Testing Strategies and Predictors for Evaluating Immediate and Delayed Reactions to Cephalosporins

Abstract

Background: Although 1% to 2% of the general population carries a cephalosporin allergy label (CAL), we lack validated testing strategies and predictors of true allergy.

Objective: To identify cross-reactivity patterns and predictors of skin test positive (STP) in geographically disparate patients with a CAL.

Methods: A total of 780 adult patients labeled with a CAL or penicillin allergy label (PAL) with unknown tolerance of cephalosporins identified from the Austin Hospital (Melbourne, Australia) (n = 410) and Vanderbilt University Medical Center (Nashville, TN) (n = 370) between 2014 and 2018 underwent a standardized skin testing.

Results: Of 328 patients with a CAL, 29 (8.8%) tested STP to ≥1 cephalosporin(s). There were no cefazolin or ceftriaxone STP, 0 of 452 (0%), in patients with a PAL only. Of 328 patients with a CAL, 16 (4.8%) were ampicillin STP. Eleven of 16 of these patients had an initial allergy label to cephalexin. Twenty of 29 cephalosporin STP patients demonstrated tolerance to a cephalosporin with a different R1 side chain, and 8 of 14 ampicillin STP patients demonstrated tolerance to ≥1 non-amino R1 group cephalosporin. Eleven of 13 patients STP to cefazolin were skin and ingestion challenge negative to all other penicillins and cephalosporins predicted by its distinct R1/R2 groups. Seven of 15 ceftriaxone STP patients demonstrated cross-reactivity with R1-similar cephalosporins. Time since the original reaction predicted STP testing to both penicillins, adjusted odds ratio (aOR) per year 0.93 (95% confidence interval [CI]: 0.90, 0.97), and cephalosporins, aOR per year 0.71 (95% CI: 0.56, 0.90).

Conclusions: Cephalosporin cross-reactivity is based on shared R1 groupings. Increasing time since the original reaction and the presence of a PAL with unknown cephalosporin tolerance predict a lower likelihood of cephalosporin STP.

Keywords: Allergy; Beta-lactam; Cephalosporin; Cross-reactivity; Immediate hypersensitivity; Penicillin; Skin testing.

FIGURE 1.

Flow diagram for selection of penicillin/cephalosporin testing as described in this article. The standard panel of testing included Pre Pen or DAP major determinant (Diater), minor determinant mix either Diater (Austin) or an in-house stock prepared solution of benzyl penicilloate (VUMC), ampicillin (25 mg/mL), and penicillin G (1000 and 10,000 IU/mL), cefazolin (1 mg/mL), and ceftriaxone (2.5 mg/mL) via skin prick and intradermal tests. Every skin test negative penicillin allergy was challenged with amoxicillin. Every skin test negative cephalosporin allergy was challenged with cephalexin. Additional skin test reagents and additional drugs were used to disprove side chainespecific allergies by selecting either the exact same drug as the patient’s index reaction, or a drug with the same side chain, based on availability in oral and sterile IV preparation, respectively. Note that 0 of 452 patients tested for a penicillin allergy label and unknown tolerance of cephalosporins had positive testing to cefazolin or ceftriaxone. *Concentrations for testing additional specific cephalosporins based on the R side chain structure are found in Table E1 (available in this article’s Online Repository at www.jaci-inpractice.org). IV, XXX; VUMC, Vanderbilt University Medical Center.

FIGURE 2.

Examples of side chain—specific cephalosporin skin tests, added in addition to the standard protocol in Figure 1, derived from published side chain patterns. *Concentrations for testing additional specific cephalosporins are found in Table E1 (available in this article’s Online Repository at www.jaci-inpractice.org). ⁺Challenges using the same R1 side chain should be considered when index reactions are of low-moderate severity when skin testing is negative, or when the patient has a specific clinical need for the implicated drug or same R1 side-chain drugs. Note: there are currently no oral drugs containing the ceftazidime/aztreonam R1.

FIGURE 3.

Flow diagram outlining cephalosporin testing results in patients with penicillin and cephalosporin allergy histories. *Patients with penicillin allergy label were tested with cefazolin and ceftriaxone only.

FIGURE 4.

Outcomes of immediate and delayed cephalosporin testing in this cohort. For individual-level data on labels, testing, and outcomes, please see Tables E2 and E5 (available in this article’s Online Repository at www.jaci-inpractice.org).

FIGURE 5.

Probability of obtaining positive immediate hypersensitivity skin testing in patients with an immediate reaction history (penicillins in the top panel, cephalosporins in the bottom panel). Predicted probabilities obtained via multivariable logistic regression modeling with adjustment for age, sex, race, and site.