Adverse Drug Reactions: Types and Treatment Options

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MARC A. RIEDL, M.D., and ADRIAN M. CASILLAS, M.D., University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California Am Fam Physician. !!" Nov #$%&'()*#+&#,#+(#. Drug hypersensitivity results from interactions between a pharmacologic agent and the human immune system. These types of reactions constitute only a small subset of all adverse drug reactions. Allergic reactions to medications represent a specific class of drug hypersensitivity reactions mediated by IgE. Immune mediated drug reactions may be discussed generally in the !ell and "oombs classification system# a widely accepted conceptual framewor$ for understanding comple% immune reactions. &owever# some reactions involve additional# poorly understood mechanisms that are not easily classified. Identifiable ris$ factors for drug hypersensitivity reactions include age# female gender# concurrent illnesses# and previous hypersensitivity to related drugs. Drug hypersensitivity is a clinical diagnosis based on available data. 'aboratory testing may be useful# with s$in testing providing the greatest specificity. Treatment is largely supportive and includes discontinuation of the offending medication# symptomatic treatment# and patient education. (atients with penicillin allergy should avoid carbapenems# and caution should be used in prescribing cephalosporins in these patients. Reactions to radiocontrast media can be limited by pretreatment with prednisone# diphenhydramine# and either ephedrine or a histamine &) receptor antagonist. Adverse dr-g reactions are co..on. Identifying tr-e dr-g allergy, ho/ever, can 0e challenging. Co.1licating factors of dr-g reactions incl-de the .yriad clinical sy.1to.s and .-lti1le .echanis.s of dr-g,host interaction, .any of /hich are 1oorly -nderstood. In addition, the relative 1a-city of la0oratory testing that is availa0le for dr-g allergy .a2es the diagnosis de1endent on clinical findings. Definitions and "lassifications 3he ter.s 4dr-g allergy,5 4dr-g hy1ersensitivity,5 and 4dr-g reaction5 are often -sed interchangea0ly. Dr-g reactions enco.1ass all adverse events related to dr-g ad.inistration, regardless of etiology. Dr-g hy1ersensitivity is defined as an i..-ne,.ediated res1onse to a dr-g agent in a sensiti6ed 1atient. Dr-g allergy is restricted s1ecifically to a reaction .ediated 0y IgE. Dr-g reactions can 0e classified into i..-nologic and noni..-nologic etiologies (Table 1). 3he .a7ority '+8 to &! 1ercent) of adverse dr-g reactions are ca-sed 0y 1redicta0le,

noni..-nologic effects.# 3he re.aining ! to 8 1ercent of adverse dr-g events are ca-sed 0y -n1redicta0le effects that .ay or .ay not 0e i..-ne .ediated. # I..-ne,.ediated reactions acco-nt for 8 to #! 1ercent of all dr-g reactions and constit-te tr-e dr-g hy1ersensitivity, /ith IgE,.ediated dr-g allergies falling into this category. ," TA*'E + Immunologic and ,onimmunologic Drug Reactions Immunologic and Nonimmunologic Drug Reactions
TYPE Immunologic Type I reaction (IgE-mediated) Type II reaction (cytotoxic) Type III reaction (immune complex) Type I! reaction (delayed" cellmediated) Specific T-cell acti$ation &as'&as ligand-induced apoptosis Anaphylaxis from -lactam antibiotic Hemolytic anemia from penicillin Serum sic ness from anti-thymocyte globulin #ontact dermatitis from topical antihistamine EXAMPLE

%orbilliform rash from sulfonamides Ste$ens-(ohnson syndrome

Toxic epidermal necrolysis

)ther

*rug-induced" lupus-li e syndrome

Anticon$ulsant hypersensiti$ity syndrome +onimmunologic

,redictable

,harmacologic side effect

*ry mouth from antihistamines

TYPE Secondary pharmacologic side effect

EXAMPLE Thrush -hile ta ing antibiotics *rug toxicity Hepatotoxicity from methotrexate Sei.ure from theophylline -hile ta ing erythromycin Sei.ure from excessi$e lidocaine (/ylocaine)

