Minocycline-induced cutaneous polyarteritis nodosa with antineutrophil cytoplasmic antibodies

Minocycline is an antibiotic widely used in the treatment of acne. Among the induced auto-immune disorders, cutaneous polyarteritis nodosa (PAN) is very rare. A new case is reported below. A 23-year-old female patient treated with minocycline for acne for 24 months developed sub-cutaneous nodules, livedo reticularis and pigmented lesions of the lower limbs. Antineutrophil cytoplasmic antibodies (ANCA) were positive at 1/320. Skin biopsy showed vasculitis of a medium-sized artery. The role of minocycline was suspected using the imputability criteria. The diagnosis of minocycline-induced cutaneous PAN with ANCA was sustained. After withdrawal of the treatment, the nodular lesions decreased spontaneously, whereas livedo disappeared and inflammatory parameters were normalized after oral corticosteroid therapy. Minocycline is a tetracycline which is efficient for treating acne. Auto-immune disorders are frequently observed. Among them, it is very rare to observe cutaneous PAN associated with positive ANCA. The pathophysiological mechanisms are discussed.     

Effect of zinc gluconate on propionibacterium acnes resistance to erythromycin in patients with inflammatory acne: in vitro and in vivo study

Tetracyclines and macrolide antibiotics have been in use for acne treatment for more than 20 years. Since 1992 increasing resistance to these antibiotics, and especially to erythromycin, is reported with Propionibacterium acnes. Zinc salts have demonstrated their efficacy in inflammatory acne treatment as well as their bacteriostatic activity against Propionibacterium acnes. The objective of our work was firstly to determine whether the clinical anti-inflammatory efficacy of zinc salts was altered in the presence of erythromycin resistant strains in vivo, and secondly to study the in vitro and in vivo effect of zinc on the sensitivity of Propionibacterium acnes strains to erythromycin. Thirty patients with inflammatory acne were treated by zinc gluconate with a daily dose of 30 mg for two months and bacteriologic samples were taken at D0, D30 and D60. In vivo, this study displayed a reduction in the number of inflammatory lesions after a 2-month treatment whether or not Propionibacterium acnes carriage was present. Concurrently, in vitro addition of zinc salts in the culture media of Propionibacterium acnes reduced resistance of Propionibacterium acnes strains to erythromycin. Thus, association of zinc salts via a systemic route and topical erythromycin treatment seems an interesting option in the light of an increasing number of patients carrying erythromycin resistant Propionibacterium acnes strains.     

Lymecycline and minocycline in inflammatory acne: a randomized, double-blind intent-to-treat study on clinical and in vivo antibacterial efficacy

BACKGROUND: Some antibiotics represent a mainstay in acne treatment. However, studies comparing their efficacies are rare. AIM: To evaluate the clinical and in vivo antibacterial effect of lymecycline and minocycline at different dosages. METHOD: Eighty-six patients with moderate to severe acne were enrolled in a randomized, double-blind, intent-to-treat study comparing in three parallel groups the effect of (1) lymecycline 300 mg daily for 12 weeks, (2) minocycline 50 mg daily for 12 weeks and (3) minocycline 100 mg daily for 4 weeks followed by 50 mg daily for 8 weeks. Evaluations were made at the screening visit and at five on-treatment visits. They consisted of clinical counts of acne lesions and evaluations of bacterial viability using dual flow cytometry performed on microorganisms collected from sebaceous infundibula by cyanoacrylate strippings. RESULTS: Patients receiving minocycline 100/50 mg had the best clinical outcome, particularly in the reduction of the number of papules. By the end of the trial, the microbial response to minocycline 100/ 50 mg was also superior to either of the other two treatments. There were less live and more dead bacteria. CONCLUSION: In this trial, minocycline 100/50 mg was superior for the treatment of inflammatory acne when compared to lymecycline 300 mg and minocycline 50 mg.     

