Minocycline-Induced Cutaneous Hyperpigmentation

To the Editor:

Cutaneous hyperpigmentation has been reported as an uncommon complication associated with minocycline therapy [1,2,3]. Most cases have been reported in patients undergoing extended therapy with large cumulative doses of the drug, generally more than 40 g [1,2,4,5,6]. Although most cases appear to be dose-related, there have been infrequent reports of hyperpigmentation after only a few weeks of therapy and cumulative doses as small as 4.2 g. These reports cast doubt on attempts to correlate pigmentary disturbance directly to drug dose [7,8].

Minocycline has consistently been associated with three distinct hues of cutaneous pigmentation: blueblack, blue-gray, and muddy brown [5,8,9]. The blueblack and blue-gray or “slate-colored” pigmentations have been reported to occur in sites of prior inflammation or previously uninvolved skin as a result of minocycline metabolite deposition [5,8,10]. The muddy brown pigmentation, or the “muddy skin” syndrome, has been associated with increased melanization and sun exposure [9]. In the cases not associated with melanin abnormality (ie, blue-black and blue-gray pigmentation), the pigment deposits have been shown to contain high concentrations of iron and calcium [3,4,6]. These pigmentary changes have previously been mistaken for hemosiderosis, stasis dermatitis, emboli infarcts, cyanosis, and bruising [2,4,5,11,12]. Most cutaneous discolorations were observed to gradually fade, at least somewhat, within months after the cessation of therapy [2,4,5,6,8,12]. Time to resolution appears to be linked to the degree of pigmentation and may be more than a year if there is extensive involvement [2].

Case Report

In March 1998, a 60-year-old man with diabetes mellitus who had been a long-time patient at the authors’ facility for care of repeated bouts of neuropathic ulceration and cellulitis presented with a dorsal ulceration of his right fifth digit. Debridement revealed that the ulcer extended to the head of the proximal phalanx. A small amount of pus was expressed and cultured; it subsequently grew methicillin-resistant Staphylococcus. Radiographs displayed osteolytic changes at the head of the proximal phalanx consistent with acute osteomyelitis. Owing to the patient’s repeated refusal of surgical intervention and intravenous antibiotic therapy, minocycline was prescribed for chronic suppression. During a July 1998 follow-up visit, the patient expressed concern regarding a new “blackish” discoloration of his left leg.

The patient’s medical history was significant for type 1 diabetes mellitus of more than 55 years’ duration, peripheral vascular disease, coronary artery disease, angina, retinopathy, hypercholesteremia, and osteoarthritis. His medications included minocycline (100 mg daily), insulin, quinapril, atenolol, pentoxifylline, simvastatin, and aspirin. He reported allergy to sulfa drugs as well as a hypersensitivity to adhesive tape. His surgical history included appendectomy (1970), popliteal–to–dorsalis pedis lower-extremity bypass graft (1994), partial amputation of the left hallux (1994), and coronary artery bypass graft (1997). The patient was very active, was an avid surfer, and spent much time outdoors.

Physical examination revealed palpable common femoral and weakly palpable pedal pulses, with the latter undetectable with a Doppler probe. The bypass graft was patent by Doppler insonation. Diffuse dark black-gray pigmentation was present on both extremities (Fig. 1, Fig. 2 and Fig. 3), with greater involvement of the left leg (Fig. 1). Areas of focal pigmentary consolidation were noted, especially about the saphenous vein harvest site of the left leg (Fig. 1). This pigmentation was macular and diascopic-negative. Laboratory studies revealed normal values for liver enzymes, complete blood count with differential, and erythrocyte sedimentation rate.

The areas of pigmentation continued to expand and intensify following their discovery in July 1998. The patient was advised that this color change was probably a result of the minocycline therapy, yet he chose to continue therapy. Confirmatory skin biopsy was refused. Minocycline therapy was discontinued in March 1999. The leg pigmentation faded significantly following discontinuation of the drug.

Discussion

In the case presented, the intensely focused slate-colored hyperpigmentation surrounding an old surgical scar suggests minocycline-induced pigmentation at a site of prior inflammation. Although the patient refused confirmatory biopsy, the timing and presentation of this disturbance in relation to implementation of minocycline therapy indicate the classically described drug-induced change. Also, extensive questioning of the patient by the authors failed to reveal other obvious causes of the hyperpigmentation. The fading of the pigmentation following cessation of therapy provides further evidence of a causal relationship.

Most cases of minocycline-induced pigmentation have occurred after prolonged drug use with a large cumulative dose. [2,7] In this case, discoloration was first noted after only approximately 4 months and a cumulative load of about 12 g. The authors offer this case presentation as an addition to the scarce reports of pigmentation after short-term, low-cumulative-dose minocycline therapy. In conjunction with the prior reports, this case casts doubt on the notion that this pigmentary disturbance is a purely dose-dependent phenomenon.