Fixating on doxycycline-induced fixed drug eruptions

By Warren R. Heymann, MD, FAAD
May 21, 2025
Vol. 7, No. 20

When reading medical journals, I am intrigued by titles that inspire me to learn more about the topic. Happening upon a letter to the editor titled “Doxycycline-induced fixed drug eruption: The new epidemic?” (1) gave me pause. Doxycycline causing a fixed drug eruption (FDE) is unsurprising, but an epidemic? Really? How many thousands of doxycycline prescriptions have I written in 45 years of practice? I have seen many patients with FDEs but am hard-pressed to recall any that I attributed to doxycycline.

An FDE is a common cutaneous adverse drug reaction that occurs following the administration of an offending drug. FDEs affect all age groups but most commonly occur in the third and fourth decade of life. According to McClatchy et al., “Classically, FDE presents as round to oval, well-demarcated erythematous-violaceous patches or edematous plaques occurring on the skin or mucous membranes. Lesions can range in size from 1–10 cm and can be single or multiple. They will demonstrate same site recurrence upon re-exposure to the drug in question. Whilst most remain asymptomatic, local symptoms such as burning or itching can be experienced by up to 24 % of patients. FDE is categorized into subgroups based on the clinical morphology. The major sub types include pigmenting or bullous FDE which can either be local or generalized. Bullous FDE (BFDE), especially when generalized (GBFDE), may resemble Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TENs)… Non-pigmenting FDE represents a rarer subtype which resolve without the post inflammatory hyperpigmentation. Commonly involved sites include upper and lower limbs, trunk, hands, head, lips, and mucosal surfaces including the oral cavity and genitals.” (2)

Although the pathogenesis of FDEs is enigmatic, they are considered delayed type 4 hypersensitivity reactions. Intraepidermal memory CD8⁺ T-cells are suspected to play a key role. Presumably, the offending drug damages the basal layer of the epidermis (vacuolar alteration and dyskeratotic keratinocytes) and activates resident CD8⁺ T cells in genetically predisposed patients. Mediator release, particularly interferon (IFN)-γ, recruits other effector cells, including CD8⁺ T cells, CD4⁺ T cells, and neutrophils. Memory CD8⁺ T cells remain in high concentrations in the basal layer even in the absence of antigen stimulation. When re-exposed to the causative drug, prompt reactivation of resident CD8⁺ T cells occurs, leading to localized epidermal injury through IFN-γ release and other cytotoxic mediators. (2,3) The very low number of peri-lesional memory T cells accounts for the same site involvement in FDEs, explaining why patch testing yields positive results only when performed on previously involved skin. (2)

The most common culprits in causing FDEs include analgesics (NSAIDs, acetaminophen, cyclooxygenase-2 inhibitors), antibiotics (trimethoprim/sulfamethoxazole, metronidazole, tetracyclines [tetracycline, minocycline, doxycycline], quinolines, penicillins, macrolides, vancomycin, cephalosporin), fluconazole, phosphodiesterase 5 inhibitors (sildenafil, tadalafil), biologics (adalimumab, ustekinumab), vaccines (including the SARS-CoV-2 vaccines), and others. (2,4) When foods are responsible (quinine, licorice, strawberries, others) the lesions are called “fixed food eruptions.” (2)

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FDEs are usually diagnosed clinically, although histology may be useful in questionable cases. Oral provocation with a drug challenge will confirm the diagnosis, although this is contraindicated in GBFDEs. Admittedly, other than an occasional skin biopsy, I have never used adjunctive testing for FDEs. I rely on a drug (and food) history and occasional drug challenges. If further testing is warranted, Traineau et al. recommend a stepwise approach utilizing in situ patch testing first; if negative, performing the in situ repeated open application test (ROAT); and, if need be, drug challenge. (3) Managing FDEs focuses on discontinuing and avoiding the inciting drug and using steroids (topical or oral) for acute lesions. Cyclosporine has successfully treated GBFDE. (5) Carefully explaining that post-inflammatory hyperpigmentation should abate with time is worthwhile.

Focusing on doxycycline, dermatologists are familiar with its common adverse effects, including gastrointestinal upset, hepatotoxicity, renal toxicity, teeth discoloration, hemolytic anemia, phototoxicity, and skin rashes (including exacerbation of cutaneous lupus erythematosus). FDEs due to doxycycline are rare adverse events. (6)

