When Antibiotics Leave a Mark: Minocycline‐Induced Hyperpigmentation

ABSTRACT

This article presents two patients with significant minocycline‐induced hyperpigmentation, illustrating the diverse clinical manifestations across various body sites. Judicious use of minocycline and early recognition of its adverse effects are crucial to reduce the risk of irreversible hyperpigmentation in patients receiving this antibiotic.

Key Clinical Message

Minocycline‐induced hyperpigmentation is a significant yet often overlooked, dose‐dependent adverse effect that can affect multiple body sites. Its reversibility depends on pigmentation type and location. Clinicians should balance therapeutic benefits with potential adverse effects and remain vigilant when prescribing this commonly used antibiotic.

Bluish discoloration of the dorsal aspects of the hands and nails.

1. Introduction

Minocycline, a second‐generation tetracycline antibiotic, is widely prescribed for both infectious and noninfectious conditions. We present two cases of minocycline‐induced hyperpigmentation, illustrating the diverse presentations as well as the significant psychosocial and cosmetic implications. The first case is a patient with extensive pigmentation affecting the skin, sclerae, teeth, gingival, and nails after 25 years of low dose minocycline use. The second case describes a patient who developed bilateral lower limb pigmentation following 20 years of high dose minocycline therapy. In this case, the diagnosis was confirmed histopathologically by the presence of pigmented dermal macrophages and positive Perls' and Fontana‐Masson stains.

Despite being well‐documented, minocycline‐induced hyperpigmentation remains significantly underrecognized, highlighting the need for increased awareness among healthcare professionals.

2. Case Presentation

Here, we present a brief case series of two patients with minocycline‐induced hyperpigmentation with various manifestations.

2.1. Case I

2.1.1. Case History and Physical Examination

A 75‐year‐old woman was referred to the dermatology outpatients at St Vincent's Hospital Melbourne, Australia with widespread hyperpigmentation. She had been taking oral minocycline 50 mg twice daily for 25 years to treat rosacea by her general practitioner. She was otherwise systemically well and not on any other medications. The hyperpigmentation was first noticed 7 years ago, primarily at post‐trauma sites on her lower limbs, which progressed to involve her hands, face, sclerae, teeth, gingivae, and nails.

On examination, she had bluish‐gray patches on her lower limbs, hands, face, and sclerae (Figure 1a–d). Bluish discolouration was also noted on her nails, teeth, and gingivae (Figure 1b,e). All other systemic examinations were otherwise unremarkable, with her visual acuity being intact.

FIGURE 1.

Clinical manifestations of minocycline‐induced hyperpigmentation in patient 1. (a) Bluish‐gray patches on the bilateral lower limbs. (b) Bluish discoloration of the dorsal aspects of the hands and nails. (c) Bluish‐gray pigmentation of the face. (d) Bluish‐gray pigmentation of the sclerae. (e) Bluish discoloration of the teeth and gingivae. (f) Marked improvement in right lower limb pigmentation 1 month after minocycline cessation.

2.1.2. Differential Diagnosis

Drug‐induced Hyperpigmentation, Post‐inflammatory Hyperpigmentation, Haemochromatosis, Addison's Disease, Wilson's Disease, Thyrotoxicosis, Erythema Dyschromicum Perstans.

2.1.3. Investigations

The patient's baseline blood tests, including full blood count, renal function, liver function, and thyroid function, were unremarkable. No skin biopsy was performed as a clinical diagnosis of minocycline‐induced hyperpigmentation was made based on examination findings and the significant history of minocycline use over the past 25 years.

2.1.4. Treatment Offered and Outcome

Upon discontinuing minocycline, the hyperpigmentation of her right lower limb began to improve significantly within 1 month (Figure 1f). Regarding her rosacea, as the patient reported no ongoing concerns, no further treatment was recommended at this point.

