The new cross reactivity study


Campagna, J.D., et al. “The use of cephalosporins in penicillin-allergic patients: A literature review.” J Emergency Medicine, 2012; 42:612-20.

This latest study was out of the University of Maryland Medical Center, Department of Emergency Medicine and the Department of Pharmacy, and the Department of Emergency Medicine, Howard County General Hospital, Johns Hopkins University, Baltimore, Maryland.

The results showed that the overall cross reactivity between penicillins and cephalosporins in individuals who report a penicillin allergy is approximately 1 %, and in those with a confirmed penicillin allergy, 2.5%. The authors concluded that there is limited correlation between allergy to a penicillin antibiotic and allergy to a cephalosporin antibiotic. Cross reactivity between penicillins and cephalosporins is overestimated and much lower than reported in early studies. Before the 1980s, drug companies used the Acremonium bacterium species to create both penicillins and cephalosporins. It is felt that contamination of the cephalosporins with the penicillin during this manufacturing process may be responsible for those early reports of the relatively high incidences of cross-allergic reactions. 

Another reason for the belief in a high rate of cross reactivity was the chemical similarities between penicillins and cephalosporins. The chemical structures of each contain the important beta-lactam ring with various carbon side chains attached. These side chains can be similar or vastly different, depending on the specific penicillin and cephalosporin. Similarities in those carbon side chains, according to the authors, correlate with the risk for cross reactivity. They cite studies showing that the type of side chain off the beta-lactam ring is the determining factor for the rate of cross reactivity. Amoxicillin and ampicillin have the same side chain as several first- and second-generation cephalosporins. They also cite studies that show that the highest observed cross-reactivity rate (27%) is with the first-generation cefadroxil, which has the exact same side chain as amoxicillin. Therefore, the authors caution that patients confirmed to be selectively allergic to amoxicillin or ampicillin should not be given those cephalosporins with similar side chains. These cephalosporins are as follows:

  • Cefaclor (second generation)
  • Cefadroxil (first generation)
  • Cefatrizine (first generation) (no US approval)
  • Cefprozil (second generation)
  • Cephalexin (first generation)
  • Cephradine (first generation)(no US approval)

The authors also mention that skin testing in penicillin-allergic patients cannot reliably predict an allergic response to cephalosporins. They cite published reports and data from pharmaceutical companies that skin testing may be useful in determining whether a true allergy to penicillin exists, but may not predict a cross reactivity to cephalosporins.

How the study was done

The authors performed a literature search of MEDLINE from 1950 to the present using search terms such as penicillins; cephalosporins; allergy, cross-react; hypersensitivity, immediate; and hypersensitivity, delayed.  Articles determined to be appropriate for the review, based on relevance to the clinical question, were collected. 

From 406 articles recovered, three of the study authors then selected the most relevant 55 after asking the question, “Does this article address cross reactivity of cephalosporins in patients with a penicillin allergy?” Examination of listed references from the 55 articles identified 12 additional articles, giving a total of 67. From those 67 articles, 40 were excluded as either review articles, letters to the editor, or background chemistry reports. The selected 27 articles were evaluated for their level of evidence and methodology by at least two of the authors using literature review guidelines published by the American Academy of Emergency Medicine. The study described in each article was then assigned a ranking of outstanding, good, adequate, poor, or unsatisfactory based on the level of evidence and methodology.

