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Minocycline for acne vulgaris: efficacy and safety.

BACKGROUND: Minocycline is a tetracycline antibiotic that is commonly used in the treatment of moderate to severe acne vulgaris. Although it is more convenient for patients to take than first-generation tetracyclines, as it only needs to be taken once or twice a day and can be taken with food, it is more expensive. Concerns have also been expressed over its safety following the deaths of two patients taking the drug. There is a lack of consensus among dermatologists over the relative risks and benefits of minocycline. As most acne prescribing is undertaken by general practitioners, it is important that guidelines issued to them are based on the best available evidence rather than personal judgements. OBJECTIVES: To collate and evaluate the evidence on the clinical efficacy of minocycline in the treatment of inflammatory acne vulgaris. Specific objectives were to compare the efficacy of minocycline with other drug treatments for acne and to collate information on the incidence of adverse drug reactions. SEARCH STRATEGY: Randomised controlled trials (RCTs) of minocycline for acne vulgaris were identified by searching the following electronic databases; MEDLINE, EMBASE, Biosis, Biological Abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group's Trial Register, Theses Online, BIDS ISI Science Citation Index and Bids Index to Scientific and Technical Proceedings. Other strategies used were scanning the references of articles retrieved, hand-searching of major dermatology journals and personal communication with trialists and drug companies. SELECTION CRITERIA: To be eligible for the review, studies had to be RCTs comparing the efficacy of minocycline at any dose to active or placebo control, in subjects with inflammatory acne vulgaris. Diagnoses of papulo-pustular, polymorphic and nodular acne were also accepted. Trials were not excluded on the basis of language. DATA COLLECTION AND ANALYSIS: 27 randomised controlled trials met the inclusion criteria and were included in this review. The comparators used were placebo (2 studies), oxytetracycline (1), tetracycline (6), doxycycline (7), lymecycline (2), topical clindamycin (3), topical erythromycin/zinc (1), cyproterone acetate/ ethinyloestradiol (1), oral isotretinoin (2), topical fusidic acid (1) and there was one dose response study. One study is ongoing and it remains to be clarified whether one further study is a RCT. Major outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors' and patients' global assessments, adverse drug reactions and drop out rates. The quality of each study was assessed independently by two assessors and an effect size calculated where possible. MAIN RESULTS: The trials were generally small and of poor quality and in many cases the published reports were inadequate for our purpose. Pooling of the studies was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data. Although minocycline was shown to be an effective treatment for acne vulgaris, in only two studies was it found to be superior to other tetracyclines. Both of these were conducted under open conditions and had serious methodological problems. A third study showed it to be more effective than 2% fusidic acid, applied topically, against inflammatory lesions in mild to moderate acne. Differences in the way adverse drug reactions were identified could have accounted for the wide variation between studies in numbers of events reported. This meant that no overall evaluation could be made of incidence rates of adverse events associated with minocycline therapy. No RCT evidence was found to support the benefits of minocycline in acne resistant to other therapies and the dose response has only been evaluated up to eight weeks of therapy. (ABSTRACT TRUNCATED)

Acne Vulgaris↗

Minocycline treatment failure in pneumonia caused by minocycline-sensitive Streptococcus pneumoniae.

A previously healthy 23-year-old white woman had fulminant pneumococcal pneumonia complicated by empyema and bilateral pneumothoraces. Despite early treatment with the recommended doses of minocycline, the disease progressed. The S pneumoniae isolate was resistant to a 30microgram tetracycline disk and showed an MIC of 3.13microgram/ml for minocycline and 12.5 microgram/ml for tetracycline; these levels are considered by the manufacturer to indicate sensitivity to minocycline and intermediate sensitivity to tetracycline. The tetracyclines, including minocycline, should not be used to treat bacterial pneumonia since resistant strains of pneumococci are not uncommon and inffective treatment can lead to rapid progression of the infection. This case suggests that the levels of minocycline considered to indicate sensitivity in vitro be reassessed.

