Toxin-mediated infections (toxic shock syndrome)

1. Description of the problem

Any staphylococcal infection may be associated with toxic shock syndrome. Classically, staph TSS has been associated with either tampon use in menstruating females or associated with surgical site infections, particularly those associated with surgical packing materials.

Any group A streptococcal infection may be associated with strep TSS, though necrotizing infections of the fascia and muscle are most common.

Gas gangrene can be related to trauma, particularly if there is interruption of the blood supply. Clostridium perfringens, C septicum and C histolyticum are the most common isolates. In the absence of trauma, so-called spontaneous gas gangrene can occur in association with gastrointestinal malignancies or neutropenia. This is most commonly caused by C septicum, an aerotolerant strain of the Clostria.

Clinical features

Staph TSS: Fever, sunburn type rash, hypotension, tachycardia and hyperemia of the tongue and conjunctiva are classic features.

Strep TSS: Fever, rarely sunburn type rash, hypotension, tachycardia, severe pain in those with necrotizing fasciitis. Gas is not found in the tissue.

Gas gangrene: Gas gangrene causes deep-seated pain, fever, toxicity and rapidly progressive destruction of skin, fascia and muscle. Late manifestations are gas in the tissue, purple violaceous bullae and skin sloughing.

Key management points

The key management points are prompt administration of appropriate antibiotics, intravenous fluid replacement and source control. For staph TSS, source control may include removal of the tampon or drainage of a surgical site infection. For strep TSS, source control may require aggressive surgical intervention in those with necrotizing soft-tissue infections.

In patients with gas gangrene, aggressive surgical debridement, which includes removal of devitalized muscle that neither bleeds or twitches with electrical stimulation.

2. Emergency Management

Aggressive fluid replacement with normal saline is crucial. Because patients have profound hypotension and diffuse capillary leak, large volumes of intravenous normal saline are required. It is not unusual that 10 to 12 liters of fluid are required the first 24 hours. Serum albumin levels may drop rapidly owing to capillary leak and hence colloid rather than crystalloid may be necessary.

Because these are toxin-related diseases, source control as described above is crucial to reduce the level of circulating toxin. In addition, antibiotics that shut off toxin production are preferred over cell-wall-active antibiotics. Thus, clindamycin or linezolid have theoretical advantages.

These same principles apply to patients with gas gangrene.

Management points not to be missed

Aggressive fluid replacement

Source control

Antibiotics that suppress toxin production

3. Diagnosis

Diagnostic approach

Clinical recognition of staph TSS syndrome is paramount and the classic features are the following: fever, hypotension, tachycardia, diffuse erythematous rash and hyperemia of the conjunctiva and tongue. A chest x-ray should be obtained since acute respiratory distress syndrome (ARDS) may develop. Gram stain and culture of any localized abscess, surgical site infection or vaginal contents in women with tampons in place should be undertaken.

In patients with strep TSS, clinical recognition or suspicion is crucial. Fever, hypotension, tachycardia and sunburn rash (10% of cases) may be all that is apparent. Severe pain is universally present in those with necrotizing fasciitis or myonecrosis. Computed tomography (CT) scans and magnetic resonance imaging (MRI) generally show edema in the deep tissues. Gas is invariably absent and abscess formation or collection of pus is rare. Surgical exploration for the purpose of obtaining diagnostic material and inspecting the deep soft tissues should be performed promptly.

Gas gangrene is recognized in patients with fever, leukocytosis, tachycardia and hypotension. The site of infection is characterized by severe pain and tenderness and crepitus.

Normal lab values

Leukocytosis with a left shift, serum creatinine greater than twice baseline (2–2.5 mg/dL), hypocalcemia, hypo-albuminemia and abnormal liver function tests support the diagnosis of both staph TSS and strep TSS. Creatine phosphokinase (CPK) levels in blood may be modestly elevated in both, but very high levels would support a deep necrotizing process of fascia and muscle associated with strep TSS.

Markedly elevated CPK levels in the blood, severe myoglobinemia and intravascular hemolysis are classic laboratory features of gas gangrene. Acute renal failure as evidence by rapidly rising serum creatinine is usually due to rhabdomyolysis and myoglobinuria. Rapid drop in hematocrit (HCT) due to toxin-induced red blood cell hemolysis is indicative of bacteremia owing to the causative strain of Clostridia.