*rug-drug interactions *rug o$erdose

0npredictable ,seudoallergic Anaphylactoid reaction after radiocontrast media Hemolytic anemia in a patient -ith 12,* deficiency after prima3uine therapy

Idiosyncratic

Intolerance

Tinnitus after a single" small dose of aspirin

G6PD = glucose-6-phosphate dehydrogenase4

3he Gell and Coo.0s classification syste. descri0es the 1redo.inant i..-ne .echanis.s that lead to clinical sy.1to.s of dr-g hy1ersensitivity (Table 2). 3his classification syste. incl-des* 3y1e I reactions 'IgE,.ediated)$ 3y1e II reactions 'cytoto9ic)$ 3y1e III reactions 'i..-ne co.1le9)$ and 3y1e I: reactions 'delayed, cell,.ediated). ;o/ever, so.e dr-g hy1ersensitivity reactions are diffic-lt to classify 0eca-se of a lac2 of evidence s-11orting a 1redo.inant i..-nologic .echanis.. 3hese incl-de certain c-taneo-s dr-g reactions 'i.e., .ac-lo1a1-lar rashes, erythroder.a, e9foliative der.atitis, and fi9ed dr-g reactions) <,8 and s1ecific dr-g hy1ersensitivity syndro.es (Table 3).%,+

TA*'E ) !ell and "oombs "lassification of Drug &ypersensitivity Reactions Gell and Coombs Classification of Drug Hypersensitivity Reactions
IMMUNE REACTION Type I (IgEmediated) MECHANISM CLINICAL MANIFESTATIONS TIMING OF REACTIONS

*rug-IgE complex binding to 0rticaria" angioedema" %inutes to hours mast cells -ith release of bronchospasm" pruritus" $omiting" after drug exposure histamine" inflammatory diarrhea" anaphylaxis mediators Specific Ig1 or Ig% antibodies directed at drughapten coated cells Tissue deposition of drugantibody complexes -ith complement acti$ation and inflammation %H# presentation of drug molecules to T cells -ith cyto ine and inflammatory mediator release Hemolytic anemia" neutropenia" thrombocytopenia !ariable

Type II (cytotoxic)

Type III (immune complex)

Serum sic ness" fe$er" rash" arthralgias" lymphadenopathy" urticaria" glomerulonephritis" $asculitis Allergic contact dermatitis" maculopapular drug rash7

5 to 6 -ee s after drug exposure

Type I! (delayed" cellmediated)

8 to 9 days after cutaneous drug exposure

MHC = major histocompatibility complex 4 7:Suspected ype !" reaction# mechanism not $ully elucidated 4

TA*'E - .pecific Drug &ypersensitivity .yndromes "aused by ,on IgE Immune /echanisms Specific Drug Hypersensitivity Syndromes Caused by Non-IgE Immune Mec anisms

CAUSATIVE DRUG Hydrala.ine (Apresoline) ,rocainamide (,ronestyl) #arbama.epine (Tegretol) ,henytoin (*ilantin) Sulfonamides Anticon$ulsants