Adult↗

Tri-minocycline: a minocycline complex for parenteral use. I. Antibacterial activity and toxicity data.

Aqueous solutions of tri-minocycline (equivalent to 20--50 mg/ml minocycline HCl) and preconstituted ready-for-use injections were prepared at the pH of blood; these exert high antibiotic activities equal to those of the parent substance. The chloroform/water distribution coefficients of tri-minocycline in the different types of injections were somewhat lower, but in the same order of magnitude as that of the parent substance. The MIC values of tri-minocycline proved to be very low and the LD50 values very high, their separation covering more than 3 orders of magnitude.

Animals↗

Photo-onycholysis from minocycline. Side effects of minocycline therapy.

Minocycline, prescribed for a patient with acne, produced a photosensitivity reaction (photo-onycholysis) involving the fingernails. The onset of this reaction coincided with an increase in sun exposure and cleared several months later, when the drug was discontinued. This type of reaction has been reported to occur in patients taking tetracycline or a member of the tetracycline group of antibiotics, of which minocycline is a member. This appears to be first report of photo-onycholysis due to minocycline.

Acne Vulgaris↗

Minocycline and the thyroid: antithyroid effects of the drug, and the role of thyroid peroxidase in minocycline-induced black pigmentation of the gland.

Minocycline (MN), a member of the tetracycline family of antibiotics, is known to induce a black discoloration of the thyroid in several species, including humans. Antithyroid effects of MN have also been reported. The aim of the present study was two-fold: (1) to determine whether thyroid peroxidase (TPO) is involved in the MN-induced black thyroid, and (2) to obtain information on the effect of MN on TPO-catalyzed iodination and coupling in model systems containing highly purified TPO. Treatment of MN with TPO in the presence of the H2O2 generating system, glucose-glucose oxidase, resulted in the formation of a black product (or products). In phosphate buffer, pH 7.0, the color intensity reached its peak in about 90 min. Control samples without TPO showed little or no color change during this interval. Formation of the black product(s) did not require the presence of iodide. Other members of the tetracycline family were not oxidized to dark products by the TPO system. These results provide definitive evidence that TPO is involved in the MN-induced black thyroid. MN is an inhibitor of TPO-catalyzed iodination in model systems, with a potency comparable to that of MMI and PTU. At low drug concentrations (approximately 25 microM), MN appeared to act as a competitive inhibitor, as previously shown for lower concentrations of MMI and PTU. However, when the drug concentration was increased, MN and the thioureylene drugs inhibited iodination by different mechanisms. With PTU and MMI, iodination was irreversibly inhibited through inactivation of TPO. However, inhibition of iodination by MN (100 microM) was not associated with inactivation of TPO and was at least partially reversible. The most potent inhibitory effect of MN was on TPO-catalyzed coupling. This was demonstrated both in a coupling test system, designed to measure coupling in the absence of iodination, and in an iodination system, in which iodination and coupling occurred simultaneously. In both systems, MN was several times more potent than PTU and MMI, or other tetracycline drugs. Based on the potent antithyroid effects of MN observed in our in vitro studies, it seems advisable to monitor thyroid function in patients receiving long-term MN therapy.

Animals↗

[Bacteriological evaluations of combination therapies with minocycline and beta-lactams for methicillin-resistant Staphylococcus aureus. I. Cefotiam plus minocycline].

