Staphylococcal Infections

Background

Staphylococcal infections are usually acquired by the animal Staphylococcus aureus. However, the accident of infections due to Staphylococcus epidermidis and added coagulase-negative staphylococci has been steadily accretion in contempo years. This commodity focuses on S aureus but additionally discusses infections acquired by coagulase-negative staphylococci back important differences exist.

Pathophysiology

S aureus is a gram-positive coccus that is both catalase- and coagulase-positive. Colonies are aureate and acerb hemolytic on claret agar. They aftermath a ambit of toxins, including alpha-toxin, beta-toxin, gamma-toxin, delta-toxin, exfoliatin, enterotoxins, Panton-Valentine leukocidin (PVL), and baneful shock affection toxin–1 (TSST-1). The enterotoxins and TSST-1 are associated with baneful shock syndrome. PVL is associated with baleful skin and lung infections and has been apparent to be a above acerbity agency for pneumonia and osteomyelitis. Coagulase-negative staphylococci, decidedly S epidermidis, aftermath an exopolysaccharide (slime) that promotes foreign-body adherence and attrition to phagocytosis.

Nienaber et al accept approved that methicillin-susceptible S aureus isolates causing endocarditis are added acceptable to be from a specific clonal array (CC30) and to acquire specific acerbity genes as compared to MSSA isolates from the aforementioned regions causing bendable tissue infection. Isolates from patients with endocarditis were added acceptable to acquire genes for 3 altered adhesins and 5 altered enterotoxins. The gene for PVL was begin in the boyhood of both groups.

In a abstraction of 42 Staphylococcus lugdunensis isolates, best isolates were able to anatomy at atomic a anemic biofilm, but the bulk of biofilm formed by isolates was amalgamate with poor alternation amid analytic severity of ache and amount of biofilm formation.

Epidemiology

Frequency

United States

Up to 80% of bodies are eventually colonized with S aureus. Best are colonized abandoned intermittently; 20-30% are agilely colonized. Colonization ante in bloom affliction workers, bodies with diabetes, and patients on dialysis are college than in the accepted population. The antecedent adenoids are the absolute armpit of colonization in adults; carrying actuality has been associated with the development of bacteremia. Added abeyant sites of colonization accommodate the throat, axilla, rectum, and perineum.

International

S aureus infection occurs worldwide. Pyomyositis due to S aureus is added accustomed in the tropics.

Mortality/Morbidity

Mortality due to staphylococcal infections varies widely. Untreated S aureus bacteremia carries a bloodshed amount that exceeds 80%. The bloodshed amount of staphylococcal baneful shock affection is 3-5%. Infections due to coagulase-negative staphylococci usually backpack a actual low bloodshed rate. Because these infections are frequently associated with prosthetic devices, the best austere aggravation is the charge to abolish the circuitous prosthesis, although prosthetic valve endocarditis may advance to death.

Thrombocytopenia is associated with added bloodshed amid patients with S aureus bacteremia.

Race

Staphylococcal infections accept no appear ancestral predilection.

Sex

The vaginal carrying amount of staphylococcal breed is about 10% in premenopausal women. The amount is alike college during menses.

Age

Staphylococcal breed arrive abounding neonates on the skin, perineum, umbilical stump, and GI tract. The staphylococcal colonization amount in adults is about 40% at any accustomed time.

The bloodshed amount of S aureus bacteremia in aged bodies is clearly increased.

Staphylococcal Infections Analytic Presentation

History

Common manifestations of staphylococcal infections accommodate the afterward types of infections. The history acquired usually depends on the blazon of infection the animal causes.

Bark infections (Many individuals who present with community-acquired bark infections are initially misdiagnosed with spider bites. These infections are generally due to methicillin-resistant S aureus [MRSA].)

Folliculitis

Furuncles

Impetigo (bullous)

Wound infections

Scalded bark syndrome

Soft-tissue infections (pyomyositis, catchbasin bursitis, catchbasin arthritis)

Baneful shock syndrome

Purpura fulminans

Endocarditis

Osteomyelitis

Pneumonia

Food poisoning

Infections accompanying to prosthetic devices

Frequently associated with coagulase-negative staphylococci

Includes prosthetic joints and affection valves and vascular shunts, grafts, and catheters

Urinary amplitude infection

Physical

Bark and soft-tissue infections

Erythema

Warmth

Draining atrium tracts

Superficial abscesses

Bullous impetigo

Baneful shock syndrome

Fever greater than 38.9°C

Diffuse erythroderma - Deep, red, "sunburned" appearance

Hypotension

Desquamation - Occurs 7-14 canicule afterwards access of illness, usually involves award and soles

Endocarditis

Regurgitant murmur

Petechiae or added cutaneous lesions.

