Cutaneous and systemic adversereactions to antibioticsdth_1494 12..22
Lucia Diaz & Ana M. CiureaDepartment of Dermatology, University of Texas Medical School at Houston;MD Anderson Cancer Center, Houston, Texas
ABSTRACT: Antibiotics cause a variety of cutaneous and systemic reactions. Reactions can rangefrom mild exanthems to life-threatening toxic epidermal necrolysis. For this reason, it is important fordermatologists to recognize common cutaneous adverse reactions caused by specific antibiotics. Thisreview highlights the clinical features and management of common adverse reactions to antibiotics.
Dermatologists are often consulted for cutaneousdrug eruptions. In the United States, drug reactionsare seen in 2–3% of inpatients and 20% of emer-gency room visits (1). Most reactions are fromantibiotics, mainly penicillins and cephalosporins.Exanthems (75–95%) and urticaria (5–6%) accountfor most drug reactions (1). Genetics, sex, immunestatus, and antibiotic characteristics determinethe risk for a drug reaction. For best outcomes,it is important to recognize reactions and with-draw the offending antibiotic as soon as possible.A good history, physical examination, and detaileddrug calendar are necessary to identify theoffending antibiotic, especially when the patientis taking multiple medications. This reviewhighlights important drug reactions, includingexanthems, urticaria, erythema multiforme (EM),serum sickness-like reaction (SSLR), fixed drugeruption (FDE), drug-induced lupus erythemato-sus (DILE), photosensitivity, vasculitis, acute gen-eralized exanthematous pustulosis (AGEP), drugrash with eosinophilia and systemic symptoms(DRESS), Stevens–Johnson syndrome (SJS) andtoxic epidermal necrolysis (TEN), bullous pem-
phigoid (BP), pigmentation, onycholysis, lichenoiddrug eruption, pseudoporphyria, and erythemanodosum (EN) Tables 1–3 list antibiotics and theircorresponding cutaneous reactions (2).
Exanthems
Exanthems (morbilliform or maculopapularreactions) are the most common cutaneous drugeruptions (1). Patients develop diffuse, pinkmacules or papules that coalesce into patches orplaques, especially on the trunk. The eruption issymmetrical, starts 7–14 days after a medication isstarted, and may generalize in 2 days. This eruptionmay be exaggerated by a coexisting viral infectionas seen when ampicillin or amoxicillin is givenduring an Epstein–Barr infection (1). In contrastto viral exanthems, drug exanthems are pruritic.
Drug exanthems can be caused by many drugs,but are most commonly seen with penicillins,sulfonamides, or anticonvulsants (1–3). Penicillinsand trimethoprin-sulfamethoxazole are the mostcommon antibiotic culprits, and trimethoprim-sulfamethoxazole causes exanthems in 40% of AIDSpatients (1).
The diagnosis is mainly clinical, and a biopsyis rarely done. Histology shows perivascular lym-phocytes with eosinophils, possible interfacedermatitis, and minimal epidermal changes (4).The differential diagnosis includes a viral exan-them, pityriasis rosea, allergic contact dermatitis,
Address correspondence and reprint requests to: Lucia Diaz,MD, Department of Dermatology, University of Texas MedicalSchool at Houston, 6655 Travis Street, suite 600, Houston, TX77030, or email: [email protected].
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Dermatologic Therapy, Vol. 25, 2012, 12–22Printed in the United States · All rights reserved
scarlet fever, acute graft versus host disease, sec-ondary syphilis, and atopic dermatitis.
Management is supportive, and the offendingagent should be withdrawn. Oral antihistaminessuch as diphenhydramine, cetirizine, or hydrox-yzine, bland emollients, and topical steroids maybe used for pruritus. The eruption usually starts todesquamate within a few days and resolve withina week, sometimes leaving post inflammatoryhyper/hypopigmentation that improves with time.
Urticaria
Urticaria is mostly caused by a type I hypersensi-tivity reaction leading to mast cell degranulation.
Patients develop edematous, pruritic, pink papulesor plaques within minutes to days after beingexposed to a triggering agent. The lesions willcome and go within 24 hours. The eruption may belocalized or generalized, sometimes forming poly-cyclic configurations. There may also be associatedangioedema or anaphylaxis.