Brehon et al. reported 15 cases of doxycycline-induced FDE, 11 of which were reported within 6 months. Doxycycline was prescribed in 14 cases either for treating sexually transmitted infections (STIs n = 11/14) or post-exposure prevention (PEP n = 3/14). Patients were not undergoing treatment except pre-exposure prophylaxis (PreP) for 12 patients. All patients experienced one or more erythematous skin or (semi) mucosal lesions after taking doxycycline. After discontinuation of doxycycline, the lesions improved in all patients. One patient who has had 3 bullous flares-up reported a scarred balano-preputial fusion. Because of the known cross-reactivity of the tetracyclines (tetracycline, minocycline, doxycycline) (4), the authors assert that these are contraindicated in doxycycline-induced FDEs. They suspect that the incidence of doxycycline-induced FDEs may increase with the use of doxycycline for PEP among men having sex with men. (1) The CDC recommendations for PEP (7) are included below. I agree with Brehon et al. that clinicians need to be aware of doxycycline-induced FDEs — especially genital FDEs — because they can easily be misdiagnosed as an STI. What I do not understand is why they saw so many cases of doxycycline-induced FDEs within 6 months of each other. The ROAT was positive in 11/15 cases (73.3%; although 78% was reported); this is higher than the 35% (14/40 cases using multiple drugs) positive ROAT obtained by Traineu et al. (3) Brehon et al. suspect that the higher positivity was because their ROAT tests were performed on a (semi) mucosal site. Perhaps they are correct, but that remains to be proven. If there is a genuine increase in doxycycline-induced FDEs, we need to understand why. Is it the doxycycline itself? Can it be due to an adulterant added in the manufacturing process? Another reason?

In conclusion, I thank Brehon et al. for reporting their cluster of doxycycline-induced FDE cases. I am pleased that they ended their letter to the editor with a question mark rather than a period or exclamation mark. Dermatologists need to be aware of their findings to determine if this is real or an aberration. If there is a true increase in the number of cases of doxycycline-induced FDEs, we have to find out why.

Point to Remember: Dermatologists routinely prescribe doxycycline. Historically, doxycycline rarely causes a fixed drug eruption. A case series of patients with doxycycline-induced fixed drug eruptions in patients receiving doxycycline for post-exposure prophylaxis or treatment of sexually transmitted disease has been reported. More study is required to determine if the incidence of doxycycline-induced fixed drug eruptions has increased, and if so, why.

Our expert’s viewpoint

Kenneth A. Katz, MD, MSc, MSCE, FAAD
Dermatologist
Kaiser Permanente – San Francisco Medical Center

The article by Brehon et al., and Dr. Heymann’s thoughtful commentary, raise important issues and concerns regarding doxycycline, fixed drug eruptions (FDEs), and genital ulcer disease. From my perspective, as a dermatologist interested in sexually transmitted infections (STIs) and LGBTQ health, these are as follows:

1. DoxyPEP is here. More patients — especially men who have sex with men (MSM) and transgender women (TGW) — are taking doxycycline intermittently (200 mg by mouth within 72 hours of a sexual encounter that puts them at risk). This regimen, commonly referred to as “doxyPEP” is evidence-based and, since 2024, CDC-recommended.

2. Include FDE in the differential diagnosis of genital ulcer disease. Epidemiologically, MSM and TGW are more likely to experience STI-related genital ulcers, including from syphilis (chancres), herpes simplex virus infection, and lymphogranuloma venereum. MSM and TGW with a history of a bacterial STI within the prior 12 months are also the populations for which CDC recommends considering doxyPEP; doxycycline-triggered FDE can present as a genital ulcer.

3. Why might there be more FDEs from doxycycline? Dr. Heymann rightly questions whether an uptick might be due to doxycycline itself, or perhaps an adulterant. Another possibility could be the intermittent dosing schedule. Of note, medications most likely to cause FDEs — NSAIDs, acetaminophen, and antibiotics (including doxycycline) – are often taken briefly and intermittently. (Notably, dermatologist-dosed doxycycline courses are often longer, and not necessarily intermittent.) Could repeated short exposures to these culprit medicines, including doxycycline used for doxyPEP, lead to FDEs?

4. What’s an epidemic? Brehon et al.’s article is subtitled “The new epidemic?” Dr. Heymann rightly questions whether this is so. It’s worthwhile reviewing epidemiologic terminology. According to the CDC, an epidemic can be defined as “the occurrence of more cases of disease than expected in a given area or among a specific group of people over a particular period of time.” Given that epidemiologic surveillance of FDEs is not routine, it’s not clear what the expected number of doxycycline-related FDEs should be. Although it does not meet the definition of epidemic, it does meet the CDC definition for a cluster: “An aggregation of cases of a disease or other health-related condition, particularly cancer and birth defects, which are closely grouped in time and place. The number of cases may or may not exceed the expected number; frequently the expected number is not known.” The CDC and others should conduct additional studies of the incidence of doxyPEP-related FDEs, including with increasing per-patient exposures, to clarify whether there is, in fact, and epidemic.