How do I know this is what the patient has?

The patient has staph TSS i or strep TSS if the clinical signs and symptoms and laboratory tests agree with the CDS definitions referenced below. The diagnosis of gas gangrene rests on the presence of gas at the site of infection, rapid progression of infection and evidence of muscle destruction.

Differential diagnosis

The most common misdiagnoses for staph TSS are gastroenteritis, sun exposure with dehydration and drug reaction. For strep TSS, because of the severe pain associated with necrotizing infections, deep vein thrombosis, arterial embolization, compartment syndrome or acute myocardial infarction are the most common misdiagnoses.

Gas gangrene can be confused with necrotizing fasciitis caused by mixed aerobic and anaerobic microbes since both can be associated with gas in the tissues.

Confirmatory tests

Staph TSS and strep TSS are caused by potent toxins produced by strains of Staphylococcus aureus or group A Streptococcus. Thus, the isolate should be sent to the local state public health laboratory, the CDC or to investigators with toxin-profiling capability, ie, Dr Patrick Schlievert at the University of Iowa, Iowa City, Iowa, or Dr Dennis Stevens, Veterans Affairs Medical Center, Boise, Idaho.

4. Specific Treatment

Effective treatment of any staphylococcal infection would include vancomycin, daptomycin or linezolid for life-threatening infections caused by S aureus including MRSA. If clinical suspicion suggests staph TSS then linezolid or clindamycin would be preferable. If nafcillin or a cephalosporin were initially utilized then coverage for MRSA and/or TSS would be preferable.

Clindamycin can be used but because of the emergency of MRSA strains with constitutive or inducible clindamycin resistance, a safer treatment would be linezolid. If no constitutive or inducible clindamycin resistance is demonstrable, clindamycin is very effective treatment and has some advantages over cell wall active agents.

Penicillin has been the treatment of choice for group A streptococcal infections. However, for strep TSS, clindamycin has emerged as the best treatment based on in vitro toxin suppression, studies in animals, and one retrospective observational study. There is increasing resistance to macrolides described from many parts of the world including the USA. Despite this In the USA and Canada, clindamycin resistance is rare. In Italy and Spain, clindamycin resistance approaches 50%.

Because of increasing resistance, the recommendation is to use both penicillin and clindamycin for strep TSS. Linezolid could be an alternative for staph or strep TSS based largely on animal studies.

Strains of Clostridia that cause gas gangrene remain susceptible to penicillins and cephalosporins. In animal models of infection, clindamycin and tetracycline showed markedly greater reduction in mortality and morbidity than penicillin.

Drugs and dosages

Linezolid 600 mg IV every 12 hours; clindamycin 600 to 800 mg IV every 8 hours; vancomycin 1g IV every 12 hours: Daptomycin 6 mg/kg IV every 12 hours; penicillin G, 2 to 4 million units every 2 to 4 hours IV for a maximum daily dose in adults of 24,000,000 units.

Refractory cases

Source control is usually the cause of poor response to treatment. Look diligently for other sites of infection that may require surgical drainage. Ensure that the tampon has been removed for menstrually related cases.

The mortality of staph TSS is only 3%, so aggressive fluid replacement, appropriate antibiotics and source control are usually effective. IVIG has been suggested, though no objective clinical trials have been performed and its efficacy would be difficult to ascertain because of the low mortality. If the albumin is below 2 g/dL, fluid replacement should include colloid and not crystalloid alone.

For strep TSS, source control plays an even more important role. Patients with necrotizing infections require aggressive and early debridement. Usually, several surgical debridements are necessary over the course of 3 to 5 days. The efficacy of IVIG is controversial. Some studies have demonstrated reduction in mortality, though patients in the IVIG study were more likely to have undergone surgical debridement and to have received clindamycin instead of beta-lactam antibiotics.

For gas gangrene, identification of the site of infection by surgical inspection and aggressive debridement are crucial. Since the margin of infection can advance rapidly, in general multiple surgical debridements are necessary over the course of the first 24 to 48 hours of admission to the hospital.

Hyperbaric oxygen therapy has been advocated for gas gangrene. Theoretically, increased oxygen delivery to the site of infection would ameliorate the anaerobic milieu and reduce the ability of these anaerobic microbes to grow. There are no double blind studies that demonstrate the efficacy of hyperbaric oxygen treatment in humans with gas gangrene. Studies in mice failed to demonstrate any efficacy of hyperbaric oxygen with or without penicillin. Clindamycin alone was associated with far greater survival.