Urticaria is mostly caused by foods, infections,or unknown triggers. There are also physical andcontact types of urticaria. Urticaria is caused bydrugs 10% of the time, usually by penicillins, sul-fonamides, aspirin, or NSAIDs (1,3). Approximately5–10% of penicillin-allergic patients are also aller-gic to cephalosporins (5). If there is history of asevere or immediate hypersensitivity reaction topenicillin, cephalosporins should be avoided (6).
Table 1. Cutaneous drug reactions caused by antibiotics
E U EM SSLR FDE DILE PS V AGEP DRESS SJS/TEN BP P O L PP EN
OxazolidinonesLinezolid x xPenicillinsAmoxicillin x x x x x x x x x x x xAmpicillin x x x x x x x x x xBacampicillin x x x x x xCarbenicillin x x x x x xDicloxacillin x x x x x x x xMethicillin x x x x x xMezloxillin x x x x xNafcillin x x x x x x x xOxacillin x x x x x x xPenicillin x x x x x x x x x x xPiperacillin x x x x x xTicaracillin x x x x x x x xQuinolonesCinoxacin x x x xCiprofloxacin x x x x x x x x x x xEnoxacin x x x x xLevofloxacin x x x x xLomefloxacin x x x x xMoxifloxacin x xNalidixic Acid x x x x xNorfloxacin x x x x x xOfloxacin x x x x x x x x x xSparfloxacin x x x x x xTrovafloxacin x x x x xRifamycinsRifampin x x x x x x xSulfonamides xSulfamethoxazole x x x x x x x x x x x x x xSulfisoxazole x x x x x x x x x x x x x
Data from Litt (2).AGEP, acute generalized exanthematous pustulosis; BP, bullous pemphigoid; DILE, drug-induced lupus erythematosus; DRESS,
drug reaction with eosinophilia and systemic symptoms; E, exanthems; EM, erythema multiforme; EN, erythema nodosum; FDE,fixed drug eruption; L, lichenoid drug eruption; O, onycholysis; P, pigmentation; PP, pseudoporphyria; PS, photosensitivity; SJS/TEN,Stevens–Johnson syndrome/toxic epidermal necrolysis; SSLR, serum sickness-like reaction; U, urticaria; V, vasculitis.
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The diagnosis is made clinically. A biopsymay be considered to exclude urticarial vasculitisif a lesion burns, persists for more than 24 hours,and leaves behind purpura (1). Histology consis-tent with urticaria shows a normal epidermis,dermal edema, and a sparse perivascular andinterstitial mixed infiltrate with eosinophils (4).Laboratory studies are usually not performedunless there is a suspicious history or exam, orchronic urticaria urticaria (>6 weeks). If there isangioedema without urticaria or itching, a C1esterase deficiency should be suspected. The dif-ferential diagnosis includes arthropod bite reac-tion, BP, urticarial vasculitis, erythema multiforme,mastocytosis, granuloma annulare, and dermatog-
raphism. Urticaria with central clearing should bedifferentiated from EM by the lack of a duskycenter.