 

Embolic lesions in accommodating with Staphylococcus aurEmbolic lesions in accommodating with Staphylococcus aureus endocarditis

 

Close-up appearance of embolic lesions in accommodating with SClose-up appearance of embolic lesions in accommodating with Staphylococcus aureus endocarditis.

Fever

Causes

Predisposing factors for staphylococcal infections accommodate the following:

Neutropenia or neutrophil dysfunction

Diabetes

Intravenous biologic abuse

Foreign bodies, including intravascular catheters

Trauma

Colonization with S aureus is common. Skin-to-skin and skin-to-fomite acquaintance are accepted routes of acquisition. Isolates can be advance by coughing or sneezing.Evidence has additionally apparent that S aureus can be advance during macho homosexual sex. Pets can additionally serve as domiciliary reservoirs.

Staphylococcal Infections Analysis & Management

Medical Care

Promptly alpha antimicrobial analysis back S aureus infection is accurate or acerb suspected. Appropriate choices depend on bounded susceptibility patterns. Admission of subinhibitory concentrations of antibiotics may advance to added assembly of PVL. The Infectious Diseases Society of America has appear abundant guidelines on the analysis of methicillin-resistant S aureus infections.

Temporary intravascular accessories should be promptly removed if infection is suspected. Long-term intravascular accessories should be removed if infection with S aureus is documented.

Multiple decolonization regimens accept been acclimated in patients with alternate staphylococcal infection. Analysis with contemporary mupirocin, chlorhexidine gluconate washes, and articulate rifampin additional doxycycline for 7 canicule eradicated methicillin-resistant S aureus (MRSA) colonization in ailing patients.

Surgical Care

Abscesses charge be drained. Infections involving a prosthetic collective usually crave abatement of the prosthesis. Added infections involving a prosthetic device, such as a prosthetic affection valve or built-in intravascular device, may or may not crave abatement of the device.

Medication Summary

Historically, isolates aggressive to oxacillin (commonly referred to as methicillin-resistant S aureus [MRSA]) were aggressive to best agents added than vancomycin, but these isolates were bound to nosocomial infections. Added recently, abounding letters accept declared community-acquired MRSA infections that accept been affected to assorted non–beta-lactam antibiotics. As such, patients with austere staphylococcal infections should be initially started on agents alive adjoin MRSA until susceptibility after-effects are available. Abounding coagulase-negative staphylococci are oxacillin-resistant. The continuance of analysis and the use of accessory combinations depend on the blazon of infection encountered. Endocarditis due to S aureus may crave a abiding advance of antibiotics.

Although abounding strains of MRSA that account community-acquired infection are affected to trimethoprim-sulfamethoxazole, analysis with trimethoprim-sulfamethoxazole has been associated with analytic failure, abnormally in the attendance of cogent tissue damage.

Vancomycin-resistant isolates accept been reported; isolates with an added minimum inhibitory absorption (MIC) to vancomycin are acceptable added accepted and accommodate both MRSA and methicillin-susceptible S aureus (MSSA). Consensus guidelines acclaim dosing vancomycin to abstain a canal of beneath than 10 mcg/mL; canal levels of 15-20 mcg/mL are recommended to amusement complicated infections

In a abstraction of 296 afterwards MRSA bacteremia episodes, several factors were predictive of aerial vancomycin MIC, including age earlier than 50 years, above-mentioned vancomycin exposure, history of MRSA bacteremia, history of abiding alarmist disease, and attendance of a nontunneled catheter.

Antibiotics

Class Summary

Empiric antimicrobial analysis charge be absolute and should awning all acceptable bacilli in the ambience of the analytic setting.

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Nafcillin (Nafcil, Unipen, Nallpen)

Preferred analysis for methicillin-susceptible S aureus (MSSA) staphylococci infections. Use parenteral analysis initially in astringent infections. Oxacillin may be commissioned for nafcillin based on hospital formulary. Change to articulate analysis as activity warrants.

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Vancomycin (Vancocin, Vancoled)

Indicated for patients who cannot accept penicillins and cephalosporins or accept infections with aggressive staphylococci. To abate the accident for toxicity, appraisal vancomycin canal levels afterwards third dosage fatigued 0.5 h above-mentioned to abutting dosing. Use CrCl to acclimatize dosage in patients diagnosed with renal impairment.

