Colonization With Exotoxin-Producing Staphylococcus Aureus

S. aureus is present in 20% to 40% of nasal cultures. In menstruating women, 26% are colonized with S. aureus in at least one of three body sites (nose, vagina, or anus). Vaginal carriage rates vary from 7% in nonmenstruating women to 33% in menstruating women and are higher during menses than at midcycle. In healthy individuals, 14% to 39% of S. aureus isolates produce TSST-1, and 7% to 14% produce staphylococcal enterotoxin B. TSST-1–positive S. aureus is present in 1% to 5% of vaginal cultures in women, 7% of nasal cultures in hospitalized patients, and 18% of nasal cultures in children. Overall up to 7% of healthy individuals at any given time are colonized at a mucosal site with TSST-1–positive S. aureus . TSST-1 producing isolates has been found in 28% of patients bacteremic with S. aureus without TSS. Presumably these patients had circulating antibody to TSST-1 that prevented the development of TSS despite S. aureus infection.

The majority of toxin-producing S. aureus isolates in both menstrual and nonmenstrual TSS cases produce TSST-1. Of the strains producing TSST-1, 60.6% also produce an enterotoxin. A clone producing both TSST-1 and staphylococcal enterotoxin A is associated with 88% of menstrual and up to 54% of nonmenstrual TSS cases. Isolates that produce TSST-1 in conjunction with staphylococcal enterotoxin C have been associated with severe respiratory tract TSS-associated infections. Staphylococcal enterotoxin B is never co-expressed with TSST-1. TSST-1–negative strains that produce staphylococcal enterotoxin B account for 38% of nonmenstrual TSS isolates. Patients with nonmenstrual disease infected with these TSST-1–negative strains may have a higher mortality rate.

While toxin producing staphylococcal strains may cluster within families, living units, and hospital settings, the occurrence of TSS clusters is a rare event. Probable TSS cases have developed within 24 hours in a husband and wife and in two mother-daughter pairs. Nosocomial acquisition and transmission of TSST-1–positive organisms have been described.

Absence of Protective Antibody Levels

Antibody formation to exotoxins is thought to result from mucosal colonization with TSST-1–positive S. aureus strains. Adults and children with persistent nasal carriage of a TSST-1–positive strain have high levels of antibody to TSST-1. Antibody titers are higher in women colonized with toxigenic S. aureus whether the colonization is persistent or transient. Patients in whom TSS develops have significantly lower levels of antibody to staphylococcal exotoxins than the general population. Following the episode of TSS, the antibody response to TSST-1 is typically absent or delayed.

The prevalence of antibody to staphylococcal exotoxins has remained stable in studies from 1960 to 1999 and is correlated with age (see Fig. 64.1 ). The increased incidence of TSS in adolescent girls is related to the lower prevalence of antibody to TSST-1 in this age group. Antibody to TSST-1 in a study of Wisconsin residents was found to be 47% at 1 year of age, 70% at 10 years, 88% at 20 years, and 96% for ages 30 to 50 years during the years 1960 to 1983. A study of women across North America in 1998 to 1999 found similar results, with 85% overall and 81% of subjects aged 13 to 18 years having positive antibody to TSST-1. Transplacental antibody is present in more than 90% of infants.

For the staphylococcal enterotoxins, by 10 years of age, the proportion of individuals with antibody titers of 1 : 100 or higher is 15% for staphylococcal enterotoxin A, 65% for staphylococcal enterotoxin B, 30% for staphylococcal enterotoxin C, 5% for staphylococcal enterotoxin D, and 20% for staphylococcal enterotoxin E. By 22 years of age, the proportion increases to 55% for staphylococcal enterotoxin A, 77% for staphylococcal enterotoxin B, and 98% for staphylococcal enterotoxin C.

