superantigen-MHC complex then interacts with the T-cell receptor and directly stimulates human T cells (up to 20% at a time) to release massive amounts of the cytokines that cause the main clinical features of TSS. These cytokines include interleukin-1β (an endogenous pyrogen); tumor necrosis factor-α and β (TNF α and β), which cause capillary leakage; and finally interferon-γ and interleukin 2, which are implicated in the typical rash.12  Additionally, interleukin 1 (IL-1) is released. It is an endogenous pyrogen and thus causes the high fevers associated with TSS. IL-1 mediates skeletal muscle proteolysis and probably accounts for the myalgia and elevated creatine phosphokinase (CPK) level seen in TSS.¹³

TNF inhibits both random and chemotactic migratory polymorphonuclear leukocyte (PMN) functions. TSST-1–producing S aureus do not engender a purulent response, which, in part, may be explained by PMN inhibition.¹⁴ The streptococcal pyrogenic exotoxin B (SpeB) probably also damages PMNs via mitochondria damage and thus impedes early immune clearance.15  TSST-1 and enterotoxin B may repress the production of other S aureus exoproteins. This may explain the absence of purulence in TSS caused by S aureus infections.16

Frequency

United States

In 1980, the rates of staphylococcal TSS ranged from 2.4-16 cases per 100,000 population.17 Subsequently, rates of menstrual-related TSS declined because of a decrease in the use of superabsorbent tampons.

The 1995-1999 epidemiology of invasive group A streptococcal disease in the United States was investigated by O'Brien et al who found 3.5 cases per 100,000 persons. Rates varied by age (higher among those <2 or ³ 65 years old), surveillance area, and race (higher among black individuals), but the rate did not increase during the study period. They found that certain subtypes (1, 28, 12, 3, and 11) accounted for 49.2% of isolates, whereas newly characterized emm types accounted for 8.9% of isolates.¹⁸

The incidence of staphylococcal toxic shock syndrome in Minneapolis-St. Paul, Minnesota, rose from 0.8 per 100,000 in January 2000 to 3.4 per 100,000 in December 2003.^8,19  Schlievert hypothesized, in aletter to the editor,²⁰ that the increase in incidence resulted partly from the emergence of 3 new strains of methicillin-resistant Staphylococcus aureus (MRSA) and partly from a decreasing age of menarche, which may have put more women at risk of menstrual TSS, and possibly because of a broader definition on the part of the reporting physicians than the strict CDC definition.  

These 3 newly emerging MRSA strains are in CDC nomenclature:

• USA 1100 (TSST-1 positive)
• USA 400 (SEB/SEC, Panton–Valentine leukocidin [PVL] positive)
• USA 300, which is positive for an unknown superantigen as well as PVL)   

Two of these are emerging worldwide. 

Schlievert and Schlievert et al found that the USA 1100 strains (which, in 2004, comprised 20% of submitted isolates, compared to none before the year 2000) were particularly virulent.^8,19 These strains produce 10-100 times more TSST-1 in vitro than their MRSA counterparts and may cause menstrual TSS even in women using lower-absorbency tampons.  

The USA 400 and USA 300 strains are also emerging and are associated with increases in nonmenstrual toxic shock syndrome. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts.^8,19

International

The prevalence and distributions of GAS in Canada have historically been similar to those in the United States. During 1993-1999, the National Centre for Streptococcus (NCS) in Canada detected 54 M types, of which 10 different M types constituted 73.5% of the samples. M1 was the most common GAS M and responsible for more than a quarter of the isolates. The most common throat isolates differed in M-type and proportion from invasive isolates.¹⁰

In Sweden in 1994 and 1995, Svensson et al found a lethality of 37% in the 113 patients who developed streptococcal toxic shock syndrome. Serotype T1 dominated during the study period. They did not describe the population incidence.²²  