SYNDROME ;upus-li e syndrome

Anticon$ulsant hypersensiti$ity syndrome

Ste$ens-(ohnson syndrome" toxic epidermal necrolysis

Un1redicta0le, noni..-ne dr-g reactions can 0e classified as 1se-doallergic, idiosyncratic, or intolerance. =se-doallergic reactions are the res-lt of direct .ast cell activation and degran-lation 0y dr-gs s-ch as o1iates, vanco.ycin ':ancocin), and radiocontrast .edia. 3hese reactions .ay 0e clinically indisting-isha0le fro. 3y1e I hy1ersensitivity, 0-t do not involve dr-g,s1ecific IgE. Idiosyncratic reactions are >-alitatively a0errant reactions that cannot 0e e91lained 0y the 2no/n 1har.acologic action of the dr-g and occ-r only in a s.all 1ercent of the 1o1-lation. A classic e9a.1le of an idiosyncratic reaction is dr-g,ind-ced he.olysis in 1ersons /ith gl-cose,%,1hos1hate dehydrogenase 'G%=D) deficiency. Dr-g intolerance is defined as a lo/er threshold to the nor.al 1har.acologic action of a dr-g, s-ch as tinnit-s after a single average dose of as1irin. Epidemiology Adverse dr-g reactions ca-sed 0y i..-ne and noni..-ne .echanis.s are a .a7or ca-se of .or0idity and .ortality /orld/ide. 3hey are the .ost co..on iatrogenic illness, co.1licating 8 to #8 1ercent of thera1e-tic dr-g co-rses.&,( In the United States, .ore than #!!,!!! deaths are attri0-ted ann-ally to serio-s adverse dr-g reactions. #! 3hree to % 1ercent of all hos1ital ad.issions are 0eca-se of adverse dr-g reactions, and % to #8 1ercent of hos1itali6ed 1atients ' . .illion 1ersons in the United States in #((<) e91erience a serio-s adverse dr-g reaction. &? ## E1ide.iologic data s-11ort the e9istence of s1ecific factors that increase the ris2 of general adverse dr-g reactions, s-ch as fe.ale gender, # or infection /ith h-.an i..-nodeficiency vir-s ';I:),#" or her1es#< (Table 4).# ?#% @actors associated /ith an increased ris2 for hy1ersensitivity dr-g reactions incl-de asth.a, #8 syste.ic l-1-s erythe.atos-s,#% or -se of 0eta 0loc2ers#8 'Table 4).# ?#% Altho-gh ato1ic 1atients do not have a higher rate of sensiti6ation to dr-gs, they are at increased ris2 for serio-s allergic reactions.#+

TA*'E 0 (atient Ris$ 1actors for Adverse Drug Reactions !atient Ris" #actors for $dverse Drug Reactions
1eneral drug reactions (nonimmune) &emale gender58 Hypersensiti$ity drug reactions (immune)

&emale gender58

Serious illness <enal insufficiency ;i$er disease ,olypharmacy HI! infection56 Herpes infection Alcoholism Systemic lupus erythematosus52

Adult HI! infection56 #oncomitant $iral infection5= ,re$ious hypersensiti$ity to chemically-related drug

Asthma5> 0se of beta bloc ers5> Specific genetic polymorphisms Systemic lupus erythematosus52

H!" = human immunode$iciency %irus4 !n$ormation $rom re$erences &'(&64

3he .ost i.1ortant dr-g,related ris2 factors for dr-g hy1ersensitivity concern the che.ical 1ro1erties and .olec-lar /eight of the dr-g. Larger dr-gs /ith greater str-ct-ral co.1le9ity 'e.g., nonh-.an 1roteins) are .ore li2ely to 0e i..-nogenic. ;eterologo-s antisera,