Zinc salts in dermatology

Zinc is an essential trace element for the human organism. It acts like cofactor for the metalloenzymes involved in many cellular processes. Its anti-inflammatory activity, which is the basis of therapeutic use, other than acrodermatitis enteropathica, is not well known: production of cytokines, antioxidant activity. Its toxicity is very low, but marked at high doses during chronic administration by the risk of hypocupremia. It is not teratogenic and can be given during pregnancy. Its absorption, through the duodenum, is inhibited by excessive phytate intake. Maximum concentration is reached after 2 to 3 hours. It is widely distributed in the organism, mainly in muscles and bone. Excretion is predominantly digestive. Its spectacular effect in acrodermatitis enteropathica, through compensation of genetically determined malabsorption was discovered in 1973. Its usefulness in acne is based on the anti-inflammatory action and was first described with zinc sulfate, then with better tolerated gluconate. Many controlled studies have shown an efficacy on inflammatory lesions. Doses varied from 30 to 150 mg of elemental zinc and studies against cyclines have shown that minocycline has a superior effect; but zinc might be an alternative treatment when cyclines are contraindicated. To date we don't have convincing data for its use in other indications (leishmaniosis, warts, cutaneous ulcers). Tolerance at usual doses (200 mg of zinc gluconate or 30 mg of elemental zinc) is good. Major side effects are abdominal with nausea, vomiting, but are fleeting and dose dependent.     

Zinc salts effects on granulocyte zinc concentration and chemotaxis in acne patients.

To explore the mechanism by which zinc acts on cutaneous inflammatory lesions, we studied granulocyte zinc levels and in vitro polymorphonuclear leukocyte chemotaxis in 20 acne patients before and after 2 months of zinc therapy (200 mg/day zinc gluconate). The zinc level was assayed by flame absorption spectrophotometry and chemotaxis was performed by agarose assay. After 2 months of treatment, a significant decrease in granulocyte zinc level associated with inhibition of chemotaxis (r = 0.69) was observed in 16 patients. This suggests that zinc anti-inflammatory action is related to inhibition of polymorphonuclear leukocyte chemotaxis induced by a decreased granulocyte zinc level.     

Comparison of combined azelaic acid cream plus oral minocycline with oral isotretinoin in severe acne.

BACKGROUND/AIMS: The primary aim of the study was to establish the clinical efficacy and safety of a combined treatment consisting of topical 20% azelaic acid (AA) cream and the oral antibiotic minocycline in the therapy of severe inflammatory acne (nodular papulopustular acne and acne conglobata) in a comparison with oral isotretinoin therapy. The secondary aim was to establish the value of AA cream as maintenance therapy in the prevention of recurrent acne. METHODS: This open-label but randomised study involved 85 patients with nodular papulopustular acne or acne conglobata (Leeds grading scale > 4) who were treated for 6 months. In an immediately subsequent 3-month second phase, eligible patients from the initial combination group used the AA cream as maintenance therapy, while the eligible patients from the isotretinoin group served as untreated control. RESULTS: A 6-month course of treatment with topical 20% AA cream plus oral minocycline in 50 patients proved to be effective in nodular forms of acne (median reduction of facial comedones: 70%; of papules and pustules: 88%; of deep inflammatory acne lesions: 100%). Overall, the combined treatment was not quite as effective as treatment with oral isotretinoin (35 patients; reduction of comedones: 83%; of papules and pustules: 97%; of deep inflammatory acne lesions: 100%). In the 3-month maintenance therapy phase, about half of the patients who received AA monotherapy maintained the very good facial result achieved by the end of phase I. A similar rate was found in the patients of the isotretinoin group, who received no further active acne treatment. In the other 50% of patients, differences existed between the groups as regards the degree of deterioration: Marked deterioration occurred more frequently under AA treatment, while only slight deterioration was more frequent in the isotretinoin group. The combination was tolerated much better than isotretinoin. The incidence of local side effects observed under the combination of AA and minocycline (36.5%, mainly transient burning and itching of mild or moderate intensity) was considerably lower than that seen with isotretinoin (65.7%). The rate of local side effects of marked intensity observed under the combination, i.e. 6%, was well within the range of 5-10% previously reported for AA. The incidence of systemic side effects was lower (8%, mainly gastrointestinal symptoms) under the combined therapy than under isotretinoin (14.3%). CONCLUSION: The combination of topical 20% AA cream and oral minocycline is an highly effective treatment in severe forms of acne. It is better tolerated and associated with fewer risks than oral isotretinoin - in particular, there is no risk of teratogenicity. The combination can be regarded as a valuable alternative in patients for whom isotretinoin is not indicated, who do not wish to use or can not tolerate isotretinoin therapy and particularly in female acne patients of child-bearing potential. Topical 20% AA cream can be used successfully as maintenance therapy to prolong the recurrence-free interval.     