Since methicillin-resistant Staphylococcus aureus (MRSA) is resistant to multiple antibiotics, only a limited number of antibacterial agents shows efficacy against this bacteria. Therefore, combination therapy is often attempted for MRSA infections. Most of the MRSA strains recently isolated, however, have been found to show very high resistance, and some of the antibiotics which had previously been effective have been failing to produce good responses in increasing numbers of patients. Thus, the drugs used for combination therapy in MRSA infections need to be reevaluated. We assessed the bacteriological efficacy of cefotiam (CTM) plus minocycline (MINO) therapy against MRSA in an in vitro system (CTM shows relatively strong antibacterial activities against MRSA with moderate resistance, and MINO shows strong antibacterial activities against highly resistant MRSA. 1. Against MINO-susceptible MRSA strains, CTM + MINO demonstrated potent antibacterial activities at MINO concentrations of MIC or sub-MIC levels, irrespective of the MIC of CTM against MRSA strains being tested. 2. Against MINO-resistant MRSA strains (strains for which MICs of MINO exceeded the upper limit of the clinically expected plasma MINO level), CTM + MINO showed no significant antibacterial activity. These results suggested that the effect of this combination was dependent on the antibacterial activity of MINO. Therefore, the usefulness of this combination in patients with MRSA infections can be predicted based on susceptibilities of involved strains to MINO. 3. The potent antibacterial effect of this combination against MINO-susceptible MRSA strains was considered to be the result of damage to the cellular membrane by MINO and the subsequent antibiotic effect of CTM.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefotiam↗

[Bacteriological evaluations of combination therapies with minocycline and beta-lactams for methicillin-resistant Staphylococcus aureus. II. cefuzonam plus minocycline].

We performed an in vitro assessment of the antibacterial activity of therapy with cefuzonam (CZON) plus minocycline (MINO) against methicillin-resistant Staphylococcus aures (MRSA) infections. 1. Studies using MINO-susceptible and MINO-resistant MRSA strains suggested that the antibacterial activity of CZON + MINO was dependent on the antibiotic action of MINO, similarly to the case with cefotiam (CTM) + MINO. 2. The antibacterial activity (including the FIC index) of this combination was slightly inferior to that of CTM + MINO. However, the time course of antibacterial efficacy of CZON + MINO in MRSA pretreated with MINO was comparable to that of CTM + MINO. 3. CZON + MINO appeared to be a very useful combination in patients with mixed infections due to MRSA and Gram-negative bacteria.

Ceftizoxime↗

[In vitro activity of minocycline against Chlamydia trachomatis clinical isolates and clinical efficacy of minocycline to C. trachomatis associated nongonococcal urethritis].

The in vitro activity of minocycline (MINO) against Chlamydia trachomatis and its efficacy in the treatment of C. trachomatis-associated nongonococcal urethritis were investigated. Six isolates of C. trachomatis were inhibited at 0.06 micrograms/ml of MINO and 5 isolates at 0.03 micrograms/ml. All cases received oral MINO twice daily for 7 or more days in doses of 100 mg. In 5 of 31 cases, 2 g of spectinomycin was intramuscularly administrated together with MINO only once. C. trachomatis was eliminated in all cases tested. Excellent results were obtained in 26 cases (84%); urethral discharge and polymorphonuclear cells (PMN) disappeared or decreased to normal levels (3 cells/hpf or less) in these cases. Ureaplasma urealyticum was isolated from 8 cases, 7 of which became free of ureaplasmal infection. MINO seemed to be less effective on the decrease of PMN in the urethral smear in cases infected coincidentally with C. trachomatis and U. urealyticum than in cases infected with C. trachomatis alone. No subjective side effects were observed in any of the 31 cases studied. In conclusion, MINO was a useful antimicrobial agent for the treatment of C. trachomatis- and U. urealyticum-associated nongonococcal urethritis.

Adult↗

The acute effect of minocycline on the pericardium: experimental and clinical findings.

