Continuing Education Activity

Minocycline is a medication used to manage and treat both infectious and non-infectious conditions. It is in the tetracycline class of antibiotics. This activity describes the indications, action, and contraindications for minocycline as a valuable agent in the treatment and management of bacterial infections and conditions such as acne, neurodegenerative conditions, periodontitis, and dermatitis. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent to members of the healthcare team involved in the treatment and management of patients with conditions mentioned above.

Objectives:

• Identify the mechanism of action of minocycline.
• Describe the potential adverse effects of minocycline.
• Summarize the appropriate monitoring for patients receiving minocycline.
• Review the importance of collaboration and communication amongst the interdisciplinary team to improve outcomes for patients receiving minocycline.

Indications

Minocycline is a semi-synthetic second-generation tetracycline antibiotic. Synthesized in 1967, it is a broad-spectrum antibiotic used in the management and treatment of many infectious and non-infectious diseases, with similar anti-infectious activity to that of other tetracyclines. Aside from anti-infectious activity against both gram-positive and gram-negative bacteria, it also has anti-inflammatory, anti-oxidant, anti-apoptotic, and immunomodulatory effects. It is known to be the most effective tetracycline derivative at providing neuroprotective effects, as it is a highly lipophilic molecule that can cross the blood-brain barrier.[1]

Susceptibility to tetracycline is typically predictive of susceptibility to minocycline.[2] Minocycline covers Borrelia recurrentis, Mycobacterium marinum, Mycoplasma pneumoniae, Staphylococcus aureus (including MRSA), Acinetobacter baumannii, Vibrio vulnificus, and susceptible strains of vancomycin-resistant enterococcus (VRE). Minocycline is also used to treat rickettsial infections, chlamydial infections, syphilis, pelvic inflammatory disease, acne, nocardiosis, brucellosis, ehrlichiosis, amebiasis, actinomycosis, anaplasmosis, leptospirosis, melioidosis, tularemia, traveler's diarrhea, Lyme disease (early stage), Legionnaire disease, and Whipple disease.[3] 

Nonantibiotic indications for minocycline include rosacea, bullous dermatoses, neutrophilic diseases, pyoderma gangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, as well as autoimmune disorders such as rheumatoid arthritis and scleroderma.[4][5]

Mechanism of Action

Protein synthesis occurs through ribosomes in both eukaryotic and prokaryotic cells, which translate messenger RNA (mRNA) codes into functioning proteins. Prokaryotic cells use the 30S and 50S subunits of ribosomes, and eukaryotic cells use the 40S and 60S subunits of ribosomes. In both prokaryotic and eukaryotic organisms, the two ribosomal subunits combine at the mRNA template to allow for transfer RNA (tRNA) to bring an amino acid and form cellular proteins via elongation of amino acid chains. 

Tetracyclines, and extension minocycline, bind to the 30S ribosomal subunit, preventing the charged tRNA from bringing an amino acid to elongate the amino acid chain and form a cellular protein. Halting this process results in a bacteriostatic effect on the prokaryotic cell, wherein the organism can no longer grow or replicate.[6]

Tetracyclines are lipid-soluble compounds capable of transportation across hydrophobic barriers such as biological membranes. Due to their lipophilicity, they are rapidly absorbed and distributed throughout the organism.

Minocycline is more lipophilic than other tetracyclines, such as doxycycline; thus, it achieves higher concentrations in the central nervous system (CNS) and skin.[7]

Minocycline is available for administration in both oral and parenteral forms. Oral forms are absorbed in the stomach and proximal small intestine. Absorption rates are dependent on the presence of food, particularly products containing divalent cations such as calcium, which chelates minocycline and other tetracyclines rendering them unabsorbable. It can also be administered intravenously (IV). The IV route has seen use in the treatment of pneumonia, bloodstream infections, as well as skin and skin structure infections.[8]

Administration

Dosage Forms: Minocycline is available in oral tablets, capsules, intravenous injection, and topical foam.

• Oral capsule: 50 mg, 75 mg, and 100 mg
• Oral capsule extended release (24 hour): 45 mg, 90 mg, and 135 mg
• Oral tablet: 50 mg, 75 mg, 100 mg
• Oral tablet extended release (24 hour): 45 mg, 55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg, and 135 mg
• Intravenous, solution reconstituted: 100 mg (each vial)
• Topical, foam: 1.5% aerosol foam, 4% aerosol foam

Adult Dose: Ingestion of adequate amounts of liquid along with oral capsules or tablets for the tetracycline drug class is recommended to reduce the risk of esophageal irritation and/or ulceration. The usual recommended oral dosage of minocycline capsules or tablets is 200 mg initially, followed by 100 mg minocycline every 12 hours. For pediatric patients age eight years or older, the usual oral dosage is minocycline 4 mg/kg,  followed by 2 mg/kg minocycline every 12 hours.

