A fixed drug eruption (FDE) is a condition characterized by recurrent erythematous skin patches arising in the same location in response to drug ingestion. More than 100 drugs, including doxycycline and erythromycin, have been implicated in causing FDEs,1 and the causative agent can be difficult to identify, particularly when the patient denies ingesting any medications. In such scenarios, there are two possibilities: either the causative agent is not a drug or the drug was contained in alternative vehicles such as food. Some FDEs resulting from food intake have been reported; the foods involved include liquorice, Japanese sand lance, and cashew nuts.2-4 However, FDEs caused by antibiotics contained in food have not been reported. We describe a patient who experienced an FDE due to doxycycline and erythromycin that occurred after ingestion of pork and/or fish.

A 57-year-old female patient visited our clinic with a 12-year history of repeated outbreaks of well-demarcated erythematous patches with hyperpigmentation over the entire body. She had no history of allergic disease or chronic medical illness. She denied taking any medication before the lesion first developed or before the recurrences. The lesions developed every 2 or 3 months, at the same sites, when she ate pork or fish. She had therefore followed a nearly vegetarian diet for more than 10 years.

Patch tests were performed using acetaminophen, the nonsteroidal anti-inflammatory drug ibuprofen, and antibiotics, including cephalosporins, amoxicillin, sultamicillin, trimethoprim-sulfamethoxazole, gentamicin, neomycin, rifampin, doxycycline, and erythromycin. There were no definite reactions to these patch tests. Oral provocation tests with the same medications were then performed. When the patient ingested 10 mg of doxycycline as a single dose, she experienced an erythematous change on an existing pigmented lesion, accompanied by an itching sensation (Fig. 1A). One month after recovery from this lesion, the oral provocation testing was continued with the remaining drugs. After an erythromycin dose of 25 mg, she again experienced more intense pruritus and erythema at the site of a previous lesion (Fig. 1B).

Interestingly, the patient had no history of taking medication, including doxycycline or erythromycin. According to the Korea Food and Drug Administration, doxycycline and erythromycin are commonly used in livestock farming and sea farming in Korea. We did not know whether antibiotics in food cooked at high temperatures could induce an FDE, so we conducted a simple experiment to assess the heat stability of doxycycline and erythromycin. Using the disk-diffusion method, we found that doxycycline and erythromycin are stable at 100℃ and even at autoclave temperatures reaching 121℃ (Fig. 2).

FDEs usually appear as solitary or multiple pruritic, well-circumscribed, erythematous patches. These lesions typically recur at the same skin sites with re-exposure to the causative drug. They resolve spontaneously upon discontinuation of the medication, leaving behind hyperpigmentation. Intraepidermal clusters of differentiated CD8-positive T cells at the FDE lesion site contribute to localized tissue damage. Resting T cells are not cytolytic, but upon activation, they kill the surrounding keratinocytes and release cytokines such as interferon gamma. More CD8-positive T cells as well as CD4-positive T cells and neutrophils are recruited to the lesion, resulting in tissue damage.5,6

In the patient, the diagnosis was not difficult; recurrent erythematous and hyperpigmented patches at the same skin sites indicated FDE. Although she did not take any medications, she had positive oral provocation tests for both doxycycline and erythromycin, which are not crosslinked. FDEs usually have a single causative drug, and polysensitivity involving two or more drugs is rare.7 Piroxicam and cotrimoxazole, tenoxicam and trimethoprim-sulfamethoxazole, and various anticonvulsants have been reported to cause polysensitive FDEs.7-9

The patient denied any history of using medication, including the two drugs that elicited her FDEs on oral challenge. We, therefore, considered the possibility of another source because there are some case reports of recurrent FDE exacerbations not linked to drug intake. Nonmedical factors such as food and ultraviolet radiation have been reported to precipitate FDE lesions.2-4,10 In the patient, it was possible that food might have caused the fixed eruptions, particularly as she thought that the lesions appeared after eating pork and/or fish. However, the lesions did not appear consistently with each of these meats ingested, and the patient refused additional provocation tests using pork or fish.

We hypothesized that pork and/or fish, acting as a vehicle, might have been the source of the causative drug. According to a document produced by the Korea Food and Drug Administration concerning the monitoring of antimicrobial resistance in food animals and their meat, tetracyclines such as doxycycline are commonly used veterinary antibiotics in Korea, as are macrolides such as erythromycin.11,12 The maximum residue limit (MRL) of doxycycline is 0.1 mg/kg for pig muscle and 0.5 mg/kg for fish; the MRL of erythromycin is 0.05 mg/kg for pig muscle and 0.2 mg/kg for fish.13,14 The MRLs of doxycycline and erythromycin are low; however, the dose represented by the MRL is the limit considered safe for public health and not the amount that might elicit an allergic reaction, which would presumably be a smaller dose. Although our patient ate only small amounts of pork and fish, the antibiotic residues might have been high enough to trigger an FDE in a sensitized individual. FDEs caused by antibiotics contained in food have not been previously reported, but there are some reports of hypersensitivity reactions caused by antibiotic residues, particularly of beta lactam and macrolide antibiotics, in food products.15 It is therefore conceivable that antibiotic residue in food can cause an FDE.

Although we had identified pork and fish as possible vehicles for our patient's drug ingestion, we still did not know whether antibiotics in these cooked meats could result in an FDE. By checking the thermostability of doxycycline and erythromycin, and by reviewing the literature, we found that doxycycline and erythromycin are heat stable, even during cooking.16,17 We propose that doxycycline and erythromycin contained in our patient's food caused her FDEs, even though the food was cooked at high temperatures. Some existing reports18,19 concerning the relationship between antibiotic residue and the cooking process state that, as we found through our experimentation, cooking does not guarantee full elimination of antibiotics present in animal tissues, particularly when it comes to doxycycline.

The limitation of the present case is that oral provocation tests for pork or fish were not performed to confirm the FDE. However, a reasonable explanation is that the patient's FDEs were elicited by residual antibiotics in food that she ate before the lesions developed.

Residual antibiotics in animal tissues are problematic in that adverse drug reactions may occur after ingestion of meat or fish, with concomitant unintended drug consumption. We report a rare case of an FDE resulting from residual antibiotics present in food. Physicians should keep in mind that drug reactions, including FDEs, can occur after eating food and without any patient history of medication use.