Doxycycline
Clinical data | |
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Pronunciation | /ˌdɒksɪˈsaɪkliːn/ DOKS-iss-EYE-kleen |
Trade names | Doxy, Doryx, Vibramycin, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682063 |
License data |
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Pregnancy category |
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Routes of administration | By mouth, intravenous[1] |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | ~100% |
Protein binding | 80–90% |
Metabolism | Negligible |
Elimination half-life | 10–22 hours |
Excretion | Mainly feces, 40% urine |
Identifiers | |
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JSmol) | |
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Doxycycline is a
Common side effects include
Doxycycline was patented in 1957 and came into commercial use in 1967.
Medical uses
In addition to the general indications for all members of the
In Canada, in 2004, doxycycline was considered a first-line treatment for chlamydia and non-gonococcal urethritis and with cefixime for uncomplicated gonorrhea.[19]
Antibacterial
General indications
Doxycycline is a broad-spectrum antibiotic that is employed in the treatment of numerous bacterial infections. It is effective against bacteria such as Moraxella catarrhalis, Brucella melitensis, Chlamydia pneumoniae, and Mycoplasma pneumoniae. Additionally, doxycycline is used in the prevention and treatment of serious conditions like anthrax, leptospirosis, bubonic plague, and Lyme disease. However, some bacteria, including Haemophilus spp., Mycoplasma hominis, and Pseudomonas aeruginosa, have shown resistance to doxycycline.[20][21] It is also effective against Yersinia pestis (the infectious agent of bubonic plague), and is prescribed for the treatment of Lyme disease,[22][23][24][25] ehrlichiosis,[26][27] and Rocky Mountain spotted fever.[28]
Specifically, doxycycline is indicated for treatment of the following diseases:[28][29]
- Rocky Mountain spotted fever, typhus fever and the typhus group, scrub typhus,[30] Q fever,[31] rickettsialpox, and tick fevers caused by Rickettsia,[32][33][34]
- respiratory tract infections caused by Mycoplasma pneumoniae,[35]
- inclusion conjunctivitis, and uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis,[28][29]
- psittacosis,[28][29]
- non-gonococcal urethritis caused by Ureaplasma urealyticum,[28][29]
- relapsing fever due to Borrelia recurrentis,[28][29]
- chancroid caused by Haemophilus ducreyi,[28][29]
- plague due to Yersinia pestis,[28][29]
- tularemia,[28][29]
- cholera,[28][29]
- campylobacter fetus infections,[28][29]
- brucellosis caused by Brucella species (in conjunction with streptomycin),[28][29]
- bartonellosis,[28][29]
- granuloma inguinale (Klebsiella species),[28][29]
- Lyme disease:[36] it can be used in adults and children. For treatment or prophylaxis of Lyme disease in children, it can be used for a duration of up to 21 days in children of any age.[37]
Gram-negative bacteria specific indications
When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-negative bacteria:[28][29]
- Escherichia coli infections,[28][29]
- Shigella species infections,[28][29]
- Acinetobacter species (formerly Mima species and Herellea species) infections,[28][29]
- respiratory tract and urinary tract infections caused by Klebsiella species.[28][29]
Gram-positive bacteria specific indications
Some
- upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae),[28][29]
- skin and soft tissue infections caused by Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus infections,[28][29]
- anthrax caused by Bacillus anthracis infection.[28][29]
Specific applications of doxycycline when penicillin is contraindicated
When penicillin is contraindicated, doxycycline can be used to treat:[28][29]
- syphilis caused by Treponema pallidum,[28][29]
- listeriosis due to Listeria monocytogenes,[28][29]
- actinomycosis caused by Actinomyces israelii,[28][29]
- infections caused by Clostridium species.[28][29]
Use as adjunctive therapy
Doxycycline may also be used as adjunctive therapy for severe acne.[39][28][29]
