Doxycycline Capsules

Doxycycline is a semisynthetic antibiotic of the tetracycline class derived from oxytetracycline. It is a bacteriostatic agent but can also exhibit bactericidal effects in high concentrations. Doxycycline, like other members of the tetracycline group, has a broad-spectrum activity against a wide range of gram-positive, gram-negative, and atypical organisms. The drug is also active against some protozoan pathogens. Clinically, doxycycline is a drug of choice for the management and treatment of many mild-to-moderate infectious diseases.

Doxycycline has immunomodulating and anti-inflammatory properties. It also has shown potential against a range of pathogens resistant to antibiotics. These include ampicillin-susceptible strains of Haemophilus influenzae, penicillin-resistant strains of Staphylococcus aureus, β-lactamase-producing strains of Moraxella catarrhalis, multidrug-resistant strains of Acinetobacter baumannii and Stenotrophomonas maltophilia, and strains of organisms resistant to other tetracyclines.

Doxycycline has excellent oral availability and a low binding affinity with calcium (Ca²⁺) ions. Unlike other tetracyclines, however, it is more lipid-soluble and has a prolonged serum half-life. Doxycycline also has high stability in normal human serum and therapeutic drug monitoring is extremely rare. The drug is available in multiple dosage forms including tablet, capsule, syrup, oral suspension, and reconstituted powder for IV. Doxycycline, along with minocycline, can be administered irrespective of meals. The US-FDA first approved doxycycline in 1967 and currently defines it as a wide therapeutic index drug. It is also included in the List of Essential Medicines by the World Health Organization as a first-choice treatment for sexually transmitted infection caused by Chlamydia trachomatis.

Doxycycline acts systemically in various tissues. It has the highest lipophilicity in comparison to other tetracyclines, which allows it to easily reach target molecules crossing multiple membranes. Doxycycline primarily permeates the cells using the transcellular transport pathway and crosses over the outer cell membrane of the susceptible bacteria via hydrophilic pores. It is thought to enter the inner cytoplasmic membrane via a pH-dependent active transport system and afterward become chelate within the cytoplasm.

Doxycycline exerts its bacteriostatic effect by reversibly binding to the 30S and possibly the 50S ribosomal subunits during protein synthesis. It further interferes with the bacterial protein synthesis by binding to the 70S ribosomes in mitochondria. These actions stall the bacterial elongation phase as well as the ternary complex binding rate. The charged aminoacyl transfer RNA (aa-tRNA) is blocked from attaching with the ribosomal A site, yielding a cessation of RNA-dependent protein synthesis. Consequently, the aa-tRNA fails to bind with the messenger RNA-ribosome complex, causing a halt to the bacterial translation process and a disruption of the essential protein production. This static state eventually kills the bacteria.

Doxycycline has shown to inhibit the apicoplast gene expression in Plasmodium falciparum late in the cell cycle. The blocking of apicoplasts leads to an impaired fatty acid biosynthesis and a subsequent failure in parasite development. Doxycycline, along with minocycline and other 2nd generation tetracyclines, is a preferred antibiotic in the treatment of acne vulgaris due to its higher lipophilicity compared to other tetracyclines and lower resistance rate of P. acnes strains against cyclines. The exact mechanism(s) by which doxycycline works against acne is not fully established. It is thought to down regulate inflammatory mediators and block P. acnes-derived lipase, which eventually decrease the number of lipase-producing bacteria by reducing the levels of follicular-free fatty acids.

Doxycycline is also found to be a potential agent for the inhibition of collagenase in patients with periodontitis. Collagenase breaks down the peptide bonds in collagen, which ultimately separate the gum from the tooth. In the treatment of periodontitis, subantimicrobial doses (SD) of doxycycline have shown anti-collagenolytic, matrix metalloproteases (MMPs) degrading, and cytokine down-regulating actions. SD Doxycycline, however, is too small to show a direct antimicrobial effect and thus should not be used as an antibacterial agent in patients with periodontitis. Other actions of doxycycline include preventing angiogenesis and apoptosis, promoting wound healing, and encouraging gingival fibroblast attachment.