Tetracycline and minocycline treatment

The effect of 1,000 mg of tetracycline hydrochloride and 200 mg of minocycline hydrochloride on Propionibacterium acnes levels and skin-surface lipid levels was measured in 15 patients with acne. Minocycline produced a significantly greater reduction in the P acnes counts that persisted even up to three weeks after discontinuation of the minocycline therapy, in contrast to the return of P acnes to baseline counts within three weeks after discontinuation of tetracycline therapy. A similar persistence of effect for reduction of skin-surface free fatty acid levels and clinical lesions was also seen with minocycline therapy.     

Minocycline: stain devil?

Minocycline is the treatment of choice for acne vulgaris, the most common form of inflammatory acne, despite the increase in awareness of rare but significant side-effects. This paper discusses the undesirable side-effect of minocycline staining in permanent teeth.     

Safety of long-term high-dose minocycline in the treatment of acne

Summary Minocycline is widely used as a second-line antimicrobial for acne vulgaris. Some patients require doses of up to 200 mg daily to control their acne. To assess the long-term safety of minocycline when used at higher doses, 700 patients treated with minocycline at doses of 100 mg daily, 100/200 mg on alternate days and 200mg daily, were recruited. The mean duration of treatment was 10·5 months. Side-effects were monitored and full blood count, blood urea, electrolytes and liver function tests were carried out on 200 of the 700 patients. Side-effects were recorded in 13·6%, and included vestibular disturbance, Candida infection, gastrointestinal disturbance, cutaneous symptoms (pigmentation, pruritus, photosensitive rash and urticaria) and benign intracranial hypertension. Pigmentation was the only side-effect found to be significantly increased in patients taking higher doses of minocycline, as compared with lower doses (P < 0·01). All patients with pigmentation had taken a total cumulative dose of over 70g. No significant abnormalities were found in any of the haematological and biochemical profiles. We conclude that minocycline, at doses of up to 200 mg/day, is safe, long-term, for acne, when such doses are clinically necessary.     

Cutaneous pigmentation induced by minocycline: 2 cases

Two new cases of cutaneous pigmentation induced by minocycline are reported, in addition to the 38 cases collected in the literature. Our first case was a 50-year old man with a history of multiple orthopaedic operations for injuries sustained in road accidents. Arthritis of the elbow, probably of bacterial origin, was treated with cephalexin and gentamicin, followed by minocycline 300 mg/day. After a total dose of 60 g of minocycline had been reached, a bluish-grey pigmentation was observed on the internal aspect of the left tibia and on the scars left by the orthopaedic operations. Subsequently, lenticular lesions of the hands developed, together with a blue area on the palate. Our second case was an 18-year old girl who presented initially with nodulo-cystic acne. Minocycline 200 mg/day was prescribed, then withdrawn on account of dizziness; no pigmentation was observed. The acne was cured after 7 months of treatment with 13-cis-retinoic acid in doses of 30 mg/day (for a patient's weight of 50 kg). A second course of minocycline 100 mg/day was prescribed; after a total dose of 3 g all the acne scars had become pigmented. A pathological study performed in the first case confirmed the data found in the literature: light microscopy displayed hyperpigmentation of the basal layer of the epidermis with Masson's silver stain, and an intrahistiocytic pigment coloured by Turnbull's stain; electron microscopy showed an increase in melanosomes within the basal keratinocytes, and a pathological accumulation of pigment in the dermis in the form of electron-dense granules usually surrounded by a membrane.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low doses of zinc gluconate for inflammatory acne

The effect of zinc on acne is unclear. In this study, only patients with an inflammatory acne were included in a double-blind trial using low doses of zinc gluconate (200 mg/day, corresponding to 30 mg zinc metal). We obtained a significantly different result between zinc and placebo groups in the inflammatory score (p less than 0.02). This efficiency could be explained by the action of zinc on inflammatory cells, especially granulocytes.     

Minocycline]

