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106 VOL 55, NO 2 / FEBRUARY 2006 THE JOURNAL OF FAMILY PRACTICE

C O R R E S P O N D E N C E

Michael E. Pichichero, MD,

University of Rochester

Medical Center, 601 Elmwood

Avenue, Box 672, Rochester,

New York 14642. E-mail:

Michael_pichichero@

urmc.rochester.edu

an allergic reaction to cephalosporins,compared with the incidence of a primary(and unrelated) cephalosporin allergy.Most people produce IgG and IgMantibodies in response to exposure topenicillin1 that may cross-react withcephalosporin antigens.2 The presence ofthese antibodies does not predict allergic,IgE cross-sensitivity to a cephalosporin.Even penicillin skin testing is generally notpredictive of cephalosporin allergy.3

Reliably predicting cross-reactivityA comprehensive review of the evidenceshows that the attributable risk of a cross-reactive allergic reaction varies and isstrongest when the chemical side chain ofthe specific cephalosporin is similar to thatof penicillin or amoxicillin.

Administration of cephalothin, cepha-lexin, cefadroxil, and cefazolin in penicillin-allergic patients is associated with asignificant increase in the rate of allergicreactions; whereas administration ofcefprozil, cefuroxime, cefpodoxime, cef-tazidime, and ceftriaxone is not.

Penicillin skin testing can accuratelypredict a penicillin-allergic reaction, butis not predictive for cephalosporin aller-gy unless the side chain of the penicillinor ampicillin testing reagent is similar tothe cephalosporin side chain being evalu-ated. Patients who have a reaction to apenicillin or a cephalosporin that is not

Practice recommendations The widely quoted cross-allergy risk

of 10% between penicillin and

cephalosporins is a myth (A).

Cephalothin, cephalexin, cefadroxil,

and cefazolin confer an increased risk

of allergic reaction among patients

with penicillin allergy (B).

Cefprozil, cefuroxime, cefpodoxime,

ceftazidime, and ceftriaxone do not

increase risk of an allergic reaction (B).

Undoubtedly you have patients whosay they are allergic to penicillinbut have difficulty recalling details

of the reactions they experienced. To besafe, we often label these patients as peni-cillin-allergic without further questioningand withhold not only penicillins butcephalosporins due to concerns aboutpotential cross-reactivity and resultant IgE-mediated, type I reactions. But even forpatients truly allergic to penicillin, is theconcern over cephalosporins justified? Itdepends on the specific agent. What is cer-tain is that a blanket dismissal of allcephalosporins is unfounded.

The truth about the myth

Despite myriad studies spanning decadesand involving varied patient populations,results have not conclusively establishedthat penicillin allergy increases the risk of

Cephalosporins can beprescribed safely forpenicillin-allergic patients

Michael E. Pichichero, MDUniversity of Rochester

Medical Center, Rochester, NY

New research findings that are changing clinical practice

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IgE mediated and not serious may receiverepeated courses of that antibiotic andrelated antibiotics.

This article provides a comprehen-sive review of the frequency of allergiccross-reactivity between penicillin/amox-icillin and cephalosporin antibiotics, sup-porting the recent American Academy ofFamily Physicians evidence-based clinicalpractice guideline on treatment of acuteotitis media recommending the use ofcefuroxime, cefpodoxime, cefdinir, andceftriaxone cephalosporins for patientsallergic to penicillin.

MethodsWe searched Medline and EMBASE data-bases for English-language articles usingthe keywords cephalosporin, penicillin,allergy, and cross-sensitivity for the years1960 to 2005. Among 219 articles iden-tified, 101 were included as source mate-rial for this review. Articles we excludedwere reviews, republication of results, orones irrelevant to our purpose.

Five articles described the rate ofrashes following use of penicillin andcephalosporins,48 and 4 articles described

rates of anaphylaxis.5,911 We included 26articles for the evidence base evaluatingpenicillin/amoxicillin cross-allergy.3,1236

Eleven articles relied on patient history ofpenicillin/amoxicillin allergy to categorizeresults and establish reaction rates and rel-ative risks for the penicillin/amoxicillinallergic vs nonallergic when receivingcephalosporins.1215,1720,27,28,31 Fourteen arti-cles relied on patient history ofpenicillin/amoxicillin allergy plus skin test-ing results to penicillin/amoxicillin to cate-gorize patients.16,2125,29,30,3237 One article3

provided data on a subset where peni-cillin/amoxicillin allergy was establishedbased on history, and a separate subsetwhere penicillin/amoxicillin allergy wasestablished by skin testing. Other articlesrelated to antibiotic chemical structures,animal studies, monoclonal antibody stud-ies, cross-reactive antibody studies, andantibiotic skin testing were also reviewed.

