Fixed Drug Eruption Due to Doxycycline Postexposure Prophylaxis

Abstract

Doxycycline is a semi-synthetic antibiotic in the tetracycline family. The three common subtypes of tetracyclines include naturally occurring, semi-synthetic, and new agents. Each subtype shares specific commonalities but is substantially different in various clinical applications. The mechanism of antimicrobial activity is the same across subtypes. The structural changes to the core naphthacene ring do not alter the mechanism of action but are thought to alter the rates of adverse effects and mechanisms of resistance. Tetracyclines as a class are known to cause fixed drug eruptions, but the majority of these adverse effects were associated with naturally occurring tetracyclines. Semi-synthetic tetracyclines have limited reports of fixed drug eruptions. Here, we present a case of fixed drug eruption in a patient who previously had multiple treatment courses with doxycycline. The case involves the use of doxycycline not for the treatment of an infection but as postexposure prophylactic (PEP) antibiotic therapy to prevent the acquisition of a sexually transmitted infection. Doxycycline PEP has been shown to reduce the rate of bacterial sexually transmitted infection in men who have sex with men (MSM). Doxycycline PEP is a single dose taken orally within 24–72 h of unprotected sexual intercourse. The dosing structure allows for ease of adherence but also repeatedly exposes individuals to doxycycline, putting them at risk for adverse events such as fixed drug eruptions, as illustrated by this case report.

1. Introduction

Tetracyclines are one of the older classes of antibiotics with continued utility. Providers use tetracyclines to treat a variety of disease states from skin and soft tissue infections to intra-abdominal pathologies. Tetracycline antibiotics include three subtypes: naturally occurring, semi-synthetic, and newer agents. Familiar naturally occurring tetracyclines include tetracycline and demeclocycline. Examples of semi-synthetic agents are minocycline and doxycycline, with newer agents represented by tigecycline (subclass glycylcycline), eravacycline, and omadacycline.

All tetracyclines share the exact mechanism of exerting their antimicrobial activity via inhibition of protein synthesis. More specifically, tetracyclines reversibly bind to the 30S ribosome at the acceptor site (A-site) on the MRNA–ribosome complex [1]. Binding to the A site on the ribosome prevents aminoacyl-tRNA from binding to the mRNA–ribosome complex and inhibits bacterial translation. The antimicrobial activity of tetracyclines is associated with their mechanism of resistance. One of the major differences among various tetracyclines is their mechanism of resistance. Resistance to tetracyclines involves efflux proteins, ribosomal protection, and enzymatic inactivation. Efflux proteins are common mechanisms of resistance, which detoxify bacterial intracellular space by pumping out various metabolic substrates, including antibiotics [2]. Newer agents can overcome the tetracycline-specific efflux proteins, allowing them to have a broader antimicrobial activity, including enteric Gram negatives [3]. The efflux pumps have the highest affinity for natural and semi-synthetic tetracyclines, with newer agents such as tigecycline and eravacycline being less affected. The newer agents have large bulky groups on the A naphthacene core ring, preventing them from being easily pumped out. Other non-tetracycline specific efflux pumps (i.e., MexCD-OprJ) can remove the entire class of tetracycline antibiotics from the bacterial cytoplasm, which limits the utility of eravacycline and tigecycline with certain bacterial organisms [4].

Commonalities among tetracycline include adverse reactions. As a class tetracyclines are known to cause specific adverse events such as photosensitivity or inhibition of skeletal development in adolescents [5]. Individual types of tetracycline antibiotics have different rates of specific adverse reactions. For example, tigecycline is known to cause high rates of nausea (31–46%) compared to doxycycline (4–33%) [6,7]. Another example of varying adverse effects is the incidence of nephrogenic diabetes insipidus with demeclocycline (60%) versus sporadic case reports with doxycycline [8,9]. Even among the semi-synthetic tetracyclines, the rates of adverse effects are significantly different. Minocycline is known to cause vestibular side effects (1–10%), such as dizziness, tinnitus, and vertigo, but these balance concerns are not commonly associated with doxycycline [10]. The different modifications to the tetracycline side chains are associated with different spectrums of antimicrobial activity and likely impact the rate of adverse effects.

