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Minocycline (Dynacin)

Minocycline in Brief
  • Generic name : Minocycline hydrochloride
  • Brand names: Dynacin, Minocin, Solodyn
  • Therapeutic class: Antibiotic
  • Pharmacologic class: Tetracycline
  • FDA Approved: June 30, 1971
  • Pregnancy Category: D
  • Originally discovered: 1960s, Lederle Laboratories, USA USA

Introduction

Minocycline is a highly lipophilic semisynthetic second-generation tetracycline antibiotic. Its antimicrobial spectrum is very similar to that of doxycycline with one important addition: minocycline has much more antistaphylococcal activity.

History

The first tetracycline, chlortetracycline, was discovered in 1948 during systematic screening of soil specimens for antibiotic-producing microorganisms. Chlortetracycline and oxytetracycline come from Streptomyces aureofaciens and Streptomyces rimosus, respectively. Tetracycline is produced semisynthetically from chlortetracycline. Minocycline is a semisynthetic derivative of tetracycline.

Minocycline was synthesized by Lederle Laboratories in 1967 and became widely available under the brand name Minocin in 197216.

Lederle Laboratories, founded in 1902, is a pharmaceutical division of Cyanamid, a large diversified American chemical manufacturer.

FDA approved uses
  • Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox and tick fevers
  • Respiratory tract infections: laryngotracheitis, tracheobronchitis, bronchitis, bronchiolitis, bronchiectasis, bronchopneumonia, pneumonia (single lobe and multilobe), lung abscess.
  • Psittacosis (Ornithosis)
  • Trachoma
  • Inclusion conjunctivitis
  • Nongonococcal urethritis, endocervical, or rectal infections in adults
  • Relapsing fever
  • Chancroid
  • Plague
  • Tularemia
  • Cholera
  • Campylobacter fetus infections
  • Brucellosis
  • Bartonellosis
  • Granuloma inguinale
  • Urinary tract infections: cystitis, pyelonephritis
  • Skin and skin structure infections: abscess, acne, cellulitis, infected dermatitis, folliculitis, furunculosis, impetigo, lymphadenitis, suppurative hydradenitis, paronychia, infected wounds.
  • Gonococcal infections
  • Syphilis
  • Yaws
  • Listeriosis
  • Anthrax
  • Vincentís infection
  • Actinomycosis
  • Infections caused by Clostridium species
  • Intestinal amebiasis: Minocycline may be a useful adjunct to amebicides

Off-label & Investigational uses

Rheumatoid arthritis

Minocycline is used as a disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory disease affecting about 1% of the adult population.

Although rheumatoid arthritis is not an infection, minocycline may improve the signs and symptoms of this disease. It may slow the progression of joint damage in arthritis and prevent disability. There is evidence that, besides its antibiotic effects, minocycline can reduce body's inflammatory responses. It decreases the production of substances causing inflammation, such as prostaglandins and leukotrienes, while increasing production of interleukin-10, a substance that reduces inflammation.

Minocycline has a slow onset - it may take 1-3 months after the start of therapy to observe an improvement. And the most benefits are seen when minocycline is used in early disease.

Results of a 48-week multicenter clinical study20 of 219 adults with rheumatoid arthritis show that minocycline reduces joint pain and swelling and is safe in mild to moderate disease. Minocycline may slow down the progression of disease and provide relief from swollen, tender joints.

According to the American College of Rheumatology, "Minocycline is prescribed for patients with symptoms of mild rheumatoid arthritis. It is sometimes combined with other medications to treat patients with persistent symptoms of this form of arthritis."