Denmark maintains a National Streptococcus Unit. In 2005, Ekelund et al reported that the incidence of invasive GAS infections in the Danish population was 2.3 per 100,000 per year, and STTS occurred in 10% of patients, of whom 56% died. Seventy-two percent of 493 emm types isolated were types 1, 3, 4, 12, 28, and 89. From 1999 to 2002, the percentage of emm 1 increased from 16% to 40%, and emm 3 decreased from 23% to 2%. The emm 1 isolates predominantly carried speA, although the frequency decreased from 94% in 1999 to 71% in 2002. During the same period, the emm1-specific prevalence of speC increased from 25% to 53%.23  

In the Netherlands, Gooskens et al reported that, in 2005, a macrolide-lincosamide-streptogramin B antibiotics resistant GAS (cMLS or iMLS phenotype) associated with streptococcal toxic shock syndrome (STSS) caused by an iMLS resistant T28 M77 Streptococcus.24   

Mortality/Morbidity

Independent predictors of death from TTS include infection with streptococci of serotype T1, diabetes, age younger than 2 or older than 75 years, presence of streptococcal toxic shock syndrome, concomitant meningitis or pneumonia, and infection with genetic variant types emm1 or emm3.  

O'Brien et al estimated that 9,600-9,700 cases of invasive GAS disease occur in the United States each year, resulting in 1,100-1,300 deaths.¹⁸

Race

Little information is available on the effect of race per se on TSS. Parsonnet et al studied more than 3000 women in North America and found that 25% were colonized by S aureus and 9% were vaginally colonized. Although the vast majority of women had adequate antibody titers, a significantly lower percentage of black women than women of white or Hispanic ethnicity were found to have high antibody titers to TSST-1.²⁶  

Related race information comes from sepsis studies. Dombrovskiy et al studied the influence of race on occurrence and outcomes of sepsis. They found that blacks who were hospitalized for sepsis were significantly younger than whites, blacks had greater hospitalization rates than whites, blacks had higher age-adjusted rates for hospitalization and mortality, but similar case-fatality rates, and concluded that hospital care was equally as good for blacks as whites. The differences, they postulated, were due to preexisting factors. Black patients had a greater likelihood of preexisting human immunodeficiency virus infection, diabetes, obesity, burns, and chronic renal failure than white patients. They had a smaller likelihood of cancer, trauma, and urinary tract infection.²⁷

Thus, the effect of race is most likely due to other factors.

Sex

• Menstrual-associated TSS is a disease affecting only women. 
• Nonmenstrual TSS affects either gender equally.

Age

Incidence: The lethality of TSS is, in part, due to the invasiveness of the organisms and, in larger part, due to the hyperstimulation of the immune system. Young adults have the most vigorous immune system and may be more likely than individuals with less reactive immune systems to develop the full toxic shock syndrome.

Death: Untreated, however, the very young, very old, and otherwise feeble are more likely to succumb to the bacterial onslaught.

• Staphylococcal TSS occurs primarily in patients aged 15-35 years.
• Streptococcal TSS occurs primarily in patients aged 20-50 years.
• mTSS predominantly occurs in young, healthy, menstruating women who use tampons.

Clinical

History

The symptoms are similar for streptococcal TSS and staphylococcal TSS.

Symptoms may include the following:

• Prodromal period of 2-3 days
• Fever and/or chills
• Nausea and/or vomiting
• Profuse watery diarrhea with abdominal pain
• Lightheadedness and/or syncope
• Myalgias and/or arthralgias
• Pharyngitis and/or headache
• Confusion (more common with staphylococcal TSS than with streptococcal TSS)
• Pain (severe) at site of infection (most common symptom of streptococcal TSS). This pain is way out of proportion to the findings, which may be trivial such as muscle strain, blunt trauma, hematoma, or joint effusion.
• Additionally, one may find concomitant meningitis, pneumonia, and soft tissue infection.

Physical

To meet CDC criteria for TSS, one must find fever, rash, shock, and multisystem involvement. See Toxic-Shock Syndrome Clinical Case Definition from the CDC.

