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Drug allergy: diagnosis and managementA Y Y W u

Summary

Drug allergy is one of the most commonly

encountered medical problems in family practice. The

symptoms may range from trivial to life threatening. As

drug use continues to increase, the incidence of drug

allergies will also continue to rise. Many drugs are

available without doctors' prescriptions, which further

increase the risk of fatal reactions. Drug allergy can

become a major problem for patients with the multiple

drug allergy syndrome, and more so with the emergence

of antibiotic resistant organisms that limits the choice of

antibiotics available. This article reviews the currentunderstanding in the mechanisms of drug allergy, the

management of patients with allergy to commonly used

drugs such as penicillins, NSAIDs, local anaesthetics and

radiocontrast media. After reading this article, the reader

should be able to recognise patients at high risk of

serious drug reactions and to formulate a management

plan for such patients.

&*** 7

HK Pract 2000;22:61-70

A Y Y Wu, MBChB(Edin) , MRCP(UK) , Amer ican Board of A l l e rgy and Immunology,

FHKAM(Medicine)

Associate Professor,Department of Medicine, The University of Hong Kong.

Correspondence to : Dr A Y Y Wu, Department of Medicine, The University ofHong Kong, Queen Mary Hospital, Hong Kong.

Introduction

Adverse reactions to drugs are important causesof morb id i ty and mor t a l i t y and are f r equen t lyencountered in family practice. It has been estimatedthat the risk of an allergic reaction for most drugs is1-3%.' Such reactions might become an importantreason for complaints or even malpractice litigation.It is therefore important that all doctors who prescribemedicines should have a basic understanding of thissubject in order to reduce the risk of adverse drugreactions in their patients. Since the subject of adversedrug reactions covers an enormous scope, this reviewwil l concentrate on immunological ly-mediated drugreactions since they are often the most dangerous typesof adverse drug reactions.

Adverse drug reactions can be classified intopredictable and unpredictable categories. Predictablereactions are often caused by the toxic side effects ofdrugs, or by the interaction of different drugs. Thesereactions occur commonly and are usually related tothe doses of the drugs. For example, bradycardiacaused by (3-blockers and headache caused by nitrates.Idiosyncratic, allergic and pseudoallergic reactions areunpredictable reactions. Chloramphenicol-inducedaplastic anaemia is an example of an idiosyncraticreaction. Only a very small proportion of patients isaffected and the reaction cannot be predicted by animaltesting.

Mechanisms of drug allergies

Allergic reactions have certain characteristics thathelp to distinguish them from other types of adversedrug reactions. These include:

1. Prior sensitisation. Allergic reactions to drugs, likeother immunologically-mediated reactions, areacquired. In other words, the immune system musthave been exposed to related drugs previously inorder to be sens i t i sed . The l ike l ihood ofsensitisation depends on the genetic predispositionof the individual, the amount of drug given, and thelength, frequency and route of exposure. Genetic

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predisposition to drug allergies appears not to berelated to other atopic diseases such as asthma,allergic rhinitis or food allergies. In general, longeror more frequent exposure will more likely lead tosensitisation, and cutaneous exposure is more likelyto sensitise than by intravenous route, and oraladministration being the least likely. Some casesof allergic reactions to drugs given apparently forthe first time may be due to cross-sensitisation orprevious occult exposure, as antibiotic use in animalfee is widespread in the farming industry.

2. Consistency in symptoms. Allergic reactions leadto a l imited and we l l - cha rac t e r i s ed set ofsymptoms. Different allergic mechanisms lead todifferent sets of symptoms that can often bedistinguished clinically. Repeated exposure willinvar iably reproduce s imi lar symptoms in anygiven ind iv idua l .

3. The severity of symptoms is often unrelated to thedose of drug given. Even minute amount of a drugfar below therapeut ic dose can lead to a fatalreaction. As a result, application of a "test dose"could be a very dangerous proposition.

4. Temporal relationship. A drug allergy reaction isalways temporally related to drug exposure. Thet iming of the react ion is dependent on themechanism of the reaction. For example, an IgE-mediated reaction usually occurs within 15 minutesto one hour of exposure.

