Doxycycline (Doryx®)

Based on "Antibiotic and Chemotherapy"
written by Roger G. Finch

History

The first member of the tetracycline group - Chlortetracycline - was discovered in the late 1940s by Dr. Benjamin Duggar of Lederle Laboratories in New York. It was derived from the soil-dwelling bacterium Streptomyces aureofaciens. Oxytetracycline was isolated soon after from S. rimosus by scientists at Pfizer Laboratories in 1950. This was further developed to Doxycycline 37.

Doxycycline (6-Deoxy-5-hydroxytetracycline) is a semi-synthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand Vibramycin. This semi-synthetic tetracycline is manufactured by a 3-step synthesis with oxytetracycline as the starting material as described in U.S. Pat. No. 3,200,149 to Pfizer (1965).

Vibramycin received FDA approval in 1967, becoming Pfizer's first once-a-day broad-spectrum antibiotic.

FDA approved uses

• Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.
• Respiratory tract infections caused by Mycoplasma pneumoniae.
• Lymphogranuloma venereum caused by Chlamydia trachomatis.
• Psittacosis (ornithosis) caused by Chlamydia psittaci.
• Trachoma caused by Chlamydia trachomatis.
• Inclusion conjunctivitis caused by Chlamydia trachomatis.
• Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis.
• Nongonococcal urethritis caused by Ureaplasma urealyticum.
• Relapsing fever due to Borrelia recurrentis.
• Chancroid caused by Haemophilus ducreyi.
• Plague due to Yersinia pestis (formerly Pasteurella pestis).
• Tularemia due to Francisella tularensis (formerly Pasteurella tularensis).
• Cholera caused by Vibrio cholerae (formerly Vibrio comma).
• Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus).
• Brucellosis due to Brucella species (in conjunction with streptomycin).
• Bartonellosis due to Bartonella bacilliformis.
• Granuloma Inguinale (donovanosis) caused by Calymmatobacterium granulomatis (preferred agent according to the CDC STD guidelines).
• Lymphogranuloma venereum (preferred agent according to the CDC STD guidelines).
• Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure).
• Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
• Syphilis caused by Treponema pallidum.
• Yaws caused by Treponema pertenue.
• Listeriosis due to Listeria monocytogenes.
• Vincent's infection caused by Fusobacterium fusiforme.
• Actinomycosis caused by Actinomyces israelii.
• Infections caused by Clostridium species.
• Acute intestinal amebiasis.
• Acne ( see Doxycycline dosage for acne)
• Prophylaxis of malaria due to Plasmodium falciparum.
• Periodontitis (Periostat®)
• Rosacea (Oracea®)

When bacteriologic testing indicates appropriate susceptibility doxycycline, it may be used to treat:

• Escherichia coli.
• Enterobacter aerogenes (formerly Aerobacter aerogenes).
• Shigella species.
• Acinetobacter species (formerly Mima species and Herellea species).
• Respiratory tract infections caused by Haemophilus influenzae.
• Respiratory tract and urinary tract infections caused by Klebsiella species.
• Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae).

Off-label & Investigational uses

• Vancomycin-resistant enterococci (VRE) (although it is not active against non-VRE enterococci) 21
• Infected animal bite wounds (Pasteurella multocida, Pasteurella pneumotropica) 22
• Lyme disease, prevention and treatment 23, 25, 26
• Rosacea 27, 28
• Rheumatoid arthritis 29, 30, 31
• Pelvic inflammatory disease 33
• Chronic inflammatory lung diseases (panbronchiolitis, asthma, cystic fibrosis, bronchitis) 18, 32
• Human ehrlichiosis 35
• Legionella infections 38, 16
• Toxoplasmosis
• Mediterranean spotted fever 8
• Sarcoidosis 39, 40
• Leptospirosis 34

Doxycycline "pros" and "cons"

Advantages:

