Minocycline

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Minocycline belongs to the tetracycline class of antibiotics and is used to manage and treat both infectious and non-infectious conditions. In addition to its effectiveness against both gram-positive and gram-negative bacteria, minocycline also exhibits anti-inflammatory, antioxidant, anti-apoptotic, and immunomodulatory properties. Furthermore, this medication is recognized as the most effective tetracycline derivative in terms of its ability to provide neuroprotective effects. This activity describes minocycline's mechanism of action, indications, and contraindications as a valuable agent in treating and managing bacterial infections and conditions such as acne, neurodegenerative diseases, periodontitis, and dermatitis. This activity also highlights the adverse event profile, dosing, pharmacodynamics, pharmacokinetics, monitoring, and other relevant interactions of minocycline. These are crucial considerations for healthcare professionals engaged in treating patients with the conditions mentioned above.

Objectives:

  • Identify the diverse indications of minocycline encompassing bacterial infections, acne, neurodegenerative disorders, periodontitis, and dermatitis.

  • Implement appropriate dosing strategies and treatment regimens for patients receiving minocycline therapy while considering their age, weight, and renal function factors.

  • Apply evidence-based guidelines and clinical protocols to optimize minocycline therapy for various conditions in specific patient populations.

  • Communicate effectively with patients about the benefits, potential risks, and expectations of minocycline therapy, ensuring informed decision-making.

Indications

Minocycline is a semi-synthetic second-generation tetracycline and a broad-spectrum antibiotic. This drug was synthesized in 1967 for managing and treating numerous infectious and non-infectious diseases. Furthermore, minocycline's anti-infectious potency aligns closely with that of other tetracyclines. In addition to its effectiveness against both gram-positive and gram-negative bacteria, minocycline exhibits anti-inflammatory, antioxidant, anti-apoptotic, and immunomodulatory properties. This medication is also recognized as the most effective tetracycline derivative in terms of its ability to provide neuroprotective effects. This distinction arises from its high lipophilicity, enabling it to traverse the blood-brain barrier with exceptional efficacy.[1]

In general, it has been observed that an individual susceptible to tetracycline may also be susceptible to minocycline.[2] Minocycline's spectrum of coverage includes Borrelia recurrentis, Mycobacterium marinum, Mycoplasma pneumoniae, Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, Vibrio vulnificus, and susceptible strains of vancomycin-resistant Enterococcus. Minocycline is also used in the treatment of rickettsial infections, chlamydial infections, syphilis, pelvic inflammatory disease, acne, nocardiosis, brucellosis, ehrlichiosis, amebiasis, actinomycosis, anaplasmosis, leptospirosis, melioidosis, tularemia, traveler's diarrhea, early-stage Lyme disease, Legionnaire disease, and Whipple disease.[3] 

According to the Infectious Diseases Society of America (IDSA) 2022 guidelines, minocycline has been recognized as an effective medication against carbapenem-resistant Acinetobacter baumannii and Stenotrophomonas maltophilia.[4]

Off-Label Uses

Various off-label uses of minocycline include rosacea, bullous dermatoses, neutrophilic diseases, pyoderma gangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, and autoimmune disorders such as scleroderma and rheumatoid arthritis, according to the American College of Rheumatology guidelines.[5][6][7]

Mechanism of Action

Protein synthesis occurs through ribosomes in both eukaryotic and prokaryotic cells, facilitating the transformation of messenger RNA (mRNA) codes into functional proteins. The ribosomes in prokaryotic cells consist of the 30S and 50S subunits, whereas in eukaryotic cells, they consist of the 40S and 60S subunits. In prokaryotic and eukaryotic organisms, the 2 ribosomal subunits converge at the mRNA template, facilitating the transfer RNA (tRNA) to transport an amino acid and form cellular proteins by elongating amino acid chains.

Tetracyclines, such as minocycline, bind to the 30S ribosomal subunit, preventing charged tRNA from delivering amino acids to elongate the protein chain and develop a cellular protein. This disruption results in a bacteriostatic impact on the prokaryotic cell, causing the organism to lose its capability to grow or replicate.[8] 

Tetracyclines are lipid-soluble compounds capable of transportation across hydrophobic barriers, including biological membranes. Their lipophilic nature enables rapid absorption and distribution throughout the organism. Among tetracyclines, minocycline exhibits greater lipophilicity than doxycycline, resulting in elevated concentrations in the central nervous system (CNS) and the skin.[9]

Minocycline is accessible for administration in both oral and parenteral formulations. The intravenous (IV) route has been used to treat conditions such as pneumonia, bloodstream infections, and skin and skin structure infections.