Racial, sexual, and geographic differences in antibody prevalence have been noted. Sera randomly selected from 87 control women were seronegative more frequently for antibody to TSST-1 (24%) than were those from 66 control men (9%). A 2003 multicenter study of 3012 women from Ohio, New Jersey, Florida, Arizona, and Manitoba, Canada, found similar rates of S. aureus colonization, but subjects from Manitoba and Arizona were significantly more likely to have a positive antibody titer than were subjects from the other locations.

Interruption of Skin or Mucosal Surface

Most cases of TSS occur in patients with an altered skin or mucosal surface. Trauma or surgery in areas of the body frequently colonized with S. aureus (nose, skin, vagina) places individuals at enhanced risk for infection and subsequent TSS. A wide variety of types of surgeries have been associated with TSS (see Box 64.2 ). Primary deep-tissue staphylococcal infections (e.g., osteomyelitis, pyarthrosis, pyomyositis, endocarditis, renal carbuncles, and bacteremia) are rarely associated with TSS. Types of skin disruptions commonly associated with TSS include burns, surgical incisions, insect bites, needle sticks, tattoos, and varicella. Infected abrasions under casts may be focal sites of TSST-1 production.

Burn wounds provide a particularly rich environment for growth of S. aureus and the production of toxins. *

* References .

TSS cases following disruption of nasopharyngeal mucosa and the respiratory tract include those associated with sinusitis, pharyngitis, parapharyngeal and submandibular abscesses, tracheitis, pneumonia, rubeola, and influenza. TSS occurring after ear, nose, and throat surgery has been associated with the use of nasal splints and packing materials that may disrupt the ciliary blanket.

The vaginal mucosa may be damaged during placement of tampons or barrier contraceptives, postpartum, or after genital surgery. Heavy colonization of the vagina without any other apparent risk factor has been associated with TSS. Vaginal mucosal infections may provide the right conditions for production of TSST-1, including an aerobic environment, high carbon dioxide concentration, neutral pH, high protein and low glucose concentrations, and low to normal magnesium concentration.

Presence of a Foreign Body

Tampon use was established as a clear risk factor for the development of TSS. Tampons create an aerobic environment in the vagina, which normally is anaerobic. Because TSST-1 production requires oxygen, the increasing concentrations of oxygen may enhance the production of toxin. Tampons may also remove vaginal substrates that normally inhibit the growth of S. aureus. Although it has been suggested that tampons may cause vaginal ulceration leading to greater bacterial growth and toxin absorption, the types of ulcerations seen are likely induced by TSST-1 because they have been found during postmortem examination in women who had never used tampons.

While TSS occurs with all brands of tampons, a greater relative risk for menstrual TSS was found with brands with higher absorbency and particular compositions. In one study, production of TSST-1 varied from undetectable levels to 300 µg/mL depending on the tampon studied. Two studies demonstrated enhanced production of TSST-1 in vitro by the Rely tampon, which was composed of cross-linked carboxymethylcellulose and polyester foam. The polyacrylate rayon and surfactant Pluronic L-92 included in some tampon brands also increase the production of TSST-1 under certain conditions.

In addition to tampons, implanted foreign material, including sutures, central venous lines, metallic or polymeric implants, Teflon splints, and gauze packing, have been documented to enhance the risk for acquiring bacterial infection. These infections are characterized by limited spread beyond the tissues in immediate contact with the implants, poor response to antibiotics, and poor healing without removal of the foreign material. The infection risk varies with the type of foreign material implanted. For example, bacterial adherence is eightfold higher for braided sutures of silk, silicone-heated blue polyester, and absorbable polyglycolic acid than for monofilament nylon. Two important distinctions between TSS and other S. aureus infections related to foreign material are the production of exotoxin and the limited inflammation around the wound.