Cephalosporins can be prescribed safely for penicillin-allergic patients

VOL 55, NO 2 / FEBRUARY 2006 107www. j f p o n l i n e . c o m

ResultsTrue incidence of reactionsto cephalosporins

The most frequent reactions to cephalo-sporins are non-pruritic, non-urticarialrashes, which occur in 1.0% to 2.8% ofpatients;48 for most, the mechanism is idio-pathic and not a contraindication forfuture use.38 Retrospective studies suggest a1% to 3% incidence of immune or allergicreactions to cephalosporins independent ofany history of penicillin/amoxicillinallergy.31 Anaphylactic reactions fromcephalosporins are extremely rare, withthe risk estimated at 0.0001% to 0.1%.31,38

A seminal study suggested approximately

0.004% to 0.015% of treatment courseswith penicillin results in anaphylaxis.5,911

Several studies suggest that cephalosporin-induced anaphylaxis occurs no morefrequently among patients with knownpenicillin allergy than among those with-out such allergy.23,27,3841

Determining cross-reactivityPenicillins and cephalosporins both possessa beta-lactam ring for antimicrobial activi-ty. They differ in that the 5-memberedthiazolidine ring of penicillin is replaced in

the cephalosporins with a 6-membereddihydrothiazine ring. After degradation,penicillin forms a stable ring, whereascephalosporins undergo rapid fragmenta-tion of their rings.42 Immunologic cross-reactivity between the penicillin andcephalosporin beta-lactam rings is, there-fore, very unlikelyan observation con-firmed by monoclonal antibody analysis.43

How the 10% cross-reactivity myth

took hold. When the first-generationcephalosporins cephaloridine and cepha-lothin were introduced in the 1960s, aller-gic and anaphylactic reactions were report-ed in patients with previous allergicreactions to penicillins. Subsequent reports,which attributed up to 10% cross-reactivitybetween the 2 drug classes, involved thesesame first-generation cephalosporins pluscephalexin and cefadroxil and a second-generation drug, cefamandole. However,these studies were flawed because the

Penicillincompoundscontaminated withcephalosporinsled to theerroneousassumption of 10%cross-reactivity

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penicillin test compounds had been contam-inated with cephalosporins. Until 1982,penicillin was produced commercially using

the cephalosporium mold.38

Many recent studies have establishedthat the rate of cross-reactivity betweenpenicillin and cephalosporins has beengrossly overestimated. In fact, the rate ofcross-reactivity between penicillin/amoxi-cillin and second- or third-generationcephalosporins is very low and may actual-ly be lower than that between penicillinsand other classes of antibiotics.44

The evidence for limited cross-reactivity.

A summary of publications evaluating38,846 children and adults with and with-

out a history of penicillin allergy is present-ed in TABLE 1. The database included 2435patients with a history of penicillin allergyand 961 patients with a history of peni-cillin allergy and positive skin-test resultsfor penicillin or amoxicillin (total peni-cillin-allergic patients=3396). The allergicreaction rate is compared with 34,047patients without a history of penicillinallergy and 1403 patients without a histo-ry of penicillin allergy and negative skin-test results for penicillin or amoxicillin(total penicillin-nonallergic patients=35,450).

When patients with a positive historyof penicillin-allergy received first-

generation cephalosporins, which share achemical side chain similar to penicillin oramoxicillin (cephalothin, cephaloridine,cephalexin, cefadroxil, and cefazolin, plusthe early second-generation cephalosporin,cefamandole), they exhibited a significantincreased risk of an allergic reaction to thecephalosporin.

Second- and third-generation cephalo-sporins modified in size and the complexi-ty of their side chains (eg, cefprozil,cefuroxime, ceftazidime, cefpodoxime,and ceftriaxone) were different enoughfrom penicillin and ampicillin that they didnot increase risk of allergic cross-reactivity(TABLE 1).

Anaphylaxis from cephalosporins israre, and the evidence suggests no increasedrisk of anaphylaxis to cephalosporins inpenicillin-allergic patients.3

Many other studies have suggestedthat cross-reactive immune responses tocephalosporins depend on side chain struc-

ture;22,23,27,32,37,38,4449

that is, cephalosporinswith a 7-position side chain similar to ben-zylpenicillin are more likely to cross-reactwith penicillin (TABLE 2). Cephalosporinsthat share a similar 7-position or 3-position side chain are more likely to cross-react with each other.

