Toxic Shock Syndrome

WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).

Toxic shock syndrome (TSS) was first described in children in 1978 but was quickly identified as an illness occurring primarily in menstruating women 12-24 years of age. During the 1979-1981 epidemic, tampon users were demonstrated to be 18 times more likely to develop menstrual TSS than non-users. Recent focus has shifted in conjunction with wound infections, postpartum endometritis and vaginitis; the predominance of cases continues to be related to menstruation. It is not known whether the abrupt decline in incidence has been due to changes in tampon use, improvements in manufacture, or reduction in disease severity due to early recognition.

The purpose of this document is to understand the pathogenesis of toxic shock syndrome (TSS), clinical picture, early diagnosis and the latest advances in treatment. Of the approximately 30 million menstruating women in USA, it is estimated that 70% use tampons and over 50% of those use super-absorbent types. Almost 1,000,000 women are at theoretic risk. The incidence in menstruating women is now 6-7: 100,000 annually. The incidence on non-menstrual disease has shown only a slight increase in the past 10 years.

Pathogenesis

The cause of toxic shock syndrome is preformed toxins produced by Staphylococcus aureus, so that colonization or infection by this microorganism must occur. TSS-toxin-1 is a protein with a molecular weight of approximately 24,000 daltons and has been proposed as the toxin responsible for TSS. Its production has been demonstrated in 90-100% of S. aureus strains recovered from women with menstrual TSS. The recovery of a single clone from the majority of individuals afflicted with TSS having a urogenital focus and from the genital tract of a large proportion of asymptomatic female carriers strongly suggests that this clone is especially well adapted for colonization of these anatomic sites.

The pathogenic mechanism for the association of tampons with TSS has not been adequately understood. How toxins gain access to the circulatory system is unknown. Regardless of the composition of the tampon, absorbency increased the odds ratio of TSS. The chemical composition of the tampons also influences the odds ratio. The greatest stimulation of TSS-1 was observed with, in decreasing order: polyester and carboxymethyl cellulose, polyacrylates, viscose rayon, gelatin foam, polyurethane, and cotton. The use of low-absorbency tampon appears to reduce the risk of TSS in tampon use. The longer a tampon is left in place, the greater the risk for development of this syndrome. Tampons may be associated with increased numbers of aerobic bacteria due to oxygen trapped in inter-fibrous spaces.

Toxic Shock Syndrome (TSS) and Contraceptives:

Different modes contraception can also cause the probability of TSS. Preliminary data have suggested that the use of oral contraceptives is a protective factor against TSS. The mechanism by which this is achieved is hypothesized to be the reduction in menstrual blood loss, which occurs in users of combined oral contraceptives. Despite the elevated odds ratio, the incidence of non-menstrual TSS in barrier contraceptive users and the risk of non-menstrual TSS attributable to barrier contraceptive use are low.

Vaginal Contraceptive Sponges -- Traumatic manipulation of the sponge, use during menstruation or the puerperium, and prolonged retention of the sponge may increase the risk of occurrence. Postpartum women and women who have had menstrual TSS previously should avoid using the contraceptive sponge. The sponge should not be used during menstruation and should not be left in place for more than 30 hours. Center for Disease Control and Prevention (CDC) had argued that despite these superficial similarities to the situation, which existed with respect to tampons in the 1980s, withdrawal of the vaginal contraceptive sponge from the market is not warranted by the data to date. Women who choose to use the sponge should read the package insertion carefully and be aware of the signs and symptoms of TSS.

Contraceptive Diaphragm -- Although a rare occurrence, recognition that TSS can occur in women using barrier contraception is important so that early diagnosis can be implemented. The prolonged use of diaphragm should be avoided, particularly in women who have previously manifested TSS. The appearance of a vaginal discharge occurring in a woman who uses diaphragm may be sufficient grounds for discontinuation of its use. The use of spermicides retards bacterial growth and may increase the length of time a device can be retained before bacterial replication and toxin production begin. Retention of the diaphragm for 12-18 hours may be relatively safe, whereas prolonged to 36 hours or more without replenishing the spermicide may increase the risk of toxin-mediated disease.

Clinical Picture:

Toxic shock syndrome is a multisystem illness. Onset is usually sudden, with high fever, watery diarrhea, and vomiting -- the triad often seen with viral gastroenteritis. Unlike most viral infections, however, this disorder may progress to hypotensive shock within several hours (usually <48 hours). Timely diagnosis is critical, and the key is the fact that the woman is menstruating or using tampons. Profound hypotension is one of the characteristic findings of full-blown TSS. A vaginal examination must be performed; if a tampon is present, it must be removed. Mucosal lesions should be sought, and a culture for S. aureus performed. If nuchal rigidity, headache, or disorientation unexplained by hypotension or fever is present, a lumbar puncture must be performed to rule out meningitis.