Laboratory Findings

Laboratory tests reflect the endogenous cytokine release, shock, and organ failure associated with TSS. Leukocytosis may not be present, but the proportion of neutrophils generally exceeds 90%. The proportion of immature neutrophils usually is 25% to 50% of the total number of neutrophils and is associated with absolute lymphopenia. Thrombocytopenia and anemia are present during the first few days and frequently are accompanied by prolonged prothrombin and partial thromboplastin times. Disseminated intravascular coagulation may be present. Sterile pyuria and cerebrospinal fluid pleocytosis are indicative of generalized involvement of the mucous membranes and serosal surfaces. Elevated blood urea nitrogen and creatinine levels reflect kidney damage, and abnormalities in liver function tests reflect liver damage and acute cholestasis. Hypoproteinemia and hypoalbuminemia reflect capillary leak, and profound hypocalcemia may reflect both hypoproteinemia and high serum levels of calcitonin. Muscle involvement is noted by an elevated creatine phosphokinase level, and the hypophosphatemia that occurs despite impaired renal function is unexplained. Most of these test results return to normal within 7 to 10 days of disease onset.

S. aureus is cultured from the cervix or vagina in more than 85% of patients with menstrual TSS and from the focus of infection in patients with nonmenstrual TSS. Positive blood culture results are rare findings. Antibody to TSST-1 or to the staphylococcal enterotoxins is absent at the onset of disease in more than 85% of patients.

Diagnosis

TSS is diagnosed clinically according to its case definition (see Box 64.1 ). Aggressive attempts to find the focus of S. aureus include culture of the cervix and vagina in patients with menses-associated illness and culture of other potentially infected sites in patients with nonmenstrual illness. S. aureus isolates can be examined for their ability to produce TSST-1, although such testing seldom is indicated. This test is of limited usefulness for nonmenstrual cases because TSST-1 is produced by only 40% to 60% of S. aureus isolates from such patients. Isolates from these patients can be examined for the presence of the other enterotoxins. Acute and convalescent sera can be tested for the presence of antibodies to TSST-1 and the other enterotoxins. Elevated levels of anti–TSST-1 in the acute-phase serum of a patient with menstrual-associated TSS is highly unusual.

In most instances, toxin detection tests are of value only for research or for patients with chronic recurrent or atypical disease. Genes for TSST-1 and the enterotoxins have been detected in S. aureus strains by polymerase chain reaction and hybridization techniques. A noncompetitive enzyme-linked immunosorbent assay allows quantitation of TSST-1 in clinical samples. Reversed passive latex agglutination has been used to detect TSST-1 and enterotoxins. Research laboratories also have developed techniques for detecting the selective expansion of V _β 2-positive T cells as evidence of host response to superantigenic toxins.

Treatment

The four general principles of treatment of TSS ( Box 64.3 ) are (1) identification and drainage of the focus of toxin production, (2) identification and susceptibility testing of the organism, (3) administration of antimicrobial therapy to block synthesis of the toxin and eradicate the organism, and (4) management of the systemic multiorgan actions of the toxins or mediators. *

* References .

Outcome and Sequelae

Death associated with TSS usually takes place within the first few days of illness, but it may occur as late as 15 days after presentation. Fatalities have been attributed to refractory cardiac arrhythmias, cardiomyopathy, irreversible respiratory failure, and, rarely, bleeding caused by coagulation defects. The duration of circulation of toxins and mediators and the associated hypotension may be the best predictors of the severity of the end-organ damage.

Sequelae that appear to be related to a prolonged period of hypotension include chronic renal failure, gangrene, and telogen effluvium. Hair and nail loss occurs 4 to 16 weeks after onset of the illness, with restoration taking place in 5 to 6 months.

Other sequelae, such as neuropsychological abnormalities, prolonged myalgia and weakness, carpal tunnel syndrome, chronic dermatitis, Raynaud syndrome, and new allergies are explained less easily. Impaired memory and concentration have been found in patients who did not require any therapy other than intravenous fluids to restore their blood pressure. Fertility patterns and pregnancy outcomes were similar in controls and women with TSS, both before and after the illness.

Recurrences

Recurrences for both menstrual and nonmenstrual TSS are well described, usually associated with inadequately treated disease. A small number of patients with menstrual disease and repeated tampon exposure have experienced as many as 6 to 12 recurrences. In most patients the first episode is the most severe. Antistaphylococcal antimicrobial therapy for 10 to 14 days and discontinuation of tampon use reduces the rate of recurrence significantly.