• Temperature ³ 38.9°C (102°F)
• Rash 
  • Initial diffuse, macular, red rash that is sometimes patchy; may have sand-paper-like texture
  • Appears initially on the trunk, then spreads to arms and legs; will involve the palms and soles
  • If the patient survives, the rash typically desquamates 1-2 weeks after onset of illness.
  • Desquamation is especially prominent on the palms and soles.

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The patient had diffuse erythroderma, a characteristic feature of the syndrome. The patient improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over palms and soles. Courtesy of Rob Green, MD.

• Hyperemia of mucus membranes, such as conjunctiva and vaginal or oral mucosa, may be a confluent version of the cutaneous rash.

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. This patient also had streptococcal pharyngitis. Courtesy of Rob Green, MD.

• Shock  
  • SBP £ 90 mm Hg (for adults); less than 5^th percentile by age for children <16 years, or
  • orthostatic drop in diastolic blood pressure ³ 15 mm Hg from lying to sitting, or
  • orthostatic syncope, or
  • orthostatic dizziness
• Multisystem involvement requires 3 or more of the following:  
  • Gastrointestinal - Vomiting or diarrhea at onset of illness 
  • Muscular - Severe myalgia or creatine phosphokinase level at least twice the upper limit of normal; necrotizing fasciitis and/or myositis
  • Mucous membrane hyperemia - Vaginal, oropharyngeal, or conjunctival
  • Central nervous system - Disorientation or alteration in consciousness without focal neurologic signs when fever has been controlled, and when hypotension is absent. CNS abnormalities particularly associated with nonmenstrual staphylococcal toxic shock syndrome.
  • Respiratory - Acute respiratory distress syndrome; pneumonia; reactive airways may be more reactive²⁸
  • Hematologic - Disseminated intravascular coagulation (DIC); thrombocytopenia
  • Renal - Renal complications are particularly associated with nonmenstrual staphylococcal toxic shock syndrome.

Causes

Toxic shock syndrome (TSS) is caused by the reaction of the human immune system to bacterial superantigens. A defect of protective immunity is postulated to be a major risk factor for recurrence of TSS.

Superantigens are produced by various species of coagulase-positive staphylococci, most notably Staphylococcus aureus but also the zoonoses S suis (common in pigs), Streptococcus mitis (in mice), and Streptococcus agalactiae. Group A beta-hemolytic streptococci notably (Streptococcus pyogenes) also produce superantigens. 

Most people acquire both streptococcal and staphylococcal infections in childhood and have some level of protective immunity against the bacteria. Immunity against the toxins is less widespread, but as many as 80% of young women have been reported to have antibodies to TSST-1.

With staphylococcal toxic shock syndrome, there is a menstrual type associated with menstruation and use of tampons and a nonmenstrual variety associated with antibiotic usage or nosocomial etiology. Risk factors include the following:

•  Body cavity packing   
  • Use of superabsorbent tampons
  • Nasal packing
  • Wound packing
  • Uterine packing after postpartum hemorrhage
  • Rhinosinusitis in children²⁹
• Other risk factors   
  • Postoperative wound infection
  • Postpartum state
  • Common bacterial infections
  • Viral infection with influenza A or varicella
  • Group A streptococcal pharyngitis in a healthy man with death in 24 hours³⁰
  • Diabetes mellitus
  • Infection with HIV
  • Chronic cardiac and/or pulmonary disease
  • An association of TSS with prior use of nonsteroidal anti-inflammatory drugs has been suggested, but a causal relationship has not been established.
  • Nipple piercing³¹

Differential Diagnoses

Other Problems to Be Considered

Rocky Mountain spotted fever, hepatitis B, antinuclear antibody, syphilis, or acute mononucleosis, other viral exanthems, erysipelas, disseminated cellulitis
Pneumococcal sepsis
Sepsis of other causes 
Drug rash with high fever
Necrotizing fasciitis (This is also a GAS infection but requires immediate surgical debridement.)
Other invasive GAS

Workup

Laboratory Studies

None of the tests below are definitive, but results may typically show the following findings: 

