Staphylococcal Scalded Skin Syndrome (SSSS)

Staphylococcal scalded skin syndrome (SSSS), also known as Ritter von Ritterschein disease (in newborns), Ritter disease, and staphylococcal epidermal necrolysis, encompasses a spectrum of superficial blistering skin disorders caused by the exfoliative toxins of some strains of Staphylococcus aureus.[1]

It is a syndrome of acute exfoliation of the skin typically following an erythematous cellulitis. Severity of staphylococcal scalded skin syndrome varies from a few blisters localized to the site of infection to a severe exfoliation affecting almost the entire body. A mild form of the illness involving desquamation of just the skin folds following impetigo has been described.[1, 2]

Staphylococcal scalded skin syndrome (SSSS) is caused by an exfoliative toxin produced by roughly 5% of Staphylococcus aureus. As the syndrome evolves, an initial infection occurs, commonly at a site such as the oral or nasal cavities, throat, or umbilicus.[3] Epidermolytic toxins are produced by the infecting Staphylococcus species; these toxins act at a remote site leading to a red rash and separation of the epidermis beneath the granular cell layer. Bullae form, and diffuse sheetlike desquamation occurs. Two types of staphylococcal scalded skin syndrome are thought to exist: a localized form, in which there is only patchy involvement of the epidermis, and a generalized form, in which significant areas of are involved, remote from the initial site of infection.[1]

Two exfoliative toxins (ETA and ETB) have been isolated and characterized, but the exact mechanism by which they cause exfoliation had until recently been uncertain. The toxins likely act as proteases that target the protein desmoglein-1 (DG-1), an important keratinocyte cell-to-cell attachment protein found only in the superficial epidermis.[4, 5, 6] The relative quantity of DG-1 in the skin differs with age and may partially explain the increased frequency of staphylococcal scalded skin syndrome in children younger than 5 years. It is theorized that immature renal function in this age group may contribute to impaired clearance of circulating exotoxins, contributing to more extensive disease. Another theory suggests that the exfoliative toxins may possess a superantigenic activity.

The decrease in frequency of staphylococcal scalded skin syndrome (SSSS) in adults is thought to be explained by the presence of antibodies specific for exotoxins and also improved renal clearance of toxins that are produced.

Initial studies suggested that phage lytic group II S aureus (subtypes 3A, 3B, 3C, 55 and 71) were solely responsible for exfoliative toxin production, but it is now known that all phage groups are able to produce exfoliative toxin and cause staphylococcal scalded skin syndrome.

Staphylococcal scalded skin syndrome differs from bullous impetigo. Both are blistering skin diseases caused by staphylococcal exfoliative toxin. However, in bullous impetigo, the exfoliative toxins are restricted to the area of infection, and bacteria can be cultured from the blister contents. In staphylococcal scalded skin syndrome, the exfoliative toxins are spread hematogenously from a localized source potentially causing epidermal damage at distant sites. Therefore, cultures of the bullous material are sterile.[1]

Staphylococcal scalded skin syndrome differs from the more severe toxic epidermal necrolysis (TEN), in that the cleavage site in staphylococcal scalded skin syndrome is intraepidermal, as opposed to TEN, which involves necrosis of the full epidermal layer (at the level of the basement membrane).

Frequency

United States

Staphylococcal scalded skin syndrome (SSSS) is most common in children and neonates. Staphylococcal scalded skin syndrome is rarer in adults, but it has been described in adults with renal failure, immunologic deficiency, and other chronic illness.[7, 8] .  The mean annual incidence of SSSS can be approximated as 7.67 (range 1.83-11.88) per million US Children, with 45.1 cases per million in US infants aged < 2 years.[9]

International

Internationally, predominance is in children as well. Overall incidence is higher in developing countries and wherever the incidence of staphylococcal infections is higher. Additionally, some geographic difference exists in the incidence of staphylococcal strains and the types of exotoxins produced.[10] Some recent reports show an increase in hospitalizations and prescriptions for staphylococcal disease, including SSSS,[11, 9]

Mortality/Morbidity

The mortality rate from staphylococcal scalded skin syndrome (SSSS) in children is very low (0.33-5%), unless associated sepsis or an underlying serious medical condition exists. The mortality rate in adults is higher (as high as 50-60%), although this may be a reflection of the underlying disorder, which increased susceptibility to SSSS, and not SSSS itself.[12, 13, 14, 9] Significant morbidity can result from hematologic or local spread of infection.[15] Complications are usually the result of sepsis, superinfection, and dehydration or electrolyte imbalance due to denuded skin.

