Cutaneous Reactions to Antibacterial Agents

Josheph A. Witkowski, MD, Lawrence Charles Parish, MD

Disclosures
In This Article

Determining the Cause

Identification of the drug that is causing the eruption, except for a few drugs and some eruptions, still depends for the most part on circumstantial evidence. There are, however, several clinical points which are of value in determining the cause: 1) the interval between the introduction of the drug and the onset of the reaction; 2) improvement or disappearance of the manifestation when the drug is withdrawn; 3) similar reactions having been reported to occur with the same or chemically related compounds; 4) alternative causes of the eruption such as infectious diseases for which the drug was used as a treatment having been excluded; and 5) readministration of the drug causing the cutaneous changes to reappear. Diagnosis by rechallenge can be practiced for non-life threatening drug reactions.

While a biopsy of the skin will not identify the causative drug, it will establish the correct morphologic diagnosis and suggest the possibility of a drug etiology. It is especially indicated when purpura, vesicles, pustules, or infiltrated lesions are present. Scratch and intradermal skin tests, as well as the radioallergosorbent test, help to diagnose the cause of some immunoglobulin (Ig)E-mediated type I hypersensitivity reactions, especially to penicillins. Intradermal and patch tests with the offending drug may be of value for discovering the cause of cell mediated type IV hypersensitivity eruptions such as eczematous eruptions, morbilliform, erythema multiforme, fixed drug eruptions,[5,6] and acute generalized exanthematous pustulosis.[7]

This is a generalized pustular eruption caused by drugs. It begins within a day or two after starting the drug with the development of fever, burning, and/or pruritic erythematous patches on the face or intertriginous areas that become generalized within hours. Hundreds of minute nonfollicular pustules appear on the patches. The clinical picture is one of a rapidly evolving widespread scarlatiniform eruption studded with small superficial pustules (Figure 1). The pustules persist for days to weeks and desquamation follows. Approximately one half of the patients will have edema of the face and hands, purpura, and target-like erythema multiforme lesions. Erosions on the mouth and tongue are present in about one quarter of the patients.[8]

Many tiny nonfollicular pustules arising from a patch of erythema.

Laboratory examination reveals a leukocytosis with elevated neutrophils. Some patients have eosinophilia, hypocalcemia, hypoalbuminemia, and evidence of renal failure. A bacteriologic culture of the pustules is negative or shows saprophytes.

Histologic examination reveals subcorneal or intraepidermal spongiform neutrophilic pustules. There is edema of the papillary dermis, a polymorphous perivascular infiltrate with eosinophils, and occasionally, leukocytic vasculitis with extravasated red blood cells. Focal necrosis of keratinocytes may be seen.[9]

The differential diagnosis includes pustular psoriasis, viral infection, Sneddon-Wilkinson subcorneal pustulosis, and follicular pustular drug reactions.

A patch test with suspected drug over an involved site is positive in 50% of cases.[7] See chart for antibacterial drugs causing acute generalized exanthematous pustulosis.

This is an acquired autoimmune subepidermal bullous disease of elderly persons. IgG and C3 are bound to the epidermal basement membrane on direct immunofluorescence. The disease is characterized by the presence of large tense bullae arising from normal skin or from erythematous patches and erosions. The lesions are most common on the lower abdomen, the flexor surfaces of the forearms, and the anterior and inner surfaces of the thighs, but may be generalized. Occasionally, the lesions are localized to the lower extremities. Oral mucous membrane erosions are seen in 10%-35% of patients.

Biopsy of a small blister shows a subepidermal vesicle with a superficial dermal infiltrate consisting of lymphocytes, histiocytes, and eosinophils.[10] Direct immunofluorescence reveals C3 and IgG in a linear pattern at the basement membrane. Thirty to eighty percent of patients have circulating IgG that binds to the basement membrane of human skin or monkey esophagus.[11]

Drug-induced bullous pemphigoid can be similar to the idiopathic disease, have fewer lesions, or present an erythema multiforme-like picture (Figure 2). Patients also tend to be younger.[12] The histology is similar but tissue bound and circulating antibasement antibodies may be absent.[13] The eruption usually clears when the offending drug is withdrawn.