• CBC
  • High WBC, with a large proportion of immature forms (77% of cases)
  • Mild anemia with abnormal cells on smear
  • Thrombocytopenia
• Electrolyte panel
  • Hyponatremia, hypokalemia, hypocalcemia out of proportion to hypoalbuminemia, hypophosphatemia, and hypomagnesemia
• Renal function tests
  • Acute renal failure manifested by creatinine or BUN at least twice the upper limit of normal for laboratory (or doubling from the patient’s recent pre-illness norm)
  • GFR <50
•  Liver function tests
  • Hyperbilirubinemia (76% of cases)
  • Aspartate aminotransferase (AST) level at least twice the upper limit of normal for laboratory (or doubling from the patient’s recent pre-illness norm) is found in 75% of cases.
  • Alanine aminotransferase (ALT) levels at least twice the upper limit of normal for laboratory (or doubling from the patient’s recent pre-illness norm) is found in 50% of cases.
• Urine analysis
  • Sterile pyuria (greater than or equal to 5 leukocytes per high-power field)
  • Myoglobinuria
  • Protein, glucose, and red cell casts
• Cultures
  • Positive blood cultures are not required to make the diagnosis but, when positive, are helpful at guiding antibiotic therapy. Positive staphylococcal blood cultures are only found in 5% of cases. More than 50% of patients with streptococcal TSS have a positive blood culture result.

Group A streptococci cause beta hemolysis on blood agar.

• • Culture all potentially infected sites. Group A streptococci may be isolated from a normally sterile site (eg, blood, cerebrospinal fluid [CSF], surgical wound). Isolation of GAS from a nonsterile site (eg, throat) does not confirm the diagnosis but may strengthen suspicion.
  • Although not strictly a culture, the rapid streptococcal test can be performed in 10-15 minutes and has a sensitivity of 87-95%.
• Arterial blood gas analysis
  • ABG analysis may show acidosis, hypoxia, and variable carbon dioxide levels.
  • This is an important part of ICU monitoring; look for acute respiratory distress syndrome.
• Serologic tests
  • Results should show absence of serologic evidence of acute Rocky Mountain spotted fever, leptospirosis, measles, German measles, hepatitis B, antinuclear antibody, syphilis, or acute mononucleosis.
  • Creatine phosphokinase or myoglobin levels may indicate rhabdomyolysis (63% of cases).
  • Lactate level is often used in diagnosing septic shock. It may be included in a "full" blood gas. Monitoring lactate levels may assist in evaluating prognosis.34
  • VDRL test and Monospot can also be obtained.
• Coagulation studies
  • Activated partial thromboplastin time (aPTT) (46% of cases) and fibrin split products are elevated.
  • Fibrinogen levels and prothrombin time (PT) usually are normal.
• Miscellaneous
  • ProCalcitonin may be helpful in predicting septic multiorgan failure.35
  • C-reactive protein (CRP) level is usually elevated, and its rise parallels the rise in brain natriuretic peptide (BNP), but CRP has not been shown superior to WBC count in diagnosing TSS, and it does not independently predict mortality.
  • BNP has been proposed as a biomarker in sepsis, but it has not been validated.

Imaging Studies

Imaging studies are primarily helpful in ruling out other illnesses.

• Chest radiographs may show pulmonary edema or ARDS. Sometimes, pneumonia can be the inciting factor for TTS; the presence of pneumonia does not rule out TTS.
• Abdominal or extremity radiographs may show air if necrotizing fasciitis is present, or an embedded foreign body may be found.
• Ultrasonography may be more effective in finding free air or embedded radiolucent foreign body.
• CT scan may be more effective than plain radiography in identifying abscess or air in tissues.
• MRI may show multiple areas of ischemic injury as in other shock syndromes.
• Echocardiography may show wall-motion abnormality suggestive of toxic cardiomyopathy.