The absent or delayed antibody response to TSST-1 found in both menstrual and nonmenstrual TSS patients probably accounts for the continued susceptibility to TSS and high recurrence rate. The fact that superantigenic toxins are not processed by antigen-processing cells and T lymphocytes as conventional antigens may provide an explanation for the poor convalescent antibody response to these antigens. In mice and one patient with TSS, in vivo TSST-1–induced proliferation was followed by hyporesponsiveness of TSST-1–responsive V _β 2 ⁺ T cells.

Culture-negative, menses-associated recurrent episodes of TSS continue to be found in a small number of patients despite discontinuation of tampon use and administration of appropriate antimicrobial therapy during the acute episode. Administration of an oral β-lactamase–resistant antistaphylococcal antimicrobial agent during menses has been tried in an attempt to prevent these recurrences but is not always successful. In recurrent cases resistant to this form of prophylaxis, consideration could be given to the empiric use of rifampin, clindamycin, erythromycin, or an oral contraceptive.

Mild Disease

Recognition of mild episodes of menstrual TSS is particularly important because of the risk of recurrence without appropriate therapy. Patients with mild TSS typically do not form antibody to TSST-1 during convalescence. A mild episode may be recognized only in retrospect, after desquamation, a recurrent episode, or both develop.

The presence of any combination of fever, headache, sore throat, diarrhea, vomiting, orthostatic dizziness, syncope, and myalgia in a menstruating woman or an individual with a potential S. aureus infection should raise suspicion of TSS. A positive culture for S. aureus is helpful but not diagnostic because S. aureus may be cultured from the cervix or vagina in up to 33% of menstruating women. Other laboratory data usually do not reflect multisystem involvement in mild disease, and assays for TSST-1 in body fluids are investigational. Support for the diagnosis of mild TSS depends on the constellation of findings present, including subsequent desquamation of the palms, soles, toes, or fingers; demonstration that S. aureus isolates from the site of infection produce TSST-1 or an enterotoxin; absence of antibody to TSST-1 or enterotoxins in acute-phase serum; and recurrent disease.

Recalcitrant Erythematous Desquamating Disorder

An atypical, subacute variant of TSS has been described in patients with acquired immunodeficiency syndrome (AIDS) and labeled recalcitrant erythematous desquamating disorder. S. aureus strains producing TSST-1 or staphylococcal enterotoxins A or B have been isolated from patients with AIDS presenting with diffuse erythema, extensive cutaneous desquamation, hypotension, and variable multiorgan involvement. The illness is recalcitrant, prolonged, and characterized by multiple recurrences. In one patient, elevated levels of TNF and IL-6 were found during severe episodes. When antitoxin antibodies have been measured during recurrence, they have been undetectable. Two patients responded well to IVIG. TSST-1 and the enterotoxins may exacerbate human immunodeficiency virus type 1 (HIV-1) infection because these toxins have been shown to activate HIV-1 gene expression in vitro. Patients with the combined cellular and humoral immunodeficiencies of AIDS may be at particular risk for the development of severe, frequent, and prolonged episodes of TSS.

Neonatal Toxic Shock Syndrome–like Exanthematous Disease

A toxic shock–like illness related to TSST-1–producing MRSA, labeled neonatal toxic shock syndrome–like exanthematous disease (NTED), was initially described in neonates in Japan and subsequently recognized in France. These infants present in the first week of life with a combination of a generalized erythematous macular rash, thrombocytopenia, elevated acute-phase reactants, and fever. Patients are colonized with a single clonal type of MRSA that produces TSST-1 and staphylococcal enterotoxin C. Although no focus of infection is present and no exotoxins are detectable in serum, analysis of T cells shows the selective expansion of V _β 2-positive T cells typically found in response to TSST-1. Maternal IgG antibody to TSST-1 plays a protective role in preventing NTED. Although complications occur in premature neonates, term infants typically recover within 5 days without active treatment. The limited disease has been attributed to the minute amount of exotoxin from colonized sites and the high susceptibility to induction of anergy in the immature T cells of neonates.