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Telavancin (Vibativ)

Lipoglycopeptide antibacterial that is a constructed acquired of vancomycin. Inhibits bacterial corpuscle bank amalgam by interfering with polymerization and cross-linking of peptidoglycan. Unlike vancomycin, telavancin additionally depolarizes the bacterial corpuscle film and disrupts its anatomic integrity. Adumbrated for complicated bark and bark anatomy infections acquired by affected gram-positive bacteria, including Staphylococcus aureus (both methicillin-resistant and methicillin-susceptible strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis (vancomycin-susceptible isolates only).

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Cefazolin (Ancef, Kefzol)

First-generation semisynthetic cephalosporin that arrests bacterial corpuscle bank synthesis, inhibiting bacterial growth. Primarily alive adjoin bark flora, including S aureus (MSSA). Typically acclimated abandoned for bark and skin-structure coverage. IV and IM dosing regimens are similar.

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Clindamycin (Cleocin)

Lincosamide for analysis of austere bark and bendable tissue staphylococci infections. Additionally able adjoin aerobic and anaerobic streptococci (except enterococcal) (MSSA). Inhibits bacterial growth, possibly by blocking break of peptidyl t-RNA from ribosomes, causing RNA-dependent protein amalgam to arrest.

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Dicloxacillin (Dycill, Dynapen)

Binds to one or added penicillin-binding proteins, which, in turn, inhibits amalgam of bacterial corpuscle walls. For analysis of infections acquired by penicillinase-producing staphylococci affected to methicillin (MSSA). Additionally alive adjoin best nonenterococcal streptococci. May use to admit analysis back staphylococcal infection is suggested.

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Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

Inhibits bacterial advance by inhibiting amalgam of dihydrofolic acid. Alive adjoin best staphylococci (MSSA), including some strains aggressive to methicillin (MRSA).

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Minocycline (Minocin)

Inhibits protein amalgam and appropriately bacterial advance by bounden to 30S and possibly 50S ribosomal subunits of affected bacteria. Alive adjoin MSSA/MRSA. Beneath alive adjoin coagulase-negative staphylococci. Doxycycline (Vibramycin) may be acclimated in abode of minocycline

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Linezolid (Zyvox)

Prevents accumulation of anatomic 70S admission complex, which is capital for bacterial adaptation process. Bacteriostatic adjoin staphylococci (MSSA/MRSA).

The FDA warns adjoin the circumstantial use of linezolid with serotonergic psychiatric drugs, unless adumbrated for life-threatening or burning conditions. Linezolid may access serotonin CNS levels as a aftereffect of MAO-A inhibition, accretion the accident of serotonin syndrome.

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Quinupristin/dalfopristin (Synercid)

Belongs to the streptogramin accumulation of antibiotics. Mechanism of activity is agnate to macrolides/lincosamides. Inhibits protein amalgam and is usually bacteriostatic. Additionally an advantage for methicillin-resistant S aureus (MRSA) infections.

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Daptomycin (Cubicin)

Indicated to amusement complicated bark and bark anatomy infections acquired by S aureus (including MRSA strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, and Enterococcus faecalis. Additionally adumbrated for right-sided endocarditis due to S aureus. First of fresh antibacterial chic alleged circadian lipopeptides. Binds to bacterial membranes and causes accelerated film abeyant depolarization, thereby inhibiting protein, DNA, and RNA amalgam and ultimately causing corpuscle death.

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Tigecycline (Tygacil)

A glycylcycline antibacterial that is structurally agnate to tetracycline antibiotics. Inhibits bacterial protein adaptation by bounden to 30S ribosomal subunit, and blocks access of amino-acyl tRNA molecules in ribosome A site. Adumbrated for complicated bark and bark anatomy infections and complicated intra-abdominal infections. Alive adjoin S aureus (including MRSA), as able-bodied as best streptococci, enterococci (including VRE), and gram-negative bacilli (including anaerobes).

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History And Examination For Skin Disorders

Although abounding bark disorders are calmly accustomed by simple inspection, the history and concrete assay are generally all-important for authentic assessment. The absolute anatomy surface, close membranes, conjunctiva, hair, and nails should consistently be advised thoroughly beneath able illumination. The color, turgor, texture, temperature, and damp of the bark and the growth, texture, caliber, and afterglow of the beard and nails should be noted. Bark lesions should be palpated, inspected, and classified on the bases of morphology, size, color, texture, firmness, configuration, location, and distribution. One charge additionally adjudge whether the changes are those of the primary bane itself or whether the analytic arrangement has been adapted by a accessory agency such as infection, trauma, or therapy. 

Primary lesions are classified as macules, papules, patches, plaques, nodules, tumors, vesicles, bullae, pustules, wheals, and cysts.

A blemish represents an about-face in bark blush but cannot be felt.

When the bane is >1 cm, the appellation application is used.