Other Tests

• The ECG may show the following:
  • Tachycardia
  • Ventricular arrhythmias
  • Bundle-branch blocks
  • First-degree heart block
  • ST-T–wave changes, with ischemia

Procedures

• Hemodynamic monitoring is mandatory. This may include arterial pressure line, cardiac monitoring, and continuous percutaneous O₂ and CO₂ monitoring.
• Lumbar puncture should be performed if the diagnosis is in question and meningitis is considered. Findings should be normal in TSS. Cultures growing S aureus do not rule out TTS.
• Patients may require large volumes of fluids for resuscitation, along with transduction of central venous pressures to guide management and pressors. Thus, central venous access may be indicated.
• Echocardiography may be useful in the ICU setting. Many patients will have hypokinesis of the ventricular wall, and echocardiography may help guide management of associated cardiac failure.

Treatment

Prehospital Care

• Oxygen should be provided.
• Aggressive fluid resuscitation should begin in the field, especially for the severely hypotensive patient.
• If toxic shock syndrome (TSS) is suspected in a menstruating woman, prior to transport, her tampon, if present, should be removed.
• If TSS is suspected in the field in a person with deep wound packing that packing should be removed.
• Rapid transport to a hospital capable of managing severe shock is definitive prehospital management.

Emergency Department Care

Early goal-directed therapy (EGDT) is aimed at hemodynamic optimization within the first 6 hours. It has been shown to reduce mortality in patients with severe sepsis and septic shock.36

Endpoints for optimization are central venous pressure (CVP), mean arterial pressure (MAP), and central venous oxygen saturation (ScvO₂).

• Start intravenous crystalloid infusion, O_2, and place continuous cardiac and pulse oximetry monitors. Pulse oximetry, (pulse co-oximetry if available), cardiac and respiratory monitoring, and continuous exhaled carbon dioxide monitoring may be useful.
• Obtain blood for above tests, also type and crossmatch.
  • Optimizing delivered oxygen may require transfusion.
• Culture all potential inciting sites.
• Hemodynamic monitoring: Treat high-grade arrhythmias.
• Oxygen and respiration
  • Maximize tissue oxygenation and correct hypoxia and/or acidosis.
  • Assisted ventilation may be required to support oxygenation or if acute respiratory distress syndrome develops.
• A Foley catheter should be placed to monitor urine output and assess adequacy of resuscitation/end-organ perfusion.
• Remove any intracavitary fibrous materials.
  • This includes vaginal and nasal tampons and any fibrous foreign body in an abscess cavity.
  • Some authorities recommend irrigating the abscess cavity or vaginal vault with isotonic sodium chloride solution to remove necrotic material and excess bacterial load.
• Fluid resuscitation may need to be massive.
  • As much as 10-20 L/day of crystalloid may be necessary.
  • Some authors suggest that colloids may decrease the risk of pulmonary edema.
• Start antibiotics.
  • Antibiotics should be started as soon as the disease is suspected. Each hour of delay in antimicrobial administration over the ensuing 6 hours after onset of hypotension decreased survival an average of 7.6%.37
  • Antibiotics best are guided by the local biogram. Please see below for empiric suggestions.
  • Calculation of the Mortality in Emergency Department Sepsis Score (MEDS) may assist in further management.²⁸
• Admit to ICU setting. 

ICU Care and Treatment

• Continue care started in ED, for example, intravenous fluids, O₂, pressors, and monitoring
• Culture blood, urine, wounds, and cavities as indicated if not already done.
• Type and crossmatch: Optimizing delivered oxygen may require transfusion.
• Calculate APACHE II score. Changes in score are an effective monitoring tool.
• Treat only high-grade arrhythmias.
• Initiate or continue early goal-directed therapy (EGDT).³⁸
  • Optimize within 6 hours
    • CVP
    • MAP
    • ScvO₂
  • EGDT was associated with a 16% absolute risk reduction for in-hospital mortality, which, to date, is the largest mortality benefit demonstrated in a sepsis randomized controlled trial. Current consensus recommendations now advocate EGDT as best practice for the first 6 hours of severe sepsis resuscitation.
• Hyperbaric oxygen therapy has been used in necrotizing soft-tissue infections, but the benefit of this intervention has not been proven in TTS.