As most drugs are small molecules incapable ofsensitising the immune system on their own, they actas haptens by b ind ing to serum prote ins , therebyal ter ing the an t igen ic determinants . The geneticpredisposition to producing active drug metabolites thatreact with serum proteins may affect the likelihood ofbecoming sensitised to drugs . Drug allergies mayinvolve many different immunological mechanisms, butcan be classified along the lines described by Gell andCoombs:

Type I or Immediate-type hypersensitivity reactions

T cells sensitised to a drug stimulate B cells toproduce antibodies of the IgE isotype against the drug.During re-exposure, cross-linking of IgE bound to thesurface of mast cells by antigen leads to mast celldegranulation and the release of mediators such as

histamine, cytokines, proteolytic enzymes, eicosanoidsand platelet activating factor. Symptoms can occurfrom 15 minutes to 1 hour after exposure. Symptomsof a n a p h y l a x i s i n c l u d e genera l i sed u r t i c a r i a ,angioedema, bronchoconstriction, hypotension or evencardiovascular collapse. Less severe reactions mayinvolve the skin only. Examples of drugs causing typeI reactions include penicillin, insulin and streptokinase.

Type n or antibody mediated cellular cytotoxicityreactions

IgG or IgM antibodies specific for drug antigensmay bind to surface of cells such as erythrocytes ,platelets or granulocytes. Binding of drug moleculesto the surface bound antibody triggers a cascade ofevents involving complement activation, leading to celllysis. These reactions may occur hours to days afterexposure . Example may inc lude p e n i c i l l i n andsulphonamides .

Type III or immune complex mediated reactions

IgG or IgM antibodies specific for drug antigensbind to drug molecules to form insoluble complexes,which get deposited in basement membrane of bloodvessels. The classic reaction in this category is serumsickness characterized by fever, cutaneous eruptions,lymphadenopathy, arthralgias, nephritis, hepatitis, andvasculitis. These reactions may occur 4 to 20 days afterexposure.4 Penicillin, anti- thymocyte globulin orheteroantisera may lead to this type of reactions.

Type IV or Delayed type hypersensitivity reactions

Sensitised T cells may directly damage the targetorgan, usually the skin in this type of reactions. Aclassic example is contact dermatitis secondary totopical antibiotics or anaesthetics. The reaction usuallyoccurs 48 to 72 hours after exposure.

There a re m a n y reac t ions w i t h complexmechanisms that cannot be neatly classified under oneof these categories. These reactions include Stevens-Johnson syndrome, erythema multiforme, mobilliformdrug rashes, fixed drug eruptions, toxic epidermalnecrolysis and many organ-specific drug reactions.

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Pseudoallergic reactions

These a re r e a c t i o n s t h a t a re c l i n i c a l l yindistinguishable from type I reactions. Drugs thatcan cause mast cell degranulation directly withoutsensitising the immune system include radiocontrastmedia, certain muscle relaxants, vancomycin andopiates. Angiotensin converting enzyme inhibitors cancause angioedema by accumulating bradykinins. Non-steroidal ant i - inf lammatory drugs (NSAIDs) mayexacerbate pre-exist ing ur t icar ia l rashes or causebronchospasm by altering eicosanoid metabolism. Sincethese reactions do not involve immune activation, noprior sensitisation is required.

Diagnosis of drug allergy

A detailed history is of utmost importance indiagnosing drug allergies. The symptoms, drug historyand the t i m i n g of r eac t ion in re la t ion to d rugadministration wi l l help to pinpoint the offending drugand the type of reaction. A previous history of drugallergies or a fami ly history of drug allergies isimportant since these factors greatly predispose thepatient to developing allergies to other drugs.2 Sullivansuggested that in people allergic to penicil l in, therewas at least a tenfold increase in reaction rate to non-beta-lactam antibiotics. As mentioned earlier, otheratopic diseases do not predispose the patient to drugallergies. A history of concomitant illness is alsoimportant. Quite frequently, viral rashes are mistakenas drug rashes caused by antibiotics given to treat theviral illness. Drugs given under some circumstancesmay also lead to a non-immunologically mediated rash.For example, ampici l l in /amoxici l l in given duringi n f e c t i o n c a u s e d by E p s t e i n - B a r r v i r u s o rcytomegalovirus, or when given to a patient with acutelymphocytic leukaemia, may lead to a drug rash.Similarly, penicillin given to a patient with syphilismay lead to the Jarisch-Herxheimer reaction. Underother circumstances, these patients will not react tothe antibiotics. AIDS also predisposes patients to drugallergies. Fifty percent of AIDS patients treated withtrimethoprim-sulfamethoxazole develop an allergicrash.3

Physical examination should focus on the skin,a frequent site of manifestation of drug allergies. Itis important to distinguish between a mobilliform rashfrom an urticaria rash; the former is usually benign

whereas the latter indicates the presence of IgEantibodies. Direct observation by the physician isimportant as patients' description may not be accurate,as discussed below. Mucosal involvement may indicateStevens-Johnson syndrome or toxic epidermalnecrolysis. Both are serious conditions. Chestexaminat ion may reveal wheezing secondary tobronchospasm, or stridor caused by laryngeal oedema.