Papules are apparent solid lesions <0.5–1 cm, admitting nodules are beyond in diameter.

Tumors are usually beyond than nodules and alter appreciably in advancement and consistency. Vesicles are raised, fluid-filled lesions <0.5 cm in diameter; back larger, they are alleged bullae. Pustules accommodate purulent material.

Wheals are flat-topped, apparent lesions of capricious size, duration, and agreement that represent dermal collections of edema fluid.

Cysts are circumscribed, thick-walled lesions that are amid abysmal in the skin; they are covered by a accustomed covering and accommodate aqueous or semisolid material.

Aggregations of papules are referred to as plaques.

Primary lesions may change into accessory lesions, or accessory lesions may advance over time area no primary bane existed. Primary lesions are usually added accessible for analytic purposes than accessory lesions. Accessory lesions accommodate scales, ulcers, erosions, excoriations, fissures, crusts, and scars.

Scales abide of aeroembolism layers of degree corneum beef that are retained on the bark surface.

Erosions absorb focal accident of the epidermis, and they alleviate afterwards scarring.

Ulcers extend into the bark and tend to alleviate with scarring. Ulcerated lesions inflicted by abrading are generally beeline or angular in agreement and are alleged excoriations.

Fissures are acquired by agreeable or cracking; they usually action in afflicted skin.

Crusts abide of matted, retained accumulations of blood, serum, pus, and epithelial bits on the apparent of a complaining lesion.

Scars are end-stage lesions that can be thin, depressed and atrophic, aloft and hypertrophic, or collapsed and pliable; they are composed of coarse affiliation tissue.

Lichenification is a agglomeration of bark with accentuation of accustomed bark curve that is acquired by abiding affliction (rubbing, scratching) or inflammation.

If the analysis is not bright afterwards a absolute examination, one or added analytic procedures may be indicated

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Impetigo

Background

Impetigo is an acute, contagious, apparent pyogenic bark infection that occurs best frequently in children, abnormally those who alive in hot boiling climates. Clinically, physicians admit two abstracted forms of impetigo—bullous and nonbullous. Bullous impetigo is acquired about alone by Staphylococcus aureus, admitting nonbullous impetigo is acquired by S aureus,group A Streptococcus (Streptococcus pyogenes), or a aggregate of both.

Pathophysiology

Impetigo best generally develops at a armpit of accessory agony or insult in which the candor of the bark is disrupted. Adroit bacilli access the epidermis. Alternatively, abrading may anon bathe bacilli below the bark surface, causing impetiginization.

The arrangement of advance of the two adroit bacilli differs. S pyogenes is advance from a being who is adulterated or colonized with the bacilli assimilate the bark of addition individual, area it may account impetigo. The animal again colonizes the adenoids and throat. S aureus, in contrast, spreads aboriginal to the nose. It again spreads to the skin, area it may account impetigo.

Epidemiology

Race

Impetigo can affect bodies of all races.

Sex

In adults, impetigo is added accepted in men.

Age

Nonbullous impetigo can affect all ages, but it best frequently affects accouchement age-old 2-5 years.

Bullous impetigo affects all ages, but, historically, it occurs added generally in newborns and earlier infants. Some authors disagree, advertence that developed cases generally go underreported. 

Impetigo Analytic Presentation

History

Patients with impetigo may address a history of accessory trauma, insect bites, scabies, canker simplex, varicella, or eczema at the armpit of infection, and any history of preexisting bark ache should accession the clinician's basis of suspicion.A nummular eczema bane on the knee, impetiginizeA nummular eczema bane on the knee, impetiginized with Staphylococcus aureus.

Lesions accept usually been present for canicule or weeks rather than months. The lesions are usually painless, although patients may address afire and pruritus.

Constitutional affection are usually absent.

Obtain a history of contacts and alive conditions; bottleneck and poor hygiene can be accidental factors to the advance of impetigo.

Clusters in families and outbreaks in institutions are occasionally reported.

One address declared an beginning amid rugby players, which demonstrates an befalling for impetigo to be advance during acquaintance sports.

Physical

Nonbullous impetigo

Lesions aboriginal activate as thin-walled vesicles or pustules on an erythematous base. The lesions promptly rupture, absolution their serum, which dries and forms a ablaze brown, honey-colored crust.

Multiple lesions about action at the aforementioned site, generally coalescing. The afflicted breadth of bark may enlarge as the infection spreads peripherally.

Bark on any allotment of the anatomy can be involved, but the face and extremities are afflicted best commonly.

Pruritus of adulterated areas may aftereffect in excoriations due to scratching.