Treatment is mainly supportive as urticariais self-limited. More than 80% of new urticariaresolves in 2 weeks and greater than 95% within3 months (7). Oral antihistamine therapy withsecond generation agents such as cetirizine, lorata-dine, or fexofenadine is recommended. This isgradually tapered over several weeks after urticariahas been stopped. Severe pruritus can be treatedwith sedative agents, such as hydroxyzine ordoxepin, or oral prednisone, which can be taperedover 3 weeks to prevent relapse. The subcutaneousadministration of epinephrine may be given every
Table 2. Cutaneous adverse reactions to antibiotics
E U EM SSLR FDE DILE PS V AGEP DRESS SJS/TEN BP P O L PP EN
TetracyclinesDemeclocycline x x x x x x x x x x xDoxycycline x x x x x x x x xMinocycline x x x x x x x x x x x xOxytetracycline x x x x x xTetracycline x x x x x x x x x x x x x xThienamycinImipenem x x x x x xAminocyclitolsAmikacin xGentamicin x x x xNeomycin x x xSpectinomycin x xStreptomycin x x x x x x x x x xTobramycin x x x xb-LactamsCefaclor x x x x x x x xCefadroxil x x x xCefamandole x x xCefazolin x x x x x x x x xCefdinir x x x x x x x xCefepime x x x x x xCefixime x x x x xCefmetazole x x xCefonicid x x xCefopoerazone x x x x xCefotaxime x x x x x xCefotetan x x x x x xCefoxitin x x x x x xCefpodoxime x x x xCefprozil x x x xCeftazidime x x x x x x xCeftibuten x x x
Data from Litt JZ (2).AGEP, acute generalized exanthematous pustulosis; BP, bullous pemphigoid; DIL, drug-induced lupus; DRESS, drug reaction with
eosinophilia and systemic symptoms; E, exanthems; EM, erythema multiforme; EN, erythema nodosum; FDE, fixed drug eruption;L, lichenoid drug eruption; O, onycholysis; P, pigmentation; PP, pseudoporphyria; PS, photosensitivity; SJS/TEN, Stevens–Johnsonsyndrome/toxic epidermal necrolysis; SSLR, serum sickness-like reaction; U, urticaria; V, vasculitis.
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10–20 minutes as needed for severe urticaria orangioedema (1).
Erythema multiforme (EM)
EM is a reactive eruption on the skin and mucousmembranes characterized by well-demarcated,targetoid, erythematous plaques or patches thatdevelop a dusky or bullous center within severaldays (FIG. 1). Lesions appear 2–14 days after expo-sure to the triggering agent. They mostly appear onthe palms, soles, dorsal hands and feet, extensorextremities, and sometimes progress to face andtrunk. Fever and fatigue may be present, andlesions can be painful or pruritic. Mucosal involve-ment is usually limited to the oral cavity and is seenin 25–30% of patients (3).
FIG. 1. Erythema multiforme.
Table 3. Cutaneous adverse reactions to antibiotics
E U EM SSLR FDE DILE PS V AGEP DRESS SJS/TEN BP P O L PP EN
Ceftizoxime x x x xCeftriaxone x x x x x x xCefuroxime x x x x x x xCephalexin x x x x x x x xCephalothin x x x xCephapirin x x x xCephradine x x x xLoracarbef x xChloramphenicolChloramphenicol x x x x x xGlycopeptidesVancomycin x x x x x x x x xLincosamidesClindamycin x x x x x x x xLincomycin x x x x xMacrolidesAzithromycin x x x x x x x xClarithromycin x x x x xDirithromycinErythromycin x x x x x x xMonobactamsAztreonam x x x xNitroimidazoleMetronidazole x x x xSulfoneDapsone x x x x x x x x x x x x xLipopeptideDaptomycin x
Data from Litt (2).AGEP, acute generalized exanthematous pustulosis; BP, bullous pemphigoid; DIL, drug-induced lupus; DRESS, drug reaction with
eosinophilia and systemic symptoms; E, exanthems; EM, erythema multiforme; EN, erythema nodosum; FDE, fixed drug eruption; L,lichenoid drug; O, onycholysis; P, pigmentation; PP, pseudoporphyria; PS, photosensitivity; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis eruption; SSLR, serum sickness-like reaction; U, urticaria; V, vasculitis.
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The majority of EM cases are caused by herpessimplex, but have been reported with multi-ple drugs, including many antibiotics as seen inTables 1–3 (2). The diagnosis is usually made onclinical grounds. If a biopsy is done, it usually showsnecrotic keratinocyes, spongiosis, basal layerliquefaction, papillary dermal edema, perivascularlymphocytes with eosinophils, and sometimesextravasated red blood cells (4). Direct immunof-luorescence is done in difficult cases to distinguishfrom immunobullous diseases, such as paraneo-plastic pemphigus or bullous lupus erythematosus,which may produce target lesions and havemucosal involvement (1). Viral cultures of lesionssuspicious for herpes may be done to support theEM diagnosis. The differential diagnosis includesimmunobullous diseases, bullous arthropod bites,FDEs, vasculitis, urticaria, and secondary syphilis.