Consultations

• Intensivist: The high mortality and morbidity rates mandate care in an intensive care environment
• Infectious disease: The worldwide emergence of MRSA and the changing sensitivities of streptococci and staphylococci suggest that local infectious diseases consultation is warranted.
• Surgical: Prompt surgical consultation may be necessary for drainage, debridement, fasciotomy, or amputation of a clearly infected site, especially if necrotizing fasciitis is suspected.

Medication

• Oxygen/respiration³⁸
  • Supplement and optimize tissue oxygenation, but avoid supranormal oxygen delivery because of potential toxicity (Surviving Sepsis Campaign).
  • Intubation and mechanical ventilation may be needed. However, a low tidal volume and limitation of inspiratory plateau pressure may reduce acute lung injury and minimize acute respiratory distress syndrome.
  • If acute lung injury/acute respiratory distress syndrome develop, consider a minimal amount of positive end-expiratory pressure.
  • Semirecumbent bed position unless contraindicated.
• Intravenous fluids
  • Crystalloid is recommended. No research has proven the benefit of one crystalloid over another.
  • Controversy remains about the benefit, if any, of colloids over crystalloids in shock.39
  • Aggressive fluid administration to normalize flow and perfusion is indicated. This may result in CHF and edema. Central intravenous access for delivery of fluid and for pressure monitoring may be required.
  • Supplement cross-matched blood to a target hemoglobin of 7-9 g/dL.
  • Fresh frozen plasma and platelets should be provided as needed for signs of coagulopathy or disseminated intravascular coagulation.
• Antibiotics
  • Cover both staphylococci and streptococci until a definitive diagnosis is made.
  • Continue antibiotics for a minimum of 7 days; 10 days may be preferable.
  • TSS requires penicillinase-resistant antibiotics.
  • Because of the increasing resistance of streptococci to penicillin G, clindamycin often is considered the drug of first choice for invasive group A streptococcal infections such as STSS.
• Pressors
  • Pressors may be needed. The Surviving Sepsis Campaign supported norepinephrine and dopamine over other pressors;⁴⁰ Patel et al disagrees and recommends vasopressin.41  
  • Vasopressin, epinephrine, norepinephrine, dopamine, dobutamine, and others remain in common clinical use with norepinephrine the preferred inotrope in septic shock.
  • Avoid low-dose dopamine for renal protection; consider dobutamine inotropic therapy.
• Steroids
  • Short courses of high-dose glucocorticoids decrease survival during sepsis, but a 5- to 7-day course of physiologic hydrocortisone with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.42
  • Long course of low-dose corticosteroids reduced 28-day all-cause mortality and intensive care unit and hospital mortality.43
• Immunoglobulins
  • The use of intravenous immunoglobulin G (IVIG) has been shown to be effective in neutralizing the TSS toxin and therefore aids in recovery. The dose is 1 g/kg and should be given within 6 hours if no rapid response to therapy. IVIG has doubled 30-day survival.⁴⁴
  • However, different batches from different manufacturers may have different efficacy.⁴⁵
  • Staphylococcal superantigens are not inhibited as efficiently as streptococcal superantigens by IVIG, and, hence, a higher dose of IVIG may be required for therapy of staphylococcal toxic shock syndrome in order to achieve protective titers and clinical efficacy.⁴⁶
  • Alimentation/hyperalimentation: Numerous studies over the years have shown that stressed patients recover better when they have a source of nutrition.
• Antioxidants: These have shown some clinical benefit.
  • Glutathione (GSH) has been used for this purpose.⁴⁷
  • Short-term intravenous infusion of N -acetyl-L-cysteine (NAC)48
  • Intravenous preparations of vitamin C
• Recombinant activated protein C: Recommended by Surviving Sepsis Campaign for patients with severe sepsis and high risk for death.³⁸