Tense bullae and erosions on normal and erythematous skin.

Most other bullous diseases can be differentiated by histology and immunofluorescence. See Table for antibacterial drugs causing bullous pemphigoid.

This is a systemic reaction to drugs characterized by fever and involvement of one or more organs. It usually begins 2-6 weeks after first exposure to the drug. Re-exposure to the same drug following a previous reaction may cause symptoms within one day. Initial manifestations are fever, malaise, pharyngitis, and tender cervical or generalized lymphadenopathy. Eighty-five percent of patients will develop an eruption near the time of the onset of the fever. The skin changes range from an exanthematous eruption, exfoliative dermatitis, pustular folliculitis, erythema multiforme, Stevens-Johnson Syndrome (SJS), or toxic epidermal necrolysis. An early hematologic abnormality is atypical lymphocytosis followed by a profound eosinophilia. Later changes include thrombocytopenia, agranulocytosis, or aplastic anemia. Fifty percent of the patients develop liver function abnormalities. Other organs such as the kidneys, central nervous system, intestinal tract, pancreas, and lungs are less commonly involved. Small groups of patients develop autoimmune thyroiditis presenting as hyperthyroidism within 2 months after the onset of drug hypersensitivity syndrome. Several months later, these patients become hypothyroid.

Differential diagnosis includes cutaneous drug eruptions, bacterial or viral infections, lymphoma, and idiopathic hypereosinophilic syndrome.

Treatment includes drug withdrawal, systemic corticosteroids 1-2 mg/kg/day if the reaction is severe. Antihistamines and topical corticosteroids may help alleviate local symptoms.[14,15] See Table for antibacterials causing drug hypersensitivity syndrome.

This is a lupus-like syndrome in a person with no previous autoimmune disease. The syndrome develops weeks to years after beginning treatment. Readministration of the drug causes a recurrence within hours to days. Onset of symptoms may be abrupt or gradual with symptoms and signs becoming increasingly severe over several weeks. Many of the patients have musculoskeletal complaints, fever, and weight loss. More than 50% of patients have pleuropulmonary involvement. Renal and neurologic changes are rare, as are erythematous, vasculitis, and urticarial eruptions. Patients often present with symmetrical small joint polyarthritis, fever, and malaise.

Laboratory abnormalities include an elevated erythrocyte sedimentation rate, positive antinuclear antibody with a homogenous pattern, and antihistone antibodies. Liver enzymes alanine aminotransferase and aspartate aminotransferase may be elevated and the antineutrophil cytoplasmic test may be positive with a perinuclear pattern.

Treatment includes stopping the offending drug, which should result in improvement within days to weeks. Some patients may require a short course of systemic corticosteroids and nonsteroidal anti-inflammatory agents to control the musculoskeletal symptoms.[16] See Table for antibacterials causing drug-induced lupus.

These eruptions, either morbilliform or scarlatiniform, are the most common cutaneous adverse reactions to drugs. They usually begin within 2 weeks after therapy has started in areas of pressure and dependency (Figure 3), rapidly becoming generalized. The face, palms, and soles are usually spared. There may be erythema of the oral mucosa. Pruritus is the most common associated symptom. A low-grade fever may also be present. The eruption generally fades with scaling of the skin and finally disappears within 1-2 weeks after the causative drug is stopped. Continued administration of the drug may result in exfoliative dermatitis or in some instances the eruption may subside. Some morbilliform eruptions may recur on readministration of the drug, usually within 2-3 days.

Erythematous maculopapular lesions first appeared under pressure from a belt.

Biopsy of the skin reveals a lymphocytic infiltrate along the dermoepidermal junction and around the blood vessels of the superficial plexus. Mild basal cell vacuolization may be seen and eosinophils may be present in the infiltrate.[17]

Treatment consisting of oral antihistamines and topical antipruritic agents or a corticosteroid is all that is usually required.