Sex

SSSS is associated with female sex with adjusted odds ratio of 1.12 (1.00-1.25).[9]

Age

Staphylococcal scalded skin syndrome (SSSS) primarily is a disease of children.

Children are more at risk because of lack of immunity and immature renal clearance capability (exfoliative toxins are renally excreted). Maternal antibodies transferred to infants in breastmilk are thought to be partially protective, but neonatal disease can still occur possibly as a result of inadequate immunity or immature renal clearance of exotoxin.[16, 17, 18, 19] There is at least one report of recurrent SSSS in a neonate.[20]

SSSS can occur individually or as outbreaks in nurseries. Outbreaks are usually due to asymptomatic carriers who spread the disease to susceptible individuals.[21]

Most children are younger than 2 years, and almost all are younger than 6 years.[9]

SSSS is rare in adults, with fewer than 50 cases formally reported in the literature. Adults with SSSS are most often chronically ill, are immunocompromised, or have renal failure. SSSS can also appear in adults in cases with a high burden of staphylococcal infection where the quantity of exotoxin is significant. There is also a case report of SSSS in an adult after tooth extraction.[22]

Staphylococcal scalded skin syndrome (SSSS) presents as a macular erythema followed by diffuse epidermal exfoliation.

A prodromal localized S aureus infection of the skin, throat, nose, mouth, umbilicus, or GI tract occurs. Such an infection often is not apparent before the SSSS rash appears.

The following may be noted:

• General malaise

• Fever

• Irritability

• Skin tenderness

The following may be noted:

• Fever, although patients may be afebrile

• Tenderness to palpation

• Warmth to palpation

• Skin erythema

• Facial edema

• Conjunctivitis

• Perioral crusting, but mucous membranes are spared

• Most patients do not appear severely ill.

• Dehydration may be present and significant.

• Nikolsky sign (gentle stroking of the skin causes the skin to separate at the epidermis)[23, 24]

Diffuse erythematous rash often begins centrally, is sandpaperlike (progressing into a wrinkled appearance, and accentuated in flexor creases. See the images below.

Bullae are flaccid and ill defined. See the image below.

Exfoliation of skin, which may be patchy or sheetlike in nature, is noted. See the images below.

Infection by group 2 phage S aureus (several types) leads to release of exotoxin.

Exotoxin is a protein and is classified as either type A or B. Most are type A.

Exotoxin causes separation of the epidermis beneath the granular cell layer.

Cases of staphylococcal scalded skin syndrome (SSSS) have been reported among infants who have breastfed from mothers with S aureus breast abscess.

A case has been reported of neonatal staphylococcal scalded skin syndrome secondary to maternal-fetal transmission at birth.

Outbreaks have been reported in neonatal and newborn nurseries.[21]

Reports implicating MRSA and community-acquired methicillin Staphylococcus aureus (CA-MRSA) as a cause of staphylococcal scalded skin syndrome are increasing.[25, 26, 27]

White blood count (WBC) may be elevated; however, often WBC is normal.

Erythrocyte sedimentation rate (ESR) frequently is elevated.

Electrolytes and renal function should be followed closely in severe cases where fluid losses and dehydration via denuded skin are a concern.

A polymerase chain reaction (PCR) serum test for the toxin is available.

Typing of staphylococcal isolates for phage and subtype and the presence of exotoxin production is usually not necessary but is available at some centers

Cultures of bullae are negative in the absence of contamination.

Blood culture is usually negative in children (but positive in bullous impetigo) and is usually positive in adults

A Gram stain and/or culture from the remote infection site may confirm staphylococcal infection.

A chest radiograph should be considered to rule out pneumonia as the original focus of infection.

A biopsy of the affected area will demonstrate separation of the epidermis at the granular layer. An inflammatory cell infiltrate is typically not present. Immunofluorescence and the presence of antibodies that are common in pemphigus foliaceous are not present in staphylococcal scalded skin syndrome (SSSS). In toxic epidermal necrolysis (TEN), an inflammatory (lymphocytic) infiltrate is present, and the plane of separation is deeper, at the level of the basement membrane.

Frozen section of the peeled skin confirms the site of cleavage as superficial. Toxic epidermal necrolysis (TEN) shows deeper cleavage below the epidermis.

In the prehospital phase, treatment will be likely limited to antipyretic therapy and treatment of the dehydration with intravenous fluid therapy during transport. Most patients are brought to the emergency department by parents or caregivers.

The major focus of ED care should be to identify staphylococcal scalded skin syndrome (SSSS) and to stabilize the patient's condition.