stre1to2inase, and ins-lin are e9a.1les of co.1le9 antigens ca1a0le of eliciting hy1ersensitivity reactions. Most dr-gs have a s.aller .olec-lar /eight 'less than #,!!! daltons), 0-t .ay still 0eco.e i..-nogenic 0y co-1ling /ith carrier 1roteins, s-ch as al0-.in, to for. si.1le che.ical,carrier co.1le9es 'ha1ten). Another factor affecting the fre>-ency of hy1ersensitivity dr-g reactions is the ro-te of dr-g ad.inistration$ to1ical, intra.-sc-lar, and intraveno-s ad.inistrations are .ore li2ely to ca-se hy1ersensitivity reactions. 3hese effects are ca-sed 0y the efficiency of antigen 1resentation in the s2in, the ad7-vant effects of re1ository dr-g 1re1arations, and the high concentrations of circ-lating dr-g antigen ra1idly achieved /ith intraveno-s thera1y. Aral .edications are less li2ely to res-lt in dr-g hy1ersensitivity. #+ "linical /anifestations 3r-e hy1ersensitivity adverse dr-g reactions are great i.itators of disease and .ay 1resent /ith involve.ent of any organ syste., incl-ding syste.ic reactions s-ch as ana1hyla9is (Table 2). Dr-g reactions co..only .anifest /ith der.atologic sy.1to.s ca-sed 0y the .eta0olic and i..-nologic activity of the s2in. 3he .ost co..on der.atologic .anifestation of dr-g reaction is .or0illifor. rashes. 3y1ically, an erythe.ato-s, .ac-lo1a1-lar rash a11ears /ithin one to three /ee2s after dr-g e91os-re, originates on the tr-n2, and event-ally s1reads to the li.0s. Urticaria is ty1ically a .anifestation of a tr-ly allergic, 3y1e I reaction, 0-t it .ay a11ear /ith 3y1e III or 1se-doallergic reactions as /ell. Severe nonallergic, hy1ersensitivity c-taneo-s reactions 'i.e., erythe.a .-ltifor.e, Stevens,Bohnson syndro.e, and to9ic e1ider.al necrolysis) re1resent 0-llo-s s2in diseases that re>-ire 1ro.1t recognition 0eca-se of their association /ith significant .or0idity and .ortality. Ec6e.ato-s rashes are .ost co..only associated /ith to1ical .edications and -s-ally re1resent contact der.atitis, /hich is classified as 3y1e I: reaction to a dr-g e91os-re. "linical Evaluation Dr-g hy1ersensitivity reactions not only sho-ld 0e incl-ded in the differential diagnosis for 1atients /ho have the ty1ical allergic sy.1to.s of ana1hyla9is, -rticaria, and asth.a, 0-t also for those /ith ser-. sic2ness,li2e sy.1to.s, s2in rash, fever, 1-l.onary infiltrates /ith eosino1hilia, he1atitis, ac-te interstitial ne1hritis, and l-1-s,li2e syndro.es. A diagnosis of dr-g hy1ersensitivity de1ends on identifying sy.1to.s and 1hysical findings that are co.1ati0le /ith an i..-ne dr-g reaction (Figure 11). Evaluation and /anagement of Drug Reaction

1I!2RE +. Algorith. for the eval-ation and .anage.ent of dr-g reaction. *--Not or !te"ens-#ohnson syn$rome%to&ic e'i$ermal necrolysis. A$a'te$ (ith 'ermission rom )&ecuti"e summary o $isease management o $rug hy'ersensiti"ity* a 'ractice 'arameter. #oint Tas+ Force on Practice Parameters, the