Exanthematous drug eruptions are more common in women.[18] Cutaneous reactions to ampicillin occur more frequently in patients with hyperuricemia[19] and in up to 80% of patients with infectious mononucleosis.[20] Up to one half of patients with acquired immunodeficiency syndrome treated with cotrimoxazole develop a drug exanthem.[21] See Table for antibacterial drugs causing exanthematous eruptions.

This syndrome, occasionally caused by drugs,[22] is characterized by generalized erythema and scaling of the skin (Figure 4). It occurs more frequently in men and may follow an exanthematous drug eruption. Mucous membranes are usually not involved but lymphadenopathy and keratoderma of the palms and soles are commonly present. The eruption is usually associated with malaise, chills, and hyperthermia or hypothermia. Tachycardia and edema are common. In some patients, high output cardiac failure might occur. Exfoliative dermatitis is a frequent presentation of the drug hypersensitivity syndrome.

Universal erythema and scaling.

Histologic examination depends on the duration of the dermatosis. In the subacute phase there is parakeratosis, spongiosis and intracellular edema, acanthosis with elongation of the rete ridges and exocytosis. There is edema of the upper dermis and a chronic inflammatory infiltrate.[23]

Treatment includes drug withdrawal, the use of topical and systemic corticosteroids, antipruritics, emollients, and baths. See Table for antibacterial drugs causing exfoliative dermatitis.

This lesion recurs at the same site with each administration of the causative drug. With continued administration of the drug, lesions may appear in new areas as well as the original site. The lesion appears within 1-2 weeks after the first exposure to the sensitizing drug. On re-exposure to the drug, the lesion recurs within a few days. It begins as a round plaque of erythema and edema that may include central vesicles or bullae (Figure 5). Local symptoms include pruritus and burning. After the acute phase subsides, gray or brown postinflammatory hyperpigmentation develops at the site. The lesions have a predilection for acral areas, the face, and genitalia. Generalized fixed drug eruption may be difficult to distinguish from the SJS or bullous pemphigoid.

Round plaque of erythema and edema with a central bulla.

Histologic examination reveals necrotic keratinocytes and hydropic degeneration of the basal cell layer. There are both superficial and deep infiltrates that include eosinophils and neutrophils with melanin-laden macrophages.[24]

Treatment includes oral antihistamines, topical compresses, and corticosteroids. See Table for antibacterials causing fixed drug eruption.

Pemphigus vulgaris, pemphigus foliaceus, and its variant, pemphigus erythematosus are idiopathic, autoimmune, acantholytic, bullous diseases in which the site of blistering is within the epidermis. Pemphigus vulgaris is a generalized eruption characterized by erosions and flaccid bullae on the skin and erosions on the oral mucosa. The split due to acantholysis is in the suprabasilar level of the epidermis. In the erythematosus and foliaceus variants, erythema, crusting, and scaling are the major clinical findings; blisters may not be evident. The split due to acantholysis occurs at the subcorneal level of the epidermis. Tissue bound and circulating autoantibodies that bind to the epidermal surface antigens are present in pemphigus.

Drug-induced pemphigus usually begins after the patient has taken the drug for months to years. A morbilliform, annular erythema, or an urticarial eruption frequently precedes this bullous condition. Pemphigus itself usually presents as pemphigus foliaceus with generalized scaling, crusting, and erosions (Figure 6); pemphigus erythematosus presents with similar lesions with a butterfly distribution or a more generalized dermatitis on seborrheic areas (Figure 7); pemphigus herpetiformis presents with some vesicles and crusted lesions arranged in an annular or gyrate pattern or urticaria-like pemphigus with lesions on polycyclically bordered wheals. The clinical picture of pemphigus vulgaris of large flaccid bullae arising on normal skin and erosions is rarely seen in drug-induced pemphigus. Mucous membrane ulcers are seen in only 50% of cases.