Trauma centers likely have better outcomes in the treatment of gas gangrene largely owing to their expertise in supportive measures, prompt surgical debridement and vascular repair. Anecdotal reports of efficacy of hyperbaric oxygen may reflect a selection bias since the sickest patients may not be candidates for the hyperbaric chamber.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Most patients respond dramatically to aggressive fluid replacement. If the albumin is low, crystalloid should be given. If a source of the staphylococcal or streptococcal infection can not be determined and the patient remains critically ill, imaging studies should commence. In gas gangrene the site of the infection is generally apparent, but routine X-rays, CT scans and MRIs are useful to identify the extent of infection and guide surgical intervention.

Incorrect diagnosis

If a sunburn type rash is not present, then many of the clinical manifestations are similar to septic shock. This type rash is present in nearly 90% of staph TSS patients but may be fleeting and present only on intertriginous areas of the body. The rash occurs in 10% or less among patients with strep TSS. In the absence of rash, blood cultures and pursuit of other sources of sepsis such as the urinary tract, gastrointestinal tract, endocarditis, or septic arthritis should be pursued.

Spontaneous gas gangrene can initially be difficult to diagnose because trauma is not a prerequisite. In this case imaging studies as described above may detect subtle infection associated with gas in the tissue.

Follow-up

Patients with menstrual staph TSS may have recurrences if they continue to use tampons. They should be told of the potential for recurrent staph TSS and instructed to use other means during their menstrual periods.

Patients with spontaneous gas gangrene commonly have bacteremia secondary to gastrointestinal abnormalities. Thus, appropriate studies to detect occult adenocarcinoma of the colon should be undertaken once the patient is stable.

Pathophysiology

Staph TSS and strep TSS are caused by toxin-producing strains of S aureus and Streptococcus pyogenes, respectively. These toxins are very potent and interact with cells of the innate immune system in unusual ways to cause a “cytokine storm.” Gas gangrene is also caused by potent toxins, most notably a phospholipase C that has marked effects on leukocyte trafficking, macrophage function and endothelial cell integrity.

The toxins responsible for staph TSS are TSST-l and staphylococcal enterotoxin B. Interestingly TSST-1 is associated with menstrual staph TSS and enterotoxin B is associated with surgical site infections. Though this association has been historical, there is great mixing of strains of staphylococci and most likely either or both will cause staph TSS in the future. In addition, though TSST-1 has been uncommon in MRSA infections, there is clear evidence that MRSA strains can produce either enterotoxin B or TSST-1.

TSST-1 and the staphylococcal enterotoxins (responsible for staphylococcal food poisoning) are considered superantigens. Superantigens interact with both macrophages and T-lymphocytes with the concomitant production of pro-inflammatory cytokines, TNF, IL-1 beta and IL-6 but also the lymphokines Interferon gamma, IL-2 and TNF beta. Thus, a cytokine storm ensues, resulting in shock and organ failure. These cytokines also cause an impressive capillary leak phenomenon.

Thus, massive peripheral edema caused by endothelial permeability and loss of albumin is characteristic. This may in part explain the massive fluid requirement for adequate hydration.

Pyrogenic exotoxin A is a potent toxin produced by strains of S pyogenes associated with strep TSS and necrotizing fasciitis. It, too, is a superantigen and induces a cytokine storm in the same manner as described above for staph TSS.

Gas gangrene is associated with the rapid destruction of tissue. Recent studies suggest that the rapid progression is due to irreversible effects of phospholipase C on vascular integrity. Specifically, phospholipase C causes platelet-neutrophil aggregation that occludes arterioles resulting in watershed downstream tissue destruction. In addition, phosholipase C causes a profound cardiomyopathy in experimental animals.

Clostridium septicum, the cause of spontaneous gas gangrene, is very aerotolerant and thus can establish infection in tissue with normal redox potential.

Epidemiology

Classically, staph TSS was described first in females during their menses and was clearly associated with the use of hyper-absorbance tampons. Subsequently, these tampons were taken off the market and the prevalence of staph TSS declined. Hospital-associated staph TSS was subsequently described in association with surgical procedures, particularly those that utilized packing material. Rhinoplasties were the greatest associated factor. Subsequently. it is clear that virtually any serious staphylococcal infection may be associated with staph TSS.