Minocycline belongs to the second generation class of cyclines. It was synthesized in 1967 and marketed in 1972. Minocycline has an antiinfectious activity with a spectrum similar to that of other cyclines, notably against Chlamydias, Treonema and Proprionibacterium acenes. The antiinflammatory activity is associated with this antiinfectious action is greater than that of first generation cyclines with specifically a modulator effect on epidermal cytokines. The pharmokinetics of minocycline is characterized by an excellent absorption, a long half-life and an important lipophilic property inducing good tissue distribution. Clinical trials of minocycline have mainly been performed in sexually transmissible diseases and in acne, a field where randomized studies are the most frequent. These trials show that the effect of minocycline is not stronger than first generation cyclines or doxycycline, but that the action is quicker than that of tetracycline at the dose of 500 mg a day. Minocycline is also efficient in nocardiasis, mycobacteriosis, leprosy, Lyme disease, pyoderma gangrenosum, autoimmune bullous dermatitis, Carteaud disease, and prurigo. However, the effect of minocycline in these different conditions has always been evaluated in open trials with a small number of patients. The usual side effects of cyclines, i.e. digestive problems, fungal infections, are less frequent than with first generation cyclines. No photosensitivity has been demonstrated although pigmentations have been described. Dizziness is a specific side effect of minocycline. Furthermore, rare but severe side effects have been reported, including hypersensitivity syndrome, autoimmune hepatitis, and lupus. Regular indications for minocycline in dermatology are acne and three sexually transmissible diseases (mycoplasm, chlamydia, treponema). Proposed dosage is 100 mg per day in sexually transmissible disease with a reduction to 50 mg per day after 15 days in acne.     

Clinical significance of brand versus generic formulations: focus on oral minocycline

Minocycline is an oral antibiotic widely prescribed throughout the world, primarily for the treatment of acne vulgaris; other uses include the treatment of rosacea and perioral dermatitis. In the United States, Propionibacterium acnes resistance is lowest with minocycline compared with other tetracyclines and with erythromycin. The availability of generic formulations of minocycline has created confusion regarding the clinical significance of brand versus generic minocycline products. This article reviews available data on minocycline use for acne vulgaris and discusses a patented brand of minocycline versus generic formulations, including evaluations of pharmacologic activity and safety.     

Minocycline-induced hyperpigmentation in patients with pemphigus and pemphigoid

BACKGROUND: Immunosuppressive medications typically used to treat the immunobullous disorders pemphigus vulgaris, pemphigus foliaceous, and bullous pemphigoid can have serious adverse effects. The tetracycline family of antibiotic drugs has been shown to be effective in the treatment of these conditions with a more favorable side effect profile. Minocycline hydrochloride use has been associated with various forms of hyperpigmentation, and its incidence is well reported in acne vulgaris and rheumatoid arthritis. We examined a series of 9 patients treated with minocycline for pemphigus or pemphigoid, most of whom have developed cutaneous hyperpigmentation. OBSERVATIONS: Seven of 9 patients treated with minocycline, 50 mg daily (1 patient) or 100 mg twice daily (8 patients), for pemphigus vulgaris, pemphigus foliaceous, or bullous pemphigoid developed hyperpigmentation, which necessitated discontinuing therapy. Five of these patients had experienced notable clinical improvement of their immunobullous disease with minocycline therapy. The average duration of treatment was 8.2 months (range, 1-25 months). The second most common adverse effect in our group was oral candidiasis, which occurred in 2 patients. CONCLUSIONS: We found a favorable response to minocycline therapy in 5 of 9 patients. However, 7 patients developed localized hyperpigmentation as early as 1 month after starting medication use. This incidence of minocycline-induced hyperpigmentation is significantly higher in immunobullous disease than in acne vulgaris or rheumatoid arthritis. This increased incidence may be related to an increase in pigment deposition complexed with collagen during the remodeling process, subclinical inflammation, or glucocorticosteroid-induced skin fragility. The hyperpigmentation process was reversible, as most of our patients had fading of their pigmentation after minocycline cessation.     

A study into minocycline as a treatment for papulopustular rosacea

Papulopustular rosacea is a disease that causes redness and inflammtory lesions (patches) on the face. It is thought to affect about 16 million Americans and 34 million people worldwide. Rosacea may impact patients in different ways, such as itching, stinging, or embarrasment and self-consciousness, or it may impact leisure or social activites. Minocycline, as a pill, has been shown to be an effective treatment for the inflammatory lesions of rosacea. However, there may be side effects to using minocycline pills. This study evaluated the clearing of inflammatory lesions on the face of patients with rosacea after using a topical minocycline gel. The study was done at 26 clinics in the U.S.A. 270 people applied either 1% minocycline gel, or 3% minocycline gel, or just the vehicle gel (no medicine) to the face at bedtime for 12 weeks. Dermatologists were asked to count the number of inflammatory lesions on the face and the severity of disease before starting the study, and then throughout the 12 weeks of treatment. The authors found that the gels were generally safe and well tolerated. They also found that there was a greater reduction of inflammatory lesions in both the 1% and 3% minocycline groups compared to the vehicle gel group, and a higher percentage of people achieved clear or almost clear skin after 12 weeks of treatment for the 3% minocycline group. This indicates that a topical minocycline gel may be a safe and effective treatment for the inflamamtory lesions of papulopustular rosacea. Linked Article:   Webster et al. Br J Dermatol 2020; 183 :471–479 .     