Erythema, scaling, and erosions on the tip of the nose and nares.

Generalized erythema with erosions, crusts, and scales.

Histologic examination reveals splitting at various levels of the epidermis in the same specimen and in other lesions from the same patient. Tissue bound and circulating antibodies are not always present, but when found they circulate in low titers. Patch tests to the offending drug may be positive.

Treatment includes eliminating the offending drug and administering 0.5-1 mg/kg/day of systemic corticosteroids for several weeks until the active disease clears, then gradually tapering the dose. Should new lesions continue to appear, conventional treatment for pemphigus should be instituted, as this may be true pemphigus.[12] See Table for antibacterial drugs causing pemphigus.

Erythema nodosum is a cutaneous reaction pattern. It is characterized by tender, subcutaneous, erythematous nodules usually located on the anterior surface of the legs and occasionally elsewhere (Figure 8). Histologic examination of a wedge-biopsy specimen of a suspected lesion reveals a septal panniculitis. Erythema nodosum caused by drugs is not distinguishable from that due to other factors. Erythema nodosum usually regresses spontaneously in a few weeks.

Tender erythematous nodules on the knees and anterior surface of the legs.

Treatments include bed rest or elastic bandages and a nonsteroidal anti-inflammatory agent. For persisting lesions, saturated solution of potassium iodide 400-900 mg daily may be helpful.[25] See Table for antibacterial drugs causing erythema nodosum.

Porphyria cutanea tarda is a disorder of porphyrin metabolism characterized by vesiculobullous and ulcerative lesions on light exposed areas, increased skin fragility to mechanical trauma (Figure 9), hyperpigmentation, and sclerodermoid plaques, milia on the fingers and hands, hypertrichosis, and photoonycholysis.

Erosions, scaling, and milia on the side of the forefinger.

In laboratory tests urine demonstrates orange red fluorescence after acidification; 24-hour urine -- more uroporphyrin than coproporphyrin; and stool -- increased coproporphyrin and protoporphyrin.[26]

Pseudoporphyria. Patients with this disease have the same clinical findings except few have hypertrichosis, hyperpigmentation, or sclerodermoid plaques.[27] Laboratory studies for porphyrins are negative.

Variegate Porphyria. Patients with this disease have the same cutaneous findings as those with porphyria cutanea tarda (PCT) along with random acute attacks of abdominal pain, constipation, nausea, vomiting, muscle weakness, and bizarre neurotic or psychotic behavior.

Laboratory examination reveals increased aminolevulinic acid and porphobilinogen during acute attacks; 24-hour urine shows more coproporphyrin than uroporphyrin; and more protoporphyrin than coproporphyrin in stool.[26]

Histologic examination of sun-exposed skin reveals a subepidermal vesicle with an undulating base. There is thickening of the walls of the papillary blood vessels demonstrated best with a periodic acid-Schiff stain. There is little or no inflammatory infiltrate.[28] See Table for antibacterial drugs causing cutaneous porphyrias.

Photosensitive drug eruptions are adverse reactions of the skin that result from simultaneous exposure to a drug and to ultraviolet radiation or visible light. There are two types of photosensitive eruptions: 1) phototoxic, which depends on the presence of a sufficient level of the drug in the skin at the time of exposure to a sufficient quantity of the appropriate wave bands of ultraviolet radiation to form free radicals or reactive oxygen species; and 2) photoallergic, which depends on the formation of a photoproduct that conjugates with protein to produce an antigen.

Photosensitive eruptions are confined to areas exposed to light. They spare the triangle behind the ear, the upper eyelid, and areas under the nose, the chin, the watchband, and ring (Figure 10).

Diffuse erythema of the forearm with sparing of the skin under the watchband.