Antibiotics

Semisynthetic penicillins have been widely used for toxic shock syndrome (TSS). Growing evidence suggests that the protein synthetase inhibitor, clindamycin, a bacteriostatic agent may be more efficacious in this illness. Accordingly, these authors recommend treating patients suspected of TSS initially with clindamycin, 900 mg IV q8h for adults (13 mg/kg IV q8h for children) in combination with a linezolid (600 mg IV q12h) or daptomycin (6 mg/kg q24h). Vancomycin is another agent to be considered at 1 g q12h instead of clindamycin, but with vancomycin resistance being reported, the authors prefer clindamycin.

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 IV q12h for 7-10 d

Pediatric

Preterm neonate <7 days: 10 mg/kg PO/IV q12h for 7-10 d
Term neonates to 12 years: 10 mg/kg PO/IV q8h for 7-10 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; 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 MAO inhibitor properties and has potential to have same interactions as other MAO inhibitors; 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

Nafcillin (Unipen)

Treats infections caused by penicillinase-producing staphylococci, and, therefore, it is used for penicillin G-resistant staphylococcal infections. Not for use in treatment of penicillin G-susceptible staphylococcus. Use parenteral therapy initially in severe infections, with very high doses for very severe infections. Change to oral therapy as the condition improves. Because of the occasional occurrence of thrombophlebitis, associated with the parenteral route, especially in elderly patients, administer parenterally only for a short term (24-48 h), and change to the oral route as soon as clinically possible.

Dosing

Adult

1-2 g IV q4h for 7-10 d

Pediatric

50-200 mg/kg/d IV divided q4-6h for 7-10 d

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; use >10-d treatment to eliminate infection and prevent sequelae (eg, endocarditis, rheumatic fever); obtain cultures after treatment to confirm infection eradication

Clindamycin (Cleocin)

DOC for invasive group A streptococcal infections (eg, 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 tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Dosing

Adult

900 mg IV q8h for 7-10 d

Pediatric

13 mg/kg IV q8h for 7-10 d

Interactions

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

Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; 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

Daptomycin (Cubicin)

First of new antibiotic class called cyclic lipopeptides. Binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis, and ultimately causing cell death.
Indicated to treat complicated skin and skin structure infections caused by S aureus (including methicillin-resistant strains), S pyogenes, S agalactiae, S dysgalactiae, and E faecalis (vancomycin-susceptible strains only).

Dosing

Adult

CrCl >30 mL/min: 6 mg/kg IV q24h infused over 30 min for 7-10 d
CrCl <30 mL/min: 6 mg/kg IV q48h (including hemodialysis or CAPD) for 7-10 d

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

Coadministration with tobramycin slightly increase daptomycin C_max and AUC and decreases tobramycin C_max and AUC; may experience additive effects with other drugs causing myopathy (eg, HMG CoA reductase inhibitors)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

Decrease dose with renal function <30 mL/min; pseudomembranous colitis may occur; may cause muscle pain or weakness, monitor CPK levels and discontinue daptomycin with elevated CPK and unexplained myopathy, or marked CPK elevation (10-times upper limits of normal); not indicated for pneumonia (higher death rate in daptomycin-treated patients during phase III trials); not compatible with dextrose-containing solutions

Vancomycin (Vancocin)

Used in prophylaxis. Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated for patients who can not receive or have failed to respond to penicillins and cephalosporins or have infections with resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora and/or anaerobes.

To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment.

Used in conjunction with gentamicin for prophylaxis in penicillin allergic patients undergoing gastrointestinal or genitourinary procedures.

Dosing

Adult

1 g IV q12h for 7-10 d

Pediatric

40 mg/kg/d IV divided tid/qid for 7-10 d

Interactions

Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants

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

Caution in renal failure, neutropenia; red man syndrome is caused by too rapid IV infusion (dose given over a few min) but rarely happens when dose given IV over 2 h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Follow-up

Further Inpatient Care

• Admit the patient with toxic shock syndrome (TSS) to the ICU for further hemodynamic monitoring and/or ventilatory support.
• Parenteral antibiotic therapy should be administered for 7 days, followed by 7 days of oral therapy.
• Some patients may require dialysis.