Once SSSS is diagnosed, the treatment consists of supportive care and eradication of the primary infection.

Patients need fluid rehydration, topical wound care similar to the care for thermal burns, and parenteral antibiotics to cover S aureus.

Consideration must be given for the sharply increasing rates of community-acquired S aureus infection (CA-MRSA). Prompt treatment with parenteral anti-staphylococcal antibiotics is essential. Most staphylococcal infections implicated in staphylococcal scalded skin syndrome have penicillinases and are resistant to penicillin. Penicillinase-resistant synthetic penicillins such as nafcillin or oxacillin should be started promptly. In areas with significant MRSA prevalence (or if MRSA is suspected), antibiotics with MRSA coverage (eg, vancomycin or linezolid) are indicated.[28, 29]

Clindamycin may also be used to inhibit bacterial ribosomal production of exotoxin.

Fluid rehydration is initiated with Lactated Ringer solution at 20 mL/kg initial bolus. Repeat the initial bolus, as clinically indicated, followed by maintenance therapy with consideration for fluid losses from exfoliation of skin being similar to a burn patient.

Topical wound care, in severe cases, in a dedicated burn center should be provided.

Cultures from the exfoliated sites as well as nose, throat, and other potential sites of the original focus of infection should be performed.

A chest radiograph should be considered to rule out pneumonia as the original focus of infection.

Steroids are not indicated and may worsen immune function.

Nonsteroidal anti-inflammatory agents and other agents that potentially reduce renal function should be avoided

Differentiating staphylococcal scalded skin syndrome (SSSS) from toxic epidermal necrolysis (TEN), which carries a much higher mortality, is important. In SSSS, the mucous membranes are spared. In TEN, the mucous membranes are almost always affected (mouth, conjunctiva, trachea, esophagus, anus, vagina).

Consultation with the following may be indicated:

• Pediatrician

• Dermatologist

• Possibly, infectious disease and burn specialists (eg, plastic surgeon)

Drug therapy for staphylococcal scalded skin syndrome (SSSS) consists of parenteral antibiotics to cover S aureus, which is considered the primary source of the toxin-mediated syndrome.

Topical therapy with agents, such as fusidic acid and/or mupirocin, can be used as adjuncts to parenteral antibiotics, but they should not be used alone in true cases of staphylococcal scalded skin syndrome (SSSS).

Class Summary

When the susceptibility of the organism is not yet known, the DOC is a penicillinase-resistant synthetic penicillin (eg, nafcillin). However, should the organism show susceptibility to penicillin G, then that drug should be chosen as the main course of therapy. A first-generation cephalosporin can be used as an alternative. In penicillin-allergic patients, macrolides or aminoglycosides may be substituted. Increasing rates of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections warrant consideration for vancomycin or linezolid therapy in patients who initially appear toxic or who fail to respond to nafcillin.

Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS, Septra DS, Sulfatrim)

Trimethoprim: Inhibits dihydrofolate reductase, thereby blocking production of tetrahydrofolic acid from dihydrofolic acid

Sulfamethoxazole: Inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid

Nafcillin (Nalipen in Dextrose)

Treats infections caused by penicillinase-producing staphylococci, and thus is DOC for penicillin G-resistant staphylococcal infections. Do not use for treatment of penicillin G-susceptible staphylococci. Use parenteral therapy initially in severe infections, using very high doses for very severe infections.

Penicillin G procaine

Long-acting parenteral penicillin (IM only) indicated in treatment of moderately severe infections caused by penicillin G-sensitive microorganisms. Useful in treatment of moderately severe infections of skin and skin structures. In adults, administer by deep IM injection only into upper, outer quadrant of buttock. In infants and small children, midlateral aspect of thigh may be better site for administration.

Amoxicillin and clavulanate (Amoclan, Augmentin, Augmentin ES-600, Augmentin XR)

Drug combination that extends antibiotic spectrum of this penicillin to include bacteria normally resistant to beta-lactam antibiotics. Indicated for skin and skin-structure infections caused by beta-lactamase-producing strains of S aureus. In children >3 mo, base dose on amoxicillin content. Because of different amoxicillin-to-clavulanic acid ratios in 250-mg tablets (250/125) vs 250-mg chewable tablets (250/62.5), do not use 250-mg tablet until child weighs >40 kg.

Cefazolin

First-generation semisynthetic cephalosporin, which, by binding to one or more penicillin-binding proteins, arrests bacterial cell wall synthesis and inhibits bacterial growth. Primarily active against skin flora, including S aureus. Typically used alone for skin and skin-structure coverage. Total daily dosages are same for IV/IM routes.