Key study results

  1. Two articles ranked as outstanding for appropriate design and methodology (Pichichero and Casey, 2007, and Anne and Reisman, 1995) were meta-analyses that showed that a cross allergy of penicillin with first-generation cephalosporins does exist with an estimated incidence between 1 to 10%. But the studies also showed that no cross allergy of second-generation cephalosporins with penicillin ever occurred. 
  2. An article by Novalbos, et al (2001), ranked as good, described penicillin-allergic patients that were challenged with cefazolin, cefuroxime, and ceftriaxone. No reactions were noted.
  3. An article by Audicana (1994), ranked as good, described penicillin-allergic patients that were challenged with cephalexin and ceftazidime. No reactions were noted.
  4. An article by Bianca (1989), ranked as good, described penicillin-allergic patients that were challenged with cefmandol and cephloridine. Two had a reaction to cefmandol only. 
  5. In an article by Beam and Spooner (1984), ranked as good, the authors questioned the reliability of a reported history of penicillin allergy. Only 2 of the 20 patients who gave a history of a type 1 hypersensitivity reaction to penicillin actually had a positive skin test.
  6. In an article by Solensky, et al (2002), ranked as good, the authors performed skin testing on 58 patients with a history of an IgE-mediated allergic response to penicillin. Fifty-three had a negative skin test and were then challenged with three 10-day courses of oral penicillin. Forty-six patients completed the protocol, and none had any increased risk of resensitization. Of 7 who dropped out, none was known to have experienced an allergic reaction. 
  7. An article by Park (2006), ranked as good, described a trial of 999 people with a history  of penicillin allergy who agreed to undergo skin testing. Fifty-three (5.3%) had a confirmed skin test. Eleven of those patients received a beta-lactam antibiotic, with no adverse reaction. Of the 946 patients with a negative skin test, 5 (0.5%) had an adverse reaction to a beta-lactam antibiotic.
  8. An article by Solensky, et al (2000), ranked as good, described a survey addressing physicians’ willingness to administer a cephalosporin to patients with penicillin allergy (survey response rate was 16%). For patients with a vague penicillin allergy, 58% and 59% of physician responders would choose a cephalosporin to treat a mild or moderate disease, respectively. Forty percent would choose something other than a cephalosporin. For patients with a convincing penicillin-allergy history and severe disease, the majority of  physicians would choose something other than a cephalosporin antibiotic.

Conclusions of the study

  1. Most cross reactivity between penicillins and cephalosporins stems from whether their beta-lactam side chains are chemically similar.
  2. On that reasoning, cross reactivity between penicillins and most second- and all third- and fourth-generation cephalopsorins is small.
  3. The overall cross reactivity between penicillins and cephalosporins in individuals who report a penicillin allergy is approximately 1 %, and in those with a confirmed penicillin allergy, 2.5%.
  4. If a patient has had an allergic response to penicillin, it is safe to administer a cephalosporin with a side chain different from that of penicillin, or to administer a third- or fourth-generation cephalosporin. Cefadroxil should be avoided in these patients.
  5. For patients with a questionable history of penicillin allergy, skin testing predicts a true penicillin allergy but does not reliably predict allergy to cephalosporins.

When a patient has a history of anaphylaxis to penicillin, caution should be used as cross reactivity is always possible, and patients should be monitored closely with introduction of a cephalosporin.

The authors’ recommendations to physicians on use of cephalosporins in penicillin-allergic patients are the following:

  1. When patients provide a history of penicillin allergy, further information should be obtained to determine whether an IgE-mediated response (anaphylaxis) occurred. In patients with a documented IgE-mediated response to penicillin, any third- and fourth-generation cephalosporins can be used generously. First- and second-generation cephalosporins with beta-lactam side chains similar to that of penicillin should be avoided. These include cefaclor, cefadroxil, cefatrizine, cefprozil, cephalexin and cephradine. First- and second-generation cephalosporins with different side chains can be given.
  2. Skin testing is not recommended for determining the safety of administration of cephalosporins to penicillin-allergic patients due to its unreliability.


For the reader’s reference, the following is a list of cephalosporins presently available. Cefuroxime (Ceftin tablets) is a second-generation orally available cephalosporin having a different beta-lactam side chain from penicillin and meets the criteria mentioned by the study authors of a cephalosporin that could be used in penicillin-allergic patients. The orally available third generations that also meet the criteria include: cefdinir, cefixime, cefpodoxime and ceftibuten. In general, third-generation cephalosporins are more specific to anaerobic bacteria and more expensive than second-generation agents. 

First generation:

  • Cefadroxil
  • Cefazolin  (parenteral only)
  • Cephalexin

Second generation

  • Cefaclor
  • Cefotetan  (parenteral only)
  • Cefoxitin  (parenteral only)
  • Cefprozil
  • Cefuroxime

Third generation

  • Cefdinir
  • Cefditoren
  • Cefixime
  • Cefotaxime (parenteral only)
  • Cefpodoxime
  • Ceftazidime  (parenteral only)
  • Ceftibuten
  • Ceftriaxone  ( parenteral only)

Fourth generation

  • Cefepime (parenteral only)

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