STUDY OBJECTIVES: To evaluate the acute effect of minocycline on the pericardium in the experimental animal and in the human with malignant pericardial disease. DESIGN: A prospective study in open-chest dogs and in humans. SETTING: Experimental surgery laboratory, medical school; coronary care unit, university hospital. METHODS: Twenty-three open-chest dogs were divided into four groups according to the solution injected intrapericardially: (1) minocycline, 5 mg/kg; (2) minocycline, 10 mg/kg; (3) normal saline solution, 100 mL, followed by minocycline, 10 mg/kg; (4) a mixture of 50 mL of the dog's own blood mixed ex vivo with minocycline, 10 mg/kg to evaluate the effect of rising pH of minocycline solution. The extent of myocardial injury is evaluated by measuring ST-T segment deviation in six standard bipolar leads and in three unipolar electrograms recorded over the left ventricular pericardial surface. The pH of the various minocycline solutions is measured. Nine consecutive patients with malignant cardiac tamponade receiving minocycline intrapericardially are evaluated for the appearance of chest pain and ECG changes. RESULTS: Minocycline (5 and 10 mg/kg) caused marked, transient ST-T segment deviation in all dogs, whether or not saline solution was previously injected into the pericardial sac. Prior mixing of minocycline with blood markedly increased the acidic pH of the minocycline solution and significantly reduced the extent of ST-T segment deviation. Four of nine patients had chest pain during minocycline injection. None had ST-T segment changes. CONCLUSION: Minocycline causes a marked, transient injury to the epicardial-pericardial surface. Our animal and in vitro studies indicate that this acute injury is probably partly related to the acidic pH of the minocycline solution. Our experimental findings suggest that this minocycline-induced injury may be reduced by raising the pH of the solution either ex vivo (eg, by mixing minocycline with previously withdrawn pericardial fluid) or in vivo (eg, by leaving 200 to 300 mL of pericardial fluid prior to minocycline injection). Limited experience in the human with malignant cardiac tamponade indicates that intrapericardial minocycline is usually well tolerated, although severe chest pain may appear.

Animals↗

In vitro response of human gingival epithelioid S-G cells to minocycline.

Minocycline, a broad-spectrum antibiotic used in the treatment of acne and periodontal disease and to control inflammatory diseases such as rheumatoid arthritis, has recently been shown to induce a spectrum of adverse health effects. In the light of these contradictory data, this research was directed to provide basic information on the toxicology of minocycline, using in vitro cell culture models, and to evaluate its efficacy in periodontal therapies, particularly for wound healing. The human gingival epithelioid S-G cell line was used as the bioindicator. The greater toxicity of minocycline over doxycycline and tetracycline, related antimicrobial agents, probably correlated with its higher lipophilicity. The cytotoxicity of minocycline was unaffected by an S9 hepatic microsomal fraction, indicating that it is a direct-acting, rather than a metabolism-mediated, cytotoxicant. In comparative toxicity studies, much variation in the degree of sensitivity to minocycline was noted for different cell types. No correlation in the extent of sensitivity to minocycline and the physiologic state of the bioindicator cell (normal, transformed or malignant) was noted. The toxicity of minocycline to the S-G cells was dependent on its concentration and length of exposure. For a continuous 3-day exposure of the S-G cells to minocycline, the midpoint cytotoxicity (or, NR(50)) value, as quantified in the neutral red (NR) assay, was 204 microg/ml on day 1, 84 microg/ml on day 2, and 59 microg/ml on day 3. For a 1-h exposure of the S-G cells in phosphate buffered saline (PBS), the NR(50) value was 780 microg/ml minocycline. Although a 1-h exposure in PBS to 200 microg/ml minocycline exerted some toxicity, the S-G cells recovered on exposure to growth medium; irreversible, progressive damage occurred at 400 microg/ml minocycline and greater. Minocycline, at 50 microg/ml, enhanced attachment of the S-G cells to a gelatin-coated surface and cell migration towards an immobilized fibronectin gradient, both biologic parameters important in periodontal wound healing. Minocycline generally had little or no effect on production of the pro-inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8), by non-activated S-G cells, the exception being stimulation of IL-6 at 48 h. IL-1beta, however, greatly stimulated IL-6 and IL-8 production, which was further increased by concurrent exposure to minocycline. This suggested that minocycline may enhance the ability of gingival epithelial cells to participate in the early, inflammatory phase of periodontal wound healing. The limitation of minocycline efficacy to a rather narrow window of concentration, centering about 50 microg/ml, and primarily for short-term exposures may possibly explain, in part, the contradictory clinical data on the health effects of this drug.

Animal Testing Alternatives↗

Minocycline microspheres: a complementary medical-mechanical model for the treatment of chronic periodontitis.