Strep TSS has been described most commonly in the very young and very old. There is also an increased risk in patients with diabetes and alcoholism. Cases are usually sporadic and not associated with epidemics. Exceptions have been in a small town in Minnesota caused by an M-type 3 strain of group A streptococcus.

In addition, there have been several reports of healthcare associated strep TSS related to surgeons performing thyroidectomies, suction lipectomies and obstetric procedures. Close contacts of patients with strep TSS have a 100-fold increased incidence of developing strep TSS. However, because the national prevalence of strep TSS is approximately 3 to 4 cases/100,000 population per year in the USA the risk is extremely low.

Interestingly, roughly 50% of patients with necrotizing fasciitis/myonecrosis have nonpenetrating trauma as a risk factor. Deep infection begins at the exact site of nonpenetrating trauma such as a muscle strain or hematoma. These patients present with deep infection, sepsis and no cutaneous evidence of infection, but do have pain out of proportion to the injury per se. Here clinical suspicion is life saving. These patients account for those with highest mortality and morbidity.

Traumatic gas gangrene can occur in any age group. Trauma with the greatest potential for gas gangrene are those injuries resulting in compound fractures, interruption of arterial blood supply and those grossly contaminated with soil, clothing or foreign objects. In wartime, the greatest incidence of gas gangrene occurred in battlefields where animal husbandry had been practiced for centuries. In contrast the incidence of gas gangrene was lowest in desert theaters of war.

Nontraumatic gas gangrene caused by C septicum occurs in patients with neutropenia of any type including cyclic neutropenia. In addition, it is described in patients with adenocarcinoma of the colon and other gastrointestinal pathologies.

Prognosis

The prognosis of staph TSS at this point in time is good. Mortality is only 3%. As strains of MSSA and MRSA acquire the bacteriophage that harbors the enterotoxin B or TSST-1 gene, this could change dramatically.

Patients with strep TSS have mortalities that are between 30% and 70% despite aggressive antibiotic therapy, surgical intervention for source control, ventilator support and vasopressors. Patients that have a definable focus of infection at the time of presentation probably have the best prognosis. Those that present with sepsis and severe pain due to a deep infection associated with nonpenetrating trauma have the worst prognosis, likely because of a delay in appropriate diagnosis.

In the past, mortalities of gas gangrene have been as high as 50% and most survivors required extensive debridement including amputations. Since World War II there has been a decline in the incidence of traumatic gas gangrene and a reduction in mortality, primarily because of more rapid evacuation, better surgical debridement of acute injuries and importantly reparative vascular surgeries.

Special considerations for nursing and allied health professionals.

Precautions for surgical site infection should be routine. Staphylococci are largely spread by personal contact, thus contact precautions are necessary. Staphylococci are not airborne pathogens. Many institutions use nasal carriage for MRSA as an indication for isolation. Unfortunately, non-MRSA strains are more likely to cause staph TSS, so this is not a good option for parameters of isolation. Thus, it is vitally important to obtain reliable cultures.

Hospitalized patients with dramatic infections like strep TSS generally cause alarm among nursing and physician staff. Group A streptococcus has been associated with a variety of epidemics of infections in postpartum patients, in military recruits in barracks, in daycare settings, schools and in the community at large in winter months for pharyngitis.

Studies done by the CDC and in Toronto, Canada indicate that the risk for hospital employees is about 100-fold greater among contacts of a case of strep TSS than the general population. Some studies have shown that the strain causing a case of necrotizing fasciitis is readily transferred to hospital employees who may have carriage or symptomatic pharyngitis.

Secondary cases of strep TSS among contacts is rare, but does occur. Thus, aggressive isolation and infection control practices of hand washing and contact precautions are prudent. In unusual situations where intimate contact has occurred, throat cultures of contacts or prophylaxis with penicillin given orally may be warranted.

There have been sporadic reports of gas gangrene occurring in patients who received cadaveric tissues for repair of tendons, etc. Undoubtedly, these cases occurred as a result of persistence of vital spores on these tissues.

What's the evidence?