  • Osteoporosis
    Minocycline has been shown to increase bone mineral density, improve bone strength and formation, and slow bone resorption in old laboratory animals with surgically-induced menopause21.
  • Lyme disease
    Lyme disease, or borreliosis, is an emerging infectious disease caused by the bacterium Borrelia burgdorferi and is transmitted to humans by the bite of infected blacklegged ticks. Minocycline may be useful for the treatment of Lyme disease19.
  • Sarcoidosis
    Sarcoidosis is a disease that results from a specific type of inflammation of tissues of the body.
    Studies24 indicate that minocycline may be beneficial for the treatment of cutaneous sarcoidosis.
  • Cystic fibrosis22-23
    Cystic fibrosis (also known as CF, mucoviscoidosis, or mucoviscidosis) is a hereditary disease that affects mainly the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure.
  • Periodontitis
    Periodontitis is a dental disorder that results from progression of gingivitis, involving inflammation and infection of the ligaments and bones that support the teeth. Minocycline is used to control bacteria and reduce the size of periodontal pockets. The periodontist puts the minocycline micro-spheres into the pockets after scaling and root planing. The particles release minocycline slowly over time.
  • Gougerot-Carteaud Syndrome 17, an uncommon dermatosis of unknown etiology.

Minocycline "pros" and "cons"

Advantages:

  • Less photosensitizing. Photosensitivity is least likely than with other tetracyclines25-26.
  • High concentrations in the tissues. Minocycline is widely distributed in body tissues27, with higher concentrations being found in cerebrospinal fluid and sputum than with other tetracyclines. As in blood, the concentration in tissues is generally 2 to 4 times higher with minocycline than with tetracycline. Equivalent blood and tissue levels achieved whether administered intravenously or orally.
  • Long half-life (from 11 to 23 hours).
  • Broader spectrum of antimicrobial activity. Against certain pathogens, minocycline is more potent than the other tetracyclines. Minocycline has excellent in vitro inhibitory activity against both Staphylococcus aureus and coagulase-negative staphylococci, particularly methicillin-resistant S. aureus and methicillin-resistant S. epidermidis strains3-5.
  • Can be used in renal impairment. Most tetracyclines should be avoided in patients with renal insufficiency. However, minocycline can be used in patients with malfunction of the kidneys. It is eliminated through the hepatobiliary and gastrointestinal tracts.
  • Low rate of bacterial resistance. Minocycline produces less antibiotic resistance than tetracycline.28-29 Bacterial cell membranes contain a lipid layer. One mechanism of building up a resistance to an antibiotic is to produce a thicker lipid layer. This layer makes it difficult for an antibiotic to penetrate. Minocycline chemical structure makes it the most lipid soluble of all the tetracyclines.

Disadvantages:

  • Expensive. Minocycline is considerably more expensive than the other generic tetracyclines.
  • Contraindicated in children. May cause enamel hypoplasia and permanent teeth discoloration.
  • Lupus-like syndrome. Minocycline is more likely than other tetracyclines to produce a lupus-like syndrome. Minocycline-induced lupus is characterized by the development of non-specific symptoms after long-term consumption of the drug, and the patient usually continues to take minocycline despite their illness as the association is not immediately obvious1. These abnormalities tend to occur after prolonged therapy (often longer than 12 months).
  • Serum sickness-like reaction. Minocycline induced serum sickness like reaction (SSLR) was first reported in 199030. This is a type of delayed allergic reaction, in which the immune system interprets the antibiotic as a foreign threat. A serum sickness-like reaction (SSLR) to drug usually consists of cutaneous rash, arthralgia/arthritis, and, often, fever.
  • Vasculitis, usually resembling cutaneous polyarteritis nodosa, may occur in association with minocycline use.
  • Intracranial hypertension (pseudotumor cerebri) is an accumulation of fluid around the brain. Minocycline can cause the rare condition of secondary intracranial hypertension31 which has initial symptoms of headache, visual disturbances, and confusion.
  • Dizziness and other vestibular side effects, that not generally shared by other tetracyclines. Minocycline can cause quite severe dizziness, nausea, vertigo and vomiting32. Vertigo has been reported in as many as 86% of individuals in some series33.
  • Hyperpigmentation. Unlike other tetracyclines, minocycline can cause a potentially irreversible slate-grey hyperpigmentation of the skin. Blue or blue-black oral pigmentation was seen in 10% of patients taking minocycline for at least 1 year; the rate increased to 20% after 4 years of continuous use2. Large daily doses of ascorbic acid (vitamin C) may prevent this phenomenon34.