American Aca$emy o Allergy, Asthma an$ -mmunology, an$ the #oint .ouncil o Allergy, Asthma an$ -mmunology. Ann Allergy Asthma -mmunol 1///013*221. :ie/ Large 3he initial history sho-ld incl-de a recording of all 1rescri1tion and non1rescri1tion dr-gs ta2en /ithin the last .onth, incl-ding dates of ad.inistration and dosage. 3he te.1oral relationshi1 0et/een dr-g inta2e and the onset of clinical sy.1to.s is critical. Unless the 1atient has 0een 1revio-sly sensiti6ed to a dr-g, the interval 0et/een initiation of thera1y and the onset of reaction is rarely less than one /ee2 or .ore than one .onth. =atients sho-ld 0e as2ed a0o-t 1revio-s dr-g e91os-res and reactions. 3he 1hysical e9a.ination .ay 1rovide f-rther infor.ation to s-11ort dr-g hy1ersensitivity. A 1r-dent initial ste1 is an eval-ation for signs and sy.1to.s of an i..ediate generali6ed reaction, 0eca-se this is the .ost severe life,threatening for. of an adverse dr-g reaction. Carning signs of i.1ending cardiovasc-lar colla1se incl-de -rticaria, laryngeal or -11er air/ay ede.a, /hee6ing, and hy1otension. Signs s-ggestive of serio-s adverse dr-g reactions incl-de the 1resence of fever, .-co-s .e.0rane lesions, ly.1hadeno1athy, 7oint tenderness and s/elling, or an a0nor.al 1-l.onary e9a.ination. A detailed s2in e9a.ination is essential, 0eca-se the s2in is the organ .ost fre>-ently and 1ro.inently affected 0y adverse dr-g reactions. Disting-ishing 0et/een the vario-s ty1es of s2in lesions is i.1ortant, 0eca-se this .ay 1rovide s-0stantial cl-es to the 1ossi0le i..-ne,.ediated .echanis. of the dr-g reaction (Table 3). TA*'E 3 "utaneous .ymptoms of Drug &ypersensitivity Reactions Cutaneous Symptoms of Drug Hypersensitivity Reactions
TYPE OF SKIN LESION Exanthematous or morbilliform eruption originating on trun 0rticaria ,urpura %aculopapular lesions -ith distribution on the fingers" toes" or soles Blistering lesions -ith mucous membrane in$ol$ement ASSOCIATED IMMUNE-MEDIATED MECHANISM OF THE DRUG REACTION #lassic ?drug rash@A most common

IgE antibody-mediated or direct mast cell stimulation !asculitis or drug-induced thrombocytopenia Serum sic ness

Ste$ens-(ohnson syndrome or toxic epidermal necrolysis

TYPE OF SKIN LESION Ec.ematous rash in sun-exposed areas Solitary circumscribed erythematous raised lesion ,apulo$esicular" scaly lesion

ASSOCIATED IMMUNE-MEDIATED MECHANISM OF THE DRUG REACTION ,hotoallergic reaction &ixed drug eruption

#ontact dermatitis

'aboratory Evaluation 3he goal of diagnostic testing is to eval-ate 0ioche.ical or i..-nologic .ar2ers that confir. activation of a 1artic-lar i..-no1athologic 1ath/ay to e91lain the s-s1ected adverse dr-g effect. La0oratory eval-ation is g-ided 0y the s-s1ected 1athologic .echanis. (Table 2)#&. TA*'E 4 Diagnostic Testing and Therapy for Drug &ypersensitivity Diagnostic %esting and % erapy for Drug Hypersensitivity
IMMUNE REACTION Type I (IgEmediated) LABORATORY TESTS S in testing <AST THERAPEUTIC CONSIDERATIONS *iscontinue drug4 #onsider epinephrine" antihistamines" systemic corticosteroids" bronchodilators4 Inpatient monitoring" if se$ere *iscontinue drug4 #onsider systemic corticosteroids4 Transfusion in se$ere cases Type III (immune complex) ES< #-reacti$e protein Immune complexes *iscontinue drug4 #onsider +SAI*s" antihistamines" or systemic corticosteroidsA or plasmapheresis if se$ere45D

Serum tryptase Type II (cytotoxic) *irect or indirect #oombsC test

IMMUNE REACTION

LABORATORY TESTS #omplement studies Antinuclear antibody" antihistone antibody Tissue biopsy for immunofluorescence studies

THERAPEUTIC CONSIDERATIONS

Type I! (delayed" cell-mediated)

,atch testing ;ymphocyte proliferation assay7

*iscontinue drug4 #onsider topical corticosteroids" antihistamines" or systemic corticosteroids if se$ere4

)*S = radioallergosorbent test+ ,S) = erythrocyte sedimentation rate+ -S*!Ds = nonsteroidal antiin$lammatory drugs4 7: his is an in%estigational test4