Cephalosporin/penicillin

cross-reactivity

Few studies have evaluated whetherpatients with primary hypersensitivity tocephalosporins will experience cross-

reactivity with penicillin. Romano et al49conducted skin tests and RASTs in patientswith immediate allergic reactions tocephalosporins to examine responsesto other cephalosporins and to classic peni-cillin determinants. About 1 in 5 patientsallergic to a cephalosporin reacted topenicillin determinants, while most hadpositive results to other cephalosporinswith the same or similar side-chains.

Limitations of skin testing

Penicillin skin testing in patients with a

history of penicillin allergy does not reli-ably predict allergy to a cephalosporinunless the side chain of the penicillin orampicillin reagent is similar to thecephalosporin side chain being tested.3 Thepositive and negative predictive values ofskin testing results for cephalosporins arenot well established; if the haptens thatcause cephalosporin allergy were known,cross-reactivity with penicillins could beassessed directly. Cephalosporin skin test-ingworks only for the specific drug anddrugs with the same side chains, and can bedone only if the drug is available in an IVor IM formulation.

Even a positive result does not guaran-

tee a clinical reaction. When penicillin andcephalosporin skin tests or radioaller-gosorbent tests (RASTs) are positive, aclinical reaction is observed in only 10%to 60% of patients, depending on thereagent and study.50 For example, among


APPLIED EVIDENCE

IgE antibodiesconfirmedby skin testing donot automaticallypredict a clinicalreaction

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T A B L E 1

CEPHALOSPORINS THAT SIGNIFICANTLY INCREASE ALLERGIC REACTIONS IN PENICILLIN-ALLERGIC PATIENTS

RR DIFFERENCE PENICILLIN/AMOXICILLIN RR DIFFERENCE

PENICILLIN/AMOXICILLIN (95% CI) ALLERGY BY HISTORY (95% CI)

DRUG (GENERATION) ALLERGY BY HISTORY* P-VALUE AND SKIN TESTING P-VALUE

YES NO YES NO

Cephalothin (1) 8/160 27/1343 +3% 2/11 2/63 +14.8%

5.0% 2.0% (+0.55%) P=.035 18% 3.2% (+0.329%) P=.20

Cephaloridine (1) 34/390 178/14,438 +7.5% 2/19

8.7% 1.2% (6.38.7%) P


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19 well-characterized patients allergic topenicillin who were studied for theirsensitivity to the cephalosporins, cephal-oridine and cefamandole (which haveidentical or very similar side chains to

penicillin and were therefore potentiallycross-reactive) only 2 (10.5%) reacted tocefamandole, while the other 17 patientstolerated both agents.26 In another studyof clinical cross-reactivity between


APPLIED EVIDENCE

T A B L E 2

7-POSITION SIDE CHAIN

COMPLETELY DISSIMILAR SIDE

SIMILAR SIDE-CHAIN CROSS-REACTIVITY CHAINS MAKE CROSS-REACTIVITY

POSSIBLE WITHIN THESE 3 GROUPS* UNLIKELY FOR THESE DRUGS

Cefoxitin (2) Cefaclor (2) Cefepime (4) Cefoperazone (3) Cefixime (3)

Cephalothin (1) Cephradine (1) Ceftizoxime (3) Cefotetan (2) Cefprozil (2)

Penicillin G Cephalexin (1) Cefpirome (4) Cefazolin (1) Cefmetazole (2)

Cefadroxil (1) Cefotaxime (3) Cefuroxime (2) Ceftibuten (3)

Amoxicillin Cefpodoxime (3) Cefdinir (3) Ceftazidime (3)

Ampicillin Ceftriaxone (3) Cefditoren (3)

3-POSITION SIDE CHAIN

DISSIMILAR

SIDE-CHAINS

MAKE CROSS-

REACTIVITY

UNLIKELY FOR

SIMILAR SIDE-CHAIN CROSS-REACTIVITY POSSIBLE WITHIN THESE 6 GROUPS THESE DRUGS

Cefadroxil (1) Cefmetazole (2) Cefotaxime (3) Ceftibuten (3) Cefuroxime (2) Cefdinir (3) Cefpodoxime (3)

Cephalexin (1) Cefoperazone (3) Cephalothin (3) Ceftizoxime (3) Cefoxitin (2) Cefixime (3) Cefprozil (2)

Cefotetan (2) Ceftibuten (3)

Ceftriaxone (3)

Cefepime (4)

Cefpirome (4)

Cefazolin (1)

Cefaclor (2)

Ceftazidime (3)

* Based on the 7-position side chain structure similarity, allergic cross-reactivity might occur among cefoxitin (second-generation

cephalosporin), cephalothin (first-generation cephalosporin), and penicillin. The same interpretation applies to the next 2 columns.