Phototoxic eruptions are most common. They usually occur on first exposure and do not recur when the drug is stopped except for those drugs having a long half-life. It is usually caused by ingested or injected drugs.[29] The eruption may be immediate, with the appearance of erythema and edema, or delayed with an exaggerated sunburn pattern at 16-24 hours. Melanin hyperpigmentation and desquamation may follow. Stinging or burning of the skin often accompanies it. Photoonycholysis may occur. It resembles sunburn histologically with necrotic keratinocytes and a sparse lymphocytic infiltrate. UV-A is most often responsible although UV-B and visible light may elicit this reaction with some drugs.

Photoallergic eruptions are less common. They rarely occur on first exposure to the drug unless the patient was previously sensitized. It usually takes 7-10 days after the first exposure and 1-2 days after subsequent exposures for development. Topically applied drugs are the most frequent cause although systemically administered drugs may also be causative. Photoallergic reactions may be due to delayed hypersensitivity. The acute eruption may resemble urticaria, eczematous dermatitis, or a lichenoid papular eruption. The chronic phase of photoallergy shows scaling and lichenification with accompanying pruritus. Histologic examination reveals epidermal spongiosis, acanthosis, and a lymphocytic infiltrate. Photoallergic reactions may continue to recur on subsequent exposure to light without reapplication of the photosensitizer.

Treatment includes identification and discontinuation of the photosensitizer. Topical compresses, corticosteroids, and oral antihistamines are often helpful. See Table for antibacterial drugs causing photosensitive eruptions.

These conditions are drug-induced or idiopathic mucocutaneous reaction patterns. Stevens-Johnson is less severe than TEN. In SJS, there is less than 10% epidermal detachment, whereas in TEN there is greater than 30% detachment. Patients with 10%-30% detachment are considered part of an overlap syndrome. Both eruptions can begin with atypical target lesions. Fifty percent of TEN begins with diffuse erythema or a morbilliform eruption. In SJS there is more involvement of the trunk and face, whereas TEN is generalized or universal. The etiology of SJS is often not clear, only 50% of cases are associated with drug exposure. In 80% of cases of TEN, there is a strong association with drug exposure, and in less than 5%, there is no history of drug use.

Both syndromes usually appear 1-3 weeks after exposure to the drug. Re-exposure to the same drug after a previous reaction may cause symptoms and signs to appear within hours to days. Initial symptoms are fever, chills, and malaise. Within 3 days skin pain, tenderness, and burning appear along with conjunctival burning and itching, and oral and urethral discomfort. Epidermal detachment and large flaccid bullae appear within poorly defined target-like red macules with purpuric centers (Figure 11) or within cyanotic exanthematous patches (Figure 12), leaving red oozing dermis. The lesions coalesce and spread within hours or a few days resulting in large denuded areas. Erythema and erosions occur in the mouth and periorificial areas in 90% of cases. Twenty-five percent of cases show conjunctivitis. The Nikolsky sign is positive.

Atypical iris lesions with purpuric centers.

Sheets of detached epidermis and red oozing dermis.

Histologic examination of an early lesion reveals vacuolization and necrosis of basal cells and individual cells in the epidermis. In late lesions, the entire epidermis is necrotic. There is a minimal inflammatory infiltrate in the dermis. Immunofluorescent testing is not diagnostic. Anemia and lymphopenia is often present. Patch testing with the offending drug is positive in many cases.[30] Except for pressure-bearing areas and periorificial sites, re-epithelialization is complete in about 3 weeks. Differential diagnosis of an early case includes erythema multiforme major, measles, scarlet fever, toxic shock syndrome, and graft vs. host disease. In a late case, erythema multiforme major, graft-versus-host disease, thermal burns, staphylococcal scalded skin syndrome, generalized fixed bullous drug eruption, and exfoliative dermatitis should be considered.

Treatment includes drug withdrawal, transferring the patient to a burn unit for wound care, intravenous fluids, pain control, and diagnosis and treatment of complications. Systemic corticosteroids should only be given if the patient is seen early in the course of the disease. Intravenous gamma globulin 0.75 g/kg for 4 consecutive days has been shown to be helpful.[31] See Table for antibacterial drugs causing these eruptions.