Most cases of EM heal within 2–3 weeks andtreatment is mainly supportive. Prophylactic oralacyclovir for 6–12 months should be considered inpatients with recurrent episodes (8). Intermittentacyclovir therapy does not change the course, andprednisone increases the frequency of attacks (3).For recalcitrant EM, dapsone (9), thalidomide (10),or cyclosporine (11) may be helpful.
Serum sickness-like reaction (SSLR)
SSLR is defined by an urticarial or morbilliformeruption, fever, and arthralgias presenting 1–3weeks after starting a medication. There are nomucous membrane lesions, and the wrists, knees,and ankles are the most common joints affected.SSLR lesions are fixed and may become purpuric.Unlike true serum sickness, this reaction is not asso-ciated with immune complexes, vasculitis, renallesions, or hypocomplementemia (12).
Cephalosporins, penicillins, minocycline,buproprion, rituximab, and sulfonamides are themain drugs known to cause this reaction, with cefa-clor being the most common (2,3). A reactive cefa-clor metabolite generated during its metabolismmay bind with tissue proteins, resulting in a SSLR(13). For cefaclor, the risk of cross reaction withother beta-lactam antibiotics is low, and othercephalosporins are usually tolerated (14).
The diagnosis is made clinically, and patientssometimes have eosinophilia. The differentialdiagnosis includes viral or drug exanthems, rheu-matoid arthritis, urticarial vasculitis, post-viralsynovitis, drug vasculitis, and urticaria.
Management involves stopping the offendingmedication. Antihistamines and topical cortico
steroids can be used for pruritus. If symptoms aresevere, a short course of oral prednisone at 1–2 mg/kg/day may be given (15).
Fixed drug eruption (FDE)
An FDE presents as one to several well-demarcated,erythematous or hyperpigmented plaques orpatches 1–2 weeks after a drug exposure (FIG. 2).They can occur anywhere, but tend to occur on theface, lips, buttocks, genitalia, hands, or upper trunk.Repeat exposure to the inciting agent will lead toskin lesions in same area within 1 day. Lesions areusually asymptomatic, occur intermittently, andpatients are unable to identify the trigger.
This reaction is usually caused by sulfona-mides, tetracyclines, metronidazole, dapsone,ampicillin, acetaminophen, aspirin, nonsteroi-dal anti-inflammatory drugs (NSAIDs), acetami-nophen, pseudoephedrine, anticonvulsants, andoral contraceptives (1–3). Sulfonamides are themost common triggers in children (3).
If unsure about the diagnosis, patch testing, abiopsy, or drug rechallenge may be considered.Patch testing with the offending medication at a10% standard dose can be done to reproduce thelesion on the affected skin (1). A biopsy may helpin generalized cases where it may be difficultto differentiate a FDE from SJS. Histology showsbasal layer liquefaction, a mixed infiltrate witheosinophils, papillary dermal fibrosis, and melaninincontinence (4). The differential diagnosis inclu-des EM, BP, erythema dyschromicum perstans, cel-lulitis, and SJS if more extensive.
The culprit medication should be avoided.Topical corticosteroids can be used as needed for
FIG. 2. Fixed drug eruption.
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pruritus. There may be postinflammatory hyper/hypopigmentation that will improve with time.
Drug-induced lupuserythematosus (DILE)
DILE is characterized by fever, myalgias, serositis,and arthralgias. It rarely has renal or neurologicalinvolvement. Patients have an elevated homog-enous ANA and positive anti-histone antibodieswith normal complements and negative anti-dsDNA (12). Anti-histone antibodies are present in95% of patients with DILE, but can also be present in50–80% of patients with idiopathic lupus erythe-matosus (16). If there are erythematous, annularpapulosquamous plaques characteristic of sub-acute lupus erythematosus, patients also havepositive SSA antibodies (1) (FIG. 3). The eruptionsappear days to years after starting the medications.Hydralazine, methyldopa, procainamide, quini-dine, hydrochlorothiazide, cimetidine, isoniazid,carbamazepine, chlorpromazine, propylthiouracil,calcium channel blockers, sulfasalazine, statins,oral contraceptives, terbinafine, griseofulvin, andNSAIDs can cause DILE (1–3). Among antibiotics,sulfonamides and tetracyclines have been reported,with minocycline being the most common trigger(2,12).