Laboratory tests may be helpful in diagnosingorgan-specific allergic reactions such as haemolyticanaemias, hepat i t i s , nephri t is etc. Anti-his toneantibodies may appear in patients taking hydralazineor procainamide, but do not necessarily indicate drug-induced lupus. In situations where anaphylaxis issuspected, a serum tryptase level drawn within 3 to 4hours of the reaction may help; the assay is howeverexpensive. Skin tests are available for diagnosingtype I reactions to penici l l in and insul in. Radio-allergosorbent tests (RAST) for penicillin, ampicillinand cephalosporin specific IgE are available but areunreliable and tend to over-diagnose allergies.

Management of drug allergies

Penicillin and other (3-lactam antibiotics

(3-lactam antibiotics are some of the most widelyused drugs and are responsible for the majority of drugallergies. These drugs can cause many different typesof allergic reactions, from minor drug rashes to fatalanaphylaxis. Fatal reactions are rare, but it is importantto distinguish the serious reactions from the trivial.One often encounters patients with a vague history ofallergy to penicillin in the past. Mendelson et al. skin-tested 240 children and adolescents with a history ofpenicillin or amoxicillin allergy and found only 8.75%to be truly allergic to these antibiotics.5 Similarly,Macy et al. skin-tested 348 patients referred to theirallergy clinic with a history of penicillin allergy, andonly 60 (17.2%) were found to have positive skin tests.6

These results suggest that without skin testing, themajority of patients labelled as 'penicillin allergic'would be avoiding these drugs unnecessarily.

Before starting a patient on p-lactam antibiotics,the physician must ascertain whether the patient isallergic to the drug, and the seriousness of the allergicreaction. In general, t r ivial drug rashes are notcontraindications to the use of these drugs if they are

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absolutely needed, since the symptoms of the reactioncan often be managed to allow the patient to completethe course of treatment. However, these drugs mustbe completely avoided if the patient has a history ofStevens-Johnson syndrome, toxic epidermal necrolysisor type I hypersensitivity reactions. The first twoentities, both serious conditions, should be easilyrecognisable. However, the patient may not be ableto distinguish a mobilliform or maculopapular rashfrom an urticarial rash. Pichichero reported that 22%of patients with a history suggestive of a non-IgEmediated rash nevertheless had positive skin tests topenicillin.7

Skin testing has proven to be very reliable inpredicting the risk of anaphylactic reactions. Penicillinis metabolised to major and minor determinants. Themajor de te rminant is p en i c i l l o y l and the minordeterminants inc lude penici l loate , peni l loate andbenzylpenicil l in (Table 1). Skin testing reagent forthe major d e t e r m i n a n t is ava i l ab l e (pen i c i l l oy lpolylysine, PrePen). Although the minor determinantsare responsible for a substantial proportion of seriousanaphylactic reactions, no skin testing reagent forminor determinants is commercially available. Sodiumamoxicillin is usually included in the panel since somepatients react to its side-chain instead of the p-lactamgroup. In Macy's study, 12 out of 60 (20%) penicillinal lergic pa t ien t s reacted to pen i l l oa t e and /o rpenicilloate only6 (Table 2). When skin testing iscarried out using major and minor determinants andamoxicillin, a very high negative predictive value isachieved. In Macy's study, only 5.2% of patients withnegative skin tests developed a reaction on oralchallenge, and all were mild. Skin testing is also safe,and only 0.3% of patients is known to develop urticariaduring the tests.