As the lesions resolve, either spontaneously or afterwards antibacterial treatment, the crusts accoutrements from the afflicted areas and alleviate after scarring.

If the advance of ache is abiding and patients do not seek treatment, as abounding as 90% will advance bounded lymphadenopathy.Following dermabrasion, this accommodating developed nonFollowing dermabrasion, this accommodating developed nonbullous impetigo in the aforementioned breadth as several canker canker lesions. 

Bullous impetigo

Lesions may anatomy on grossly accustomed or ahead traumatized skin.

The vesicles do not breach as calmly or bound as in nonbullous lesions, but they do enlarge into bullae that are usually 1-2 cm in diameter. The bullae initially accommodate a bright chicken aqueous that after turns blurred and aphotic yellow.

Afterwards 1-3 days, the lesions breach and leave a thin, ablaze brown, varnishlike crust.

Central healing after-effects in circinate lesions.

In adverse to nonbullous impetigo, bullous impetigo may absorb the buccal close membranes, but bounded lymphadenopathy is rare.Bullous impetigo on the buttocks. Courtesy of MediBullous impetigo on the buttocks. Courtesy of Medical University of South Carolina, Department of Dermatology. 

Causes

Nonbullous impetigo

S aureus, accumulation A streptococcus (S pyogenes), or both may be the adroit agent(s) in nonbullous impetigo, but advisers disagree about which animal added generally plays the primary role in infection.

Early studies acicular to streptococci, but contempo investigations advance that S aureus is added the primary communicable organism, abnormally in automated nations.

Evidence indicates that the primary animal varies with cartography and climate; streptococcal impetigo is added accepted in developing nations and balmy climates.

Streptococci are the best accepted primary account back both bacilli are present.

Bullous impetigo

S aureus phage accumulation II blazon 71 is the absolute adroit organism. This ache of bacilli produces an exfoliatin adulteration that causes subcorneal epidermal cleavage.

In immunodeficient or immunocompromised patients, the adulteration may advertise hematogenously and advance to ambiguous staphylococcal scalded bark syndrome.

Impetigo Analysis & Management

Medical Care

Medical administration may absorb contemporary analysis abandoned or a aggregate of systemic and contemporary therapies.

Contemporary therapy

First, abolish the adulterated crusts and bits with soap and water. If the infection is balmy and localized, contemporary mupirocin abandoned may be the alone all-important therapy. Studies announce this contemporary antibiotic, although expensive, is as able as articulate erythromycin for alleviative impetigo. Furthermore, the amount aberration amid these two treatments may be account by the added accident of adverse furnishings associated with erythromycin.

Disadvantages of contemporary analysis are that it cannot eradicate bacilli from the respiratory amplitude and applying contemporary medications to all-encompassing lesions is difficult.

No studies announce that added contemporary antibiotics are as able as systemic therapy.

Systemic therapy

Back infection is abstinent to astringent or accompanied by lymphadenopathy, systemic analysis is indicated.

The biologic adopted for impetigo acquired by S pyogenes is penicillin. Substitute clindamycin in patients who are allergic to penicillin.

In cases acquired by S aureus, clindamycin or cephalexin may be used.

Treat erythromycin-resistant S aureus impetigo with a cephalosporin (eg, cephalexin, clindamycin)

Medication Summary

The goals of pharmacotherapy are to eradicate the infection, to abate morbidity, and to anticipate complications.

Antibiotics

Class Summary

Empiric antimicrobial analysis charge be absolute and should awning all acceptable bacilli in the ambience of the analytic setting.

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Penicillin V (Penicillin VK, Veetids)

Interferes with corpuscle bank mucopeptide amalgam during alive multiplication, consistent in antibacterial action adjoin affected microorganisms. Not recommended for staphylococcal impetigo.

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Cephalexin (Keflex)

Recommended for impetigo acquired by S aureus aggressive to erythromycin. First-generation cephalosporin arrests bacterial advance by inhibiting bacterial corpuscle bank synthesis. Antibacterial action adjoin rapidly growing organisms. Primary action adjoin bark flora. Acclimated for bark infections or prophylaxis in accessory procedures.

Amoxicillin clavulanate (Augmentin)

Indicated for bark and bark anatomy infections acquired by beta-lactamase–producing strains of S aureus that are aggressive to erythromycin.

Administration with aliment may abatement GI adverse effects.

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Clindamycin (Cleocin)

Alternative analysis for S aureus aggressive to erythromycin. Lincosamide for analysis of austere bark and bendable tissue staphylococcal infections. Also able adjoin aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking break of peptidyl tRNA from ribosomes, causing RNA-dependent protein amalgam to arrest.