A biopsy and basic work-up for systemiclupus erythematosus should be done. Histology
shows hyperkeratosis, follicular plugging, epider-mal atrophy, liquefaction degeneration, melaninincontinence, a thickened basement membrane,increased mucin, perivascular and periadenexallichenoid lymphocytes, and sometimes plasmacells (4). Direct immunofluorescence revealsgranular deposits of IgM, IgG, and complements atthe dermal-epidermal junction (17). Evidence ofsystemic involvement includes transaminitis, pro-teinuria, an elevated ESR, and leukopenia or leuko-cytosis (12). Patients with minocycline DILE willalso sometimes have a positive p-ANCA (12). Mostcases of minocycline DILE have been reported inyoung females being treated with minocycline foracne for about 2 years (16). The differential diagno-sis for DILE includes tinea corporis, erythemaannulare centrificum, sarcoidosis, syphilis, atopicdermatitis, seborrheic dermatitis, contact dermati-tis, rosacea, phototoxic eruptions, and other con-nective tissue diseases.
The offending medication in DILE should beimmediately discontinued. Resolution of symp-toms occurs in weeks to months after a drug isstopped; however, the ANA can remain positivefor 6–12 months (16). NSAIDs can be used formusculoskeletal pain (14). Sun protection shouldbe enforced. Short courses of oral prednisone ortopical corticosteroids may be utilized as neededfor symptoms.
Photosensitivity
Photosensitive reactions mainly involvemedications that are phototoxic or photoallergic.Phototoxic drug reactions are the most commonand occur several hours after exposure. Theyare caused by a combination of medication andsun exposure, mainly due to UVA. Photoallergicreactions, unlike phototoxic reactions, are not dosedependent and take 48–72 hours to develop, mainlydue to UVB. The eruptions have various morpholo-gies that appear in photodistributed areas, withsparing of areas behind the ears, under the nose,and under the chin. Common causes of photosen-sitive reactions includes hydrochlorothiazide, furo-semide, tetracyclines, sulfonylureas, quinilones,retinoids, phenothiazine, griseofulvin, and NSAID(1–3). Tetracyclines cause most phototoxic drugreactions, while griseofulvin causes most photo-allergic drug reactions (1,2).
A biopsy is often done to help make thediagnosis. Histological findings may vary, butmay show spongiosis, perivascular lymphocytes,and necrotic keratinocytes (4). The differentialFIG. 3. Drug-induced subacute lupus erythematosus.
Cutaneous and systemic adverse reactions
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diagnosis includes sunburns, porphyria cutaneatarda, pseudoporphyria, connective tissue dis-eases, contact/irritant dermatitis, and immunob-ullous diseases.
Treatment includes stopping the offendingagent, sun protection, and vigorous moisturiza-tion. Oral antihistamines may be given for pruritus.Photopatch testing may be considered in photo-allergic drug reactions.
Vasculitis
Drug-induced vasculitis presents as purpuricpapules in crops, mostly in dependent areas. Therecan be joint, gastrointestinal, renal, brain, andheart involvement. Common drug causes includeangiotensin converting enzyme inhibitor (ACE)inhibitors, amiodarone, cimetidine, NSAIDs, ampi-cillin, sulfonamides, diuretics, and coumadin (1,2).
A biopsy is usually done to confirm the diagno-sis of vasculitis. The histological findings are notspecific for drug-induced vasculitis. Histology mayshow necrosis of vessel walls as well as fibrin andinflammatory cells, usually neutrophils in vesselwalls and within the dermis (4).
Management includes withdrawing the medica-tion and treating with oral or topical corticoster-oids. A systemic vasculitis workup is needed insome cases. The differential diagnosis includesother causes of vasculitis, such as connectivetissue diseases, infections, Wegener’s granuloma-tosis, cryoglobulinemia, polyarteritis nodosa, andHenoch–Schonlein purpura.