Locally delivered antimicrobials represent an expanding class of therapeutics that may complement conventional mechanical treatments for chronic periodontitis. Currently available locally delivered antimicrobials include a tetracycline fiber, chlorhexidine chip, doxycycline gel, and newly approved minocycline microspheres. This last therapeutic is formulated to contain 3 mg polyglycolide-co-dl lactide (PGLA) copolymer and 1 mg of minocycline per unit (pocket) dose. As the polymer microspheres resorb, minocycline is released locally within the periodontal pocket at effective concentrations for at least 14 days. Recently, three phase 3 human clinical trials were conducted to assess the efficacy and safety of minocycline microspheres in patients with moderate-to-advanced chronic periodontitis. Data from an open-label trial involving 173 subjects indicated that minocycline microspheres plus scaling and root planing (SRP) at baseline produced significant improvements in pocket depth (PD) (> or = 1.5 mm) at 1 and 3 months. Retreatment with minocycline microspheres at 3 and 6 months maintained these improvements for 12 months. Two concurrent, blinded studies cumulatively recruited 748 periodontitis subjects who were randomized to SRP plus minocycline microspheres, SRP plus vehicle (placebo), or SRP alone at baseline. Minocycline microspheres or the vehicle were readministered per the randomization at 3 and 6 months. Patients receiving minocycline microspheres plus SRP exhibited significantly greater PD reduction at 1, 3, 6, and 9 months compared to patients receiving SRP plus vehicle or SRP alone. Overall, mean PD reduction with adjunctive minocycline-microsphere treatment increased when patients with more advanced periodontitis (mean PD > or = 6 mm or 7 mm) were considered. Similarly, significant improvements in clinical attachment level and percent bleeding on probing were observed among advanced periodontitis patients treated with SRP plus minocycline microspheres relative to controls. Patients treated with minocycline microspheres plus SRP were 50% more likely to shift to an overall mean PD < 5 mm or to a more maintainable case definition. No increased incidence of adverse events or tetracycline resistance were observed with minocycline-microsphere treatment. The data from these clinical trials indicate that minocycline microspheres plus SRP are safe in patients and more effective than SRP alone in reducting the signs of chronic periodontitis.

Analysis of Variance↗

Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data.

OBJECTIVE: Minocycline is an antibacterial drug used in the treatment of acne. Concern has been expressed over the possibility of severe adverse reactions to minocycline, including hepatitis. This study set out to identify and characterise reported cases of hepatotoxicity associated with the use of minocycline. METHODS: A systematic review of the literature including a search of computerised databases and analysis of data from the Uppsala Monitoring Centre (WHO Collaborating Centre for International Drug Monitoring) was conducted. The review involved a search for original case reports involving liver damage in people using minocycline. Patients taking minocycline for reasons other than acne or those given intravenous minocycline were excluded. The search strategy involved an enquiry of computerised databases and a search for secondary references. Cases were then classified appropriately. RESULTS: 65 reported cases of hepatitis or liver damage in association with minocycline from either case reports or case series were identified from the literature review. 58% of cases occurred in females and 94% were aged under 40 years. For 20 case reports there was insufficient information to classify the type of event, but for the remaining 45, 2 types of hepatic reaction were recognised: autoimmune hepatitis associated with lupus-like symptoms occurring after a median duration of exposure to minocycline of 365 days in females (n = 20) and 730 days in males (n = 9), hypersensitivity reaction associated with eosinophilia and exfoliative dermatitis occurring within 35 days of therapy (n = 16). Reports to the WHO of hepatic adverse drug reactions associated with minocycline accounted for 6% (493) of all minocycline-related adverse drug reactions (8025). The pattern of distribution in relation to exposure demonstrated 2 groups, similar to that described by the case reports. CONCLUSIONS: Severe cases of minocycline-associated hepatotoxicity appear to be a hypersensitivity reaction and occur within a few weeks of commencing therapy. An autoimmune hepatitis usually presents after exposure to minocycline of a year or more, is more common in women and is sometimes associated with lupus-like symptoms.

