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This article explains that cephalosporin-penicillin cross-reactivity largely depends on similarities in side-chain structures rather than the shared β-lactam core, with older data overstating risk at 5–10%. Recent studies show significant cross-reactivity only occurs when cephalosporins and penicillins share nearly identical side chains—e.g., cephalexin with ampicillin—and highlight that cephalosporins with dissimilar side chains are generally safe alternatives for penicillin-allergic patients.
Authored By: Meghan Jeffres, Pharm.D.
(@PharmerMeg on Bluesky)
Originally published June 2017, revamped July 2025
Beta-lactams are the cornerstone of antimicrobial stewardship due to their superior efficacy and safety profile.(1) Beta-lactams are less likely to cause collateral damage (e.g., C. difficile) and less likely to result in subsequent resistant infections.(2)
Over twenty years ago, it was well documented that patients with beta-lactam allergy histories are more likely to receive non-beta-lactam antibiotics leading to worse clinical outcomes.(3) Avoidance of beta-lactam antibiotics in patients with beta-lactam allergy labels is still happening.(4, 5) Some institutions and healthcare systems have taken a more progressive approach to antibiotic selection for patients with beta-lactam allergies have created and implemented rudimentary grids denoting which beta-lactams share similar chemical structures. The underpinning of this approach is based on research largely from one allergy clinic in Italy.
Romano et al have published multiple studies in the past 10 years in which they test patients with index penicillin allergies to multiple other beta-lactams.(6-11) Piecing through the data from the allergy clinic in Italy, and comparing side chains of beta-lactams, the R1 side chain was identified as the most likely shared antigen causing cross-reactivity among patients with an index natural penicillin (penicillin, amoxicillin, ampicillin) allergy. Based on the Romano data, patients with an immediate or Type I (anaphylaxis) allergy to penicillin have a 40% chance of testing positive for an allergy to other beta-lactams with the same side chain. Patients with a delayed allergy to penicillin (Type I-IV) have a 20% chance of cross-reactivity when exposed to another beta-lactam with the same R1 side chain as the natural penicillins. The r2 side chain and beta-lactam ring appear to be unimportant in terms of cross-reactivity.
In 2016, the University of Colorado Hospital implemented an “R1 side chain–based” approach to antibiotic selection for patients with beta-lactam allergy labels. The most recent version of the grid is below and in this handout.
This strategy was based on the observation that cross-reactivity among beta-lactams is largely driven by shared R1 side chains, rather than the beta-lactam ring or R2 side chain. The current grid at our institution is below. The application of this grid increased the use of beta-lactams and decreased the use of clindamycin, vancomycin, and fluoroquinolones for the past decade. The biggest success of this approach is the utilization of cefazolin for nearly all patients undergoing procedures that require surgical site infection prophylaxis.(12-14)
Other institutions that have implemented a grid have similarly demonstrated an improvement in beta-lactam prescribing for patients with beta-lactam allergies.(15) Download the side chain handout here.
Since the first side chain grid was published on this website in the original 2017 posting, more cephalosporins have been FDA-approved. Ceftobiprole and ceftaroline are newer cephalosporins unique among other cephalosporins based on activity against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.(16, 17)
Ceftaroline was approved for use in the US in 2010 and ceftobiprole was approved in 2015 for use in Europe in 2024 for use in the US. Ceftobiprole medocaril is the prodrug of ceftobiprole and ceftaroline fosamil is the prodrug of ceftaroline.(18, 19) The structures of each prodrug have dissimilar R1 side chains. After they are metabolized in the plasma to their active form, the R1 side chains differ only by an additional ethyl group on ceftaroline that is present even in inactive metabolites (ceftaroline M1).(20) (Fig 1, below) Considering the leading theory of beta-lactam cross-reactivity is that the R1 side chain is the antigenic component, it is unknown if this minor structural difference is enough to categorize ceftobiprole and ceftaroline as having dissimilar side chains.
Ceftolozane-tazobactam was approved for use in the US in 2014 and cefiderocol was approved in 2019. These cephalosporins offer expanded coverage against resistant Gram-negative pathogens, included carbapenem-resistant Enterobacteriaceae (CRE).(21-23) The R1 side chains for ceftolozane and cefiderocol are similar (Fig 2). Ceftolozane has a thiadiazole (two 2 nitrogen atoms in the 5 atom ring) compared to a thiazole ring with a the single nitrogen ring on cefiderocol, ceftazidime, and aztreonam. Similar to the slight differences between ceftobiprole and ceftaroline, it is unknown if this minor structural difference is enough to categorize ceftolozane as having a dissimilar side chain to cefiderocol, ceftazidime, and aztreonam.
Figure 1. Chemical structures of ceftolozane, cefiderocol, ceftazidime, and aztreonam. Matching R1 side chains are in pink boxes. All figures from PubChem.
While the utilization of the R1 side chain grid has been a game-changer regarding beta-lactam utilization for patients with beta-lactam allergies, there is significant work to be done. Data supporting the R1 side chain approach is largely from one patient population in Italy with an index natural penicillin allergy. There is a gap in knowledge about the cross-reactivity of cephalosporins and monobactams that share the same or similar R1 side chain and how the index allergy pathology (e.g. anaphylaxis vs delayed rash) modifies the risk of cross-reactivity. Let the research begin!
References
1. Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding β-lactams in patients with β-lactam allergies. J Allergy Clin Immunol. 2015.
2. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014;133(3):790-6.
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12. Fosnot S, Currier K, Pendell J, Jeffres MN. Comparison of immediate hypersensitivity reactions to preoperative antibiotics in patients labeled as penicillin allergic. Surgery. 2021.
13. Norvell MR, Porter M, Ricco MH, Koonce RC, Hogan CA, Basler E, et al. Cefazolin vs Second-line Antibiotics for Surgical Site Infection Prevention After Total Joint Arthroplasty Among Patients With a Beta-lactam Allergy. Open Forum Infect Dis. 2023;10(6):ofad224.
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