Developing an adverse effect with one type of tetracycline may be a class effect, but incidences may vary based on the subtype. One of the known adverse effects associated with tetracyclines is fixed drug eruptions. Fixed drug eruptions (FDEs) are Type B adverse reactions, which are classified as a cutaneous drug reaction [11]. FDEs are due to the migration and activation of CD8+ T cells in the epidermis. The resulting activation of the T cells induces cytokine (interferon-gamma and TNF-alpha) expression and adopt natural killer cell activity in addition to increasing expression of other cytotoxic molecules (cell surface molecule CD56, granzyme B, and perforin) in the epidermis [12]. These responses cause the epidermal necrosis seen in FDEs. Early reports of FDEs described culprit natural tetracyclines with the first case report described with aureomycin [13]. The majority of cases of drug eruptions are associated with the older natural tetracyclines. The number of cases of FDEs due to doxycycline has been minimal in comparison to the natural tetracyclines [14,15,16,17,18,19,20]. Differences in the chemical side chain have been hypothesized to cause the different rates of hypersensitivity reactions [21]. A small study by Tham and colleagues evaluated the cross-reactivity between tetracyclines in 16 individuals. The study found a 63% cross-reactivity between tetracycline and doxycycline and no cross-sensitivity between minocycline and doxycycline in 38% of the individuals tested [22]. There have been multiple instances of successful doxycycline use after reactivity to another type of tetracycline. Bargman described two cases of tetracycline-induced balanitis that did not recur with challenges to doxycycline or minocycline [23]. Two additional cases of drug reactions occurred in patients receiving tetracyclines but did not recur when the patients were challenged with doxycycline [24]. Similarly, a fixed drug eruption from tetracycline did not manifest when a patient was retreated with doxycycline for nonspecific urethritis [25]. Newman and Castles demonstrated successful use of doxycycline following minocycline-induced lupus [26]. In contrast to Newman and Castles’ case, there was a report of a cutaneous reaction to minocycline after a previous reaction to doxycycline [27]. From these reports, we can speculate that natural tetracycline, compared to semi-synthetic agents, has varying degrees of cross-reactivity and may elicit fixed drug eruptions at different rates.

Further illustrating that tetracyclines are not entirely interchangeable is each agent’s antimicrobial effect. Each type of tetracycline is nearly an island on its own with a specific niche. Among the newer agents, tigecycline and eravacycline are commonly used for intra-abdominal infections and possess activity against anaerobic enteric Gram negatives [28]. In comparison, omadacycline is indicated for community-acquired pneumonia [29]. Between the older agents, demeclocycline is used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [30], and tetracycline is more commonly employed for the treatment of acne vulgaris and Helicobacter pylori infection [5]. Regarding the semi-synthetic agents, minocycline is commonly prescribed for the treatment of acne vulgaris and rosacea [31], whereas doxycycline has a broader usage and is recommended for various treatment guidelines from Lyme disease, community-acquired pneumonia, skin infections, and sexually transmitted infections [32,33,34,35].

2. Case Report

The patient is a 31-year-old male with HIV, type-2 diabetes, and a history of hepatitis C status-post successful treatment and multiple sexually transmitted infections who developed a fixed drug eruption likely caused by doxycycline. The patient was seen in June for routine care and was prescribed doxycycline for postexposure prophylaxis (PEP) to prevent sexually transmitted infections. The instructions for doxycycline PEP therapy were 200 mg orally once within 24 h of condomless sex, not to exceed 200 mg per day. A thirty-day medication supply was provided. During the June clinic visit when doxycycline PEP was first initiated, no dermatological problems were observed with the patient.

During a follow up clinic visit in November, the patient stated that a rash emerged soon after starting the doxycycline with a skin lesion developing after the second dose. He reported that the lesion increased in size and darkened in color; subsequently, new lesions appeared on other parts of the body. These lesions were red-purple and found on his back, hip, right lower leg, and between the fingers on the left hand. The patient continued to take doxycycline PEP without seeking medical care for the lesions; a doxycycline refill was requested during this time period, indicating that the patient had multiple exposures to the drug. At the time of his follow-up clinic visit in November, the patient stated that the lesions were present for several months.