• excellent safety record
• among currently available tetracyclines, doxycycline has the least affinity for calcium
• unlikely to cause tooth staining in children9
• Suitable for patients with impaired kidney function. Unlike other tetracyclines, doxycycline is eliminated by nonrenal mechanisms and does not accumulate significantly in patients with renal insufficiency.
• long half-life permits once- or twice-daily dosing
• blood and tissue levels are equivalent whether doxycycline is administered orally or intravenously
• highly effective against all of the common pathogens that cause upper respiratory tract infections
• quite active against Streptococcus pneumoniae, the most important respiratory tract pathogen in otitis, sinusitis, bronchitis, and community-acquired pneumonia 17
• active against penicillin-resistant pneumococci 12, 19
• active against all common typical (Streptococcus pneumoniae, Haemophilus influenzae) and atypical (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species) pathogens that cause pneumonia 17, 38, 36, 24
• anti-inflammatory effects 5, 9, 18
• inhibition of metalloproteinases (enzymes that inhibit collagen and gelatin production) 20
• can slow the progression of osteoarthritis 13, 14
• can inhibit pathologic collagenolysis 15
• intestinal flora is not affected by doxycycline due to it's almost complete absorption 42
• inexpensive

Disadvantages:

• Use during tooth development may cause permanent discoloration of the teeth and enamel hypoplasia in young children. This is because tetracyclines are readily bound to calcium and are deposited in calcifying areas in bone and teeth.
• prolonged use may result in superinfection, including oral or vaginal candidiasis
• photosensitivity reaction
• absorption may be decreased by 20% when given with food or milk
• not active against penicillinase-producing Neisseria gonorrhoeae
• poorly active against Haemophilus influenzae (common pathogen causing pneumonia) 11, 17
• risk of intracranial hypertension
• risk of esophageal ulceration (if the capsules for some reason do not reach the stomach but remain in the esophagus)

Mode of action

Antibacterial action

Bacteria need to synthesize proteins in order to ensure their reproduction. This biological activity requires the capture of nutrients from the surrounding environment at the expense of the host. Among those nutrients are the amino acids, which are incorporated in the bacteria's ribosomes, the cell organites where protein synthesis takes place.

Doxycycline is generally bacteriostatic against a wide variety of organisms, both gram-positive and gram-negative. In gram-negative bacteria, transportation of the doxycycline into the cell occurs either by passive diffusion or through an energy-dependent active transport system. The latter system is also believed to exist in gram-positive bacteria. Doxycycline is more lipophilic than the other tetracyclines, which allows it to pass easily through the lipid bilayer of bacteria.

Doxycycline penetrates the bacterial cell and interferes with the protein biosynthesis, stopping the process of bacteria reproduction. Bacteria cannot reproduce and die or are killed by the defense mechanisms (white cells) of the host. Doxycycline can also alter the cytoplasmic membrane and this in turn causes leakage of nucleotides and other compounds out of the cell. This does not directly kill the bacteria but instead inhibit it.

Non-antibiotic properties

Antibiotics also have non-antibiotic properties, which are not well understood. These nonantibioitc properties include:

• Anti-inflammatory effects
• Inhibition of metalloproteinases (enzymes that inhibit collagen and gelatin production)
• Reduction of new blood vessel formation (angiogenesis)
• Reduction of programmed cell death (apoptosis)

At subantimicrobial doses, doxycycline reduces inflammation via anticollagenolytic, antimatrix-degrading metalloproteinase, and cytokine down-regulating properties 2.

In the treatment of periodontitis doxycycline works by inhibiting collagenase 15 which breaks down connective tissue and leads to the separation of the gum from the tooth.

Doxycycline inhibits the nitric oxide synthesis. This activity is another possible pathway by which tetracyclines may function as anti-inflammatory compounds 9. The data suggests that the direct inhibition of nitrate release is the main mechanism of the anti-inflammatory activity of doxycycline in septic shock 10.

Doxycycline may slow OA progression by inhibiting the degradation of type XI collagen, reducing levels of collagen-degrading enzymes, and inhibiting messenger RNA for nitric oxide synthesis, which results in secretion of matrix MMPs in the chondrocyte.

Time for Doxycycline to clear out of the system

The half-life is 18 to 22 hr. Approximately 40% excreted by the kidneys in 72 hr.

Further reading

• Doxycycline vs Minocycline
• Doxycycline vs Malarone®
• Doxycycline vs Tetracycline
• Doxycycline for Cellulitis

References

• 1. Physicians’ Desk Reference, 54th ed; Medical Economics, Thomson Healthcare: Montvale, NJ; 2000.
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Published: March 31, 2008
Last updated: July 28, 2019