Based on the 7-position side chain structure uniqueness, allergic cross-reactivity would be highly unlikely for all of these cephalosporins with

each other and with all other cephalosporins as well as penicillins.

Based on the 3-position side chain structure similarity, allergic cross-reactivity might occur between cefadroxil (first-generation

cephalosporin) and cephalexin (first-generation cephalosporin). The same interpretation applies to the next 5 columns.

Based on the 3-position side chain structure uniqueness, allergic cross-reactivity would be highly unlikely for all these cephalosporins with

each other and with all other cephalosporins as well as penicillins.

Side-chain similarity determines cross-reactivity among cephalosporinsand between penicillins and cephalosporins

To use this Table clinically, check the antibiotic your patient is allergic to for possible cross-reactivity with other

antibiotics based on both the 7-position and 3-position side chains. Avoid drugs that share structural similarity of

either side chain position. Antibiotics that do not share similarity of either side chain are unlikely to exhibit cross-

reactivity and can be recommended.



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amoxicillin and cefadroxil in patientsallergic to amoxicillin with good toler-ance of penicillin, only 12% had an

immediate allergic reaction to cefadroxil,despite the 2 drugs sharing an identicalside chain.33 In a third study, allergeniccross-reactivity with cefadroxil andcefamandole was studied among 21patients selectively allergic to amoxi-cillin; 8 (38%) had a positive response tocefadroxil (same side chain) and none tocefamandole (different side chain).32

DiscussionSensible approach

to penicillin-allergic patientsQuestion patients who report penicillinallergy. In many cases, penicillin may notactually have been taken, or patients mayhave had non-immunologic adverse eventssuch as vomiting, diarrhea, or nonspecificrash; toxic effects; or contemporaneousside effects inappropriately attributed tothe drug. These patients can receive peni-cillin, amoxicillin, or the cephalosporins.

Without the ability to detect patientswith IgE antibody to penicillin prospective-ly or to distinguish true IgE immunologic

reactions from idiopathic reactions inpatients receiving cephalosporins, it isimpossible to definitely claim that increasedimmune or IgE-mediated reactions tocephalosporins occur in true penicillin-allergic (IgE) patients.

When a cephalosporin is/is not safe for

a penicillin-allergic patient. Only IgE-medi-ated reactionssuch as anaphylaxis orhypotension, laryngeal edema, wheezing,angioedema, or urticariaare likely tobecome more severe with time. Therefore,with a patient who has had a true IgE-medi-ated reaction to a penicillin, avoid usingcephalosporins with a similar side chain.You may, however, give cephalosporins thathave different side chains. Cephalosporinsmay also be used for patients who have hadnon-IgE-mediated adverse reactions (non-type I allergy)21 to a penicillin, such as anon-pruritic, non-urticarial morbilliform ormaculopapular rash.

How prevalent is primary cephalo-

sporin allergy? Even if the patient is notallergic to penicillin, cephalosporins can

cause allergic or immune-mediated reac-tions in approximately 1% to 3% ofpatients. A patient who had an allergic reac-tion to a specific cephalosporin probablyshould not receive that cephalosporin again.The risk of a reaction with a differentcephalosporin is very low to nonexistent ifthe side chains of the 2 drugs are dissimilar.

Bottom line. Penicillin-allergic patientshave indeed shown an increased incidenceof allergic reactions to cephalothin,cephaloridine, cephalexin, cefadroxil, cefa-zolin, and cefamandole. However, the risk

has been overestimated because most stud-ies reporting this cross-reactivity wereflawed (because penicillins were contami-nated with cephalosporins) and then failedto account for the fact that penicillin-allergicpatients have a 3-fold increased risk of aller-gic reactions even to nonrelated drugs.51

For patients truly allergic to penicillin,the risk of a reaction from a cephalosporinwith side chains that differ from peni-cillin/amoxicillin (cefuroxime, cefpo-doxime, cefdinir, and ceftriaxone, asendorsed by the AAFP) is so low that use

is justified and medico-legally defensible bythe currently available evidence.

C O N F L I C T S O F I N T E R E S T

The author reports that he has received research grants orhonoraria from Abbott Laboratories, Bristol-Myers/Squibb,Eli Lilly, GlaxoSmithKline, ID Biomedical, Johnson &Johnson, Medimmune, Sanofi Aventis, and Sanofi Pasteur.He is not an employee of, affiliated with, or has any finan-cial interest in any pharmaceutical/vaccine manufacturers.

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Help patientsreconstruct theallergic episodeto rule outnon-immunologicadverse eventsthat do notcontraindicatecephalosporins


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Even for patientstruly allergicto penicillin,the risk of areaction froma cephalosporinwith a differentside chainis quite low


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