Skin tests for penicillin should be by intradermalinjections only, since prick puncture is not sufficientlysensit ive. Appropriate solutions for skin testinginclude penicilloyl polylysine (Schwarz Pharma),p e n i c i l l o a t e ( 0 . 0 1 M ) , p e n i l l o a t e ( 0 . 0 1 M ) ,benzylpenici l l in (0.01M) and amoxycillin (0.01M).Since penicilloate and penilloate are not commerciallyavailable, they must be prepared and stored in thefreezer. 0 .02ml of the solut ions are injectedintradermally and the wheal and flare reaction is readafter 15 minutes. Histamine and saline are used aspositive and negative controls respectively. Positive

Table 1: Skin-test reagents for penicillin allergy

Major determinant

- Penicilloyl polylysine (PrePen) 10-6 M

Minor determinant mix (MDM)

- Potassium penicillin G 0.01M

- Sodium benzylpenicilloate 0.01M

- Benzylpenicilloyl-n-propylamine 0.01M

0.01MSodium amoxicillin

Histamine

Saline control

mg/ml

Table 2: Type and specificity of positive penicillin skin

test reactions in 384 patients

Reagent Puncture Intradermal(no. of patients)(no. of patients)

PrePen

Penicilloate 2

Penilloate 1

Penicilloate + penilloate

Penicillin + PrePen

Penicillin

Amoxicillin

All other combinations* 3

Total 6

24

2

6

1

6

2

1

12

54

* All of these subjects had positive responses to at least one of thecommercially available skin test materials: amoxicill in (3 of 15),PrePen (11 of 15), and penicillin (1 of 15).

From:Macy E, Richter PK, Falkoff R, et al. J Allergy Clin Immunol 1997;100:586-591.

responses consist of a wheal of 5 mm or more indiameter with surrounding erythema greater than thewheal, a negative response to control solution and apositive response to histamine.

The incidence of skin test positivity declines withtime following the initial reaction, and is down to lessthan 10% after 10 years. This is because of waningpenicillin-specific IgE levels in the absence of antigenicstimulation. A new course of penicillin in this situationmay provoke IgE production again by the memory Bcells. Skin testing with penicillin can theoreticallyalso restimulate IgE synthesis. It is therefore importantto tell patients that a negative skin test does not

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guarantee any safety to take repeated courses ofpenicillin; retesting is required before each subsequentcourse of penicillin. It is best to perform skin testingjust before the course of antibiotics is needed. Sinceanaphylaxis is a first dose phenomenon, the danger isminimal after the first dose of a course is tolerated,as long as there is no interruption in treatment. Anin te r rup t ion of 3 days or longer runs the risk ofresensitisation and subsequent reaction when the courseof treatment is resumed.

The issue of cross-reactivity between penicillinsand cephalosporins is less clear. Both classes of drugscontain a (3-lactam r ing s t ructure . Some studiessuggested that increased hypersensi t ivi ty to first-generation cephalosporins exists in those patients whohave histories of penic i l l in allergy.8 However, thesestudies were not supported by skin-test results. Theincidence of cross-reactivity between penici l l in andsecond- and third- generation cephalosporins appearsto be low.9 Cross-react ivi ty between pen ic i l l ins andcephalosporins with s imilar side chains appears to bemore frequent. Miranda reported that in 21 patientsallergic to a m o x i c i l l i n , 8 (38%) also reacted tocefadroxil, but none reacted to cefamandole.10 If acephalosporin is used in a penicillin allergic patient,inclusion of the drug in the skin test panel is advisable.In a patient with known allergy to a cephalosporin,another cephalospor in wi th a d i f ferent side cha instructure is usual ly safe. Imipenem, a carbipenemantibiot ic widely used in hospi ta ls in Hong Kong,carries a 50% risk of cross reactivity with penicillin."Aztreonam, a monobactam, does not cross-react withpenicil l in.1 2

In summary, if a patient with a history of penicillinallergy requires antibiotics, subst i tut ing a chemicallyunrelated antibiotic should be the first course of action.If penicillin is absolutely required, skin testing withmajor and minor determinants and amoxic i l l in willreliably assess the risk of a serious reaction. If thepatient 's skin test is negat ive, a test dose of oralamoxicillin should be given under medical supervisionand the patient observed for one hour before startingthe course of treatment. The patient must understandthat skin test ing w i l l only predict anaphylac t icreactions and minor skin rashes may still occur. Ifthe pat ient ' s skin test is posi t ive , an alternativea n t i b i o t i c should be used. Unde r except ionalcircumstances where penicillin is absolutely necessary,

e.g. tertiary syphilis, the patient can be desensitised.Desens i t i sa t ion can be achieved by the oral orintravenous methods. In both methods, the patient isgiven minute doses of the (5-lactam drug starting at0.05 mg orally or 0.01mg intravenously. The nexthigher dose is given after a 15-minute interval if thereis no reaction. The dose is gradually increased overthe next 4 hours unti l the patient can tolerate a fulltherapeutic dose of the drug. This should be carriedout by an allergist experienced with the procedureunder strict medical observation. After desensitisation,treatment must begin immediately and must not beinterrupted. After a successful course of treatment,the patient must be desensitised again jus t beforesubsequent courses of penicill in in the future.