• Uncomplicated gonococcal infections other than urethritis or anorectal infections in men are treated for four days or more, with post-therapy cultures done within 2-3 days.
• Uncomplicated gonococcal urethritis in men is treated for five days.
• Syphilis is treated for 10 to 15 days with close follow-up, including laboratory tests.
• For treatment of meningococcal carrier state, the recommended minocycline dosage is 100 mg every 12 hours for a total of five days.
• Mycobacterium marinum infection treatment optimal doses are not established, but 100 mg every 12 hours for six to eight weeks has been used successfully in a limited number of patients.
• Uncomplicated endocervical, urethral, or rectal infections in adults caused by Chlamydia trachomatisor Ureaplasma urealyticum: 100 mg orally, every 12 hours for seven days or more.

Extended-release Formulation Dose: The recommended oral dosage of minocycline extended-release form is usually 1 mg/kg once daily for 12 weeks. Higher doses haven't shown additional benefit in treating inflammatory acne lesions and might be associated with a higher frequency of acute vestibular side effects. 

Intravenous Dose: IV therapy is indicated only when a patient can not take it orally or oral therapy is inadequate. Switch to oral therapy as soon as possible. If IV therapy is given over prolonged periods, thrombophlebitis may result. Rapid administration should be avoided.

• The initial adult dose is 200 mg, followed by 100 mg administered IV over 60 minutes every 12 hours, not to exceed 400 mg in 24 hours.
• The usual pediatric dose is  4 mg/kg of the first dose, then 2 mg/kg minocycline administered over 60 minutes every 12 hours, should not exceed the adult dose recommendations.

The lyophilized powder for injection should be reconstituted with 5 mL sterile water for injection USP and immediately further diluted in (100 mL-1,000 mL with dextrose injection USP, sodium chloride injection USP, and dextrose/sodium chloride injection USP, or 250 mL-1000 mL lactated ringer's injection USP). It should not be diluted with any solutions with calcium as precipitate might form especially in neutral or alkaline solutions. Once diluted into an IV bag, the injection may be stored at room temperature for up to 4 hours or refrigerated at 36 to 46°F for up to 24 hours. Any unused portions must be discarded after that period.

Topical Foam: It should be applied as a thin layer overall area of the face for the treatment of inflammatory lesions of rosacea in adults. It is applied approximately the same time each day, at least 1 hour before bedtime, and the patient should not shower, bathe, or swim for at least 1-hour post-application of medicine.

Specific Patient Population

• Patients with Renal Impairment: In patients with renal impairment, the total daily dosage of minocycline should be decreased by either reducing the indicated individual patient doses and/or extending the time intervals between the doses.

• Pregnancy: It is classified as FDA-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.[9] Topical minocycline product is not contraindicated in pregnancy.

• Breastfeeding Women:  Available literature indicates that short-term use of minocycline in nursing mothers is acceptable as minocycline is excreted in low amounts and further absorption by the infant is inhibited by the calcium in breastmilk. Avoid prolonged or repeated courses during breastfeeding. Consider monitoring the breastfed infant for rash, diarrhea, or candidiasis (thrush, diaper rash). Black discoloration of breastmilk is reported with the use of minocycline.[10]

Adverse Effects

More common adverse effects of minocycline include gastrointestinal distress and photosensitivity. Hyperpigmentation of skin and discoloration of nails is also possible. Staining of teeth and bone growth inhibition is more likely to occur in children than adults, although it has been reported in adults. The prevalence of tooth discoloration due to minocycline is 3% to 6%.[11][12] 

Hepatotoxicity may occur due to minocycline use, and exacerbation of preexisting renal failure is also a risk to consider. Pill esophagitis - symptoms of which present as chest pain, odynophagia, and dysphagia - have also been reported and may be avoided by taking oral forms of minocycline with adequate water and standing upright after intake. 

Although side effects are rare, the higher concentrations of minocycline in the CNS than other tetracyclines contribute to the dose-limiting vestibular side effects (such as nausea, vomiting, vertigo, dizziness, or change in hearing).[13][14] Research has also found a correlation between tetracycline use and idiopathic intracranial hypertension (pseudotumor cerebri).