Serum sickness-like reaction is a clinical syndrome consisting of fever, arthralgia, and a cutaneous eruption. Unlike serum sickness, which is caused by injections of foreign proteins and is a type III Gell and Coombs hypersensitivity reaction, the pathogenesis is unknown. It begins 1-3 weeks after initiation of therapy and resolves when the drug is stopped. In most instances, it occurs after repeated exposure to the drug. The associated eruption has been reported as being urticarial, morbilliform, or erythema multiforme-like. Mucous membranes are usually not involved. The joints affected are usually the wrists, ankles, and knees. Lymphadenopathy and eosinophilia may be present. Internal organ involvement is usually absent.

Treatment includes withdrawal of the drug, antihistamines, topical antipruritics, or corticosteroids. If symptoms are severe, systemic corticosteroids 1-2 mg/kg/day may be used.[14] See Table for antibacterials causing drug-induced serum sickness-like reactions.

Vasculitis is characterized by inflammation and necrosis of blood vessel walls having many causes. It involves small blood vessels, typically the post-capillary venule. It is a type III Gell and Coombs hypersensitivity reaction. Drugs cause about 10% of cutaneous vasculitis.

The hallmark of vasculitis is a palpable purpuric papule (Figure 13). Other lesions that may be seen are urticaria-like lesions that persist longer than 24 hours, purpuric plaques and nodules, hemorrhagic vesicles or bullae, and ulcers. The lesions occur in crops and on dependent locations initially. The joints, gastrointestinal tract, kidneys, central nervous system, heart, and liver may be involved.

Purpuric papules and plaques.

Histologic examination of a purpuric papule reveals polymorphonuclear leukocytes with leukocytoclasis around the blood vessels, extravasation of red blood cells, and fibrinoid necrosis of the vessel walls.[32]

Differential diagnosis includes Henoch-Schönlein purpura, cryoglobulinemia, polyarteritis nodosa, Wegener's granulomatosis, infections, and collagen vascular diseases. Treatment includes drug withdrawal, elimination of other causes, and systemic corticosteroids. See Table for antibacterials causing drug induced vasculitis.

An urticarial eruption is the second most common reaction to drugs. Urticarial lesions are evanescent, edematous, papules and plaques. The lesions are often round or oval but may coalesce to form large irregularly shaped plaques or lesions with annular, arcuate, or polycyclic shapes (Figure 14). The lesions are pale to red and are surrounded by pallor or erythema. Urticarial lesions do not scale and on involution do not cause any pigmentary change. The lesions are pruritic and last less than 24 hours, but new lesions can continue to form as long as the cause is present. The eruption is generalized, bilateral, and symmetrical. Biopsy of a lesion shows edema of the reticular dermis with a sparse perivascular infiltrate. Eosinophils may be present.[33]

Erythematous polycyclic plaques.

Angioedema occurs when the swelling involves the dermis and subcutis. The lesions are large, have poorly defined borders, and are pale to skin colored. They are often slightly painful or pruritic. Angioedema is usually asymmetrical and frequently involves the face, genitals, hands, and feet. The larynx, gastrointestinal tract, and urinary bladder are less often involved. Biopsy of the lesion shows edema and a lymphocytic infiltrate extending into the subcutis.[33]

In anaphylaxis, urticaria and angioedema may occur in conjunction with bronchospasm, hypotension, and eosinophilia that is manifested by respiratory distress, diaphoresis, vascular collapse, and/or shock.

In previously sensitized patients, urticaria usually occurs within minutes or hours of re-exposure to the causative agent. Occasionally, the reaction occurs after an interval of several days. Withdrawal of the offending drug is the most important measure in the treatment of urticaria and angioedema. Antihistamines and doxepin often provide symptomatic relief. Subcutaneous epinephrine is useful for treatment of acute urticaria and angioedema. Treatment of anaphylaxis includes intravenous fluids, parenteral epinephrine, antihistamines, aminophylline, and systemic corticosteroids.[34] See Table for antibacterial drugs causing these reactions.

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