Acute generalized exanthematouspustulosis (AGEP)
AGEP is a rare skin disorder with an incidence ofone to five cases per million per year (1). It is char-acterized by sudden erythroderma with hundredsof small monomorphous sterile nonfollicularpustules that occur 1–14 days after a drug exposure(FIG. 4). There is usually associated pruritus andfever. Mucous membrane involvement can occur,but usually only in one area. Most commonly,AGEP is caused by penicillins, beta-lactam antibi-otics, tetracyclines, sulfonamides, macrolides, qui-nolones, clindamycin, and terbinafine (1–3).
Although the diagnosis is suspected clinically, abiopsy is usually done to aid with the diagnosis.Neutrophilia >7000/cm3 and mild to moderateeosinophilia are present in one-third of cases (18).
Histology shows subcorneal or epidermal pustules,mild spongiosis, mild papillary dermal edema, anda superficial mixed interstitial and perivascularinfiltrate with eosinophils. The presence of eosino-phils and papillary dermal edema can help distin-guish AGEP from pustular psoriasis (4). However,without a history of psoriasis or psoriatic changeselsewhere, distinction between these entities isdifficult. The differential diagnosis includes mil-iaria, pustular psoriasis, subcorneal pustulosis,and infectious or drug-induced folliculitis.
Treatment includes removing the offendingagent and supportive care. Topical and oral corti-costeroids and oral antihistamines may be given.Etanercept (19), infliximab (20), and cyclosporine(21) have also been used in severe reactions.
Drug rash with eosinophilia andsystemic symptoms (DRESS)
DRESS is characterized by a morbilliform eruptionthat may progress to an exfoliative dermatitis withvisceral symptoms, including lymphadenopathy,hepatitis, myocarditis, pericarditis, pneumonitis,and nephritis (18) (FIG. 5). Initial symptomsinclude fever and malaise. The cutaneous findingsvary, and the reaction begins 1–8 weeks after a drugexposure. Aromatic anticonvulsants, allopurinol,minocycline, dapsone, sulfonamides, and terbin-afine are the most common drugs that causeDRESS (1–3).
A rash with unexplained systemic symptoms orabnormal labs should make one suspect DRESS.A biopsy is nonspecific, as skin eruptions vary.Transaminitis, eosinophilia >1500/mm3, andan atypical lymphocytosis are common (22). The
differential diagnosis includes other drug reac-tions, infections, lymphoma/leukemia, and hyper-eosinophilic syndrome.
Treatment is mainly supportive. Symptoms,especially eosinophilia and tranaminitis, canpersist for weeks. A complete blood count, livertransaminases, urinalysis, thyroid functions tests,and creatinine should be checked at baseline andthen as needed. A thyroid stimulating hormone(TSH) should be checked up to 3 months afterthe eruption because of a possible autoimmunethryoiditis (12). Systemic corticosteroids should beused for visceral manifestations (18). If the patientis immunocompromised, however, corticosteroidsmay lead to HHV6 reactivation (22). Educating thepatient’s primary team on DRESS is essential.
SJS and TEN are serious cutaneous eruptionsdefined by extensive exfoliation and mucosal mem-brane involvement (FIG. 6). Epidermal detach-ment is present in <10% in SJS, 10–30% in SJS/TENoverlap, and >30% in TEN. Patients can have eryth-roderma, targetoid lesions, extensive erosions, orbullae in addition to erosions in two mucosal sites.Lesions usually start on the face and upper trunkbefore spreading to other areas, often involving thepalms and soles. Prodromal symptoms commonlyincludes fever, sore throat, malaise, diarrhea, head-ache, and cough.
SJS or TEN can be caused by antibiotics, such assulfonamides, tetracyclines, and dapsone, amongother drugs (1–3). A few series have found herpes to
cause 6–19% of SJS cases and mycoplasma to causeup to 25% of SJS cases (1).
The diagnosis is suspected clinically, but may beconfirmed with a biopsy. Histology shows subepi-dermal vesiculation or necrosis with a minimalinflammatory infiltrate (4). The differential diagno-sis includes EM, Kawasaki disease, bullous lupuserythematosus, and pemphigus vulgaris.
