Composite Quantum Chemistry Calculations of Spin Traps and Reaction Products

We are reporting an exceptional case of angioedema shortly after initiation of Piperacillin/Tazobactam and Vancomycin therapy. A 62 y old male with history of chronic polymicrobial right diabetic foot ulcer, previously treated with Amoxicillin-Clavulinic acid, presented for increased swelling, pain and erythema of his right foot. He had no known drug allergy. Physical examination was unremarkable except for well demarcated 3ˣ3 cm ulcer at the base of the right great toe. He had leukocytosis at 13500 with 82% neutrophils. Foot X-ray was consistent with osteomyelitis. Piperacillin/Tazobactam and Vancomycin were started. He received first dose of the former at 1 PM and second dose at 7 PM. The latter was given at 2:30 PM and later at 2:30 AM. At 3:30 AM, the patient started developing right sided tongue swelling in the absence of dyspnea, lip swelling, rash or hypotension. The swelling rapidly progressed to involve the entire tongue. He was transferred to intensive care unit and was given epinephrine and dexamethasone. Antibiotics were stopped and the angioedema resolved the next day. C4 level along with C1 inhibitor level and activity were normal. Two different types of angioedema must be distinguished: mast cell-mediated angioedema and Bradykinin-mediated angioedema. The latter is isolated and not associated with urticaria. It’s divided into two categories: angioedema associated with C1 inhibitor deficiency and angioedema with normal C1 inhibitor. The first category includes hereditary angioedema type 1 and 2 and acquired angioedema. The second category includes hereditary angioedema with normal C1 inhibitor formerly designed as type 3 along with idiopathic and drug induced angioedema. Our patient had localized angioedema of the tongue with secondary rapidly progressive macroglossia. His angioedema was believed to be Bradykinin-mediated since it was isolated. The initial screening test is C4. Since the clinical suspicion was high, we ordered C1 inhibitor level and activity too because C4 was reported to be normal in some cases of Bradykinin-mediated angioedema. C4 level as well as C1 inhibitor level and activity were normal. Those results narrowed the differential to hereditary angioedema with normal C1 inhibitor, idiopathic angioedema and drug induced angioedema. Our patient didn’t meet the diagnostic criteria of hereditary angioedema with normal C1 inhibitor as depicted by Zuraw in 2012. In addition, the definition of idiopathic angioedema which consists of 3 or more episodes of edema over 6-12 months with no clear cause was not met. Thus, we believe that our patient had drug induced Bradykinin angioedema. The most important intervention is the immediate discontinuation of the offensive drug. In most cases, the symptoms will subside within 2-5 days. Although corticosteroids, epinephrine and antihistamines are usually given in such cases, their efficacy remains minimal or absent. The adverse reactions witnessed in this case can be related either to Piperacillin/Tazobactam or Vancomycin. In either case, it would be an exceptional reaction since cases of beta lactams induced angioedema believed to be Bradykinin-mediated are very few and Vancomycin induced Bradykinin mediated angioedema was not yet reported to the best of our knowledge.