Cephalexin (Keflex)

First-generation cephalosporin that inhibits bacterial growth by inhibiting bacterial cell wall synthesis. Bactericidal and effective against rapidly growing organisms forming cell walls. Primarily active against skin flora. Typically used for skin-structure coverage and as prophylaxis in minor procedures.

Clindamycin (Cleocin)

Lincosamide useful as treatment against serious skin and soft-tissue infections caused by most staphylococci strains. Inhibits bacterial protein synthesis by inhibiting peptide chain initiation at bacterial ribosome, where it binds preferentially to 50S ribosomal subunit, inhibiting bacterial growth.

Gentamicin

Aminoglycoside antibiotic used for gram-negative bacterial coverage. Commonly used in combination with both agent against gram-positive organisms and one that covers anaerobes.

Not antibiotic of first choice. Consider using only if penicillins or other less toxic drugs are contraindicated, when bacterial susceptibility tests and clinical judgment indicate its use, and in mixed infections caused by susceptible strains of staphylococci and gram-negative organisms.

Dosing regimens are numerous and are adjusted based on CrCl and changes in volume of distribution, as well as body space into which agent needs to distribute. Dose of gentamicin may be given IV/IM. Each regimen must be followed by at least trough level drawn on third or fourth dose, 0.5 h before dosing; may draw peak level 0.5 h after 30-min infusion.

Tobramycin

Used in skin, bone, and skin-structure infections caused by S aureus, Pseudomonas aeruginosa, Proteus species, Escherichia coli, Klebsiella species, and Enterobacter species. Indicated in serious staphylococcal infections when penicillin or other potentially less toxic drugs contraindicated and when bacterial susceptibility testing and clinical judgment indicate use. To prevent increased toxicity caused by excessive blood levels do not exceed 5 mg/kg/d, unless serum levels monitored.

Erythromycin (E.E.S., Ery-Tab, Eryped, Erythrocin, PCE)

Indicated for treatment of infections caused by susceptible strains including S aureus. Inhibits RNA-dependent protein synthesis, possibly by stimulating dissociation of peptidyl t-RNA from ribosomes. This inhibits bacterial growth.

Age, weight, and severity of infection determine proper dosage. When bid dosing desired, half of total daily dose may be taken q12h. For more severe infections, double dose.

Vancomycin

Indicated for patients who cannot receive or have failed to respond to penicillins and cephalosporins or have infections with resistant staphylococci. To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment.

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

Linezolid (Zyvox)

Binds to bacterial 23S rRNA of the 50S subunit to prevent protein translation; also elicits nonselective MAO inhibition.

Oxacillin (Bactocill)

Bactericidal antibiotic that inhibits cell wall synthesis by binding to one or more of the penicillin binding proteins. Used in the treatment of infections caused by penicillinase-producing staphylococci. May be used to initiate therapy when a staphylococcal infection is suspected.

Class Summary

 These agents are used to treat open excoriations and erosions and can be used as adjuncts to parenteral antibiotics, but they should not be used alone in true cases of staphylococcal scalded skin syndrome.

Mupirocin (Bactroban, Bactroban Nasal, Centany, Centamy AT)

Bactericidal; inhibits protein synthesis in susceptible bacteria by reversibly binding to bacterial isoleucine-tRNA ligase (isoleucyl-tRNA synthetase), the enzyme that catalyzes the formation of isoleucyl-tRNA from isoleucine and tRNA

Further inpatient care for patients with staphylococcal scalded skin syndrome (SSSS) involves fluid rehydration, local burn/wound care, and eradication of the underlying infection.

Patients with severe disease may require ICU or burn unit care.

Deterrence and prevention may involve the following:

• Avoidance of the primary staphylococcal infection that may lead to the toxic syndrome

• Timely treatment of established staphylococcal infections

• Identification and treatment of asymptomatic carriers

Complications of staphylococcal scalded skin syndrome may include the following:

• Dehydration

• Shock

• Hypothermia

• Generalized bacteremia and/or sepsis

• Local or remote spread of infection

• Secondary infections

• Scarring, disability, and death

Prognosis of staphylococcal scalded skin syndrome (SSSS) in children is excellent, with complete healing typically occurring in 10 days without significant scarring.

Prognosis of staphylococcal scalded skin syndrome in adults depends on the host's immune status, the speed in initiating proper treatment, the course of the infection, and the occurrence of complications. Staphylococcal scalded skin syndrome in adults carries significant rates of morbidity and mortality.