What is the cross-reactivity between oxacillin (Oxacillin) and nafcillin (Nafcillin) and cefazolin (Cefazolin) in a patient with a history of anaphylaxis to cefazolin (Cefazolin) who has tolerated Zosyn (Piperacillin/Tazobactam)?

Cross-Reactivity Between Oxacillin, Nafcillin, and Cefazolin in Patients with Cefazolin Anaphylaxis

Patients with a history of anaphylaxis to cefazolin who have tolerated Zosyn can safely receive oxacillin or nafcillin, as these penicillins have different R1 side chains from cefazolin with negligible cross-reactivity. 1, 2

Understanding Beta-Lactam Cross-Reactivity

The cross-reactivity between beta-lactam antibiotics is primarily determined by the similarity of their R1 side chains, not the shared beta-lactam ring structure. This has important implications:

• Cefazolin has a unique R1 side chain that differs from penicillins (including oxacillin and nafcillin)
• Cross-reactivity between penicillins and cefazolin is significantly lower than the outdated 10% estimate mentioned in older drug labels 3, 4
• Recent evidence shows the cross-reactivity between penicillins and cefazolin is approximately 1% 5

Clinical Significance of Zosyn Tolerance

The patient's ability to tolerate Zosyn (piperacillin/tazobactam) is clinically significant because:

• Piperacillin is a penicillin derivative with a beta-lactam ring
• Tolerance to Zosyn indicates the patient is not allergic to the beta-lactam core structure
• The anaphylaxis to cefazolin was likely due to an IgE-mediated reaction to cefazolin's unique side chain, not the beta-lactam ring 1, 6

Risk Assessment for Oxacillin and Nafcillin

The risk of cross-reactivity between cefazolin and oxacillin/nafcillin is extremely low for several reasons:

• Oxacillin and nafcillin have different R1 side chains from cefazolin
• The 2022 practice parameter update from the Journal of Allergy and Clinical Immunology indicates that cross-reactivity between cefazolin and penicillins is approximately 0.7% (95% CrI: 0.1%-1.7%) in patients with unverified penicillin allergy 1
• In patients with confirmed penicillin allergy, the reaction rate to cefazolin was only 0.8% (95% CI: 0.13%-4.1%) 1
• The patient's tolerance to Zosyn further reduces this risk

Management Algorithm

For patients with cefazolin anaphylaxis who have tolerated Zosyn:

1. First-line approach: Administer oxacillin or nafcillin without prior skin testing

   • These penicillins have different side chains from cefazolin
   • The patient's tolerance to Zosyn indicates lack of beta-lactam core allergy

2. If oxacillin/nafcillin are required urgently:

   • Administer with standard dosing
   • Monitor for 30-60 minutes after first dose
   • Have emergency medications available

3. If time permits and there is concern:

   • Consider skin testing with oxacillin or nafcillin
   • A negative skin test should be followed by a drug challenge
   • A positive skin test would suggest rare multiple beta-lactam sensitivities (<1% of cases) 6

Important Caveats

• The cross-reactivity pattern described applies to IgE-mediated reactions (like anaphylaxis)
• This recommendation does not apply to patients with history of severe delayed immunologic reactions such as Stevens-Johnson Syndrome, drug-induced liver injury, or acute interstitial nephritis 1
• In extremely rare cases (<1%), patients may have multiple beta-lactam sensitivities not predictable based on side chain structure 6

The evidence strongly supports that oxacillin and nafcillin can be safely administered to patients with cefazolin anaphylaxis who have tolerated Zosyn, as the risk of cross-reactivity is minimal due to the different R1 side chain structures.