Introduction

  • Fewer than 5% of people who say they are penicillin allergic are truly allergic (Copaescu 2023; Shenoy 2019).
  • True IgE-mediated penicillin allergies that cause anaphylaxis are rare.
  • An IgE-mediated penicillin allergy can diminish over time — about 80% of patients become tolerant after a decade.
  • Patients with a documented penicillin allergy may be inappropriately exposed to alternative antibiotics, resulting in increased treatment failures, adverse effects, and antimicrobial resistance.
  • Penicillins, cephalosporins, and carbapenems all share a beta-lactam core, raising the potential for cross-reactivity among these agents.

Pharmacology

Beta-lactam core structures (penicillin, cephalosporin, carbapenem, monobactam) showing R-group side-chain positions
  • The drugs within each group below may cross-react with each other because they share similar side chains.
  • Cross-reactivity between penicillins and cephalosporins is about 2% (Shenoy 2019), and about 1% for later-generation cephalosporins (Challen 2026).
  • Cefazolin is NOT likely to cross-react with penicillin (its R1 side chain is not similar to that of any current FDA-approved beta-lactam; Chaudhry 2019). For patients with a history of anaphylaxis to a penicillin, the 2022 drug allergy practice parameter suggests that a cephalosporin with a structurally dissimilar R1 side chain can be given without testing or additional precautions (Khan 2022, statement 12; conditional recommendation, moderate certainty), and its executive summary names cefazolin as an example.
  • Cross-reactivity between penicillins and monobactams (e.g., aztreonam) is very low (Gaeta 2015; Wurpts 2020). Aztreonam and ceftazidime share an identical side chain, so use caution between those two. The 2022 practice parameter suggests aztreonam may be given without prior testing to patients with a penicillin or cephalosporin allergy unless there is a history of ceftazidime allergy (Khan 2022, statement 18; conditional recommendation, moderate certainty).
  • Cross-reactivity between penicillins and carbapenems is <1%. The 2022 practice parameter suggests a carbapenem may be given without testing or additional precautions to patients with a penicillin or cephalosporin allergy (Khan 2022, statement 17; conditional recommendation, moderate certainty).
Group 1Group 2Group 3Group 4
Penicillin
Cefoxitin		Amoxicillin
Ampicillin
Cefaclor
Cephalexin
Cefadroxil		Ceftriaxone
Cefotaxime
Cefuroxime
Cefepime
Cefpodoxime
Ceftaroline
Ceftolozane		Aztreonam
Ceftazidime

These groupings reflect structural side-chain similarity (Chaudhry 2019; Wurpts 2020), a theoretical predictor of risk. Observed clinical cross-reactivity is low (about 1 to 2%; Shenoy 2019; Campagna 2012), and documented tolerance can override the chart: cefuroxime, for example, is listed here by side-chain similarity but was tolerated in challenges with cefuroxime axetil and ceftriaxone by all 244 penicillin-allergic patients who had negative cephalosporin skin tests in Romano 2018.