Aspirin and other NSAIDs

NSAIDs are some of the most frequently prescribeddrugs in the world. They are also hidden componentsof m a n y ove r - the -coun te r cold and flu remedies .Allergic reactions to NSAIDs are common and involvemany d i f f e r e n t m e c h a n i s m s . They can causeexacerbation of rhinitis and asthma in patients withaspirin sensit ive asthma. They may also exacerbatesymptoms in pat ients with idiopathic ur t icar ia andangioedema. True immune-mediated allergic reactionsto NSAIDs also lead to ur t icar ia , angioedema andanaphylaxis . Lastly, these drugs may rarely causeaseptic meningit is and pneumonitis .

Up to 15% of adult asthmatics have been estimatedto have aspirin sensitive asthma (ASA). ASA is adistinct disease entity. The typical patient with ASAis an adult of either sex aged 20 to 40, suffering fromasthma, rhinitis, sinusitis and nasal polyps.13 Anosmiais frequently found as is sinus opacification on x-ray.The lower airway is sometimes spared but most patientshave moderate to severe asthma, they require high doseinhaled corticosteroids or even oral corticosteroids.The severity of asthmatic symptoms appears to parallelthe severity of rhinosinusitis, as treatment of the sinusdisease, e.g. by surgery, will also improve asthmacontrol. Improvement after surgery is usually short-lived as nasal polyps and sinusitis tend to recur.

The hallmark of this disease is the exacerbationof as thma wi th in 15 min to 3 hours of NSAIDingestion. Patients may develop conjunc t iv i t i s ,

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rhinorrhoea, nasal congestion, a slow and sustainedbronchoconstriction and occasionally laryngospasm.These reactions may last 1 to 24 hours. This isfollowed by a refractory period of 2 to 5 days whenpatients can take NSAIDs without any reaction. Theaetiology of this disease is known to be a disorder ofleukotr iene synthesis. The cysteinyl-leukotrienesleukotriene C4 (LTC4) and LTD4 are the most potentnaturally-occurring bronchoconstrictors known, and canalso mediate eosinophilic inflammation. ASA patientsproduce increased amounts of LTC4 and LTD4, reflectedby the raised levels of urinary LTE., (breakdown productof LTC4 and LTD4) as compared to control asthmatics.The urinary LTE4 is substantially increased after aspirinchallenge in ASA subjects but not control asthmatics.14

Their bronchial responsiveness to inhaled LTE4 is alsohigher than non-ASA asthmatics.15

The diagnosis of ASA can be confirmed by nasall y s i n e - a s p i r i n cha l lenge , inha led l y s i n e - a s p i r i nchallenge or oral aspirin challenge. Nasal challengetest is less reliable but is useful in diagnosing aspirin-sensitive upper airway disease. Inhaled lysine-aspirinchallenge is the test of choice for diagnosing ASA.16

It is safe, the symptoms are usually limited to the lowerairways and are rapidly reversed. Oral challenge mayproduce prolonged symptoms and is therefore morehazardous. However, oral challenge can be followedby aspirin desensitisation. Following desensitisation,patients can take NSAIDs indefinitely as long as thecourse of treatment is not interrupted by more than 2days . F u r t h e r m o r e , desens i t i sa t ion leads toimprovemen t in both upper and lower a i r w a ysymptoms17 and should be considered for patients withdifficulty in controlling ASA.

It is important to bear in mind that ASA is a classeffect and all strong inhibitors of cyclooxygenase willprovoke reactions in these patients. Paracetamol hasbeen shown to cross-react at high doses (1000 mg orgreater) in 28% of ASA patients.18 Recent anecdotalevidence claims that nimesulide, a new COX-2-selectiveinh ib i to r , does not provoke symptoms in ASApatients.1 9 Although Zileuton, a 5-lipoxygenaseinhibitor, has been found to protect ASA patients fromaspirin-induced bronchospasm,20 this has not beenshown in clinical practice. The new anti-leukotrienedrugs, while useful in improving asthma control in ASApatients, should not be used to enable patients to takeNSAIDs. ASA patients requiring NSAIDs shouldundergo desensitisation.

