AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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

INTRODUCTION

Section 2 of 11  

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

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

The syndrome gained notoriety after the publication in 1981 of an association between TSS and tampon use in healthy menstruating women.³ The findings of the informal Working Group on Severe Streptococcal Infections, published in 1993, differentiated TSS from other severe invasive group A streptococci (GAS) infections by the early development of hypotension.⁴ The disease has subsequently been described in patients of all ages and races and in both genders.  

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.

For a CME activity, see Invasive Group A Streptococcal Disease in Nursing Homes, Minnesota, 1995-2006.

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. The structures of the specific toxins vary by bacterial genetic subtype.

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).⁶ Not all of these factors are expressed by every bacterium that has been implicated in 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.⁷ 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-1.⁸ 

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.)⁹

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.¹⁰ 

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.¹¹ 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.¹²

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.¹³ The streptococcal pyrogenic exotoxin B (SpeB) probably also damages PMNs via mitochondria damage and thus impedes early immune clearance.¹⁴ 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.¹⁵

Frequency

United States

In 1980, the rates of staphylococcal TSS ranged from 2.4-16 cases per 100,000 population.¹⁶ 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 ³65 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.¹⁷

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.^{7, 18} Schlievert hypothesized, in a letter to the editor,¹⁹ 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.^{7, 18} 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 TSS. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts.^{7, 18}

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.⁹

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.²¹ 

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 emm1 increased from 16% to 40%, and emm3 decreased from 23% to 2%. The emm1 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%.²² 

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.²³  

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.¹⁷

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-1.²⁵ 

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.²⁶

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

Section 3 of 11  

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

History

The symptoms are similar for streptococcal TSS and staphylococcal TSS.

• 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 at site of infection (most common symptom of streptococcal TSS)
• 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 ³38.9°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.
  • Hyperemia of mucus membranes, such as conjunctiva and vaginal or oral mucosa, may be a confluent version of the cutaneous rash.
• 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 ³15 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
  • Respiratory - Acute respiratory distress syndrome; pneumonia; reactive airways may be more reactive²⁷
  • Hematologic - Disseminated intravascular coagulation (DIC); thrombocytopenia

Causes

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.

Risk factors include the following:

•  Body cavity packing   
• • Use of superabsorbent tampons
  • Nasal packing
  • Wound packing
  • Uterine packing after postpartum hemorrhage
• Other risk factors   
• • Postoperative wound infection
  • Postpartum state
  • Common bacterial infections
  • Viral infection with influenza A or varicella
  • 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.

Antibody responses 

Both streptococci and staphylococci are prevalent in the environment, and most persons encounter both the bacteria and their toxins in early life without developing toxic shock syndrome. About 75% of adults have antibodies against TSST-1, and by mid-adult life, the percentage is more than 90%.^{28, 12} Unfortunately, some persons fail to develop antibodies to some of the less common staphylococcal enterotoxins. Patients with clinical TSS lack antibody to TSST-1 and often fail to develop appropriate antibodies even in convalescent serum.²⁹ Individuals with TSS may fail to develop an appropriate antibody response because superantigen-mediated production of IFN-gamma inhibits polyclonal immunoglobulin production.⁸ These people are more likely to relapse after a first episode of TSS.

DIFFERENTIALS

Section 4 of 11  

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

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

Section 5 of 11  

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

Lab 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. More than 50% of patients with streptococcal TSS have a positive blood culture result. 
  • 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.³⁰
  • 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.³¹
  • 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

Section 6 of 11  

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

Prehospital Care

• Oxygen should be provided.
• Aggressive fluid resuscitation should begin in the field, especially for the severely hypotensive patient.
• If 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.³²

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%.³³
  • 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.²⁷
• 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).³⁴
• • 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

Section 7 of 11  

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

• Oxygen/respiration³⁴
• • 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.³⁵
  • 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 gm/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;³⁶ Patel et al disagrees and recommends vasopressin.³⁷ 
  • Vasopressin, epinephrine, norepinephrine, dopamine, dobutamine, and others remain in common clinical use.
  • 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.³⁸
  • Long course of low-dose corticosteroids reduced 28-day all-cause mortality and intensive care unit and hospital mortality.³⁹
• Immunoglobulins
• • The use of intravenous immunoglobulin G (IVIG) has been shown to be effective in neutralizing the TSS toxin and therefore aids in recovery.
  • However, different batches from different manufacturers may have different efficacy.⁴⁰
  • 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.⁴¹
  • 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.⁴²
  • Short-term intravenous infusion of N-acetyl-L-cysteine (NAC)⁴³
  • Intravenous preparations of vitamin C
• Recombinant activated protein C: Recommended by Surviving Sepsis Campaign for patients with severe sepsis and high risk for death.³⁴

Drug Category: Antibiotics

Semisynthetic penicillins have been widely used for TSS. Growing evidence suggests that the protein synthetase inhibitor, clindamycin, may be more efficacious in his illness. Accordingly, the author recommends treating patients suspected of TSS initially with clindamycin, 900 mg IV q8h for adults (13 mg/kg IV q8h for children) alone or in combination with a cell-wall-active agent such as a semisynthetic penicillin or vancomycin.

FOLLOW-UP

Section 8 of 11  

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

Further Inpatient Care

• Admit the patient with 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 TSS 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

Section 9 of 11  

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

Medical/Legal Pitfalls

• Lack of early surgical control of the infection

ACKNOWLEDGMENTS

Section 10 of 11  

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

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.

REFERENCES

Section 11 of 11

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

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Article Last Updated: Sep 12, 2008