The Use of Cephalosporins in Penicillin-allergic Patients

A Literature Review

James D. Campagna, MD; Michael C. Bond; Esteban Schabelman; Bryan D. Hayes

J Emerg Med. 2012;42(5):612-620.

Abstract and Introduction

Abstract

Background The practice of avoiding cephalosporin administration to penicillin-allergic patients persists despite the low rate of cross reactions between both groups of antibiotics.
Objective The purpose of this literature review is to evaluate the published evidence regarding the commonly held belief that patients with a history of an allergic reaction to penicillin have a significantly increased risk of an allergic reaction to cephalosporins.
Materials and Methods Articles were identified through a computerized search of MEDLINE from 1950 to the present using the search terms "penicillin$," "cephalosporin$," "allerg$," "hypersensitivity," and "cross-react$." All articles were reviewed, and additional sources cited in them were added to the literature review.
Results Penicillins have a cross allergy with first-generation cephalosporins (odds ratio 4.8; confidence interval 3.7–6.2) and a negligible cross allergy with second-generation cephalosporins (odds ratio 1.1; confidence interval 0.6–2.1). Laboratory and cohort studies confirm that the R1 side chain is responsible for this cross reactivity. Overall cross reactivity between penicillins and cephalosporins is lower than previously reported, though there is a strong association between amoxicillin and ampicillin with first- and second-generation cephalosporins that share a similar R1 side chain.
Conclusions Although a myth persists that approximately 10% of patients with a history of penicillin allergy will have an allergic reaction if given a cephalosporin, the overall cross-reactivity rate is approximately 1% when using first-generation cephalosporins or cephalosporins with similar R1 side chains. However, a single study reported the prevalence of cross reactivity with cefadroxil as high as 27%. For penicillin-allergic patients, the use of third- or fourth-generation cephalosporins or cephalosporins with dissimilar side chains than the offending penicillin carries a negligible risk of cross allergy.

Introduction

Classic teaching is that patients with a history of an allergy to penicillin have a 10% risk of an adverse reaction if they are given a cephalosporin.^[1–2] Early studies in the 1960s and 1970s reported cross-reactivity rates of 8–18%.^[3,4] Articles published by Petz and Dash during this period are the main source of the pervasive belief in the 10% risk theory.^[5,6] The notion that such high cross reactivity exists translates to clinical practice as the complete avoidance of cephalosporins in penicillin-allergic patients, even when a cephalosporin is indicated as first-line treatment.

When treating a penicillin-allergic patient with an infection for which a cephalosporin is first-line treatment, it is necessary to consider the risks and benefits of using a cephalosporin as well as of avoiding the drug. Avoidance may lead to administration of an antibiotic that is less effective or associated with a greater risk for development of pathogen resistance and side effects. Understanding the true risk of adverse events resulting from cephalosporin use in penicillin-allergic patients is critical to providing the highest quality of care.

In this article, we review published information on the cross reactivity of penicillin and cephalosporins to determine if classic teachings are justified.

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Next Section

Table 1. List of Articles Reviewed
Authors, Year of Publication, Reference Number	Type	Grade	Ranking
Pichichero & Casey, 2007 (2)	Meta-analysis	A	Outstanding
Anne & Reisman, 1995 (29)	Meta-analysis	A	Good
Antunez et al., 2006 (43)	Cohort	C	Adequate
Atanaskovic-Markovic et al., 2005 (44)	Cohort	C	Poor
Romano et al., 2004 (21)	Cohort	C	Adequate
Novalbos et al., 2001 (22)	Cohort	C	Good
Romano et al., 2000 (18)	Cohort	C	Adequate
Miranda et al., 1996 (17)	Cohort	C	Adequate
Audicana et al., 1994 (13)	Cohort	C	Good
Blanca et al., 1989 (14)	Cohort	C	Good
Beam & Spooner, 1984 (23)	Cohort	C	Good
Solensky et al., 2002 (24)	Cohort	C	Good
Thoburn et al., 1966 (3)	Cohort	C	Poor
Park et al., 2006 (45)	Cohort	C	Good
Daulat et al., 2004 (26)	Retro cohort	D	Poor
Goodman et al., 2001 (27)	Retro cohort	D	Adequate
Apter et al., 2006 (28)	Retro cohort	D	Adequate–Poor
Fonacier et al., 2005 (20)	Survey	D	Adequate–Poor
Solensky et al., 2000 (30)	Survey	E	Good
Arndt & Garratty, 2002 (12)	Laboratory	E	Adequate
Mauri-Hellweg et al., 1996 (16)	Laboratory	E	Adequate
Dhar & Kulkarni, 1994 (46)	Laboratory	E	Adequate
Katsutani & Shionoya, 1993 (15)	Laboratory	E	Adequate
Tsuchiya et al., 1979 (10)	Laboratory	E	Adequate
Mine et al., 1970 (9)	Laboratory	E	Adequate
Batchelor et al., 1966 (8)	Laboratory	E	Adequate–Poor
Assem & Vickers, 1974 (47)	Laboratory	E	Poor
Girard, 1968 (34)	Laboratory	E	Poor

Table 2. Literature Review Guidelines: Level of Evidence
Grade A	Randomized clinical trials or meta-analyses (multiple clinical trials) or randomized clinical trials (smaller trials) directly addressing the review issue
Grade B	Randomized clinical trials or meta-analyses (multiple clinical trials) or randomized clinical trials (smaller trials) indirectly addressing the review issue
Grade C	Prospective, controlled, non-randomized, cohort studies
Grade D	Retrospective, non-randomized, cohort or case-control studies
Grade E	Case series, animal/model scientific investigations, theoretic analyses, or case reports
Grade F	Rational conjecture, extrapolations, unreferenced opinion in literature, or common practice