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Retapamulin (Altabax)

Topical antibacterial accessible as a 1% ointment. Aboriginal of fresh antibacterial chic alleged pleuromutilins. Inhibits protein amalgam by bounden to 50S subunit on ribosome. Adumbrated for impetigo acquired by S aureus or S pyogenes

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Erythema Multiforme

Background

Erythema multiforme (EM) is an acute, self-limited, and sometimes recurring skin condition that is considered to be a type IV hypersensitivity reaction associated with certain infections, medications, and other various triggers.
 
Erythema multiforme may be present within a wide spectrum of severity. Erythema multiforme minor represents a localized eruption of the skin with minimal or no mucosal involvement. The papules evolve into pathognomonic target lesions or iris lesions that appear within a 72-hour period and begin on the extremities (see the following image). Lesions remain in a fixed location for at least 7 days and then begin to heal. Lesions may also appear as arcuate lesions (see the second image below). Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus (EBV), and histoplasmosis. Because this condition may be related to a persistent antigenic stimulus, recurrence is the rule rather than the exception, with most affected individuals experiencing 1-2 recurrences per year.
 
Target lesion of erythema multiforme.
 
Raised atypical targets and arcuate lesions.  
 Raised atypical targets and arcuate lesions. Raised atypical targets and arcuate lesions.

Erythema multiforme major and Stevens-Johnson syndrome (SJS), however, are more severe, potentially life-threatening disorders (see the image below). Lesions of Steven-Johnson syndrome typically begin on the face and trunk. They are flat, atypical lesions, described as irregular purpuric macules with occasional blistering. Most patients also have extensive mucosal involvement. More than 50% of all cases are attributed to medications.

Note extensive sloughing of epidermis. 
Courtesy ofNote extensive sloughing of epidermis. Courtesy of David F. Butler, MD.
 Erythema multiforme vs SJS and TENS

Controversy exists in the literature with regard to the clinical definitions of erythema multiforme and Steven-Johnson syndrome and whether they are distinct entities or whether they represent a spectrum of one disease process. International collaborators have suggested that erythema multiforme and Steven-Johnson syndrome could be separated as 2 distinct clinical disorders with similar mucosal reactions but different patterns of cutaneous lesions.

The confusion between these 2 separate clinical entities began in 1950, when Thomas coined the terms erythema multiforme minor and erythema multiforme major to describe conditions he encountered. Erythema multiforme minor was applied to patients with the illness originally described by Ferdinand von Hebra as erythema multiforme (acute, self-limited condition with characteristic red papular skin lesions) (1860). Erythema multiforme major was applied to patients who also displayed oral mucosal involvement, similar to that described by Stevens and Johnson (mucocutaneous disorder; febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption) (1922).
Up to 50% of patients with herpes simple virus (HSV)–associated erythema multiforme have been found to have oral ulcers. However, this is now recognized as a variant of erythema multiforme, rather than Steven-Johnson syndrome. Erythema multiforme and Steven-Johnson syndrome have different precipitating factors and different clinical patterns and are generally recognized to be separate clinical entities. Erythema multiforme with mucosal involvement is now termed bullous erythema multiforme.
Consensus classification

According to a consensus definition, Steven-Johnson syndrome was separated from the erythema multiforme spectrum and added to toxic epidermal necrolysis. Essentially Steven-Johnson syndrome and toxic epidermal necrolysis (TEN) are considered severity variants of a single entity. The 2 spectra are now divided into the following: (1) erythema multiforme consisting of erythema minor and major and (2) Steven-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN).

The clinical descriptions are as follows:

    Erythema multiforme minor - Typical targets or raised, edematous papules distributed acrally
    Erythema multiforme major - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area (TBSA).
    SJS/TEN - Widespread blisters predominant on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment is less than 10% TBSA for Steven-Johnson syndrome / toxic epidermal necrolysis and 30% or more for toxic epidermal necrolysis.
Historical information

Stevens-Johnson syndrome was considered an extreme variant of erythema multiforme for many years, whereas toxic epidermal necrolysis (TEN) was considered a different entity. However, in 1993, a group of medical experts proposed a consensus definition and classification of erythema multiforme, Steven-Johnson syndrome, and toxic epidermal necrolysis based on a photographic atlas and extent of body surface area involvement.
See also Dermatologic Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Oral Manifestations of Drug Reactions.
 Pathophysiology

The pathophysiology of erythema multiforme (EM) is still not completely understood, but it is probably immunologically mediated and appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli, particularly bacterial, viral, or chemical products.

