Testing for Cephalexin Allergy in Drug-Naïve Patients
For a patient who has never taken cephalexin, routine allergy testing is not recommended—the drug can be administered directly without prior skin testing or other precautionary measures, unless the patient has a history of anaphylaxis to another cephalosporin. 1
Direct Administration Without Testing
Patients without any prior cephalosporin allergy history can receive cephalexin by direct challenge or full therapeutic dose without any testing. 2
The American Academy of Allergy, Asthma, and Immunology explicitly states that skin testing with cephalexin has "no clear utility" in clinical practice. 1
This approach applies even to patients with unverified penicillin allergy, though cephalexin should be avoided in this population due to high cross-reactivity (see below). 1
Critical Exception: Penicillin Allergy History
If the patient has a history of anaphylactic penicillin allergy (specifically to amoxicillin or ampicillin), cephalexin should be avoided entirely without testing, as it shares an identical R1 side chain and carries a 12.9% cross-reactivity rate. 3
Cephalexin, along with cefaclor, cefadroxil, and cefprozil, are classified as aminocephalosporins that share R1 side chains with aminopenicillins (amoxicillin/ampicillin). 1, 3
The cross-reactivity rate of 16.45% (95% CI: 11.07-23.75) for aminocephalosporins in patients with proven penicillin allergy makes these high-risk options. 1
In this scenario, select an alternative cephalosporin with a dissimilar R1 side chain (such as cefazolin, ceftriaxone, or cefepime) which can be given directly without testing. 3
When Skin Testing Might Be Considered
Skin testing to cephalexin is only advisable in highly specific circumstances: 1, 2
Patients with multiple documented drug allergies (due to possibility of coexisting sensitivities to the beta-lactam ring itself). 1
Patients with significant anxiety about receiving the medication who cannot be reassured by clinical discussion. 2
Patients with a history of severe or recurrent reactions to other medications. 1
Skin Testing Protocol (If Performed)
If skin testing is deemed necessary despite limited utility, use nonirritating concentrations: 1
- Step 1 (Epicutaneous/prick test): 200 mg/mL
- Step 2 (Intradermal): 2.0 mg/mL
- Step 3 (Intradermal): 20 mg/mL
However, the negative predictive value and clinical utility of cephalexin skin testing remain poorly validated. 1, 4, 5
Common Pitfalls to Avoid
Do not perform routine skin testing in drug-naïve patients—this adds unnecessary cost, delay, and patient anxiety without clinical benefit. 1
Do not confuse "never taken cephalexin" with "penicillin-allergic"—these require completely different management algorithms. 1, 3
Do not rely on the outdated 10% cross-reactivity estimate between penicillins and cephalosporins cited in the FDA label. 6 Modern evidence shows cross-reactivity is <5% for unverified penicillin allergy and approximately 2% for confirmed allergy when using cephalosporins with dissimilar side chains. 2
Do not assume tolerance to one cephalosporin predicts tolerance to all cephalosporins—side chain-specific reactions can occur. 7
Alternative Approach for Penicillin-Allergic Patients
If cephalexin is specifically needed in a patient with anaphylactic penicillin allergy (which is generally inadvisable): 1
- Consider penicillin skin testing first to confirm the allergy
- If penicillin skin testing is negative, proceed with an oral amoxicillin challenge to delabel the penicillin allergy
- Only after successful delabeling can cephalexin be safely administered
However, the preferred strategy is simply selecting a different cephalosporin with a dissimilar R1 side chain (cefazolin, ceftriaxone, cefepime, ceftazidime, or cefpodoxime), which can be given directly without any testing. 3