Streptococcal Toxic Shock Syndrome

An increase in the incidence and severity of S. pyogenes was recognized in the 1980s. These infections included septicemia, necrotizing fasciitis, and a toxic shock–like syndrome. In 1993, the Working Group on Severe Streptococcal Infections proposed a consensus definition for streptococcal TSS based on clinical criteria including isolation of group A streptococci from a normally sterile site, hypotension, and two or more of the following: renal impairment, coagulopathy, liver dysfunction, acute respiratory distress syndrome, erythematous macular rash, and soft tissue necrosis.

Since the 1990s, the rate of severe streptococcal infections has approximated 2 to 4 cases/100,000 per year. In adults, streptococcal TSS comprises 10% to 15% of severe streptococcal infections, with a mortality rate of 30% to 70%. Streptococcal TSS is less common in children and carries a lower mortality rate than in adults. A multicenter study covering a US population of 29.7 million from 2000 to 2004 identified 5400 cases of invasive group A streptococcal infection (3.5 per 100,000 per year), including 572 children younger than 10 years of age. Of the 572 children with severe streptococcal infection, 26 (4.6%) developed streptococcal TSS with a 7.2% case-fatality rate.

Streptococcal TSS is similar to staphylococcal TSS in that it is mediated by superantigenic toxins and results in endothelial damage, hypotension, and multisystem organ involvement. Both cell-associated and soluble streptococcal virulence factors, including M protein and pyrogenic exotoxins A and B, have been implicated as superantigens mediating the systemic effects of streptococcal TSS. It differs from staphylococcal TSS in numerous respects, including severe generalized hyperesthesia; extreme pain at the site of skin involvement; a slower onset over the course of several days; typical absence of vomiting, diarrhea, and conjunctival injection; and the frequent absence of erythroderma or the presence of only a sandpaper-like rash. In a multinational European study conducted from 2003–04, streptococcal TSS was most often associated with skin and soft tissue infections, particularly cellulitis and necrotizing fasciitis, followed by septic arthritis, bacteremia, sepsis, and meningitis. Notably, 50% of the cases of necrotizing fasciitis were complicated by streptococcal TSS.

Treatment follows the same principles as for staphylococcal TSS: identification of the focus of toxin production, identification and susceptibility testing of the organism, administration of antibiotic therapy to kill the organism and block synthesis of the toxin , and management of the systemic multiorgan actions of the toxins. Although penicillin is the drug of choice for treatment of most group A streptococcal infections, initial broad gram-positive coverage with vancomycin and clindamycin has been advocated given the clinical overlap between streptococcal and staphylococcal TSS. The addition of clindamycin to inhibit protein synthesis is beneficial in cases of streptococcal as well as staphylococcal TSS. In a mouse model of myositis caused by S. pyogenes , clindamycin was more efficacious than penicillin.

IVIG as adjunctive therapy for streptococcal TSS has been supported by in vitro studies and case reports in humans, but clinical studies have been inconclusive. Downregulation of the lymphokine production induced by streptococcal pyrogenic exotoxin A by IVIG has been demonstrated in vitro. A multicenter, randomized, double-blind, placebo-controlled trial to study IVIG for streptococcal TSS in adults showed 3.6-fold higher mortality in the placebo group. However, statistical significance was not achieved because the study identified only 10 IVIG recipients and 11 placebo patients before premature termination due to slow patient recruitment. As with staphylococcal TSS, IVIG has been advocated for cases of streptococcal TSS that are refractory to aggressive therapy or for patients with an inaccessible focus of infection.

Several patients with TSS have been reported to be simultaneously infected with S. aureus and S. pyogenes. Determining which infection primarily was responsible for the manifestations or whether an amplified effect of exotoxins from both organisms was present was not possible.