Subantimicrobial-dose doxycycline (SDD) is widely used as an adjunctive treatment to scaling and root planing for
Doxycycline is used as an adjunctive therapy for acute intestinal amebiasis.[44]
Doxycycline is also used as an adjunctive therapy for chancroid.[44]
As prophylaxis against sexually transmitted infections
As well as being used to treat some sexually transmitted infections, doxycycline can also be used as a preventative measure, i.e. as post-exposure prophylaxis (often referred to as "doxyPEP"). Three randomised controlled trials have demonstrated efficacy in the prevention of syphilis and chlamydia, and to a lesser extent gonorrhoea, in gay and bisexual men, as well as trans women.[45] A study conducted with heterosexual women in Kenya was unsuccessful, probably due to poor adherence.[46] Appropriate use of doxycycline in this way is supported by guidelines from the US Centers for Disease Control and Prevention (CDC)[47] and the Australasian Society for HIV Medicine.[48] The rapid uptake of "doxyPEP" among gay and bisexual men in San Francisco is credited with reducing the incidence of chlamydia and syphilis in 2023.[49]
Use in combination
The first-line treatment for brucellosis is a combination of doxycycline and streptomycin and the second-line is a combination of doxycycline and rifampicin (rifampin).[50]
Antimalarial
Doxycycline is active against the erythrocytic stages of Plasmodium falciparum but not against the gametocytes of P. falciparum.[51] It is used to prevent malaria.[52] It is not recommended alone for initial treatment of malaria, even when the parasite is doxycycline-sensitive, because the antimalarial effect of doxycycline is delayed.[53]
Doxycycline blocks protein production in apicoplast (an organelle) of P. falciparum—such blocking leads to two main effects: it disrupts the parasite's ability to produce fatty acids, which are essential for its growth, and it impairs the production of heme, a cofactor. These effects occur late in the parasite's life cycle when it is in the blood stage, causing the symptoms of malaria.[54] By blocking important processes in the parasite, doxycycline both inhibits the growth and prevents the multiplication of P. falciparum. It does not directly kill the living organisms of P. falciparum but creates conditions that prevent their growth and replication.[55]
The World Health Organization (WHO) guidelines state that the combination of doxycycline with either artesunate or quinine may be used for the treatment of uncomplicated malaria due to P. falciparum or following intravenous treatment of severe malaria.[56]
Antihelminthic
Doxycycline kills the
Spectrum of susceptibility
Doxycycline has been used successfully to treat sexually transmitted, respiratory, and ophthalmic infections. Representative pathogenic genera include Chlamydia, Streptococcus, Ureaplasma, Mycoplasma, and others. The following represents minimum inhibitory concentration susceptibility data for a few medically significant microorganisms.[59]
- Chlamydia psittaci: 0.03 μg/mL[59]
- Mycoplasma pneumoniae: 0.016–2 μg/mL[59]
- Streptococcus pneumoniae: 0.06–32 μg/mL[59]
Sclerotherapy
Doxycycline is also used for
Routes of administration
Doxycycline can be administered via oral or intravenous routes.[1]
The combination of doxycycline with dairy, antacids, calcium supplements, iron products, laxatives containing magnesium, or bile acid sequestrants is not inherently dangerous, but any of these foods and supplements may decrease absorption of doxycycline.[61][62]
Doxycycline has a high oral bioavailability, as it is almost completely absorbed in the stomach and proximal small intestine.[15] Unlike other tetracyclines, its absorption is not significantly affected by food or dairy intake.[15] However, co-administration of dairy products reduces the serum concentration of doxycycline by 20%.[15] Doxycycline absorption is also inhibited by divalent and trivalent cations, such as iron, bismuth, aluminum, calcium and magnesium.[15] Doxycycline forms unstable complexes with metal ions in the acidic gastric environment, which dissociate in the small intestine, allowing the drug to be absorbed. However, some doxycycline remains complexed with metal ions in the duodenum, resulting in a slight decrease in absorption.[15]