“Defining the group A streptococcal toxic shock syndrome: Rationale and consensus definition”. JAMA. vol. 269. 1993. pp. 390-1. (This paper describes the clinical and laboratory criteria necessary to define a definite and/or probable cause of strep TSS.)

Stevens, DL. “The toxic shock syndromes”. Infect Dis Clin North Am. vol. 10. 1996. pp. 727-46. (Detailed review article that compares and contrasts the clinical presentation of staph and strep TSSs. In addition, it supplies in-depth discussion of pathogenic mechanisms, important virulence factors and concepts important in the treatment of these conditions.)

Bryant, AE, Bayer, CR, Chen, RYZ, Guth, PH, Wallace, RJ, Stevens, DL. “Vascular dysfunction and ischemic destruction of tissue in infections. The role of SLO-induced platelet/neutrophil complexes”. J Infect Dis. vol. 92. 2005. pp. 1014-22. (These experimental results demonstrate that streptolysin O causes a rapid reduction of blood flow that is irreversible and associated with platelet and neutrophil complexes that occlude both arteries and veins. This provides a mechanism for the rapid destruction of tissue in patients with strep TSS associated with necrotizing fasciitis and myonecrosis.)

Stevens, DL, Bisno, AL, Chambers, HF, Dellinger, EP, Goldstein, EJ, Gorbach, SL, Hirschmann, JV, Kaplan, SL, Montoya, JG, Wade, JC. “Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 59. 2014 Jul 15. pp. e10-52. (This manuscript reviews the evidence and provides guidelines for treating and diagnosing all types of skin and soft-tissue infections including strep and staph TSSs.)

Stevens, DL, Wallace, RJ, Hamilton, SM, Bryant, AE. “Successful treatment of staphylococcal toxic shock syndrome with linezolid: A case report and in vitro evaluation of TSST-1 production in the presence of antibiotics”. Clin Infect Dis. vol. 42. 2006. pp. 729-30. (With the emergence of MRSA strains, some of which are also resistant to clindamycin by either constitutive or inducible mechanism, additional empiric strategies to treat severe staphylococcal infections were warranted. This study demonstrates that linezolid was efficacious in treating such a patient and that in vitro linezolid and clindamycin had potent toxin-suppressing effects.)

Stevens, DL, Ma, Y, Salmi, DB, McIndoo, E, Wallace, RJ, Bryant, AE. “Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant “. J Infect Dis. vol. 195. 2007. pp. 202-11. (This study demonstrates that beta-lactam antibiotics such as nafcillin upregulate TSST-1, alpha toxin and the Panton-Valentine leukotoxin in subinhibitory concentrations and this translates to increased production of those same toxins. In contrast, linezolid and clindamycin suppress toxin production because they are both protein-synthesis inhibitors.)

Hamilton, SM, Bayer, CR, Stevens, DL, Lieber, RI, Bryant, AE. “Muscle injury, vimentin expression, and nonsteroidal anti-inflammatory drugs predispose to crypti group A streptococcal necrotizing infection”. J Infect Dis. vol. 198. 2008. pp. 1692-8. (This study investigates the mechanism whereby 50% of the patients with strep TSS develop the initial infection at the exact site of nonpenetrating trauma such as a muscle strain or hematoma. Investigators demonstrated that vimentin expressed by injured muscle cells avidly binds group A streptococci. This process is enhanced in the presence of certain nonsteroidal anti-inflammatory agents.)

Zimbleman, J, Palmer, A, Todd, J. “Improved outcome of clindamycin compared with beta-lacam antibiotic treatment for invasive infection”. Pediatr Infect Dis J. vol. 18. 1999. pp. 1096-1100. (This retrospective study in children showed that treatment with clindamycin was associated with better outcomes than treatment with beta-lactam antibiotics.)

Norrby-Teglund, A, Stevens, DL. “Novel therapies in streptococcal toxic shock syndrome: attenuation of virulence factor expression and modulation of the host response”. Curr Opin Infect Dis. vol. 11. 1998. pp. 285-91. (This review article describes the evidence and strategies for reducing and neutralizing toxins produced by group A streptococcal strains.)

Stevens, DL, Bryant, AE, Jong, EC, Stevens, DL. “Life-threatening skin and soft tissue infections. In Netter's Infectious Diseases”. 2010. pp. 94-101. (A general review of gas gangrene; clinical presentation, pathogenesis and treatment with excellent illustrations.)

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