There is a reported association between systemic lupus erythematosus (SLE) with minocycline use (risk of 8.8 cases per 100,000 person-years).[15] Tetracycline use also has correlations with drug-induced pancreatitis.[16]

As with all antibiotics, minocycline increases the risk of developing Clostridium difficile infection; however, the risk is lower than with other antibiotics.[17]

Minocycline use is associated with dermatological reactions, including drug rash with eosinophilia and systemic symptoms (DRESS) resulting in death. If DRESS is recognized while on minocycline, it should be discontinued immediately.

Minerals (calcium, magnesium, folate, or iron): Use of this product or any containing this mineral can decrease the blood concentration of minocycline. If possible, avoid taking at the same time. If coadministration cannot be avoided, give those at least 2 hours before or 4 hours after oral administration of minocycline.

Contraindications

All tetracyclines can cross the placental barrier and are contraindicated in pregnancy, including minocycline. Hepatotoxicity in the pregnant mother is also a risk factor to consider and another reason not to use it.[18][19]

Generally, any patients under the age of 16 should avoid using minocycline as the risk of permanent teeth discoloration in unerupted teeth is present. Ideally, avoid minocycline until after all crowns are complete (13 to 19 years).[20]

Although most tetracycline group medication should be avoided in patients with chronic renal failure, minocycline elimination is independent of renal function.[21] High doses of minocycline have been shown to increase urea excretion in healthy subjects. On the other hand, in patients with kidney impairment, aggravation of uremia may occur due to minocycline's catabolic effects. Therefore it is important to monitor the therapeutic doses of minocycline and renal function in patients with renal failure to avoid further aggravation of uremia.[22]

Monitoring

A long-term therapeutic dose of minocycline of up to 200 mg/day is generally safe and well-tolerated. Most adverse effects, such as nausea and dizziness, occur early after administration and disappear shortly after discontinuation of the medication. The recommendation is that after six months of minocycline treatment, all patients be monitored at three-month intervals for adverse effects such as hepatotoxicity, pigmentation, and SLE initiation or worsening.[5] 

Minocycline achieves peak serum concentrations ranging from 3 to 8.75 mg/L following 200 mg intravenous administration.[8] The half-life of minocycline can range from 13 hours (dose and route: 200 mg orally single dose) to 21 hours (dose and route: 200 mg IV single dose). Serum concentration has been shown to have no relationship to renal function, and fecal elimination accounts for about 20 to 35% of the dose. Thus, the serum concentration and half-life of minocycline are not significantly affected by either renal impairment or end-stage renal disease.[23]

The anti-anabolic effect of minocycline may cause an increase in BUN. Patients with normal renal function don't get adverse effects, while in patients with significantly impaired renal function, it can lead to azotemia, hyperphosphatemia, and acidosis. Under these conditions, monitoring of BUN and creatinine is recommended.

Toxicity

Common adverse effects, rarer autoimmune reactions, and hepatotoxicity warrant discontinuation of minocycline and switching to an antibiotic outside of the tetracycline class. It is important to note that minocycline carries a significantly higher risk of developing SLE than other tetracyclines. Thus a high index of suspicion and immediate discontinuation of the medication and supportive measures is recommended if symptoms develop.[15][3]

The adverse events more commonly observed in minocycline overdose are dizziness, nausea, and vomiting. There is no specific antidote for minocycline. In the case of minocycline overdosage, discontinue the medicine, treat the patient symptomatically, and institute supportive measures. Minocycline can not be removed in significant quantities by hemodialysis or peritoneal dialysis.

Enhancing Healthcare Team Outcomes

While minocycline use has decreased due to safety concerns such as irreversible pigmentation, high cost, and teratogenic effects, it is vital to understand both the indications and adverse effects when considering this medication. Increased antibiotic resistance in the community might make this antibiotic more useful and commonly prescribed again in the future.

Using targeted drug-susceptibility therapy will benefit not only the patient but also society as a whole. The entire healthcare team must work collaboratively to ensure that minocycline is the appropriate agent and that the patient understands both the risks and benefits of the medication. Patients should receive instruction from the physician and pharmacist on what signs and symptoms to watch out for, pertaining to the possible adverse effects. 

Collaboration within the interprofessional healthcare team will improve patient outcomes in reducing adverse drug reactions, which will increase the likelihood of patient compliance to medication and decrease morbidity and mortality.[24] This interprofessional team includes clinicians (MDs, DOs, NPs PAs), specialists, nursing staff, and pharmacists, all working as a cohesive unit, contributing from their areas of expertise, and engaging in open communication regarding the patient's case and interventions, monitoring, and status changes, to bring about the best possible results with the fewest adverse effects. [Level 5]