Pharmacokinetics

Absorption: Oral forms are absorbed within the stomach and proximal small intestine. Absorption rates depend on the presence of food, especially items containing divalent cations such as calcium. These cations chelate with minocycline and other tetracyclines, rendering them non-absorbable.[10]

Distribution: Due to its enhanced lipophilicity compared to other tetracyclines, such as doxycycline, minocycline attains elevated concentrations in the CNS and the skin. Minocycline achieves a greater concentration in saliva compared to tetracycline and doxycycline, accounting for the drug's effectiveness in addressing the meningococcal carrier stage. The volume of distribution ranges from 0.14 to 0.7 L/kg.[9]

Metabolism: The primary metabolic pathways for minocycline involve hydroxylation and N-demethylation, primarily mediated by the enzyme CYP3A4.[11]

Elimination: The serum half-life of minocycline varies between 11 and 24 hours, with an average of 17 hours. Approximately 5% to 12% of minocycline is eliminated unchanged in the urine.[12]

Administration

Available Dosage Forms and Strengths

Minocycline is available in various forms, including oral tablets, capsules, IV injections, and topical foam. The available dosage forms and strengths of minocycline are as follows:

  • Oral capsules: These are available in strengths of 50 mg, 75 mg, and 100 mg.
  • Extended-release oral capsules (24-hour): These are offered in strengths of 45 mg, 90 mg, and 135 mg.
  • Oral tablets: These are provided in strengths of 50 mg, 75 mg, and 100 mg.
  • Extended-release oral tablets (24-hour): These are available in strengths of 45 mg, 55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg, and 135 mg.
  • IV solution: IV solution, when reconstituted, provides a concentration of 100 mg per vial.
  • Topical foam: This is available in 2 variations, including a 1.5% aerosol foam and a 4% aerosol foam.

Adult Dosage

Consuming adequate amounts of liquid when ingesting oral capsules or tablets from the tetracycline drug class is recommended to mitigate the risk of esophageal irritation and ulceration. The standard recommended oral dosage regimen for minocycline capsules or tablets typically involves an initial dose of 200 mg, followed by 100 mg of minocycline every 12 hours. The typical oral dosage for pediatric patients aged 8 or older is 4 mg/kg of minocycline initially, followed by 2 mg/kg of minocycline every 12 hours.

The below points outline the diverse applications of minocycline in medical treatment, emphasizing distinct treatment durations and dosage recommendations for optimal outcomes.

  • Acne vulgaris finds an effective remedy in minocycline, as underscored by the American Academy of Dermatology guidelines.[13]
  • Uncomplicated gonococcal infections, excluding urethritis or anorectal infections in men, undergo a 4-day treatment regimen with minocycline, complemented by post-therapy cultures conducted within 2 to 3 days.
  • Uncomplicated gonococcal urethritis in men necessitates a 5-day minocycline treatment course for effective resolution.
  • Syphilis management entails a treatment period of 10 to 15 days with minocycline, accompanied by meticulous follow-up and laboratory assessments.
  • For individuals with the meningococcal carrier state, the advised minocycline dosage is 100 mg every 12 hours for 5 days.
  • In treating M marinum infection, while optimal doses of the medication remain unspecified, a successful approach has been observed with 100 mg of minocycline administered every 12 hours for 6 to 8 weeks, albeit in a limited patient cohort.
  • For adults dealing with uncomplicated endocervical, urethral, or rectal infections attributed to Chlamydia trachomatis or Ureaplasma urealyticum, an effective regimen involves an oral dosage of 100 mg of minocycline administered every 12 hours for a minimum duration of 7 days.

Extended-release formulation dosage

The recommended oral dosage for the extended-release form of minocycline is 1 mg/kg, administered to patients once daily and sustained over 12 weeks. Notably, administering higher doses of minocycline to patients has not demonstrated added advantages in addressing inflammatory acne lesions, potentially leading to an increased occurrence of acute vestibular adverse effects. 