Mode of action

Antibacterial

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis.

Minocycline is a semisynthetic derivative of tetracycline and is active against many tetracycline resistant strains of organisms such as staphylococci, streptococci and E. coli. Thus the combined results of many studies show its activity against approximately 87% of tetracycline resistant staphylococci. Minocycline is also active against many strains of staphylococci which are resistant to penicillin G and certain semisynthetic penicillins.

Neuroprotective effect

Minocycline and other tetracycline derivatives have neuroprotective effects unrelated to their antimicrobial properties. Minocycline has the greatest permeability of all tetracyclines through the blood-brain barrier and is well suited for treatment of CNS disorders.

Minocycline can reduce neuronal death after excitotoxicity and ionizing radiation in culture6-7 and in animal models of stroke7-9, Parkinson's disease10-11, Huntington's disease12, and amyotrophic lateral sclerosis13. The neuroprotective effects of minocycline have been attributed both to reduced inflammation and a direct effect on neuronal survival.

Anti-inflammatory effect

Minocycline induces anti-inflammatory and antinociceptive effects unrelated to its antimicrobial activitiy15. Although the exact mechanisms of minocycline anti-inflammatory effects are still poorly understood, they may include the inhibition of matrix metalloproteinase-2 activity, the inhibition of inducible nitric oxide synthase14, prostaglandin E2, caspase-1, caspase-3, and COX-2 expressions and the impairment of cytokine production.

Time to clear out of the system

Minocycline half-life is 16 hours (range: 11-23 hours).