Contraindications
Severe
Pregnancy and lactation
Doxycycline is categorized by the
Adverse effects
Adverse effects are similar to those of other members of the
An
Unlike some other members of the tetracycline group, it may be used in those with renal impairment.[72]
Doxycycline use has been associated with increased risk of inflammatory bowel disease.[73] In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohn's disease.[74]
Interactions
Previously, doxycycline was believed to impair the effectiveness of many types of hormonal contraception due to CYP450 induction. Research has shown no significant loss of effectiveness in oral contraceptives while using most tetracycline antibiotics (including doxycycline), although many physicians still recommend the use of barrier contraception for people taking the drug to prevent unwanted pregnancy.[75][72][76]
Pharmacology
Doxycycline, like other tetracycline antibiotics, is bacteriostatic. It works by preventing bacteria from reproducing through the inhibition of protein synthesis.[77]
Doxycycline is highly lipophilic, so it can easily enter cells, meaning the drug is easily absorbed after oral administration and has a large volume of distribution. It can also be re-absorbed in the renal tubules and gastrointestinal tract due to its high lipophilicity, giving it a long elimination half-life, and it is also prevented from accumulating in the kidneys of patients with kidney failure due to the compensatory excretion in faeces.[68][78] Doxycycline–metal ion complexes are unstable at acid pH, therefore more doxycycline enters the duodenum for absorption than the earlier tetracycline compounds. In addition, food has less effect on absorption than on absorption of earlier drugs with doxycycline serum concentrations being reduced by about 20% by test meals compared with 50% for tetracycline.[79]
Mechanism of action
Doxycycline is a broad-spectrum bacteriostatic antibiotic. It inhibits the synthesis of bacterial proteins by binding to the 30S ribosomal subunit, which is only found in bacteria.[67][78] This prevents the binding of transfer RNA to messenger RNA at the ribosomal subunit meaning amino acids cannot be added to polypeptide chains and new proteins cannot be made. This stops bacterial growth giving the immune system time to kill and remove the bacteria.[80]
Pharmacokinetics
The substance is almost completely absorbed from the upper part of the
Doxycycline
Chemistry
Expired tetracyclines or tetracyclines allowed to stand at a pH less than 2 are reported to be nephrotoxic due to the formation of a degradation product, anhydro-4-epitetracycline[84][85] causing Fanconi syndrome.[86] In the case of doxycycline, the absence of a hydroxyl group in C-6 prevents the formation of the nephrotoxic compound.[85] Nevertheless, tetracyclines and doxycycline itself have to be taken with caution in patients with kidney injury, as they can worsen azotemia due to catabolic effects.[86]
Chemical properties
Doxycycline, doxycycline
Solubility in | Doxycycline | Doxycycline monohydrate | Doxycycline hyclate |
---|---|---|---|
Water | very slightly | very slightly | freely |
Ethanol | very slightly | very slightly | sparingly |
Aqueous acids | freely | freely | |
Alkali hydroxyde solutions | freely | freely | |
Chloroform | very slightly | practically insoluble | practically insoluble |
Diethyl ether | insoluble | practically insoluble | practically insoluble |
History
After
As its patent grew near to expiring in the early 1970s, the patent became the subject of lawsuit between Pfizer and International Rectifier[87] that was not resolved until 1983; at the time it was the largest litigated patent case in US history.[88] Instead of a cash payment for infringement, Pfizer took the veterinary and feed-additive businesses of International Rectifier's subsidiary, Rachelle Laboratories.[88]
In January 2013, the FDA reported shortages of some, but not all, forms of doxycycline "caused by increased demand and manufacturing issues".