IV dosage

Minocycline IV therapy is recommended for patients who cannot tolerate the oral form of the treatment. However, oral therapy should be initiated at the earliest convenience. Prolonged IV therapy might lead to thrombophlebitis; therefore, caution is advised against rapid administration to mitigate such risks.

  • The recommended initial IV dosage of minocycline for adults is 200 mg, followed by an additional 100 mg administered intravenously over 60 minutes every 12 hours. Notably, the total dosage should not exceed 400 mg within a 24-hour time frame.
  • The standard initial dosing of minocycline for pediatric patients is 4 mg/kg, followed by 2 mg/kg of the medication administered over a 60-minute duration every 12 hours. Notably, pediatric dosages should not exceed the recommended adult dosage recommendations.

The lyophilized powder for injection necessitates reconstitution of minocycline with 5 mL of sterile water for injection USP, followed by immediate additional dilution in a solution of 100 mL to 1000 mL containing dextrose injection USP, sodium chloride injection USP, dextrose or sodium chloride injection USP, or 250 mL to 1000 mL of lactated Ringer injection USP. Minocycline should not be diluted with calcium solutions due to the risk of precipitate formation, particularly in neutral or alkaline solutions. After dilution into an IV bag, the injection can be stored at room temperature for a maximum of 4 hours or refrigerated at 36 °F to 46 °F (or 2 °C to 8 °C) for up to 24 hours. Any remaining unused portions of the medication must be discarded after the designated time frame.

Topical foam 

The minocycline topical foam should be gently applied as a thin layer over the affected facial area to treat inflammatory lesions of rosacea in adults. This application should occur around the same time each day, with a recommended interval of at least 1 hour before bedtime. In addition, patients are advised to refrain from showering, bathing, or swimming for at least 1 hour after applying the medication.[14]

Specific Patient Populations

Hepatic impairment: No dosage adjustment is necessary for patients with impaired hepatic function. However, it is essential to exercise caution, as cases of hepatotoxicity have been reported with minocycline use.[15]

Renal impairment: For patients with compromised renal function, it is advisable to lower the total daily minocycline dosage by reducing the prescribed individual patient doses or extending the time intervals between them.

Pregnancy considerations: Minocycline is classified by the U.S. Food and Drug Administration (FDA) as a pregnancy Category D medicine. Due to their potential for permanent discoloration of teeth and impairment of long bone growth in the fetus, pregnant women should avoid tetracyclines.[16] Notably, the use of topical minocycline products is not contraindicated during pregnancy.

Breastfeeding considerations: Existing literature suggests that short-term usage of minocycline by nursing mothers is deemed acceptable. This is attributed to the low levels of minocycline excreted in breast milk and the fact that the calcium present in breast milk inhibits the infant's additional absorption of the drug. Caution should be exercised against prolonged or repeated courses of minocycline during breastfeeding. The breastfed infant must be vigilantly observed for any signs of rash, diarrhea, or candidiasis, which includes symptoms such as thrush or diaper rash. In addition, nursing mothers should be aware that minocycline usage has been associated with instances of black discoloration in breast milk.[17]

Pediatric patients: According to IDSA guidelines, minocycline is recommended for treating infections caused by S aureus in patients aged 8 and older.[18]

Older patients: Due to the potential for impaired hepatic and renal function, it is prudent to commence with a lower starting dose of minocycline for older populations. In addition, caution must be exercised when treating patients concurrently taking multiple medications with minocycline due to the potential for drug interactions.[19]

Adverse Effects

Frequently encountered adverse effects of minocycline encompass gastrointestinal distress and heightened photosensitivity. Instances of skin hyperpigmentation and nail discoloration are also feasible. Although children are more prone to teeth staining and bone growth inhibition, reports indicate that these effects may occur even in adults. The prevalence of tooth discoloration attributed to minocycline use is estimated to be within the range of 3% to 6%.[20][21] Notably, hepatotoxicity is a potential concern associated with minocycline usage, and therefore a risk of exacerbating preexisting renal failure should also be considered.[15]

Pill esophagitis, characterized by symptoms such as chest pain, odynophagia, and dysphagia, has been documented as an adverse effect of minocycline. This effect can be mitigated by consuming oral minocycline formulations with sufficient water and maintaining an upright posture after ingesting the medication.[22] Although adverse effects caused by minocycline treatment are infrequent, the elevated concentrations of the drug in the CNS compared to other tetracyclines contribute to the dose-limiting vestibular adverse effects such as nausea, vomiting, vertigo, dizziness, or hearing loss.[23][24] Studies have additionally established a connection between the utilization of tetracyclines and the occurrence of idiopathic intracranial hypertension, also known as pseudotumor cerebri.