2.2. Case II

2.2.1. Case History and Physical Examination

A 57‐year‐old man was referred to the dermatology outpatients with an 8‐month history of hyperpigmentation on his bilateral lower limbs. The areas of hyperpigmentation were not associated with pruritus or pain. He was otherwise systemically well. He had been taking oral minocycline 250 mg twice daily for 2 years as prophylaxis against osteomyelitis and cellulitis following recurrent severe cellulitis. The patient's medical history also includes epilepsy and depression, for which he was taking zonisamide and citalopram.

Examination revealed perifollicular blue‐gray pigmentation with faint blue‐gray discolouration of the surrounding skin on his bilateral shins (Figure 2a). All other systemic examinations were unremarkable.

FIGURE 2.

Clinical manifestations and histopathological features of minocycline‐induced hyperpigmentation in patient 2. (a) Perifollicular blue‐gray pigmentation and faint discoloration of the surrounding skin on the bilateral shins. (b) Dermal macrophages containing pigmented material on punch biopsy of the left shin (hematoxylin and eosin stain, ×400). (c) Positive Perls' stain indicating haemosiderin deposition (×400). (d) Positive Fontana‐Masson stain confirming melanin presence (×400).

2.2.2. Differential Diagnosis

Drug‐induced Hyperpigmentation, Post‐inflammatory Hyperpigmentation, Chronic Venous Insufficiency, Pigmented Purpuric Dermatoses, Erythema Dyschromicum Perstans, Lichen Planus Pigmentosus.

2.2.3. Investigations

Histology from a punch biopsy of the left shin showed dermal macrophages containing pigmented materials (Figure 2b). Both Perls' and Fontana‐Masson stains were positive, indicating the presence of haemosiderin and melanin (Figure 2c,d). A clinical diagnosis of minocycline‐induced hyperpigmentation was hence made.

2.2.4. Treatment Offered and Outcome

Due to prior unsuccessful trials of alternative antibiotics like cephalexin and flucloxacillin, minocycline remained the best option. After discussing the risks and benefits, including the potential for further skin pigmentation, the patient chose to continue minocycline.

3. Discussion

When evaluating patients with acquired hyperpigmentation, it is essential to consider a broad differential diagnosis, as this finding can result from a wide range of systemic, dermatological, and drug‐induced causes. Systemic conditions such as thyrotoxicosis, Addison's disease, and haemochromatosis are well‐recognized contributors to diffuse hyperpigmentation [1]. Dermatological causes are also common, with examples including melasma, post‐inflammatory hyperpigmentation (PIH), and acquired dermal macular hyperpigmentation [2]. The latter is an umbrella term that encompasses lichen planus pigmentosus, Riehl's melanosis, pigmented contact dermatitis, and erythema dyschromicum perstans [2]. Drug‐induced hyperpigmentation is another important consideration, with medications such as antimalarials, prostaglandins, minocycline, and phenothiazines known to cause skin hyperpigmentation [3].

In both of our patients, clinical history and evaluation excluded systemic and other dermatological causes. Of the potential medications, only minocycline was identified as a likely cause of their skin hyperpigmentation. In patient 2, this diagnosis was further supported by histopathological findings from skin biopsy.

Minocycline belongs to the tetracycline class of antibiotics. First generation tetracyclines include tetracycline and oxytetracycline; second generation tetracyclines include minocycline, doxycycline, metacycline; and third generation tetracyclines include tigecycline [4]. A systematic review of drug‐induced hyperpigmentation reports spanning 1970 to 2012 noted that minocycline, tetracycline, metacycline and tigecycline are all associated with hyperpigmentation [3]. However, only minocycline is likely to have a causal relationship. The associations of tetracycline, metacycline, doxycycline and tigecycline with hyperpigmentation are primarily derived from case reports, case series and pharmacovigilance data [3, 5]. It has also been postulated that hyperpigmentation is more frequently associated with minocycline than with other tetracycline antibiotics, potentially due to the greater cumulative dose and overall drug exposure [3]. To the best of our knowledge, no direct randomized trials have compared different tetracyclines and their effects on hyperpigmentation. As such, for the patient in case 2, it is difficult to determine whether switching from minocycline to another tetracycline antibiotic would be truly beneficial, as there may still be a risk of hyperpigmentation.