Minocycline in Acne Vulgaris

Minocycline is a semi-synthetic, second-generation tetracycline. It was introduced in 1972 and has both antibacterial and anti-inflammatory properties. Minocycline is used for a variety of infectious diseases and in acne. Even today, new indications beyond the antibacterial indications are being investigated such as its use in neurologic diseases. Formerly, minocycline was thought to have a superior efficacy in the treatment of inflammatory acne, especially with respect to antibacterial-resistant Propionibacterium acnes. A thorough review of the literature, however, shows that minocycline is not more effective in acne than other tetracyclines. Compared with first-generation tetracyclines, minocycline has a better pharmacokinetic profile, and compared with doxycycline it is not phototoxic. However, minocycline has an increased risk of severe adverse effects compared with other tetracyclines. It may induce hypersensitivity reactions affecting the liver, lung, kidneys, or multiple organs (Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS] syndrome) in the first weeks of treatment and, with long-term treatment, may cause autoimmune reactions (systemic lupus erythematosus, autoimmune hepatitis). In addition, CNS symptoms, such as dizziness, are more frequent compared with other tetracyclines. Long-term treatment may induce hyperpigmentation of the skin or other organs. Resistance of P. acnes to minocycline also occurs, dependent on the prescribing behavior. Considering the aspects of efficacy, its adverse effect profile, resistance, price, and alternatives, minocycline is no longer considered the first-line antibacterial in the treatment of acne.     

Efficacy and safety study of two zinc gluconate regimens in the treatment of inflammatory acne

This double-blind study was conducted on 67 patients with inflammatory acne who received one of two zinc gluconate regimens (Rubozinc) for three months. One was a constant-dose regimen and the other included an initial three-week loading dose, but both regimens provided the same cumulative dose at three months. The primary assessment criteria was the change with respect to baseline in the total number of superficial inflammatory lesions (papules and pustules). The two treatment groups were not statistically significantly different, with respect to this criteria, after three, five, seven or thirteen weeks of treatment. Therefore, the regimen that included a loading-dose provided no additional benefit. The results of this study are in favor of the conventional therapeutic regimen of two capsules daily for three months, as defined in the marketing authorization.     

Oral minocycline in the treatment of vitiligo – A preliminary study

For effective treatment of vitiligo, it is as important to arrest the progression of the disease, as it is to induce repigmentation. Epidermal oxidative stress has been documented in vitiligo patients, and there is much support for a free‐radical‐mediated damage as an initial pathogenic event in melanocyte degeneration in vitiligo. Minocycline possesses a wide repertoire of anti‐inflammatory, immunomodulatory, and free‐radical scavenging actions in addition to their well‐characterized antimicrobial effects. Recently, it has been shown that minocycline can rescue melanocytes from oxidative stress in vitro. Minocycline 100 mg was tried in this study to elucidate its role in arresting disease activity. Thirty‐two patients with gradually progressive (slow spreading) vitiligo were enrolled in this study. The patients were advised to take minocycline 100 mg once daily. In 29 patients, the progression of the disease was arrested, and only three patients showed development of new lesions and/or enlargement of existing lesions. Ten patients showed arrest of further depigmentation after 4 weeks of treatment. Thus, minocycline offers a unique and potentially powerful approach to the management of arresting the activity of the disease. The present study showed the effectiveness of minocycline in the treatment of vitiligo. Further controlled studies should be undertaken to confirm its efficacy.     

Picosecond alexandrite laser is superior to Q-switched Nd:YAG laser in treatment of minocycline-induced hyperpigmentation: A case study and review of the literature

Background: Minocycline is a commonly prescribed tetracycline antibiotic used for the treatment of a number of dermatological conditions including acne and rosacea. Long-term adverse effects of minocycline include cutaneous hyperpigmentation. Various treatment options have been suggested for the treatment of minocycline pigmentation. We report a case of a patient on long-term low-dose minocycline for the treatment of rosacea with type III minocycline hyperpigmentation. A comparison was made between Q-Switch Nd:YAG and picosecond laser over a nine 9-period with treatments spaced 1 month apart, with a clearance in the patient pigmentation after four treatments with picosecond laser.