A reported association exists between minocycline use and systemic lupus erythematosus (SLE), with a reported risk of 8.8 cases per 100,000 person-years.[25] In addition, tetracycline usage has been associated with correlations to drug-induced pancreatitis.[26] Similar to other antibiotics, minocycline increases the risk of Clostridium difficile infection development. However, the risk is comparatively lower than that associated with other antibiotics.[27] Minocycline use is associated with dermatological reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), leading to fatal outcomes. As a result, immediate discontinuation of minocycline is imperative if symptoms of DRESS are identified.

Drug-Drug and Drug-Food Interactions

Understanding the potential interactions between minocycline and other drugs or food is crucial for optimizing treatment efficacy and patient safety.

Minerals: Supplements or food containing minerals, such as calcium, magnesium, folate, or iron, can lead to a reduction in the blood concentration of minocycline. Hence, whenever feasible, patients are advised to refrain from taking both the medication and minerals simultaneously. When coadministration cannot be circumvented, it is recommended to administer these substances at least 2 hours before or 4 hours after the oral administration of minocycline.[28] This principle also extends to calcium-rich foods; therefore, individuals should avoid consuming dairy products, such as milk, yogurt, cheese, or ice cream, along with their medication. However, patients do not have to eliminate dairy from their diet, but they should ensure that these foods are consumed at least 1 hour before or 2 hours after taking minocycline.

Antacids: Antacids, including aluminum hydroxide, calcium carbonate, and magnesium hydroxide, can reduce the absorption of tetracyclines by creating insoluble chelate complexes with these medications.[29]

Isotretinoin: The simultaneous use of isotretinoin and minocycline should be avoided during therapy due to the elevated risk of pseudotumor cerebri.[30]

Ergotism: Combining tetracycline derivatives with ergot alkaloids, such as ergotamine and dihydroergotamine, can result in a heightened risk of ergotism and acute limb ischemia. Consequently, it is advised to steer clear of this combination.[31]

Drug-laboratory test interactions: The administration of minocycline therapy can generate false-positive urinary catecholamine levels, even in the absence of pheochromocytoma.[32]

Contraindications

As all tetracyclines, including minocycline, can cross the placental barrier, they are contraindicated during pregnancy. The additional risk associated with hepatotoxicity in pregnant individuals is also a factor that underscores the importance of avoiding the use of this drug in such cases.[33][34] Individuals aged 8 or younger should avoid using minocycline to prevent permanent teeth discoloration for teeth that have not yet erupted. Therefore, pediatric patients between the ages of 13 and 19 should avoid minocycline use until all of their tooth crowns have developed.[35] Clinicians should be aware that the administration of expired tetracyclines can lead to the development of Fanconi syndrome.[36]

Although avoiding most tetracycline group medications in patients with chronic renal failure is generally recommended, it is essential to note that renal function does not influence minocycline elimination.[37] Higher doses of minocycline have been observed to elevate urea excretion in healthy individuals. However, in cases of kidney impairment, minocycline's catabolic effects can potentially exacerbate uremia. Hence, closely monitoring both minocycline therapeutic doses and renal function in patients with renal failure is essential to prevent the worsening of uremia.[38]

Monitoring

A prolonged therapeutic dosage of minocycline up to 200 mg daily is considered safe and well tolerated. The majority of adverse effects, such as nausea and dizziness, typically manifest shortly after the administration of minocycline and tend to subside soon after discontinuing the medication. Baseline measurements of blood urea nitrogen (BUN) and serum creatinine should be obtained for patients, and regular monitoring should be maintained thereafter. Clinicians advise that after 6 months of minocycline treatment, all patients should undergo an assessment every 3 months to detect potential adverse effects, including hepatotoxicity, pigmentation issues, and the onset or progression of SLE.[7] 