Further reading
References
  • 1. T. M. Lawson, N. Amos, D. Bulgen, B. D. Williams. Minocycline-induced lupus: clinical features and response to rechallenge. Rheumatology 2001; 40: 329-335 PubMed
  • 2. Eisen D. Minocycline-induced oral hyperpigmentation [letter]. Lancet 1997;349:400
  • 3.Qadri SM, Halim M, Ueno Y, Saldin H. Susceptibility of methicillin-resistant Staphylococcus aureus to minocycline and other antimicrobials. Chemotherapy 1994;40:26-29
  • 4. Yuk JH, Dignani MC, Harris RL, Bradshaw MW, Williams TW Jr. Minocycline as an alternative anti-staphylococcal agent [letter]. Rev Infect Dis 1991;13:1023-1024
  • 5. Archer GL, Climo MW. Antimicrobial susceptibility of coagulase-negative staphylococci. Antimicrob Agents Chemother 1994;38:2231-2237
  • 6. Tikka T, Usenius T, Tenhunen M, Keinanen R, Koistinaho J. Tetracycline derivatives and ceftriaxone protect neurons against apoptosis induced by ionizing radiation. J Neurochem. 2001 Sep;78(6):1409-14. PubMed
  • 7. Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res. 2005 May 17;1044(1):8-15. PubMed
  • 8. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500. PubMed
  • 9. Fox C, Dingman A, Derugin N, Wendland MF, Manabat C, Ji S, Ferriero DM, Vexler ZS. Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2005 Sep;25(9):1138-49. PubMed
  • 10. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. Journal of Neuroscience. 2002 Mar 1;22(5):1763-71.
  • 11. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14669-74. PubMed
  • 12. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000 Jul;6(7):797-801. PubMed
  • 13. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002 May 2;417(6884):74-8. PubMed
  • 14. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA. 1996 Nov 26;93(24):14014-9. PubMed
  • 15. Bastos LF, Merlo LA, Rocha LT, Coelho MM. Characterization of the antinociceptive and anti-inflammatory activities of minocycline in different experimental models. Eur J Pharmacol. 2007 Dec 8;576(1-3):171-9. PubMed
  • 16. Bernier C, Dreno B. Minocycline Ann Dermatol Venereol. 2001 May;128(5):627-37. PubMed
  • 17. Davis MD, Weenig RH, Camilleri MJ. Confluent and reticulate papillomatosis (Gougerot-Carteaud syndrome): a minocycline-responsive dermatosis without evidence for yeast in pathogenesis. Br J Dermatol. 2006 Feb;154(2):287-93. PubMed
  • 19. Muellegger RR, Zoechling N, Soyer HP, Hoedl S, Wienecke R, Volkenandt M, Kerl H. No detection of Borrelia burgdorferi-specific DNA in erythema migrans lesions after minocycline treatment. Arch Dermatol. 1995 Jun;131(6):678-82.
  • 20. Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, Clegg DO, Leisen JC, Buckley L, Cooper SM, Duncan H, Pillemer SR, Tuttleman M, Fowler SE. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann Intern Med. 1995 Jan 15;122(2):81-9. PubMed
  • 21. Williams S, Wakisaka A, Zeng QQ, Barnes J, Martin G, Wechter WJ, Liang CT. Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats. Bone. 1996 Dec;19(6):637-44. PubMed
  • 22. Kurlandsky LE, Fader RC. In vitro activity of minocycline against respiratory pathogens from patients with cystic fibrosis. Pediatr Pulmonol. 2000 Mar;29(3):210-2.
  • 23. Patterson PR. Minocycline in the antibiotic regimen of cystic fibrosis patients: weight gain and clinical improvement. Clin Pediatr (Phila). 1977 Jan;16(1):60-3. PubMed
  • 24. Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol. 2001 Jan;137(1):69-73.
  • 25. Glette J, Sandberg S. Phototoxicity of tetracyclines as related to singlet oxygen production and uptake by polymorphonuclear leukocytes. Biochem Pharmacol. 1986 Sep 1;35(17):2883-5. PubMed
  • 26. Bjellerup M, Ljunggren B. Photohemolytic potency of tetracyclines. J Invest Dermatol. 1985 Apr;84(4):262-4.
  • 27. Saivin S, Houin G. Minocycline clinical pharmacokinetics. Clin Pharmacokinet. 1988 Dec;15(6):355-66. Review. PubMed
  • 28. Eady EA, Jones CE, Gardner KJ, Taylor JP, Cove JH, Cunliffe WJ. Br J Dermatol. 1993 May;128(5):556-60. PubMed
  • 29. Kuck NA, Forbes M. Uptake of minocycline and tetracycline by tetracycline-susceptible and -resistant bacteria. Antimicrob Agents Chemother. 1973 Jun;3(6):662-4.
  • 30. Sarma N, Malakar S, Lahiri K, Banerjee U. Serum sickness like reaction with minocycline. Indian J Dermatol Venereol Leprol. 2004 Jan-Feb;70(1):43-4. FullText
  • 31. Chiu AM, Chuenkongkaew WL, Cornblath WT, Trobe JD, Digre KB, Dotan SA, Musson KH, Eggenberger ER. Minocycline treatment and pseudotumor cerebri syndrome. Am J Ophthalmol. 1998 Jul;126(1):116-21. PubMed
  • 32. Drew TM, Altman R, Black K, Goldfield M. Minocycline for prophylaxis of infection with Neisseria meningitidis: high rate of side effects in recipients. J Infect Dis. 1976 Feb;133(2):194-8. PubMed
  • 33. Jacobson JA, Daniel B. Vestibular reactions associated with minocycline. Antimicrob Agents Chemother. 1975 Oct;8(4):453-6. PubMed
  • 34. Bowles WH, Baylor College of Dentistry, Texas A&M University System Protection against minocycline pigment formation by ascorbic acid, J Esthet Dent, 10(4):182-6 1998

Published: July 01, 2008
Last updated: July 24, 2014

Interesting facts
Minocycline facts
  • Minocycline is the least frequently prescribed of the three tetracyclines, but it has the largest fraction of repeat prescriptions.
  • In addition to its antibiotic activity, minocycline has anti-inflammatory properties.
  • Minocycline may cause rare but very serious side effects, including hypersensitivity syndrome, autoimmune hepatitis, and lupus.
  • Aside from its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death.
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