What is the recommended test dose for piperacillin (antibiotic)/tazobactam (beta-lactamase inhibitor) in patients with a history of allergies to penicillins (beta-lactam antibiotics)?

Recommended Test Dose for Piperacillin-Tazobactam in Patients with Penicillin Allergies

For patients with a history of penicillin allergies, skin testing with a nonirritating concentration of piperacillin-tazobactam should be performed, although the ideal skin testing concentration has not been firmly established. 1

Skin Testing Protocol for Piperacillin-Tazobactam

Initial Assessment

• Evaluate the nature and severity of the previous penicillin reaction, as this will guide testing approach 1
• Recent or severe reactions may require more cautious testing approaches 1

Skin Testing Procedure

• Begin with skin prick testing followed by intradermal testing if prick test is negative 1
• Use appropriate controls:
  • Positive control: histamine
  • Negative control: saline 1

Recommended Testing Concentrations

• For piperacillin-tazobactam specifically:
  • First perform skin testing with penicillin major and minor determinants:
    • Major determinant: PPL (Pre-Pen) at 6 × 10⁻⁵ mol/L
    • Minor determinant: penicillin G at 10,000 units/mL 1
  • If these are negative, proceed with piperacillin-tazobactam skin testing 1
  • While the ideal concentration is not firmly established, testing should be done with a nonirritating concentration 1

Interpretation of Results

• A positive test is defined by a wheal that is ≥3 mm larger than the negative control with a ≥5 mm flare 1
• Penicillin skin testing is safe with <2% of skin test-positive patients experiencing systemic reactions 1

Challenge Testing After Negative Skin Tests

• Following negative skin test results, an elective challenge with piperacillin-tazobactam is recommended 1
• The challenge is typically completed in 1 step, but a 2-step challenge may be considered if the reaction history is severe and/or recent 1
• For patients with negative skin tests, approximately 1.7% may still have adverse reactions to beta-lactams 2
• One study reported a patient who developed flushing and urticaria 3 hours after a test dose of piperacillin-tazobactam despite negative skin testing 2

Important Clinical Considerations

• Piperacillin-tazobactam may be an exception to usual penicillin allergies:
  • Up to 32.4% of patients with suspected piperacillin-tazobactam allergy may have a true allergy 3
  • The negative predictive value of skin testing for piperacillin-tazobactam may be lower (71.9%) than for other penicillins (>95%) 3
• Cross-reactivity between penicillins and other beta-lactams is generally low, but selective sensitization to piperacillin-tazobactam can occur 4
• Some patients may be allergic to the tazobactam component (beta-lactamase inhibitor) rather than the piperacillin component 4

Pitfalls and Caveats

• Skin testing should only be performed by personnel trained and skilled in the application and interpretation of this type of testing, with preparedness to treat rare anaphylaxis 1
• Penicillin skin testing should not be performed on patients with histories of severe non-IgE-mediated allergic reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis 1
• The negative predictive value of penicillin skin testing is generally >95%, but may be lower specifically for piperacillin-tazobactam 1, 3
• Drug provocation testing remains the gold standard for accurate diagnosis of piperacillin-tazobactam allergy 3