After administering 200 mg of minocycline intravenously, peak serum concentrations are observed within a range of 3 to 8.75 mg/L.[10] The half-life of minocycline can vary from 13 hours for a single oral dose of 200 mg to 21 hours for a single IV dose of 200 mg. Studies indicate that serum concentration levels of minocycline do not correlate with renal function, and approximately 20% to 35% of the dose is eliminated through feces. Consequently, neither renal impairment nor end-stage renal disease significantly impacts the serum concentration or half-life of minocycline.[39]

Minocycline's anti-anabolic effect can potentially result in an elevation of BUN. Patients with normal renal function typically do not encounter adverse effects. However, in significantly impaired renal function cases, minocycline administration can lead to complications such as azotemia, hyperphosphatemia, and acidosis. Given these circumstances, conducting regular monitoring of BUN and creatinine levels is advisable.[40]

Regularly monitoring the prothrombin time–international normalized ratio (PT/INR) and making appropriate dosage adjustments for warfarin is recommended when coadministering with minocycline.[41][42]

Toxicity

Common adverse effects and autoimmune reactions necessitate discontinuing minocycline and transitioning to an alternative antibiotic outside the tetracycline class. Interprofessional healthcare team members should be aware that minocycline carries a significantly higher risk of developing SLE than other tetracyclines. Consequently, a heightened level of suspicion is essential, and if symptoms manifest, immediate discontinuation of the medication alongside appropriate supportive measures is strongly recommended.[25][3]

The adverse events that are more frequently observed in cases of minocycline overdose include dizziness, nausea, and vomiting. There is no specific antidote available for minocycline. In the case of minocycline overdosage, the appropriate precautionary steps include discontinuing the medication, addressing the patient's symptoms symptomatically, and implementing supportive measures.[15]

Minocycline cannot be effectively removed substantially through hemodialysis or peritoneal dialysis. The underlying mechanism behind drug-induced hepatotoxicity associated with minocycline is immunological. Autoimmune hepatitis caused by minocycline can lead to fatal outcomes; therefore, discontinuing minocycline usage is recommended. Corticosteroids and immunosuppressive agents are used to treat minocycline-induced autoimmune hepatitis.[15]

Enhancing Healthcare Team Outcomes

Although minocycline utilization has diminished due to apprehensions about factors such as irreversible pigmentation, high cost, and teratogenic effects, it remains imperative for the interprofessional healthcare team to have a comprehensive understanding of the drug's indications and potential adverse effects when contemplating its use. The escalating prevalence of antibiotic resistance within the community could potentially lead to a resurgence in the utility and widespread prescription of this antibiotic. Dermatologists frequently prescribe minocycline for the treatment of acne. Seeking consultation from infectious disease specialists is critical to address cases involving carbapenem-resistant microorganisms.

Using targeted drug-susceptibility therapy not only benefits individual patients but also contributes to the well-being of society as a whole. Infectious disease specialists and pharmacists typically possess the most recent antibiogram data, making their expertise invaluable in this approach. The entire interprofessional healthcare team must engage in collaborative efforts to ascertain the suitability of minocycline as the appropriate therapeutic agent. In addition, it is essential to ensure that the patient comprehends both the potential risks and benefits associated with the medication. Clinicians and pharmacists should provide patients with comprehensive guidance concerning potential adverse effects and the importance of adhering to the prescribed regimen. In instances of pseudotumor cerebri, seeking consultation from both a neurologist and an ophthalmologist is essential. In cases of minocycline-induced autoimmune hepatitis, seeking consultation from a gastroenterologist or hepatologist is imperative. Emergency medicine physicians, advanced practice practitioners, and nursing staff should swiftly stabilize patients in the event of an overdose.

Effective collaboration within the interprofessional healthcare team is critical in enhancing patient outcomes by diminishing the occurrence of adverse drug reactions. This approach enhances the likelihood of patient compliance with medication regimens and contributes to a reduction in morbidity and mortality rates.[43] 

The interprofessional team approach involves a collective effort of physicians, specialists, advanced practice practitioners, nursing staff, and pharmacists, with a specific emphasis on infectious disease specialty pharmacists. This team collaborates cohesively, leveraging their respective expertise, fostering open communication, and participating in shared decision-making to optimize patient outcomes related to minocycline therapy and minimize preventable adverse drug reactions.

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Simon Nazarian

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Hossein Akhondi

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