5. If you don’t think of a disease, you can’t diagnose it. Most U.S.-based dermatologists are familiar with diagnosing and treating FDEs, which present acutely. In my experience, most non-dermatologists are not. In the U.S., it’s not clear that patients with doxycycline-induced FDEs will have quick access to dermatologists. It’s important that clinicians prescribing doxyPEP and working in sexual health generally — again, in the U.S., not typically dermatologists — become familiar with FDEs. Unfortunately, CDC doxyPEP guidelines do not — but should — specifically include FDEs as a possible adverse effect of doxyPEP.

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References

1. Brehon A, Lourenco J, Badaoui A, Amsler E, Lopez Zaragoza JL, Soria A, Barbaud A. Doxycycline-induced fixed drug eruption: The new epidemic? J Eur Acad Dermatol Venereol. 2025 Apr;39(4):e303-e305. doi: 10.1111/jdv.20280. Epub 2024 Aug 9. PMID: 39120097.

2. McClatchy J, Yap T, Nirenberg A, Scardamaglia L. Fixed drug eruptions - the common and novel culprits since 2000. J Dtsch Dermatol Ges. 2022 Oct;20(10):1289-1302. doi: 10.1111/ddg.14870. Epub 2022 Oct 9. PMID: 36210056.

3. Traineau H, Milpied B, Soria A, Assier H, Tetart F, Bernier C, Le Bouëdec MF, Gener G, Kurihara F, Bauvin O, Delauney J, Amsler E, Bara C, Pelletier F, Valois A, Castelain F, de Risi Pugliese T, Hamelin A, Barbaud A. In Situ Patch Test and Repeated Open Application Test for Fixed Drug Eruption: A Multicenter Study. J Allergy Clin Immunol Pract. 2024 Feb;12(2):460-468. doi: 10.1016/j.jaip.2023.10.021. Epub 2023 Oct 19. PMID: 37863314.

4. Tham SN, Kwok YK, Chan HL. Cross-reactivity in fixed drug eruptions to tetracyclines. Arch Dermatol. 1996 Sep;132(9):1134-5. PMID: 8795565.

5. Anderson HJ, Lee JB. A Review of Fixed Drug Eruption with a Special Focus on Generalized Bullous Fixed Drug Eruption. Medicina (Kaunas). 2021 Sep 1;57(9):925. doi: 10.3390/medicina57090925. PMID: 34577848; PMCID: PMC8468217.

6. Nitya S, Deepa K, Mangaiarkkarasi A, Karthikeyan K. Doxycycline induced generalized bullous fixed drug eruption - A case report. J Young Pharm. 2013 Dec;5(4):195-6. doi: 10.1016/j.jyp.2013.12.001. Epub 2013 Dec 25. PMID: 24563602; PMCID: PMC3930098.

7. Bachmann LH, Barbee LA, Chan P, Reno H, Workowski KA, Hoover K, Mermin J, Mena L. CDC Clinical Guidelines on the Use of Doxycycline Postexposure Prophylaxis for Bacterial Sexually Transmitted Infection Prevention, United States, 2024. MMWR Recomm Rep. 2024 Jun 6;73(2):1-8. doi: 10.15585/mmwr.rr7302a1. PMID: 38833414; PMCID: PMC11166373.

8. CDC Clinical Guidelines on the Use of Doxycycline Postexposure Prophylaxis for Bacterial Sexually Transmitted Infection Prevention, United States, 2024
   
   No vaccines and few chemoprophylaxis options exist for the prevention of bacterial sexually transmitted infections (STIs) (specifically syphilis, chlamydia, and gonorrhea). These infections have increased in the United States and disproportionately affect gay, bisexual, and other men who have sex with men (MSM) and transgender women (TGW). In three large randomized controlled trials, 200 mg of doxycycline taken within 72 hours after sex has been shown to reduce syphilis and chlamydia infections by >70% and gonococcal infections by approximately 50%. This report outlines CDC’s recommendation for the use of doxycycline postexposure prophylaxis (doxy PEP), a novel, ongoing, patient-managed biomedical STI prevention strategy for a selected population. CDC recommends that MSM and TGW who have had a bacterial STI (specifically syphilis, chlamydia, or gonorrhea) diagnosed in the past 12 months should receive counseling that doxy PEP can be used as postexposure prophylaxis to prevent these infections. Following shared decision-making with their provider, CDC recommends that providers offer persons in this group a prescription for doxy PEP to be self-administered within 72 hours after having oral, vaginal, or anal sex. The recommended dose of doxy PEP is 200 mg and should not exceed a maximum dose of 200 mg every 24 hours. Doxy PEP, when offered, should be implemented in the context of a comprehensive sexual health approach, including risk reduction counseling, STI screening and treatment, recommended vaccination and linkage to HIV PrEP, HIV care, or other services as appropriate. Persons who are prescribed doxy PEP should undergo bacterial STI testing at anatomic sites of exposure at baseline and every 3-6 months thereafter. Ongoing need for doxy PEP should be assessed every 3-6 months as well. HIV screening should be performed for HIV-negative MSM and TGW according to current recommendations.

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