Essentials of Diagnosis:

  • Fever of 38.9 C (102 F) or higher
  • Diffuse macular rash
  • Desquamation (1-2 weeks after onset of illness; affects particularly palms and soles)
  • Hypotension (systolic >90 mm Hg for adults, or orthostatic syncope)
  • Involvement of 3 or more of the following organ systems: gastrointestinal, muscular, mucous membrane, renal, hepatic, hematologic, central nervous system

On the fifth to the twelfth day following the onset of illness, the patients will experience a danderous-like desquamation involving the face, trunk, and extremities. A full-thickness peeling of the palms and soles of the feet follow this. Despite the extensiveness of the process, healing is without scar formation. Vaginal examination in women with tampon-induced TSS reveals mucosal hyperemia with varying degrees of inflammation.

Laboratory Findings:

Since this is a multisystem syndrome, a battery of tests should be performed. These tests should initially include a complete blood count with differential, electrolyte measurements, urinalysis, urea nitrogen measurement, creatinine measurement, and hepatic function tests. Urinalysis usually shows pyuria (5-10 white blood cells per high-power field) and proteinuria, but cultures (in absence of an unrelated urinary tract infection) are sterile. Gram stains of vaginal or cervical secretions generally show polymorphonuclear leukocytes and very sparse gram-positive cocci in singlets, doublets, or clumps. Moderate elevations in liver function tests are common, and serum amylase may be elevated. Most patients have elevations in the blood urea nitrogen (BUN) and creatinine and a few have required dialysis. Elevation of creatinine phosphokinase (CPK), often dramatic may occur.

Severe illness may be accompanied by other findings. The platelet count often drops below 100,000/ mm3 in the first week of illness, and disseminated intravascular coagulation uncommonly occurs. EKG abnormalities include sinus or supraventricular tachycardia, non-specific ST segment changes, and first-degree heart block. T-wave inversion is sometimes recorded in precordial leads, as are funnel branch, premature atrial and ventricular extrasystole. Patients with TSS may have evidence of pulmonary involvement, which may be mild, or progress to frank adult respiratory distress syndrome. The development of adult respiratory distress syndrome indicates a poorer prognosis for these patients.

Differential Diagnosis:

Recognition and definitive documentation of TSS is difficult. There is no definitive test for TSS. Other diseases characterized by rash, fever, and systemic complications should be considered. The diagnosis is based on recognition of a constellation of signs and symptoms indicative of multi-organ involvement, which meets the Center for Disease and Prevention (CDC) criteria. Any woman who becomes ill with fever, headache, diarrhea, myalgia or any combination thereof should be suspected of having TSS. Scarlet fever must be excluded. Rocky Mountain spotted fever, leptospirosis, and measles may be excluded by appropriate serologic tests. Gram-negative sepsis must be excluded by both blood and cerebrospinal fluid cultures.

Treatment:

Aggressive supportive therapy is imperative for a successful outcome. Appropriate initial management begins with fluid and electrolyte resuscitation -- up to 12 L/d. Blood cultures for S. aureus should be obtained. The initial therapy is that of aggressive volume replacement. Because of the large volume of fluids necessary, it is strongly recommended that a Swan-Ganz catheter be placed and Anesthesia be alerted that difficult respiratory distress syndrome may develop in this particular patient. Central venous or pulmonary wedge pressures and urine output must be monitored to guide therapy. Concomitantly, local therapy should be directed to remove as much toxin as possible from the portal of infection, it is recommended that the vagina be thoroughly dried out using cotton drumsticks. Extensively irrigating with saline and then cleansing with hydrogen peroxide or Betadine iodine are advocated, immediately prior to the institution of antimicrobial therapy. Cultures must be obtained early. Dopamine infusion at 2-5 micro g/kg/min may be necessary if fluid volume alone does not correct hypotension. Mechanical ventilation may be necessary if adult respiratory syndrome develops, and hemodialysis may be necessary if renal failure develops. Corticosteroid therapy (methyl-prednisolone 30 mg/kg, or dexamethasone 3 mg/kg as a bolus and repeated every 4 hours as necessary), if instituted early may reduce the severity of illness and duration of fever. Naloxone had resulted in reversal of hypotension in seriously compromised patients by antiendorphin activity.