Aspirin and other NSAIDs have been found toexacerbate symptoms in some patients with idiopathicurticaria. This is probably related to inhibition ofprostaglandin synthesis common with all NSAIDs.However, NSAIDs can also elicit IgE-mediatedreactions leading to u r t i ca r i a , angioedema andanaphylaxis. Since this effect is immunologically-mediated, cross-reactivity between different NSAIDsis low and only confined to drugs with similar chemicalstructure. Unfortunately, there is no reliable test invivo or in vitro to confirm the diagnosis. Treatmentis by avoidance since previous attempts at desensitisingthese patients have failed.

Local anaesthetics

Al le rgy to local anaes the t ics is a f requen tcomplaint from patients, especially in dental practice.The usual symptoms include flushing, tachycardia andsyncope during or immediately after injection. Whilec o n t a c t d e r m a t i t i s t o t o p i c a l l y app l i ed localanaesthetics is common, systemic allergic reactions tothese drugs are extremely rare. It is possible that someof the reported cases were caused by reactions topreservatives in the multidose vials. Most of the caseswere anxiety reactions, vasovagal syncope or reactionscaused by direct intravenous injections of preparationscontaining adrenaline. In these situations, test bysubcutaneous injections of incremental doses of theanaesthetic in question would be very useful in allayingthe patient's fear.21

Drugs which cause pseudoallergic reactions

Many clinicians and radiologists still believe thatallergy to radiocontrast media (RCM) is related toallergies to iodine or even seafood. While iodine cancause dermatitis, allergy to shellfish is caused by IgEdirected against muscle proteins, components that arenot present in any radiocontrast medium. RCMs, byvirtue of their hyperosmolar nature, can directly causemast cell degranulation when injected intravenously.The use of RCM in procedures such as cystograms andmyelograms poses no risk. Patients with cardiacdisease, atopy or drug allergies, or who are taking(3-blockers are at risk of serious reactions. A historyof prior RCM reactions increases the risk of futurereactions to 30% or greater. The use of premedicationswith prednisolone 40 mg, 13, 7 and 1 hour before, and

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Key messages

1. Allergic drug reactions should be distinguishedfrom other forms of adverse drug reactions.

2. Allergic drug react ions are immunolog ica l lymediated. This requires prior exposure and theclinical manifestations are diverse.

3. The more serious types of allergic drug reactionssuch as anaphylaxis, Steven-Johnson syndrome andtoxic epidermal necrolysis should be recognised.

4. Some drugs such as radiocontrast media, opiates,muscle relaxants, dextran and vancomycin cancause anaphylactoid reactions by directly causingmast cell degranulation.

5. Skin testing is u s e f u l in predicting the risk ofanaphylaxis to drugs such as penicillin in patientswith prior history of allergic reactions to thosedrugs. Skin testing patients without a prior historyis not indicated.

6. In most cases, an al ternat ive drug that does notcross-react should be subs t i tu ted . Under certainc i rcumstances , d rug desens i t i sa t ion can beperformed.

diphenhydramine and ephedrine 1 hour before the

procedure can greatly reduce the risk of reaction.22

Premedications should be given to all patients withprior history of RCM reactions and to other patients

without such a history but are at high risk. The newernon-ionic RCM cause fewer reactions than their

hyperosmolar counterparts, but are substantially moreexpensive. These agents should be reserved for patients

with prior history of serious reactions.

The use of vancomycin is increasing because ofthe e m e r g e n c e o f the m e t h i c i l l i n - r e s i s t a n t

staphylococci. Vancomycin can cause the so-called red

man syndrome, which is related to the rate of infusion.True IgE-mediated anaphylaxis also occurs but is muchless common. Skin testing does not predict the severityof red man syndrome,23 but can sometimes help

distinguish IgE-mediated reactions.24 Slowing theinfusion rate is usually sufficient to control the red

man syndrome. Five hundred milligrams of the drugcan be infused over as long as 8 hours. Premedicationwith corticosteroids and antihistamines are also helpful.

If all else fails, desensitisation can be attempted.

