What are the considerations for using sulfonamides (sulfa) in patients with a known allergy to penicillin, given the potential for cross-reactivity?

From the Guidelines

Sulfonamide antibiotics can generally be safely used in patients with penicillin allergies as true cross-reactivity between these drug classes is rare, with a risk of cross-reactivity approximately 1-3% 1. When considering the use of sulfonamides in patients with a known allergy to penicillin, it is essential to take a detailed allergy history, including the nature and severity of the penicillin reaction.

• The chemical structures and allergic mechanisms of penicillins and sulfonamides are different, with penicillin allergies involving the beta-lactam ring structure and sulfonamide antibiotic reactions typically involving the N1 substituent on the sulfonamide group.
• Caution is still warranted in patients with severe or multiple drug allergies, as they may have a higher predisposition to developing allergic reactions to any medication.
• For patients with severe or anaphylactic penicillin allergies, consider starting with a lower dose or using more cautious monitoring during initial administration. The decision to use sulfonamides should be based on the clinical indication, severity of the patient's previous allergic reactions, and availability of alternative agents, as suggested by the Dutch Working Party on Antibiotic Policy guideline for the approach to suspected antibiotic allergy 1.
• This guideline recommends a more liberal approach towards patients with a suspected antibiotic allergy, as systematic literature review confirmed that far <10% of patients that report an antibiotic allergy is truly allergic, and that the risk of cross-reactivity is smaller than previously assumed.
• The guideline also emphasizes the importance of prudent decision-making regarding reported antibiotic allergy and antibiotic use, as an important component of antibiotic stewardship 1. It is also worth noting that sulfonamide non-antimicrobials, such as alpha-blockers, antiarrhythmics, and anticonvulsants, have no or weak evidence of cross-reactivity in patients with a history of a sulfonamide antimicrobial adverse reaction, as outlined in the 2022 practice parameter update on drug allergy 1.

From the FDA Drug Label

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents

There is no direct information in the provided drug labels about cross-reactivity between penicillin and sulfonamides. The mention of cross-sensitivity is in relation to other types of drugs, not penicillin. No conclusion can be drawn about the considerations for using sulfonamides in patients with a known allergy to penicillin based on the provided information 2.

From the Research

Considerations for Using Sulfonamides in Patients with a Known Allergy to Penicillin

• The potential for cross-reactivity between penicillin and sulfonamides is a concern when considering the use of sulfonamides in patients with a known allergy to penicillin 3.
• However, cross-reactivity is unlikely between sulfonamide antimicrobials and sulfonamide non-antimicrobials, and there is no evidence to suggest that sulfonamide antimicrobials and other sulfonamide non-antimicrobials would cross-react in patients who develop reactions to a sulfonamide non-antimicrobial 3.
• Patients with a known allergy to penicillin may still be able to tolerate sulfonamides, and drug challenges can be a useful tool for determining tolerance 3.
• The role of sulfamethoxazole desensitization is controversial, as rates of hypersensitivity reactions are similar between desensitization and drug challenge 3.

Evaluation of Penicillin Allergy

• Evaluation of penicillin allergy is an important tool for antimicrobial stewardship, as many patients report allergies to penicillin that may not be clinically significant 4, 5.
• Penicillin skin testing and amoxicillin challenge can be used to evaluate patients with a reported penicillin allergy, and can help to identify patients who are not truly allergic 4, 5.
• Patients with a low-risk history of penicillin allergy can be evaluated with a direct amoxicillin challenge, while patients with a moderate-risk history may require penicillin skin testing 4.

Management of Penicillin Allergy

• Management of penicillin allergy depends on the type of reaction and the clinical setting, and may include penicillin discontinuation, epinephrine, antihistamines, and/or glucocorticoids 6.
• Desensitization may be used in some cases where treatment with penicillins is essential, but this should be done with caution and under close medical supervision 6.
• Most beta-lactams may be safely used in penicillin-allergic patients, with the possible exception of first-generation and second-generation cephalosporins 6.