Cell-mediated immunity appears to be responsible for the destruction of epithelial cells. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, whereas the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. In some patients, circulating T cells transiently demonstrate (for < 30 d) a T-helper cell type 1 (TH1) cytokine response (interferon [IFN] gamma, tumor necrosis factor [TNF] alpha, interleukin [IL] 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.

Other evidence supports the hypothesis that the disease is the result of cell-mediated immune reactions. Individuals possessing human leukocyte antigen (HLA)–B12 are 3 times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response. 
Herpes simplex virus

A major cause of erythema multiforme is the herpes virus (HSV). In fact, recent or recurrent herpes has been reported as the principle risk factor for erythema multiforme.

Herpes-associated erythema multiforme (HAEM) appears to represent the result of a cell-mediated immune reaction associated with HSV antigen. The immunologic reaction affects HSV-expressing keratinocytes. Cytotoxic effector cells, CD8+ T lymphocytes in the epidermis, induce apoptosis of scattered keratinocytes and lead to satellite cell necrosis. Neighboring epidermal cells are HLA-DR positive.

A relationship exists between HLA types A33, B35, B62 (B15), DR4, DQB1*0301, DQ3, and DR53 and recurrent erythema multiforme. In particular, HLA-DQ3 is especially related to recurrent erythema multiforme and may be a helpful marker for distinguishing HAEM from other cutaneous diseases.
Drug hypersensitivity

The disease process also often involves an abnormal metabolism of a responsible drug. As noted above, the keratinocyte is the ultimate target of this disease process, with keratinocyte necrosis being the earliest pathologic finding.

Patients frequently display an altered metabolism of the responsible drug, and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction.
 Etiology

Many suspected etiologic factors have been reported to cause erythema multiforme (EM). Both erythema multiforme and Steven-Johnson syndrome may be induced by medications, but infectious agents are also considered to be a major cause of erythema multiforme. However, approximately 50% of cases are idiopathic, with no precipitating factor identified.

A previous history of erythema multiforme and male sex has also been reported as risk factors, but pregnancy may contribute to development of erythema multiforme as well.

Postvaccination causes include Bacille Calmette-Guérin (BCG) vaccination, oral polio vaccine, vaccinia, and tetanus/diphtheria. 
HSV and other infections

Infectious causes are more common in children and are implicated more commonly in erythema multiforme.

Erythema multiforme minor is regarded as being commonly triggered by herpes simplex virus (HSV) (types 1 and 2), and HSV is the most common cause in young adults; in fact, many instances of idiopathic erythema multiforme minor may be precipitated by subclinical HSV infection. Among other infections, Mycoplasma species appear to be a common cause.

Bacterial

Bacterial infections include borreliosis, catscratch disease, diphtheria, hemolytic streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium avium complex, M pneumoniae, pneumococci, tuberculosis, Proteus/Pseudomonas/Salmonella/Staphylococcus/Yersinia species, Treponema pallidum, tularemia, Vibrio parahaemolyticus, Vincent disease, and rickettsial infections. Chlamydial infections include lymphogranuloma venereum and psittacosis.

Viral

Viral infections include Adenovirus, coxsackievirus B5, cytomegalovirus (CMV), echoviruses, enterovirus, Epstein-Barr virus (EBV), hepatitis A / B / C viruses (HAV / HBV / HCV), HSV, influenza, measles, mumps, paravaccinia, parvovirus B19, poliomyelitis, varicella-zoster virus (VZV), and variola.

Virus-drug interactions include CMV infection–terbinafine and EBV infection–amoxicillin.
Other

Fungal infections include coccidioidomycosis, dermatophytosis, and histoplasmosis.

Parasitic infections include Trichomonas species and Toxoplasma gondii. 
Drugs

More than 50% of cases are related to medication use, but no test reliably proves the link between a single case and a specific drug.

Regarding medications, sulfa drugs are the most common triggers (30%). A slow acetylator genotype is a risk factor for sulfonamide-induced Steven-Johnson syndrome.
The second most commonly involved agents are the anticonvulsants, including barbiturates, carbamazepine, hydantoin, phenytoin, and valproic acid. Prophylactic anticonvulsants after surgery for a brain tumor combined with cranial irradiation may result in life-threatening Steven-Johnson syndrome.
Causative antibiotics include penicillin, ampicillin, tetracyclines, amoxicillin, cefotaxime, cefaclor, cephalexin, ciprofloxacin. erythromycin, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, and vancomycin.

Antituberculoid agents such as rifampicin, isoniazid, thiacetazone, and pyrazinamide are also known offenders. Antipyretic agents as triggers include analgesics, especially aspirin as well as phenylbutazone, oxyphenbutazone, and phenazone.

