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Frequently Asked Questions

What is the cross-reactivity of cephalosporins and carbapenems in a patient with a penicillin allergy?

Cephalosporins and carbapenems are antimicrobials that have a broad spectrum of activity against gram-positive and gram-negative bacteria.1 Cephalosporins and carbapenems are utilized for the treatment of a variety of common infections. A documented allergy to penicillin automatically flags a patient against the use of a cephalosporin or carbapenem, which can limit therapeutic options for treatment of infection. It is important to appropriately evaluate a patient’s allergy to medication since this can aid in the assessment of whether or not to use a related medication for treatment.2

Many patients will report an allergy to a medication, but in fact the reaction is more likely due to intolerance to the medication, not a true allergy.2 Allergies to penicillin are frequently documented, but the reaction is rarely documented. This is an important piece of information that is useful in determining whether or not a patient is eligible to receive other antimicrobial therapies. Allergic reactions are classified into 4 different types, as listed in Table 1.2-4 Each type of allergic reaction has a different causative antibody, clinical manifestation and onset. The type I allergy, also known as anaphylactic or immediate hypersensitivity, is mediated by IgE antibodies, occurs within 60 minutes of administration, causing symptoms from urticaria to bronchoconstriction to circulatory collapse. This is the most serious type of allergic reaction due to the potential severity of reactions.

Table 1. Gell and Combs Allergy Classification.2-4

Type of Allergic Reaction 2-4

Antibody Class

Onset

Clinical Manifestation

Type I

(anaphylaxis)

IgE

Within 60 min

Bronchoconstriction, hypotension, circulatory collapse, urticaria

Type II

(cytotoxic)

IgG, IgM

5-12 hrs

Thrombocytopenia, hemolytic anemia, granulocytopenia

Type III

(immune complex)

IgG, IgM

3-8 hrs

Glomerulonephritis, serum sickness, drug fever

Type IV

(cell-mediated)

None known

24-48 hrs

Contact dermatitis, graft rejection

Cephalosporins are semi-synthetic beta-lactam antibiotics, with similarities to penicillin in structure and spectrum of activity.3 There are currently 4 generations of cephalosporins which have activity against both gram positive and gram-negative bacteria; more gram-negative coverage with the increase in generation. Cephalosporins are beta-lactam antibiotics and contain a beta-lactam ring. One of the structural differences between penicillins and cephalosporins is the type of ring the beta-lactam ring is fused to. Penicillins have a beta-lactam ring fused to a 5-membered thiazolidine ring, whereas cephalosporins are fused to a 6-membered dihydrothiazine ring. Another structural difference between penicillins and cephalosporins is in the side chains on the base structure. Penicillins have only 1 side chain located on position 6, whereas cephalosporins have 2 side chains located on positions 7 and 3. These side chains determine activity and pharmacokinetic parameters within the drug class.

Carbapenems are beta-lactam antibiotics also structurally similar to penicillins but with a spectrum of activity that is one of the broadest amongst antimicrobial agents.3,4 Carbapenems have a beta-lactam ring fused with a 5-membered ring, similar to penicillin, but the main difference in the 5-membered ring structure is the sulfur atom at position 1 is replaced by a carbon atom in the carbapenem ring.

Literature Review

Literature has reported that penicillin allergy occurs in up to 20% of patients.5,6 Older literature reported that cephalosporins had a cross-reactivity rate of about 7-18%; however this is thought to be falsely elevated due to a non-allergic adverse drug reaction (ADR) being documented as an allergy.3,7,8 The studies were also open-label, not single or double-blinded. Also it is thought that cephalosporins may have been contaminated with penicillin product during manufacturing, which may be cause for elevated allergy rates historically.3,6 Studies that evaluate the cross-reactivity of cephalosporins in subjects with confirmed penicillin allergies via skin testing are considered to be more reliable.5 In more recent studies that enrolled patients who were penicillin-allergic documented by skin testing the rates of cross-reactivity were approximately 2%.

The mechanism behind cross-reactivity of cephalosporins with penicillin is thought to have more to do with the similarity between the side chains rather than the beta-lactam ring structure.9 Studies have shown that drugs with similar side chains will have a higher likelihood of cross-reactivity than those with structurally different side chains.10 First generation cephalosporins have similar side chain structures with penicillin, hence in increase incidence of cross-reactivity.6 Whereas second and third generation cephalosporins have a higher variability within the side chain structures, decreasing the probability of cross-reactivity with penicillins. Figure 1 documents the similar side chains between various penicillins and cephalosporins. This mechanism of side-chain comparison can be used to evaluate antimicrobial management of a truly penicillin allergic patient. For example, if a patient has a documented allergy to amoxicillin, there would be a higher potential for cross-reactivity with cephalexin than with cefepime.