Confir.ation of s-s1ected 3y1e I hy1ersensitivity reactions re>-ire the detection of antigen, s1ecific IgE. S2in testing is a -sef-l diagnostic 1roced-re in these 1atients. S2in testing 1rotocols are standardi6ed for 1enicillin, and are /ell descri0ed for local anesthetics #( and .-scle rela9ant agents. ! It also .ay 0e infor.ative /hen testing high,.olec-lar,/eight 1rotein s-0stances s-ch as ins-lin, vaccines, stre1to2inase, 1olyclonal or .onoclonal anti0odies, and late9. #, =ositive s2in testing to s-ch reagents confir.s the 1resence of antigen,s1ecific IgE and is s-11ortive of the diagnosis of a 3y1e I hy1ersensitivity reaction in the a11ro1riate clinical setting. Negative s2in testing is hel1f-l only in 1enicillin s2in testing 0eca-se the test s1ecificity has 0een ade>-ately esta0lished. "Cith other dr-g agents, a negative s2in test does not effectively r-le o-t the 1resence of s1ecific IgE. In vitro testing for IgE is availa0le for a li.ited n-.0er of dr-gs in the for. of radioallergosor0ent tests that are historically less sensitive than s2in testing for deter.ining s1ecific IgE levels. # In addition, the i..-nogenic deter.inants of .any dr-gs are -ndefined, /hich .a2es the 1redictive val-e of in vitro tests 1oor. < La0oratory tests .eas-ring .ast cell activation .ay 0e hel1f-l if o0tained /ithin fo-r ho-rs of onset of the s-s1ected allergic reaction. Chile ser-. hista.ine levels 1ea2 five .in-tes after ana1hyla9is and ret-rn to 0aseline /ithin "! .in-tes, ser-. try1tase levels 1ea2 one ho-r after ana1hyla9is and re.ain elevated for t/o to fo-r ho-rs after the event. 8 ;ista.ine, try1tase, and 0etatry1tase levels have 1roved -sef-l in confir.ing ac-te IgE,.ediated reactions, 0-t negative

res-lts do not r-le o-t ac-te allergic reactions. %, + 3y1e II cytoto9ic reactions to a dr-g res-lt in he.olytic ane.ia, thro.0ocyto1enia, or ne-tro1enia evident /ith a co.1lete 0lood co-nt. ;e.olytic ane.ia .ay 0e confir.ed /ith a 1ositive direct andDor indirect Coo.0sE test, reflecting the 1resence of co.1le.ent andDor dr-g,ha1ten on the red cell .e.0rane. In 3y1e III i..-ne co.1le9 reactions to a dr-g, elevation of nons1ecific infla..atory .ar2ers s-ch as erythrocyte sedi.entation rate and C,reactive 1rotein .ay occ-r. If availa0le, .ore s1ecific la0oratory testing for co.1le.ent levels 'C;8!, C", C<) or circ-lating i..-ne co.1le9es can 0e cond-cted. =ositive tests hel1 confir. the clinical diagnosis$ negative tests do not e9cl-de the diagnosis of i..-ne co.1le9 disease. Syste.ic vasc-litides ind-ced 0y .edication .ay 0e detected 0y a-toanti0ody tests s-ch as antin-clear anti0ody or antihistone anti0ody. & 3y1e I: i..-ne reactions -s-ally 1resent as allergic contact der.atitis ca-sed 0y to1ical .edications. In s-ch instances, 1atch testing for s1ecific dr-g agents, as o-tlined in Table 4, is an a11ro1riate diagnostic ste1. @eat-res of erythe.a, ind-ration, and a 1r-ritic vesic-lo1a1-lar rash develo1ing <& ho-rs after 1atch a11lication s-11ort the diagnosis of a 3y1e I: i..-ne reaction. TA*'E 5 Dermatitis .uggested (atch Testing (rocedures for Drug Induced "ontact