Evidence

Author, yearDesignIntervention & comparisonOutcome
Mechanism — why cross-reactivity?
Nagakura, 1991 & Mayorga, 1995Laboratory (monoclonal antibody) studiesMonoclonal antibodies raised against ampicillin (Nagakura) and amoxicillin (Mayorga) protein conjugatesMayorga: 92% of the antibodies recognized an epitope in which the side chain was a major constituent. Nagakura: one antibody bound the ring and cross-reacted widely; the other bound the side chain and cross-reacted only with drugs sharing it (ampicillin, cephalexin). The side chain is a major target of the antibody response
Cephalosporin cross-reactivity
Goodman, 2001Retrospective review (n = 2933)Orthopedic patients; 413 were penicillin allergic and most (300, per Chaudhry 2019) received a cephalosporin, usually cefazolin, during the procedureOnly 1 patient may have had a reaction (about 0.3%, 1 of 300); patients with severe or anaphylactic histories were probably excluded
Daulat, 2004Retrospective review (n = 606)Penicillin-allergic patients receiving cephalosporinsOnly 1 reaction in 606 patients (about 0.2%, as tabulated in Michaud 2023)
Apter, 2006Retrospective cohort (UK primary care database; 3,375,162 penicillin recipients, 506,679 later given a cephalosporin)Penicillin prescription followed by a cephalosporin prescription; allergic-like events within 30 daysAbsolute risk of anaphylaxis after a cephalosporin was less than 0.001%. A prior allergic-like event after penicillin raised the risk of an event after a cephalosporin (risk ratio 10.1) and after a sulfonamide antibiotic (7.2), so cross-reactivity does not fully explain it
Romano, 2018Prospective study (n = 252)IgE-mediated penicillin hypersensitivity: cefaclor specific-IgE assay + skin tests to 9 cephalosporins; challenges if skin tests negative99 (39.3%) had positive cephalosporin tests, mostly to agents sharing side chains with penicillins; all 244 challenged (negative skin tests) tolerated cefuroxime axetil and ceftriaxone; 7 reacted to cefaclor or cefadroxil
Carbapenem cross-reactivity
Romano, 2006Prospective study (n = 112)Penicillin skin-test-positive patients skin tested to imipenemOnly 1 positive imipenem skin test (cross-reactivity 0.9%)
Romano, 2007Prospective study (n = 104)Penicillin skin-test-positive patients skin tested to meropenem; if negative, escalating-dose challengeOnly 1 positive meropenem skin test (cross-reactivity 0.9%); all 103 skin-test-negative patients tolerated the challenge
Atanaskovic-Markovic, 2008Prospective study in children (n = 108)Children with penicillin allergy skin tested to penicillin and meropenem; if negative, challengeOnly 1 positive meropenem skin test (cross-reactivity 0.9%); all 107 skin-test-negative children tolerated the challenge
Recent evidence (2020–2026) — risk-stratification & de-labeling
Trubiano, 2020 (PEN-FAST)Derivation & validation cohorts (622 derivation and internal validation; 945 external validation)Clinical decision rule to risk-stratify reported penicillin allergyA PEN-FAST score <3 = low risk; only 17 of 460 low-risk patients (3.7%) had a positive allergy test (negative predictive value 96.3%) — supports challenge without prior skin testing
Khan, 2022 (Practice Parameter)Practice parameter (consensus-based statements)2022 drug allergy practice parameter update; only statements 4, 8, 9, 12, 17 and 18 are cited on this pageStrong recommendations (moderate certainty): make a proactive effort to delabel penicillin allergy (statement 4); do not skin test before a direct amoxicillin challenge in children with a benign cutaneous reaction (statement 8). Conditional (low certainty): consider direct amoxicillin challenge in adults whose benign cutaneous reaction was more than 5 years ago (statement 9). Conditional (moderate certainty): a structurally dissimilar R1 cephalosporin after penicillin anaphylaxis (statement 12), a carbapenem (statement 17), or aztreonam unless ceftazidime allergy (statement 18), each without testing
Copaescu, 2023 (PALACE)Randomized noninferiority trial (n = 377)Direct oral penicillin challenge vs. skin testing followed by oral challenge in low-risk penicillin allergyPositive reactions 0.5% (1/187) with direct oral challenge vs. 0.5% (1/190) with skin-test-first — direct oral challenge was noninferior
He, 2026Systematic review (18 guidelines, 2014 to 2024)Compared the scope and recommendations of penicillin allergy de-labeling guidelines and rated their quality (AGREE II)Many supported direct de-labeling or direct challenge in low-risk patients, but risk tools and eligibility rules differed and only 2 of 18 guidelines were high quality
Kosztulska, 2026Systematic reviewBasophil activation test and specific IgE for suspected immediate penicillin allergyBoth have limited sensitivity and specificity, and no clear guideline says where they fit; drug provocation testing remains the gold standard
Zimmer, 2026Retrospective pre-post study (n = 235)Patients with intermediate-, high-, or severe-risk penicillin allergy labels, before vs. after a penicillin-cephalosporin cross-reactivity alert was removed from the electronic health recordCephalosporin use rose from 27% to 67% (P < 0.001); no patient had an allergic reaction to a cephalosporin

Conclusions

  • True penicillin allergies are less common than reported, and anaphylaxis is uncommon.
  • Cross-reactivity among penicillins and cephalosporins is attributed to similarity in side chains.
  • Cephalosporin cross-reactivity with penicillins is much lower than reported in early studies, partly because early cephalosporin preparations were most likely contaminated with a small amount of penicillin (Wurpts 2020).
  • Cross-reactivity between penicillins and cephalosporins is about 2%, and with carbapenems is <1%.
  • These cross-reactivity rates have not materially changed; what has shifted is practice toward penicillin-allergy de-labeling. Validated risk-stratification (PEN-FAST, 2020) identifies low-risk patients in whom direct oral penicillin challenge without prior skin testing was safe and noninferior to skin testing first in a randomized trial (PALACE RCT 2023). Guidelines still differ on who qualifies, so follow your site's protocol (He 2026).
  • The 2022 drug allergy practice parameter recommends a proactive effort to delabel patients with a reported penicillin allergy, if appropriate (Khan 2022, statement 4; strong recommendation, moderate certainty).
  • For direct amoxicillin challenge, the 2022 practice parameter recommends against penicillin skin testing first in children with a benign cutaneous reaction (statement 8; strong recommendation, moderate certainty). In adults it suggests considering a direct amoxicillin challenge only when the reaction was benign, cutaneous, and more than 5 years ago (statement 9; conditional recommendation, low certainty).
  • For low-risk patients, de-labeling often makes cross-reactivity calculations unnecessary. When a true penicillin allergy is confirmed, selecting a cephalosporin or carbapenem with a dissimilar side chain (e.g., cefazolin) keeps cross-reactivity low.

References

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