Figure 1. Penicillin-cephalosporin side chain similarities.3

Amoxicillin Ampicillin Cefadroxil Cephalexin Cefotetan Cefoxitin Cefuroxime Cefdinir Cefixime Cefotaxime Ceftazidime Ceftriaxone Cefepime
Amoxicillin X X X                  
Ampicillin X X X                  
Cefadroxil X X X                  
Cephalexin X X X                  
Cefotetan                        
Cefoxitin           X            
Cefuroxime           X            
Cefdinir               X        
Cefixime               X        
Cefotaxime                     X X
Ceftazidime                        
Ceftriaxone                   X   X
Cefepime                   X   X
Any “X” in a column represents similarity between side-chains.

Carbapenem cross-reactivity has been documented to have a wide range of incidence from 1-50%.4,6 Like the data with cephalosporins, early studies evaluating carbapenem cross reactivity were poorly designed. More recently, well-designed trials indicate a cross-reactivity of ~1%.4

Table 2. Carbapenem Cross-reactivity Studies.4

Trial

PCN allergic/Total patients (%)

PCN allergy verification

Carbapenem allergy verification

Results of cross-sensitivity (%)

Romano (2006)

112/112 (100)

Skin testing

Skin test, IM challenge

1/112 (0.9%) in skin test- positive patients

Romano (2007)

104/104 (100)

Skin testing

Skin test, IV challenge

1/104 (1%; CI 0.02-5.2%) in skin test-positive patients

Atanaskovic-Markovic (2008)

108/128 (84)

Skin testing

Skin test, IV challenge

1/108 (0.9) in skin test- positive patients

IM=intramuscular; IV=intravenous

Conclusions

Based on the information available in the current literature, the cross-reactivity between penicillin, cephalosporins, and carbapenems tends to be less than older literature suggests. The cross-reactivity between cephalosporins and penicillin appears to be dependent on the side-chains of the antibiotics with a general rule being the higher you go up in generation of cephalosporin, the lower the incidence of cross-reactivity. Overall, the incidence of cross-reactivity with cephalosporins is ~1%, but the incidence may be higher with the first and second-generation cephalosporins. With carbapenems, the latest data suggest the incidence of cross-reactivity with penicillins is about 1% as well.

For patients with a non-type I allergy, the use of cephalosporins or carbapenems has less potential for harm. For patients with true type I allergic reactions to penicillin, cephalosporins with dissimilar side chains, typically in the newer generations, appear to have a low probability of allergic reaction. Carbapenem use in a true type-I allergy is cautioned, but still has a low probability of allergic reaction. With any challenge of a new agent in a patient with a historical allergy, caution and frequent monitoring should be utilized and documented appropriately.

References

  1. Petri WJ. Penicillins, Cephalosporins and Other β-Lactam Antibiotics. In: Brunton LL, Parker KL, eds. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006:728-750.
  2. Golembiewski J. Allergic Reactions to Drugs: Implications for Perioperative Care. J Perianesth Nurs. 2002;17(6):393-398.
  3. DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc. 2008;48(4):530-540.
  4. Frumin J, Gallagher JC. Allergic Cross-Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the Chances? Ann Pharmacother. 2009;43(2):304-315.
  5. Solensky R. Use of cephalosporins, carbapenems, and monobactams in penicillin allergic patients. Up-To-Date. http://www.uptodate.com/online/content/topic.do?topicKey=drugalle/9961&selectedTitle=1~150&source=search_result. October 15, 2009. Accessed February 8, 2009.
  6. Weiss ME, Adkinson NF. Β-lactam allergy. In: Mandell GL, Bennett JE, Dolin R. Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Maryland Heights, MO: Churchill Livingstone; 2009:347-354.
  7. Kelkar PS, Li JT. Cephalosporin allergy. N Eng J Med. 2001;345(11):804-809.
  8. Robinson JL, Hameed T, Carr S. Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic. Clin Infect Dis. 2002;35(1):26-31.
  9. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115(4):1048-1057.
  10. Mayorga C, Obispo T, Jimena L, et al. Epitope mapping of betalactam antibiotics with the use of monoclonal antibodies. Toxicology. 1995;97(1-3):225–234.

By: Megan Prasse, PharmD