Table 3. Literature Review Guidelines: Methodology
Ranking	Design Consideration Present	Methodology Consideration Present	Both Considerations Present
Outstanding	Appropriate	Appropriate	Yes, both present
Good	Appropriate	Appropriate	No (either present)
Adequate	Adequate with possible bias	Adequate	No (either present)
Poor	Limited or biased	Limited	No (either present)
Unsatisfactory	Questionable/none	Questionable/none	No (either present)

Table 4. Summary of Pertinent Articles
First Author, Year of Publication, Reference Number	Confirmed True Penicillin Allergy *	Number of Patients with Alleged or Confirmed Allergy †	Number of Reactions to a Cephalosporin	Notes
Apter, 2006 (28)	No	3920	43 (1%)	Retrospective study of 534,810 patients who received a prescription for penicillin followed by cephalosporin; 3920 reported an allergic event to penicillin, and 43 of them also reported a reaction to a cephalosporin.
Assem, 1974 (7)	Yes	24	3 (12.5%)	Twenty-four penicillin-allergic patients were challenged with cephaloridine. Three had a reaction. Penicillin and cephaloridine were obtained from the same manufacturer.
Audicana, 1994 (13)	Yes	12	0	Penicillin-allergic patients were challenged with cephalexin and ceftazidime. No reactions were noted.
Blanca, 1989 (14)	Yes	19	2 (10.5%)	Penicillin-allergic patients were challenged with cefamandole and cephaloridine. Two had a reaction to cefamandole.
Dault (26)	No	606	1 (0.16%)	Retrospective review of 23,270 hospital records. One reaction was noted in a patient with a penicillin allergy and 15 in patients who did not have a penicillin allergy.
Fonacier, 2005 (20)	No	83	7 (8.4%)	Surveys were sent to 186 patients with a history of penicillin allergy who received a cephalosporin; 83 completed the survey; 7 self-reported an allergic reaction to a cephalosporin. Four patients reacted to a first-generation and 3 to a second-generation cephalosporin. No reactions to any third-generation cephalosporins were documented.
Girard, 1968 (34)	Yes	23	2 (8.7)	Penicillin-allergic patients were challenged with cephaloridine.
Goodman, 2001 (27)	No	300	1 (0.33%)	Penicillin-allergic patients were given cefazolin for surgery.
Macy, 2002 (25)	Yes	83	7 (8.4%)	Followed a total of 249 patients (83 with confirmed penicillin allergy) over 6 years and documented the number of reactions to any antibiotic. The adverse reaction rate for those with a known penicillin allergy was 8.4%, and 4.2% for those without a known allergy. The difference was not statistically different (p = 0.31).
Miranda, 1996 (17)	Yes	21	8 (38%)	Patients were challenged with cefadroxil and cefamandole after being confirmed allergic to amoxicillin. Eight patients had a reaction to cefadroxil. No reactions to cefamandole were noted.
Novalbos, 2001 (22)	Yes	41	0	Penicillin-allergic patients were challenged with cefazolin, cefuroxime, and ceftriaxone; no reactions were noted.
Park, 2006 (45)	Yes	11	0	Trial of 999 people with a history of penicillin allergy who agreed to undergo skin testing. Fifty-three (5.3%) had a confirmed or equivocal skin test. Eleven of these patients received a β-lactam antibiotic, with no adverse reaction. Of the 946 patients who had a negative skin test, 5 (0.5%) had an adverse reaction to a β-lactam.
Romano, 2004 (21)	Yes	75/128	0	Penicillin-allergic patients were challenged with cephalothin and cefamandole. No reactions were seen in the 75 patients with negative skin tests to cephalosporins. Five patients were not challenged due to a positive skin test for a cephalosporin, and 22 refused challenge.
Sastre, 1996 (19)	Yes	16	2 (12.5%)	576 patients with a suspected history of penicillin allergy; 76 (13%) were confirmed allergic to a penicillin, and 16 were allergic specifically to amoxicillin. The 16 allergic to amoxicillin were challenged with cefadroxil; 2 had an allergic reaction.
Saxon, 1987 (38)	Yes	62	1 (1.6%)	Penicillin-allergic patients were challenged with unknown cephalosporins. One reaction was noted.
Solley, 1982 (48)	Yes	27	0	Performed penicillin skin testing on 778 patients with a history of penicillin allergy; 108 (14%) had a positive skin test. Among the 27 patients who had a positive skin test and received a cephalosporin, there were no reactions. The skin test was for penicillin, ampicillin, and methicillin.
Thoburn, 1966 (3)	Yes	11	2 (18.2%)	51 patients who were receiving cephalothin were observed; 7 patients who experienced an allergic reaction to cephalothin underwent skin testing. Three of the 7 patients had a positive skin test to cephalothin, and 2 had a positive skin test to penicillin. One patient had a positive skin test for both penicillin and cephalothin.
*Study confirmed that the patient was allergic to penicillin by either skin testing or radioallergosorbent testing, or both. †Number of patients with confirmed penicillin allergy in studies that did confirmation testing; otherwise, number of people who had reported penicillin allergy.

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The Use of Cephalosporins in Penicillin-allergic Patients

A Literature Review

Abstract and Introduction

Abstract

Introduction

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