Minocycline‐induced hyperpigmentation affects 2.4%–14.8% of patients and can involve the skin, nails, oral mucosa, eyes, thyroid and bones [6, 7]. It is classified into four types: Type 1 presents as blue‐black hyperpigmentation in areas of prior inflammation or scarring and is reversible, caused by iron‐chelated minocycline complexes within macrophages. Type 2 appears as reversible blue‐gray hyperpigmentation on previously normal skin, resulting from the deposition of pigmented minocycline metabolites in the skin. Type 3 manifests as non‐reversible muddy brown discoloration primarily on sun‐exposed areas caused by increased melanin levels in epidermal macrophages. Finally, type 4 occurs only in preexisting scars and is non‐reversible, resulting from increased melanin levels in dermal macrophages [6, 7].

Our cases illustrate two distinct presentations of minocycline‐induced hyperpigmentation. The first case demonstrated a combination of Type 1 and Type 2 hyperpigmentation after prolonged low‐dose use. The blue‐gray hyperpigmentation on the face at sites previously affected by rosacea falls under Type 1, while the hyperpigmentation on the hands and lower limbs corresponds to Type 2. Conversely, the second case primarily showed Type 2 hyperpigmentation on the lower limbs, developing more rapidly due to higher dosing. These findings corroborate existing literature on the dose‐dependent nature of this adverse reaction, typically occurring after cumulative doses exceeding 100 g [6, 7].

Notably, our first patient exhibited rare manifestations of minocycline‐induced hyperpigmentation, including pigmented sclerae, which affect only 2.9% of patients, and teeth staining, a permanent side effect seen in less than 6% of patients [7, 8]. Interestingly, this case aligns with literature indicating that almost all patients who develop scleral pigmentation also exhibit nail pigmentation [7]. This correlation was indeed observed in our patient, further supporting the documented pattern of these rare manifestations.

To reduce the risk of hyperpigmentation, it is recommended that oral minocycline use should be limited to 6–12 months, particularly in conditions like rosacea, where the British Association of Dermatologists guidelines recommend against its use unless no alternative treatment options are available [7, 9]. Similarly, Australian therapeutic guidelines also advise against prolonged use of minocycline for rosacea treatment due to potential adverse effects such as hyperpigmentation and hepatotoxicity [10]. However, our first patient continued treatment for 25 years for rosacea, with her hyperpigmentation going unrecognized for 7 years and misdiagnosed by her general practitioner as bruising. The hyperpigmentation significantly impacted the patient's quality of life, causing her to feel self‐conscious and often wear long sleeves in public. This highlights the importance of increasing awareness of this adverse effect among healthcare professionals and regularly reviewing all prescribed medications.

Management of minocycline‐induced hyperpigmentation begins with discontinuation of the drug. Time to resolution, however, ranges from months to years, with some persisting indefinitely. Traditional treatment options include Q‐switched lasers such as Nd:YAG, ruby and alexandrite lasers, which have shown varying degrees of success [11, 12, 13]. More recently, combining chemical peels with intense pulsed light therapy has also been reported as effective [11]. In addition, recent case series and reports describe the successful use of picosecond‐domain lasers, including the 730 nm: Ti:sapphire and 755 nm alexandrite lasers for treating recalcitrant hyperpigmentation [14, 15].

4. Conclusion

In summary, these cases highlight the importance of carefully considering the adverse effects of long‐term minocycline therapy, particularly regarding dose and duration. Clinicians must balance therapeutic benefits with potential adverse effects, educate patients before initiating treatment, and remain vigilant for signs of minocycline‐induced hyperpigmentation. Further research into prevention and treatment strategies is crucial to improve patient outcomes.

Author Contributions

Clarissa Ting: conceptualization, writing – original draft, writing – review and editing. Benjamin S. Daniel: supervision, writing – review and editing. Timothy O'Brien: supervision, writing – review and editing. Aaron J. Robinson: supervision, validation, writing – review and editing.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from all patients.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.