Society and culture
Doxycycline is available worldwide under many brand names.[98] Doxycycline is available as a generic medicine.[1][10]
Research
Research areas have included:
- Macular degeneration[99]
- Rheumatoid arthritis instead of minocycline (both of which have demonstrated modest efficacy for this disease)[100]
Anti-inflammatory agent
Some studies show doxycycline as a potential agent to possess anti-inflammatory properties acting by inhibiting proinflammatory cytokines such as
A potential explanation of doxycycline's anti-inflammatory properties is its inhibition of matrix metalloproteinases (MMPs), which are a group of proteases known to regulate the turnover of extracellular matrix (ECM) and thus are suggested to be important in the process of several diseases associated with tissue remodeling and inflammation.[104][105][106][107] Doxycycline has been shown to inhibit MMPs, including matrilysin (MMP7), by interacting with the structural zinc atom and/or calcium atoms within the structural metal center of the protein.[108][109][110]
Doxycycline is used to treat acne vulgaris and rosacea.[111][112][15] However, there is no clear understanding of what contributes more: the bacteriostatic properties of doxycycline, which affect bacteria (such as Propionibacterium acnes[15]) on the surface of sebaceous glands even in lower doses called "submicrobial"[113][114] or "subantimicrobial",[115][116][117][15] or whether doxycycline's anti-inflammatory effects, which reduce inflammation in acne vulgaris and rosacea, including ocular rosacea,[43] contribute more to its therapeutic effectiveness against these skin conditions.[118] Subantimicrobial-dose doxycycline (SDD) can still have a bacteriostatic effect, especially when taken for extended periods, such as several months in treating acne and rosacea.[119] While the SDD is believed to have anti-inflammatory effects rather than solely antibacterial effects, SDD was proven to work by reducing inflammation associated with acne and rosacea. Still, the exact mechanisms have yet to be fully discovered.[120] One probable mechanism is doxycycline's ability to decrease the amount of reactive oxygen species (ROS). Inflammation in rosacea may be associated with increased production of ROS by inflammatory cells; these ROS contribute toward exacerbating symptoms. Doxycycline may reduce ROS levels and induce antioxidant activity because it directly scavenges hydroxyl radicals and singlet oxygen, helping minimize tissue damage caused by highly oxidative and inflammatory conditions.[121] Studies have shown that SDD can effectively improve acne and rosacea symptoms,[122] probably without inducing antibiotic resistance.[123]
Doxycycline's dual benefits as an antibacterial and anti-inflammatory make it a helpful treatment option for diseases involving inflammation not only of the skin, such as rosacea and acne, but also in conditions such as osteoarthritis or periodontitis.[124] Nevertheless, current results are inconclusive, and evidence of doxycycline's anti-inflammatory properties needs to be improved, considering conflicting reports from animal models so far.[125][126][127] Doxycycline has been studied in various immunological disorders, including rheumatoid arthritis, lupus, and periodontitis.[128] In these conditions, doxycycline has been researched to determine anti-inflammatory and immunomodulatory effects that could be beneficial in treating these conditions. However, a solid conclusion still needs to be provided.[129][130][131][132]
Doxycycline is also studied for its neuroprotective properties which are associated with antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. In this context, it is important to note that doxycycline is able to cross the blood-brain barrier. Several studies have shown that doxycycline inhibits dopaminergic neurodegeneration through the upregulation of axonal and synaptic proteins.[133][134] Axonal degeneration and synaptic loss are key events at the early stages of neurodegeneration and precede neuronal death in neurodegenerative diseases, including Parkinson's disease (PD). Therefore, the regeneration of the axonal and synaptic network might be beneficial in PD.[135] It has been demonstrated that doxycycline mimics nerve growth factor (NGF) signaling in PC12 cells. However, the involvement of this mechanism in the neuroprotective effect of doxycycline is unknown. Doxycycline is also studied in reverting inflammatory changes related to depression.[116] While there is some research on the use of doxycycline for treating major depressive disorder, the results are mixed.[116][136][137]
After a large-scale trial showed no benefit of using doxycycline in treating COVID‑19, the UK's National Institute for Health and Care Excellence (NICE) updated its guidance to not recommend the medication for the treatment of COVID‑19.[138][139] Doxycycline was expected to possess anti-inflammatory properties that could lessen the cytokine storm associated with a SARS-CoV-2 infection, but the trials did not demonstrate the expected benefit.[140] Researchers also believed that doxycycline possesses anti-inflammatory and immunomodulatory effects that could reduce the production of cytokines in COVID-19, but these supposed effects failed to improve the outcome of COVID-19 treatment.[141][142]
Research reagent
Doxycycline and other members of the
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