Prevention of drug allergies and the multiple drugallergy syndrome

As mentioned previously, patients with allergy topenicillin are 10 times more likely to become allergicto other drugs. This susceptibility not only appliesto anaphylactic type reactions, but also extends to drugrashes, exfo l ia t ive de rmat i t i s , tox ic epidermalnecrolysis and Stevens-Johnson syndrome. In a studyof 120 patients with antibiotic allergies, 19% wereallergic to at least one other antibiotic; 15.8% reactedto three or more antibiotics. Forty-two percent of thosepatients allergic to two or more antibiotics were allergicto NSAIDs, in contrast to only 18% of those patientsallergic to one antibiotic. The presence of atopy wasnot a risk factor for multiple drug allergies.25 It istherefore clear that some patients are highly susceptibleto developing allergies to a large number of drugs.

Preventing drug allergy is the responsibility ofmedical pract i t ioners . Frequent, short courses ofantibiotics are responsible for sensitising many patientsto these drugs. I once saw a 4-year-old girl referredto me by a hospital paediatrician because he could notfind an antibiotic that he could use to treat the girl'spneumonia. The girl's mother listed 21 occasions inthe past three years when the girl was given antibioticsfor the treatment of viral upper respiratory tractinfections. She was otherwise a normal healthy childand there was no sign of immunodeficiency. By thetime she visited my clinic, she had already beenadmitted three times for drug-induced anaphylaxis,once requiring intubation. Examples such as this areadmittedly rare, but I see a fair number of patients withantibiotic allergies caused by overuse. We must educateour patients and ourselves when antibiotics are trulyindicated. By avoiding inappropriate use, the incidenceof drug allergies will decrease, which will ultimatelybenefit our patients and prevent a lot of problems forourselves. •

References

1. DeSwarte RD. Drug allergy. In: Patterson R, Grammer LC, GreenbergerPA, et al (eds): Allergic Diseases: Diagnosis and Management, ed 4.Philadelphia, JB Lippincott, 1993;395-551.

2. Sullivan TJ, Ong RC, Gilliam LK. Studies of the multiple drug allergysyndrome. J Allergy Clin Immunol 1989;83:270.

3. Shapiro LE, Knowles SR, Shear NH. Sulfonamide allergies - managementin the nineties. Allergy and Clinical Immunology International 1996;8:5-8.

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4. Vial T, Pont J, Pham E, et al. Cefaclor-associated serum sickness-likedisease: Eight cases and review of the literature. Ann Pharmacother 1992;26:910-914.

5. Mendelson LM, Ressler C, Rosen JP, et al. Routine elective penicillinallergy skin testing in children and adolescents: study of sensitization.J Allergy Clin Immunol 1984:73:76-81.

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Clin Immunol 1997;100:586-591.7. Pichichero ME, Pichichero DM. Diagnosis of penicillin, amoxicillin, and

cephalosporin allergy: Reliability of examination assessed by skin testingand oral challenge. J Pediatr 1998;132:137-143.

8. Petz LD. Immunolog ic cross reac t iv i ty between p e n i c i l l i n andcephalosporins: a review. J Infect Dis 1978;137:S74-S79.

9. Anne S, Reisman RE. Risk of administering cephalosporin antibiotics topatients with histories of penicillin allergy. Ann Allergy Asthma Immunol

1995;74:167-170.10. Miranda A, Blanca M, Vega JM, et al. Cross-reactivity between a penicillin

and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98:671-677.

11. Saxon A, Adelman DC, Patel A, et al. Imipenem cross-reactivity withpenicillin in humans. J Allergy Clin Immunol 1988;82:2I3-217.

12. Saxon A, Massner A, Swabb EA, et al. Lack of cross-reactivity betweenaztreonam, a monobactam antibiotic, and penicillin in penicillin-allergicsubjects. J Infect Dis 1984;149:16-22.

13. Stevenson DD, Simon RA. Sensitivity to aspirin and non-steroidal anti-inflammatory drugs. In: Middleton EJ, Reed CE, Ellis EF, et al (eds):Allergy: Principles and Practice, ed 4. St. Louis, CV Mosby, 1993, p. 1747.

14. Christie PE, Tagari P. Ford-Hutchinson AW, et al. Urinary leukotriene E4after lysine-aspirin inhalat ion in asthmatic subjects. Am Rev Respir Dis.1992;146:I53I-I534.

15. Christie PE, Schmitz-Schumann M, Spur BW, et al. Airway responsiveness

to leukotriene C4 (LTC4), leukotriene E4 (LTE4) and histamine in aspirin-

sensitive asthmatic subjects. Eur Respir J. 1993:6:1468-1473.

16. Phi l l ips GD, Foord R, Holgate ST. Inhaled lys ine-aspi r in as a

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