Suggested !atc %esting !rocedures for Drug-Induced Contact Dermatitis

)btain patch test chambers (strips)4 ,lace suspected topical agent in chambers as drop of li3uid or mixed -ith petrolatum4 Apply patch test strips firmly against s in on the bac 4 )utline s in surrounding patch test strips -ith in 4 *ocument position of each allergen in medical records4 Instruct patient to eep patch test sites dry4 <emo$e patch test strips after =D hours4 <ead test sites at =D hours and again at 98 to E2 hours after applicationF 5G (Erythema)

8G (Edema or $esiculation of less than >HI of patch test site)

6G (Edema or $esiculation of more than >HI of patch test site)

*etermine if patch test reactions are rele$ant to patientCs clinical condition4 If necessary" perform ?use test@ -ith application of suspected agent to antecubital fossa t-ice daily for one -ee 4

Diagnosis 3he diagnosis of dr-g hy1ersensitivity is -s-ally 0ased on clinical 7-dg.ent, 0eca-se definitive, confir.atory dr-g,s1ecific testing is often diffic-lt. Table 1 o-tlines the general criteria for the diagnosis of dr-g hy1ersensitivity reactions. TA*'E 6 !eneral "riteria for Drug &ypersensitivity Reactions General Criteria for Drug Hypersensitivity Reactions
The patientCs symptomatology is consistent -ith an immunologic drug reaction4 The patient -as administered a drug no-n to cause such symptoms4 The temporal se3uence of drug administration and appearance of symptoms is consistent -ith a drug reaction4 )ther causes of the symptomatology are effecti$ely excluded4 ;aboratory data are supporti$e of an immunologic mechanism to explain the drug reaction (not present or a$ailable in all cases)4

Ance the diagnosis has 0een esta0lished, a11ro1riate doc-.entation sho-ld 0e incl-ded in the .edical record s1ecifying the ca-sative dr-g and the nat-re of the adverse effect. I..-ne, .ediated dr-g hy1ersensitivity reactions ty1ically 1ose a 1redicta0le, .ore serio-s health ris2 /ith re,e91os-re to a dr-g. Noni..-ne dr-g reactions tend to 0e less severe and less re1rod-ci0le. 3he contin-ed -se of an offending dr-g .ay 0e a11ro1riate if the ris2 of not treating the -nderlying disease is greater than the ris2 of contin-ing the dr-g, and if no s-ita0le alternative e9ists. In these cases, it is essential that the 1atient 0e closely .onitored 0y an e91erienced 1hysician. Chen discontin-ing a dr-g, the 1atient sho-ld 0e 1rovided /ith a list of s-0stit-te .edications for f-t-re -se. Therapy and /anagement