Antimicrobial therapy requires administration of a beta-lactamase-resistant semisynthetic penicillin such as oxacillin or nafcillin. A single dose of netilmicin is advocated because of its synergistic effect with the semisynthetic penicillins. Because of the possibility of underlying renal damage, a second dose is rarely administered. The choice of netilmicin over gentamicin or tobramycin is based on its being the least nephrotoxic of all the aminoglycosides. Nafcillin, oxacillin, or methicillin (1 g intravenously every 4 hours) should be given. If penicillin allergy is present, vancomycin 500 mg every 6 hours should be given. Dose reduction is necessary with renal impairment. Until gram-negative sepsis has been excluded, an aminoglycoside should be included with caution, since there will be altered renal failure. Although bacteremia in TSS is a very rare event, when it does occur it has significant therapeutic connotations. Patients with documented bacteremia due to S. aureus should be treated for a minimum of three to four weeks with a combination of parenteral and oral therapy to preclude the delayed development of metastatic complication such as osteomyelitis or brain abscess. If adult respiratory distress develops, mechanical ventilation with a high Fl O2 and positive end-respiratory pressures from 5-15 cm of H2O are often required.

Patients who do not respond readily to fluid replacement are at high-risk for multi-organ failure and should be immediately transported to centers, which can effectively deal with tertiary complications involving lungs, kidneys, and other vital organs. The mortality rate associated with toxic shock syndrome is 3%-6%. The three major causes of death are adult respiratory distress syndrome, intractable hypotension, and hemorrhage secondary to disseminated intravascular coagulopathy.

Recurrent Toxic Shock Syndrome (TSS):

Recurrence of TSS in cases related to menstruation has been reported to be as high as 34%. Retrospective antistaphylococcal antibiotic administration, risk of recurrence is decreased to approximately 5%. The incidence of recurrence or relapse in non-menstruating cases is not known due to an incomplete database. The greatest risk for recurrence is during the first 3 menstrual periods following treatment, and the recurrent episode may be less or more severe than the initial one. The incidence is reduced to less than 5% if antistaphylococcal antibiotic therapy is given during therapy of the initial occurrence. Eradication of the causative agent at the site of disease is mandatory to preclude relapse of non-menstruating TSS.

Methicillin-Resistant Staphylococcus aureus (MRSA) -- Prevalence and Management:

Staphylococcus aureus, including MRSA (Methicillin-resistant Staphylococcus aureus), often colonize the anterior noses in humans. Recent data from a nationally representative survey between 2001 and 2004 found that the prevalence of nasal colonization with MRSA is increasing (from 0.8% to 1.5% of the population between 2001 and 2004) despite an overall decrease in S aureus nasal colonization. These data suggest that more than 4 million persons in the United States carry MRSA in their noses. Other body sites can also harbor MRSA; recto-vaginal MRSA colonization rates of 0.5-3.5% during pregnancy have been reported. Only a fraction of those who have MRSA colonization go on to develop infection. The most recent population-based survey of invasive MRSA disease, from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core surveillance program, placed the incidence of invasive MRSA infections at 32 per 100,000 population, with significant variation by region and by age, sex, and racial background. Reports of TSS caused by MRSA have been relatively rare, but have been increasing in frequency. Health care-associated S aureus is defined epidemiologically as: Methicillin-resistant S aureus (MRSA) infections associated with exposure to invasive medical devices, surgery, hospitalization, dialysis, or long-term care facility in the prior 12 months. Healthcare-associated S aureus can be further classified as "community-onset" or "hospital-onset". Hospital onset infections are those in which symptom onset or positive cultures are obtained more than 48 hours after hospital admission. Community-associated methicillin-resistant S aureus is epidemiologically defined as: cases with none of the above health care-associated risk factors, and which have their onset in the community.

Outpatient antimicrobial choices for methicillin-resistant Staphylococcus aureus skin/soft tissue infection:

  • Clindamycin 150 -- 450 mg by mouth every 6 hour; concern for higher rate of Clostridium difficile disease.
  • Tetracyclines
    1. Doxycycline 100 mg twice daily; not recommended during pregnancy or children under 8 years of age.
    2. Minocycline 200 mg loading dose, then 100 mg twice daily; less experience against group A streptococcal infection.
  • Trimethoprim-sulfamethoxazole, 1-2 double strength tablets twice daily; may not provide therapy for group A streptococci. There is theoretical concern for use in neonates and women in third trimester.
  • Linezolid 600 mg twice daily; expensive and causes myelosuppression, neuropathy, or lactic acidosis may be seen with prolonged therapy.
  • Rifampin 600-900 mg daily, in divided doses; cannot be used as single agent due to rapid emergence of resistance; drug-drug interactions are common; and no data to suggest that adding rifampin to the above agents improves outcome.
  • Fluroquinolones and macrolides are not optimal therapy for suspected methicillin-resistant Staphylococcus aureus skin and soft tissue infections due to high prevalence of resistance or potential to develop resistance rapidly.

