A Case of Angioedema to Oral Doxycycline and Cross-Reactivity to Minocycline

To the Editor,

Doxycycline and minocycline are second-generation tetracycline antibiotics with similar chemical structures and a comparable antibacterial spectrum. ¹ Although cross-reactivity in patients with tetracycline-induced fixed drug eruptions has been reported, no studies have reported cross-reactivity to immediate hypersensitivity reactions between doxycycline and minocycline.^2,3 Herein, we report a case of angioedema after minocycline treatment in a patient with previous doxycycline-induced angioedema.

A 28-year-old woman presented to a local gynecology clinic with pelvic pain. The physician thought that pelvic inflammatory disease was the cause of the symptoms, and the patient was prescribed oral doxycycline (100 mg) twice daily. Thirty minutes after the initial doxycycline administration, she developed angioedema of the upper lip. She discontinued doxycycline and used antihistamine agents (levocetirizine, 10 mg) to relieve the symptoms. To identify the drug that caused the allergic reaction and get advice on alternative treatment of pelvic inflammatory disease, she visited our allergy clinic.

To clarify the agent that caused drug-induced angioedema and determine whether minocycline could cause cross-reactivity, we conducted the following tests: skin tests and graded oral challenge based on previously described procedures in the literature. ⁴ Skin prick tests with doxycycline (10 mg/mL) and minocycline (0.2 mg/mL) revealed negative results (Figure 1a). The intradermal tests with doxycycline at 0.0001, 0.001, and 0.01 mg/mL and minocycline at 0.0002, 0.002, and 0.02 mg/mL also showed negative results (Figure 1b). We conducted a drug challenge to identify the suspected drug reaction to doxycycline. No symptoms were observed after administering 10 mg of doxycycline. Twenty minutes after administering 30 mg of doxycycline, she developed numbness and angioedema of the lips (Figure 1c). Therefore, we discontinued the drug challenge and concluded that doxycycline was the cause of the hypersensitivity reaction. This case could be diagnosed with doxycycline-induced angioedema based on the drug challenge test and the Naranjo Adverse Drug Reaction Probability scale (score: 7, probable). ⁵

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Figure 1.

(a) Skin prick test for doxycycline and minocycline. (b) Intradermal test for doxycycline and minocycline. (c) Lip swelling during the doxycycline challenge test. (d) Lip swelling during the minocycline challenge test.

A drug challenge with minocycline was also performed to check cross-reactivity, and 30 minutes after minocycline (10 mg) administration, she developed angioedema of the eyelid (Figure 1d). We stopped the test and concluded that minocycline could be a cross-reacting drug in patients with doxycycline-induced angioedema. Based on the initial negative skin test, the drug-induced angioedema may have been a non-immunoglobulin E (IgE) hypersensitivity reaction.

Doxycycline is the most tolerable agent within the tetracycline analogs. ² This is supported by several studies describing doxycycline hypersensitivity, with fewer adverse effects compared with those of other tetracycline classes.^2,6 Compared with delayed drug hypersensitivity reactions, immediate drug hypersensitivity reactions have rarely been reported.^2,4,6 Physicians should be aware that angioedema may occur as an immediate hypersensitivity reaction to doxycycline.

Drug-induced edema is associated with allergic and nonallergic reactions. ⁷ In patients with drug-induced angioedema, a skin test could be the first diagnostic test for drugs with unknown mechanisms of action. If the skin test result was negative, a drug challenge to confirm the causative agent would have been beneficial. Drug-induced angioedema through a non-IgE mechanism might be associated with direct mast cell degranulation and kinin dependent. ⁷

The rate of cross-reactivity between minocycline and doxycycline has not been established, and studies on the cross-reactivity are lacking.^2,4 To the best of our knowledge, this is the first report of angioedema after minocycline treatment in a patient with documented doxycycline-induced angioedema. Clinicians must be aware of the potential cross-reactivity when prescribing these tetracycline analogs, which are widely used in the treatment of various infectious diseases such as pelvic inflammatory disease, pneumonia, and skin and soft-tissue infections.

Jieun Yu, MD Da Woon Sim, MD, PhDDepartment of Allergy and Clinical Immunology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, South Korea