Management includes fluid replacement, nutri-tional support, skin care, and antibacterial therapyonce the offending mediation has been removed(18). Ophthalmology should be consulted forocular involvement. Systemic corticosteroids earlyin the course may be beneficial, but increasesrisk for infections (23). A few studies have showncyclosporine (24), plasmapheresis (25), and IVIG(26) to be helpful. One cycle of IVIG at 3 g/kg over3–5 days has been recommended (27). Mortalityis 1–5% in SJS and 25–35% in TEN where patientsshould be managed in the burn unit (28). TheSCORTEN (Table 4), a severity-of-illness score, isused to determine a patient’s prognosis in TEN(29).
Bullous pemphigoid (BP)
In drug-induced BP, large tense bullae developin previously normal skin. Lesions mainly occuron the abdomen, forearms, and thighs, but canbe generalized. There may be oral involvement.Neuroleptics, ACE inhibitors, d-penicillamine, sul-fasalazine, and penicillins are common causes ofdrug-induced BP (1,2).
Histology and immunofluorescence can helpmake the diagnosis. Histology shows eosinophilicspongiosis, subepidermal vesiculation, and
FIG. 5. Drug rash with eosinophilia and systemicsymptoms.
FIG. 6. Toxic epidermal necrolysis.
Cutaneous and systemic adverse reactions
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perivascular lymphocytes. Sometimes, there maybe papillary dermal edema with eosinophils andneutrophils in the dermal papillae (4). Immunof-luorescence of perilesional skin shows linear IgGand complement deposits at the basement mem-brane in the lamina lucida (4). The differentialdiagnosis includes linear IgA dermatosis, dermati-tis herpetiformis, EM, urticaria, epidermolysisbullosa acquisita, cicatricial pemphigoid, edema ordiabetic bullae, bullous lupus erythematosus, andbullous drug reactions.
Management is similar to that in idiopathic BP.After the offending drug is stopped, patients arecommonly treated with systemic corticosteroidsand mycophenolate mofetil or azathioprine (12).
Pigmentation
Drug-induced pigmentation of the skin, hair, andnails is from postinflammatory hyperpigmenta-tion, melanin synthesis, or deposition (2). Therecan also be pigmentation in the thyroid, sclera,bone, conjunctiva, nail bed, oral mucosa, teeth,and ear cartilage (1). Tetracycline causes brownstaining of teeth in the area proximal to gingival,while minocycline leads to a green discoloration inthe central part of teeth. Amiodarone, antimalari-als, clofazimine, zidovudine, chlorpromazine, gold,silver, diltiazem, and chemotherapy agents areother agents leading to skin pigmentation (1,2).
Minocycline induces three types of pigmenta-tion – type I: blue pigmentation in previous scars;type II: blue/gray pigmentation on the bilateralshins; and type III: generalized brown hyperpig-mentation in sun exposed areas (1). Type I and IIreactions may appear after months to years oftreatment. Histology for minocycline type II and III
pigmentation shows brown dermal pigment posi-tive with iron and melanin stains. Minocycline typeII pigmentation only shows epidermal and dermalmelanin (4). The differential diagnosis includesendocrine conditions, exogenous ochronosis, orother pigmentation disorders.
The inciting medication should be stopped.Cutaneous hyperpigmentation with minocyclineimproves with time, but tooth discoloration is per-manent. A Q-switched laser or fractional thermoly-sis can be used to improve skin pigmentation (1).
Onycholysis
Onycholysis is a known side effect of multipledrugs. Although psoralens, chemotherapy agents,chlorpromazine, oral contraceptives, penicillins,and quinilones may cause onycholysis, mostdrug-induced onycholysis cases are caused by tet-racyclines (1–3). The differential diagnosis for ony-cholysis includes infection (yeast, dermatophyte,or bacterial), trauma, psoriasis, eczema, manifes-tation of internal disease, and congenital ony-cholysis. Stopping the offending medication, sunprotection, and avoiding nail trauma will improvenails.