3he .ost i.1ortant and effective thera1e-tic .eas-re in .anaging dr-g hy1ersensitivity reactions is the discontin-ation of the offending .edication, if 1ossi0le. Alternative .edications /ith -nrelated che.ical str-ct-res sho-ld 0e s-0stit-ted /hen availa0le. 3he clinical conse>-ences of .edication cessation or s-0stit-tion sho-ld 0e closely .onitored. In the .a7ority of 1atients, sy.1to.s /ill resolve /ithin t/o /ee2s if the diagnosis of dr-g hy1ersensitivity is correct. Additional thera1y for dr-g hy1ersensitivity reactions is largely s-11ortive and sy.1to.atic (Table 2). Syste.ic corticosteroids .ay s1eed recovery in severe cases of dr-g hy1ersensitivity. 3o1ical corticosteroids and oral antihista.ines .ay i.1rove der.atologic sy.1to.s. 3he severe dr-g reactions of Stevens,Bohnson syndro.e and to9ic e1ider.al necrolysis re>-ire additional intensive thera1y. ( (E,I"I''I, A''ER!7 Cross reactivity 0et/een a F,lacta. ring and 1enicillin restricts the -se of car0a1ene.s in 1atients /ho are allergic to 1enicillin."! GEvidence level H, nonrando.i6ed clinical trialI A6treona. 'A6acta.) cross,reactivity is e9tre.ely rare in these 1atients. "#," :arying degrees of cross,reactivity 0et/een ce1halos1orins and 1enicillins have 0een doc-.ented. ;o/ever, since #(&! the rate of cross,reaction 0et/een 1enicillin and second, or third,generation ce1halos1orins has 0een fo-nd to 0e 8 1ercent or less. % 3he degree of cross,reactivity a11ears to 0e greater for first,generation ce1halos1orins."" Chile the incidence of tr-e cross,reactivity 0et/een 1enicillins and ce1halos1orins is lo/, the 1ossi0le reactions incl-de ana1hyla9is, /hich can 0e fatal."< Ca-tion is advised /hen ad.inistering ce1halos1orin thera1y to 1atients /ith a history of 1enicillin allergy. A .ore conservative a11roach incl-des 1enicillin s2in testing 0efore initiation of ce1halos1orin thera1y, 1artic-larly for 1atients /ith a history of serio-s allergic reactions to 1enicillin.#,"8 GReference #JEvidence level C, consens-sDe91ert o1inionI RADIO"O,TRA.T /EDIA REA"TIO,. 3he case of 1atients /ith severe reactions to radiocontrast .edia sho-ld 0e identified 0y a thoro-gh history that incl-des 1revio-s reactions. A s1ecific g-ide to treating these 1atients is incl-ded in Table /. !,"% TA*'E 8 (retreatment (rotocol for (atients with (revious R"/ Reactions9 !retreatment !rotocol for !atients &it !revious RCM Reactions'
0se a nonionic" lo-er osmolarity <#%4 ,retreat -ith the follo-ingF 5) ,rednisone" >H mg orally at 56" 9" and 5 hour before the procedure4 8) *iphenhydramine (Benadryl)" >H mg at 5 hour before the procedure4

6) Ephedrine" 8> mg orally at 5 hour before the procedure"J or a histamine H 8-receptor antagonist 5 hour before the procedure48H"62

)CM = radiocontrast media4 7: here is no e%idence that sensiti%ity to sea$ood or iodine is predicti%e o$ )CM reactions 4 J:May be .ithheld in patients .ith unstable angina# hypertension# arrhythmias# or other contraindications4

The Authors MARC A. RIEDL, M.D., is a fello/ in clinical i..-nology and allergy at the University of California, Los Angeles 'UCLA) David Geffen School of Medicine, Center for the ;ealth Sciences. Dr. Riedl received his .edical degree fro. the University of Chicago =rit62er School of Medicine. ;e co.1leted an internal .edicine residency at Harnes,Be/ish ;os1ital and Cashington University School of Medicine, St. Lo-is. ADRIAN M. CASILLAS, M.D., is assistant 1rofessor of .edicine and director of the fello/shi1 training 1rogra. in the Division of Clinical I..-nology and Allergy at the UCLA David Geffen School of Medicine. Dr. Casillas received his .edical degree fro. the UCLA School of Medicine, /here he also co.1leted an internal .edicine residency and a clinical i..-nology and allergy fello/shi1. A$$ress corres'on$ence to A$rian 5. .asillas, 5.6., 7.8A 6a"i$ 9e en !chool o 5e$icine, 6e'artment o 5e$icine, 6i"ision o .linical -mmunology an$ Allergy, 1:133 8e .onte A"e., 32;143 .<!, 8os Angeles, .A /::/3 (e-mail* acasillas=me$net.ucla.e$u). >e'rints are not a"ailable rom the authors. The authors than+ .am ?il$er o the 6a"i$ 9e en !chool o 5e$icine at 7.8A -55)@ ProAect or her assistance in the 're'aration o the manuscri't. The authors in$icate that they $o not ha"e any con licts o interests. !ources o un$ing* none re'orte$.