Others drugs that may cause erythema multiforme include acarbose, albendazole, allopurinol, arsenic, bromofluorene, quinine (Chinine), cimetidine, clofibrate, corticosteroids, diclofenac, didanosine, dideoxycytidine, diphosphonate, estrogen, etretinate, fluconazole, griseofulvin, gabapentin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hydralazine, indapamide, indinavir, lamotrigine, methazolamide, mefloquine, methotrexate, meprobamate, mercurials, minoxidil, nifedipine, nevirapine, nitrogen mustard, nystatin, nonsteroidal anti-inflammatory drugs (NSAIDs), phenolphthalein, piroxicam, pyritinol, progesterone, potassium iodide, sulindac, suramin, saquinavir, thiabendazole, thiouracil, terbinafine, theophylline, verapamil, and dihydrocodeine phosphate.
Contact exposure

Contactants include ammoniated mercury, budesonide, bufexamac, capsicum, chloromethylnaphthalene, desoximetasone, dinitrochlorobenzene (DNCB), disperse blue 124, diphenylcyclopropenone, fire sponge (Tedania ignis), herbal medicines (eg, Alpinia galanga), isopropyl-p -phenylenediamine of rubber, nickel, nitrogen mustard, oxybenzone, phenylbutazone, poison ivy, proflavin, resin, rosewood, and triamcinolone acetonide. 
Other etiologic factors

The following have also been reported as causes of erythema multiforme:

    Flavorings and preservatives, such as benzoic acid and cinnamon    Immunologic disorders, such as transient selective C4 deficiency of infancy, collagen diseases, vasculitides, sarcoidosis, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, and polycythemia
    Physical or mechanical factors, such as tattooing, radiotherapy, cold, and sunlight
    Foods, including salmon berries and margarine
    Malignancy
    Hormonal
Epidemiology

The exact incidence of erythema multiforme (EM) in the United States is unknown; however, as many as 1% of dermatologic outpatient visits are for erythema multiforme. Globally, the frequency of erythema multiforme is estimated at approximately 1.2-6 cases per million individuals per year.

Before the human immunodeficiency virus (HIV) epidemic among young males, there was a slight female predominance of this disease. However, erythema multiforme is currently more common in younger males (male-to-female ratio, range of 3:2 to 2:1) (mainly second to fourth decades, but can include children and adolescents [20%] ). The condition is rare in children younger than 3 years and in adults older than 50 years.

The following medical conditions seem to predispose individuals to a higher risk of developing the disorder: HIV infection, corticosteroid exposure, bone marrow transplant, systemic lupus erythematosus (SLE), graft versus host disease (GVHD), and inflammatory bowel disease (IBD). Individuals undergoing radiation, chemotherapy, or neurosurgery for brain tumors are also at higher risk. 
Prognosis

Most cases of erythema multiforme (EM) are self-limited. In erythema multiforme minor, the lesions evolve over 1-2 weeks and ultimately subside within 2-3 weeks without scarring. However, the recurrence of erythema multiforme minor is common (up to one third of cases) and mostly preceded by apparent or subclinical herpes simplex virus (HSV) infection.

Erythema multiforme major has a mortality rate of less than 5% and is directly proportional to the total body surface area of sloughed epithelium. It usually has a more protracted course than erythema multiforme minor; clearing may require 3-6 weeks. Skin lesions usually heal with hyperpigmentation and/or hypopigmentation. Scarring is usually absent, except after secondary infection. Sepsis secondary to loss of the cutaneous barrier is the principle cause of death.

Advanced age, visceral involvement, increased serum urea nitrogen level, and previous bone marrow transplantation are poor prognostic factors. Surprisingly, although the incidence of erythema multiforme is increased among individuals with human immunodeficiency virus (HIV) infection (approaching 1 case per 1000 individuals per year), they do not appear to have a higher mortality rate. 
Continuous and persistent erythema multiforme

Two additional rare clinical forms of erythema multiforme have been reported. Continuous erythema multiforme manifests as a prolonged course with overlapping attacks and may be associated with systemic administration of glucocorticoids.

Persistent erythema multiforme has a protracted clinical course over months, is commonly associated with atypical skin lesions, and is commonly resistant to conventional treatment. It has been reported in association with inflammatory bowel disease (IBD), occult renal carcinoma, persistent or reactivated Epstein-Barr virus (EBV) infection, and HSV infection. 
Patient Education

Educate patients with erythema multiforme (EM) about appropriate symptomatic treatment, and provide reassurance that disease is usually self-limited. In addition, advise patients of the significant risk of recurrence and emphasize the avoidance of any identified etiologic agent. (See Monitoring and Prevention.)

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