Lichenoid drug eruptions
Lichenoid drug eruptions include symmetric,violaceous, polygonal pruritic papules that mayalso be eczematous (FIG. 7). Lesions favor the trunkand extremities, with occasional involvement ofthe buccal mucosa. Lichenoid drug eruptionsappear weeks to years of starting the offending
Table 4. SCORTEN to evaluate risk and prognosisin TEN
SCORTEN parameter Points
Age >40 years 1 pointInitial surface of epidermal detachment >10% 1 pointTachycardia (>120/min) 1 pointSerum urea >10 mm/L 1 pointSerum glucose >14 mmol/L 1 pointBicarbonate >20 mmol/L 1 pointMalignancy 1 point
Data from Harr and French (29).SCORTEN, severity-of-illness score for TEN; TEN, toxic epi-
dermal necrolysis.
FIG. 7. Lichenoid drug eruption.
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medication. Furosemide, gold, thiazides, antima-larials, captopril, beta blockers, calcium channelblockers, NSAIDs, griseofulvin, anticonvulsants,and tetracycline are the most common causes (1–3).
The diagnosis is made on clinical grounds, but abiopsy can be done to confirm. Histology showscompact hyperkeratosis with parakeratosis, hyper-granulosis, colloid bodies, liquefaction degenera-tion of the basal layer, a lichenoid infiltrate inpapillary dermis,eosinophils, and melanin inconti-nence (4). The presence of eosinophils and par-akaratosis makes a drug-induced lichen planuseruption more likely. The differential diagnosisincludes pityriasis rosea, psoriasis,scabies, syphilis,and eczema.
Treatment includes discontinuing the incitingdrug and treating with systemic, topical, or intrale-sional corticosteroids, topical calcineurin inhibi-tors, antihistamines, or phototherapy. Lesions maytake months to year to resolve once the medica-tion is stopped. Severe cases can be treated withcyclosporine, cellcept (30), or low molecular weightheparin (31).
Pseudoporphyria
Pseudophorphyria is characterized by a photo-distributed vesiculobullous eruption on the faceand hands, as well as skin fragility. Scarring cansometimes be seen. NSAIDs, Cox-2 inhibitors, tet-racyclines, furosemide, and dapsone are commoncauses.
A biopsy is often done. Histology shows subepi-dermal vesiculation with minimal inflammatoryinfiltrate, festooning of dermal papillae, and cater-pillar bodies, as seen in porphyria cutanea tarda(4). Direct immunefluorescence shows immuno-globulin and complement deposition perivascu-larly and at the dermoepidermal junction (4).Serum and urine porphyrins are normal. The dif-ferential diagnosis includes porphyria cutaneatarda, epidermolysis bullosa acquisita, erythropoi-etic porphyria, epidermolysis bullosa, and bullouslupus erythematosus.
Management includes stopping the offendingagent and local wound care. Resolution of symp-toms may take multiple months.
Erythema nodosum (EN)
EN is defined by erythematous subcutaneousnodules on bilateral shins, usually in young women.Patients often experience malaise, arthralgias,
and fever. Infections (especially streptococcal phar-yngitis, coccidiosis, or tuberculosis), drugs, inflam-matory bowel disease, pregnancy, malignancy,and sarcoidosis can cause EN (1). Sulfonamides,penicillins, dapsone, and oral contraceptives arecommon causes of drug-induced EN (1,2).
The diagnosis is confirmed with a biopsy.Histology shows a septal panniculitis with mixedinflammatory infiltrate (4). A throat culture of anti-streptolysin O (ASO) titer can be done to rule outstreptococcus, and a chest x-ray or tuberculin skintest should be done if tuberculosis is suspected(1). The differential diagnosis includes cellulitis,erythema induratum, and other forms of pannicu-litis, including those caused by infections.
Management includes removing the offendingagent and treating symptoms with systemic,intralesional, or topical corticosteroids, NSAIDs,and rest. Oral potassium iodide may also beconsidered (32). Acute EN usually resolves in 3–6weeks.
Conclusion
There are many important drug-induced cutane-ous and systemic reactions, most being causedby antibiotics. Although most reactions are mildand limited to the skin, recognition of the life-threatening ones is essential in dermatology. Wehope that this review provides a quick reference forthe busy clinician.
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