Managing pregnant patient who is colonized with MRSA:

  • Decolonization regimens are not routinely recommended for those with asymptomatic MRSA colonization.
  • For MRSA colonized patients who develop infections, treat the infection and reinforce good hygiene and wound care. If recurrent infections occur, consider consultation with an infectious diseases physician regarding the use of decolonization regimens.
  • The most commonly used decolonization regimens include twice daily application of mupirocin ointment in both nares, along with daily chlorhexidine bathing.
  • For gastrointestinal or vaginal MRSA carriage, oral antibiotics or vaginal chlorhexidine washes may be necessary for decolonization.
  • CDC guidelines recommend the use of contact precautions (use of gowns and gloves for direct contact with the patient or her environment) for those patients who are found to have MRSA infection or carriage, as well as for newborns born to colonized or infected mothers.

Breastfeeding in women with MRSA:

MRSA carriage or infection is not a contraindication to breastfeeding. In general, mastitis is treated with antimicrobial therapy and continued breastfeeding. All draining lesions should be covered to limited bacterial exposure to the infant. If a breast abscess is diagnosed, one might consider temporary cessation of breastfeeding on the affected breast for 1 to 2 days after surgical drainage of abscess. However, breastfeeding should continue on the opposite (unaffected) breast.

Summary:

The TSS-like syndrome usually occurs in patients with severe soft-tissue infections due to Streptococcus pyogenes (group-A streptococci). Close examination of cases of presumed staphylococcal TSS have revealed a multisystem disorder that shares many of the features of staphylococcal toxic shock syndrome, but is caused by toxins elaborated by group A beta-hemolytic streptococcus. Clinically, the non-menstrual patients fulfill the criteria for the clinical diagnosis of TSS: fever, hypotension, multi-system dysfunction, and diffuse macular erythroderma followed by desquamation.

Early detection and early treatment is the key to the success. Instructions and information about the recurrence TSS should be given to the patient upon discharge. The reason for abrupt decline in incidence in USA since 1980 is not known; whether the abrupt decline has been due to changes in tampon use, improvements in manufacture, or reduction in disease severity due to early recognition. The incidence of non-menstrual disease has shown only a slight increase in the past 10 years.

Acknowledgment: Special thanks to Dr. Robert P. Hoffman, Chairman, Department of Infectious Diseases, Mercy Medical Center, Springfield, MA (USA) for the assistance in developing this manuscript.

Suggested Reading:

  1. Data from Centers for Disease Control and Prevention. Case Definitions for Infectious Conditions Under Public Health Surveillance. Available at: http://www.cdc.gov/ncphi/disss/nndss/casedef/toxicsscurrent.htm Retrieved October 24, 2008
  2. Gorwitz RJ, Kruszon-Moran D, McAllister SK et al. Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 2001-2004. J Infect Dis 2008;197:1226-1234
  3. Chen KT, Huard RC, Della-Latta P et al. Prevalence of methicillin-resistant Staphylococcus aureus in pregnant women. Obstet Gynecol 2006;108:482-487
  4. Andrews WW, Schelonka R, Waites K et al. Genital tract methicillin-resistant Staphylococcus aureus: risk of vertical transmission in pregnant women. Obstet Gynecol 2008;111:113-118
  5. Klevens RM, Morrison MA, Nadle J et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007;298:1763-1771
  6. Centers for Disease Control. Outpatient management of CA MRSA Skin and Soft Tissue Infections. Available at: http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_skin.html Retrieved October 28, 2008
  7. van Rijen MM, Bonten M, Wenzel RP et al. Intranasal mupirocin for reduction of Staphylococcus aureus in surgical patients with nasal carriage: a systemic review. J Antimicrob Che-mother 2008;61:254-261
  8. Buehlmann M, Frei R, Fenner L et al. Highly effective regimen for decolonization of methicillin-resistant Staphylococcus aureus carriers. Infect Control Hosp Epidemiol 2008;29:510-516
  9. Perl TM, Cullen JJ, Wenzel RP et al. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N Engl J Med 2002;346:1871-1877
  10. Andews JI, Shamshirsaz AA, Diekema DJ. Non-menstrual toxic shock syndrome due to methicillin-resistant Staphylococcus aureus. Obstet Gynecol 2008;112:933-938

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