Adolescent↗

Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat.

It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 microl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection. These results demonstrate the anti-nociceptive effect of minocycline on formalin-induced inflammatory pain. In addition to the well-known inhibitory action of minocycline on microglial activation, the anti-edematous action in peripheral tissue, as well as the inhibition of synaptic transmission in SG neurons, is likely to be associated with the anti-nociceptive effect of minocycline.

Animals↗

Safety of doxycycline and minocycline: a systematic review.

OBJECTIVE: The goal of this review was to summarize the available literature covering the safety profiles of oral doxycycline and minocycline. METHODS: Scientific literature published between 1966 and August 2003 was searched using the MEDLINE, EMBASE, and Biosis databases (search terms: minocycline or doxycycline, each paired with adverse reaction, adverse event, and side effect, and doxycycline or minocycline with the limits English language, human, and clinical trials). Safety information was collected from case reports and clinical trials. Adverse event (AE) rates in the United States were calculated by comparing data from the MedWatch AE reporting program used by the US Food and Drug Administration (FDA) with the number of new prescriptions dispensed for each drug from January 1998 to August 2003. RESULTS: Between 1966 and 2003, a total of 130 and 333 AEs were published in case reports of doxycycline and minocycline, respectively. In 24 doxycycline clinical trials (n = 3833) and 11 minocycline trials (n = 788), the ranges in incidence of AEs were 0% to 61% and 11.7% to 83.3%, respectively. Gastrointestinal AEs were most common with doxycycline; central nervous system and gastrointestinal AEs were most common with minocycline. From January 1998 to August 2003, the FDA MedWatch data contained 628 events for doxycycline and 1099 events for minocycline reported in the United States. Approximately 47,630,000 doxycycline and 15,234,000 minocycline new prescriptions were dispensed in the United States during that period, yielding event rates of 13 per million for doxycycline and 72 per million for minocycline, based on FDA data. CONCLUSIONS: Between 1998 and 2003, doxycycline was prescribed 3 times as often as minocycline. The incidence of AEs with either drug is very low, but doxycycline had fewer reported AEs. Although more head-to-head clinical trials are needed for a direct comparison of AE frequency, these preliminary data from separate reports suggest the possibility that AEs may be less likely with doxycycline than minocycline.

Acne Vulgaris↗

Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine.

The effects of minocycline on behavioral changes and neurotoxicity in the dopaminergic neurons induced by the administration of methamphetamine (METH) were studied. Pretreatment with minocycline (40 mg/kg) was found to attenuate hyperlocomotion in mice after a single administration of METH (3 mg/kg). The development of behavioral sensitization after repeated administration of METH (3 mg/kg/day, once daily for 5 days) was significantly attenuated by pretreatment with minocycline (40 mg/kg). A reduction in the level of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenyl acetic acid (DOPAC), in the striatum after the repeated administration of METH (3 mg/kg x 3, 3-h interval) was attenuated in a dose-dependent manner by pretreatment with and the subsequent administration of minocycline (10, 20, or 40 mg/kg). Furthermore, minocycline (40 mg/kg) significantly attenuated a reduction in DA transporter (DAT)-immunoreactivity in the striatum after repeated administration of METH. In vivo microdialysis study demonstrated that pretreatment with minocycline (40 mg/kg) significantly attenuated increased extracellular DA levels in the striatum after the administration of METH (3 mg/kg). In addition, minocycline was not found to alter the concentrations of METH in the plasma or the brain after three injections of METH (3 mg/kg), suggesting that minocycline does not alter the pharmacokinetics of METH in mice. Interestingly, METH-induced neurotoxicity in the striatum was significantly attenuated by the post-treatment and subsequent administration of minocycline (40 mg/kg). These findings suggest that minocycline may be able to ameliorate behavioral changes as well as neurotoxicity in dopaminergic terminals after the administration of METH. Therefore, minocycline could be considered as a useful drug for the treatment of several symptoms associated with METH abuse in humans.

Animals↗