Further Outpatient Care

• Close follow-up is recommended, because some patients can have sequelae.
• Patients with one episode of toxic shock syndrome are at higher risk than the general population for further episodes. A recurrence may occur in 40-50% of cases.

Complications

• Reversible loss of hair and nails
• Prolonged neuromuscular abnormalities
• Late-onset rash
• Gangrene and/or cyanotic extremities
• Memory and/or concentration difficulties
• Recurrence of TSS

Prognosis

• The prognosis generally is poor for streptococcal TSS, with mortality rate as high as 70%.
• Recurrences may occur in 40-50% of patients.
  • Most recurrences occur sooner than 2 months after the initial episode.
  • Recurrences generally are less severe than the initial episode, but deaths have been reported.

Patient Education

• eMedicine's Women's Health Center eMedicine's patient education article Toxic Shock Syndrome.
• Merck Manual On-Line Patient Education resource
• Ohio State University Medical Center
• McGraw Hill’s Access Medicine
• University of Pittsburgh Medical Center’s Patient Education site includes Spanish language information
• New York-Presbyterian Hospitals Patient Education Site
• NYU Medical Center Patient Information Center also includes Spanish language information
• The Toxic Shock Syndrome information service (TSSIS) 
• Children’s Medical Center of Dallas gears their information toward parents of small children
• Main Line Health "Kids Health"
• Answers.com

Miscellaneous

Medicolegal Pitfalls

• Lack of early surgical control of the infection

Multimedia

Media file 1: Group A streptococci cause beta hemolysis on blood agar.

Media file 2: Group A streptococci on Gram stain of blood isolated from a patient who developed toxic shock syndrome. Courtesy of T. Matthews.

Media file 3: Progression of soft tissue swelling to vesicle or bullous formation is an ominous sign and suggests streptococcal shock syndrome. Courtesy of S. Manocha.

Media file 4: A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The leg was incised to exclude underlying necrotizing infection. Courtesy of Rob Green, MD.

Media file 5: A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. This patient also had streptococcal pharyngitis. Courtesy of Rob Green, MD.

Media file 6: A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The patient had diffuse erythroderma, a characteristic feature of the syndrome. The patient improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over palms and soles. Courtesy of Rob Green, MD.

Media file 7: Necrotizing cellulitis of toxic shock syndrome.

Media file 8: Soft tissue infection secondary to group A streptococci, leading to toxic shock syndrome.

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Keywords

toxic shock syndrome, TSS, toxic shock, toxins, endotoxin, exotoxin,  toxin-1, TSST-1, Streptococcus pyogenes exotoxin A, SPEA, S pyogenes exotoxin B, SPEB, streptococcal TSS, staphylococcal TSS, streptococcal toxic shock syndrome, staphylococcal toxic shock syndrome, pyrogenic toxin superantigens, pyrogenic toxin super-antigens, menstrual toxic shock, non-menstrual toxic shock

Contributor Information and Disclosures

Author

Vicken Y Totten, MD, MS, FACEP, FAAFP, Assistant Professor, Case Western Reserve University School of Medicine; Director of Research, Department of Emergency Medicine, University Hospitals, Case Medical Center
Vicken Y Totten, MD, MS, FACEP, FAAFP is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Theodore J Gaeta, DO, MPH, FACEP, Clinical Associate Professor, Department of Emergency Medicine, Joan and Sanford Weill Medical College at Cornell University; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine
Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: Alliance for Clinical Education, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council of Emergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Mark L Plaster, MD, JD, Executive Editor, Emergency Physicians Monthly
Mark L Plaster, MD, JD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians
Disclosure: M L Plaster Publishing Co LLC Ownership interest Management position

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Dane Salandy, MD†, and previous editor, Charles V Pollack, Jr, MD, to the development and writing of this article.

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