He was immediately referred to dermatology to evaluate the numerous violaceous plaques for possible fixed drug eruption versus Kaposi Sarcoma (Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5). A skin punch biopsy showed a superficial perivascular and lichenoid inflammatory cell infiltrate that contains lymphocytes, histiocytes, and melanophages obscuring the dermo-epidermal junction where there are necrotic keratinocytes. The interpretation was interface dermatitis with melanophages, consistent with a resolving fixed drug eruption.

The appearance and location of the patient’s well-demarcated, oval, dusky plaques on the back, hip, leg, and hand supported the diagnosis of a fixed drug eruption as did the pathologic report. In contrast to some other drug eruptions or rashes due to infection, a FDE lacks systemic symptoms such as fever or malaise; the patient was clinically well, again fulfilling diagnostic criteria. While there are multiple fixed drug eruption variants, this patient’s presentation comprised a generalized fixed drug eruption wherein the typical lesions were multiple and disseminated, involving the trunk and extremities, and sparing the mucosa.

The patient was instructed to stop taking the doxycycline, but the hyperpigmentation required over six months to resolve. This starkly contrasts with other case reports, where eruptions become substantially better after discontinuing the causative agent [14,25]. A patch test and/or provocation testing were considered but were not performed because the only new agent introduced to the patient was doxycycline and it was discontinued with clinical improvement. The patient was instructed to monitor for new lesions and resolution of previous lesions after discontinuing the doxycycline. No new lesions have developed since the doxycycline therapy was discontinued. Fixed drug eruptions may take days to weeks to resolve, the time to recovery is variable, and hyperpigmentation may persist even longer [36].

Prior to developing the FDE, the patient was on metformin, bictegravir/emtricitabine/tenofovir alafenamide. The patient had been on metformin and bictegravir/emtricitabine/tenofovir alafenamide since 2021, which was two years prior to the FDE. Metformin is known to cause fixed drug eruptions, but since the patient has been adherent to therapy since initiation, the likelihood of it being the cause of the FDE is less likely compared to a newly introduced medication. Adherence to therapy was based on dose history and timely refill requests. The patient had also been consistently taking his bictegravir/emtricitabine/tenofovir alafenamide since initiation. The patient’s adherence to his antiretroviral therapy was demonstrated by his consistent undetectable viral load for the past three years and CD4 counts exceeding 400 cells/mm³, which also reduced the suspicion of it being the cause. The remaining potential culprit causing the FDE is doxycycline, which was started 5 months prior to the symptom onset.

An interesting aspect of the case is that in the two years prior to starting doxycycline PEP, the patient completed three separate 7–10-day treatment courses of doxycycline for episodes of scalp cellulitis and C. trachomatis. These treatment courses were at least six months apart and without any incidents of cutaneous reactions.

3. Discussion

Descriptions of a FDE have been long documented with older tetracyclines [37]. There have been many reports of a FDE to tetracycline over the years, but to the best of our knowledge, less than 20 published reports have been documented with doxycycline [15,19,20]. Fixed drug eruptions to tetracycline do not equate to intolerability of doxycycline. Reports have suggested that there may be limited to no cross-reactivity between the different tetracycline agents [23,25]. Despite being a known and less documented adverse reaction, a FDE remains a concern.

A major concern is the potential for increased use of doxycycline as the primary treatment for chlamydial infections and as a preventative measure. There have been two paradigm shifts of increasing doxycycline utilization in the outpatient setting for sexually transmitted infections. The first paradigm shift occurred in 2020 when the CDC recommended that standard chlamydia therapy transition from azithromycin to doxycycline [38]. This shift likely contributed to the increased number of dispensed tetracyclines as a class, from 69 prescriptions per 1000 in 2020 to 81 prescriptions per 1000 in 2022 [39].

The second paradigm shift is the use of doxycycline to prevent rather than treat sexually transmitted infections. Instead of providing an antibiotic to treat a small number of individuals, doxycycline is being given to a large number of healthy individuals to prevent infection. Luetkemeyer and Molina championed the idea of using doxycycline to prevent sexually transmitted infections [40,41]. These randomized control trials aimed to determine whether doxycycline given as postexposure prophylaxis reduces the incidence of sexually transmitted bacterial infections in men who have sex with men and transgender women [40,41]. The intervention groups were asked to take 200 mg of oral doxycycline within 24 h after unprotected sex and no later than 72 h. Luetkemeyer and colleagues found a 21.2% absolute reduction in at least one sexually transmitted infection and a 0.34 (95% CI: 0.24–0.46) relative risk in the doxycycline group compared to standard of care. Molina and colleagues found that the time to the first sexually transmitted infection occurrence was lower in the doxycycline group than non-doxycycline with a hazard ratio of 0.53 (95% CI 0.33–0.85), p = 0.008. The drivers of reduced infection occurrence were statistically significant for reducing syphilis (HR 0.27, 95% CI 0.07–0.98, p = 0.047) and chlamydia (HR 0.30, 95% CI 0.13–0.70, p = 0.006). Doxycycline did not reduce the rates of gonococcal infection (HR 0.83, 95% CI 0.47–1.47, p = 0.52) [41]. These study findings contributed to the development of the 2024 US Centers for Disease Control and Prevention guidelines on doxycycline as postexposure prophylaxis for the prevention of bacterial sexually transmitted infection [42]. We expect that an increase in doxycycline utilization will likely reduce the public health risk of sexually transmitted infections. However, the growth in antibiotic consumption and subsequent societal benefits may come at the cost of increased individual risk for adverse events and potential of antibiotic resistance. One of the known but infrequently reported adverse effects associated with doxycycline is a FDE.

The rate of FDE associated within the class of tetracyclines is broad-ranging. In Singapore, tetracycline had been identified as the most common cause of a FDE, accounting for 63% of proven cases [43]. A more recent study from Singapore found that doxycycline has been associated with 5% of definite and probable cases of FDEs [44]. Doxycycline has the fewest case reports of dermatological adverse effects among the tetracyclines [45]. Additionally, the development of a drug eruption to a tetracycline may occur within one day of therapy up to as long as two years later [23,46]. In one case report, a patient had five courses of tetracycline therapy before developing a FDE [47]. Our case report parallels that of Tarnowski et al., where the development of a FDE occurred after many exposures to tetracycline, but in our case, doxycycline was the likely offending agent. A single case of FDE was reported in Luetkemeyer and colleagues’ study despite the small study size, which illustrates the continued need to describe this adverse event as the use of doxycycline becomes more prevalent [40]. Recently, three individuals have been identified as developing FDEs secondary to doxycycline postexposure prophylaxis [15]. The majority of the bullous FDEs presented as genital ulcers, whereas this case report the drug eruption presented on the trunk and extremities. Both cases had patients with previous exposures to doxycycline without skin eruptions. Obviously, development of genital ulcers among patients at risk for sexually transmitted infections is of particular concern.

In the field of dermatology, there is a particular concern regarding the safe usage of doxycycline due to the possibility of adverse reactions such as sun sensitivity and risk of pseudotumor cerebri when isotretinoin and doxycycline are used concomitantly. It also seems probable that patients will share their doxycycline with sexual partners and, thus, potentially cause adverse effects in people who have not been prescribed the drug. As the utilization of doxycycline expands and the number of repeated exposures grows larger, continued physician and patient education and awareness should include fixed drug eruptions.

While the decrease in sexually transmitted infections seen with increased use of doxycycline is gratifying [48], we must acknowledge the potential drawbacks of employing doxycycline PEP, such as increased resistance in bacteria such as gonorrhea and staphylococcus aureus and unintended changes to the microbiome. While our case report focuses on the occurrence of a FDE with the use of doxycycline PEP in a single individual and others like him, only time will reveal whether there are more considerable risks to public health. However, there is insufficient evidence at this time to restrict or avoid the use of doxycycline.

4. Conclusions

This case report highlights a previously known and infrequently reported adverse effect associated with doxycycline. Postexposure prophylaxis for sexually transmitted infection repeatedly exposes individuals to doxycycline, which may increase the risk for FDE. The historical tolerance of doxycycline does not eliminate the risk of future adverse events. Renewed education and awareness of fixed drug eruptions need to be emphasized for doxycycline, primarily as utilization increases to prevent bacterial sexually transmitted infections.