Ribosomal protection proteins such as Tet(O), Tet(K) and Tet(M) are primarily responsible for the development of bacterial resistance to tetracyclines. These proteins employ various resistance mechanisms to prevent the activity of tetracyclines including efflux, rRNA mutations, permeability reduction, and enzymatic degradation. They inhibit tetracyclines from binding to the target ribosomal subunit and amplify the disassociation constant (Kd). These actions ultimately resume the protein synthesis by allowing the attachment of tRNA with the ribosome. Culture and susceptibility testing is therefore recommended before initiating tetracyclines.

Doxycycline is shown to have an excellent absorption. Following oral administration, the drug is rapidly but almost completely absorbed in the stomach and small intestine. It has an absolute bioavailability of 90– 100% for 100–200 mg oral dose. Doxycycline can be traced in blood within 15 minutes when administered orally. A single oral dose of 200 mg doxycycline reaches a peak plasma concentration of approximately 2.6 µg/mL within 2–3.5 hours. The absorption of doxycycline, unlike tetracycline and minocycline, is also not affected by food or dairy products. Studies reported no significant difference in mean serum concentrations of 100-200 mg oral doxycycline between the fasted and fed states. Because doxycycline has a low binding affinity with calcium, the metal complexes it forms with the food are not stable to endure the highly acidic environment of the stomach. Thus, it enters the duodenum as free drug. The absorption of doxycycline, however, is significantly affected by the presence of multivalent cations.

The serum half-life of doxycycline varies from 12 to 24 hours depending on the dose, and renal impairment has little effect on it. The drug attains peak serum levels within approximately 2–3 hours following oral administration. Doxycyline is about 80-95% bound to plasma protein. It achieves a wide distribution in body tissues and fluids due to its highly lipophilic nature. Doxycycline has little metabolism, and no metabolites have been identified. However, enzyme inducers may reduce its half-life. The volume of distribution for a 200 mg oral dose is measured to be around 0.7 L/kg and about 50–80 L for the same IV dose.

The elimination of doxycycline occurs via both the renal and biliary routes in a biologically active form. About 40% of the administered dose is excreted through glomerular filtration and the rest in the feces. Studies reported a renal clearance of 1.8–2.1 liter per hour. In patients with renal insufficiency, more doxycycline is excreted in feces and the renal excretion may fall as low as 1-5%/72 hours (creatinine clearance < 10 mL/min).

Doxycycline has been used in a wide variety of infections caused by susceptible organisms. However, it is recommended that appropriate culture and susceptibility tests should be performed when possible for specific infections prior to its initiation. This FDA label includes a complete list of microorganisms for which bacteriologic testing is recommended. Doxycycline may be indicated for the treatment of following infections.

Respiratory tract infections: Pneumonia, influenza, ornithosis, tonsillitis, pharyngitis, bronchitis, otitis media, sinusitis, and other infections where bacterial resistance is not a concern.

Rickettsial infections: Rocky mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers.

Genitourinary tract infections: Pyelonephritis, urethritis, cystitis, gonorrhea, epididymitis, syphilis, chancroid, lymphogranuloma venereum and granuloma inguinale.

Skin and Soft Tissue Infections: Anthrax, impetigo, cellulitis, abscess, furunculosis, Carrion’s disease, wound infections, paronychia.

Ophthalmic infections: Trachoma, retinitis, and conjunctivitis.

Gastrointestinal diseases: Whipples disease, tropical sprue, blind loop syndrome, campylobacter fetus infections.

Bacillary infections: Tularemia, brucellosis, travelers’ diarrhea, listeriosis, cholera.

Acne: Acne vulgaris, acne conglobata and other forms of acne.

Absolute contraindications for doxycycline include the following:

• Age below 8 years
• Pregnancy or lactation
• Hypersensitivity to any of the tetracyclines
• Concomitant use with penicillin, isotretinoin, or multivalent cations

Relative contraindications for doxycycline include the following:

• Exposure to direct sunlight or ultraviolet light
• Recent colitis caused by antibiotic use
• History of yeast infections and/or lupus
• Patients with porphyria, systemic lupas erythematosus, diarrhea from C. Dificile, severe hepatic disorder, and myasthenia gravis

The effects of doxycycline on pregnant women has not been studied in an adequate and well-controlled manner. Case studies published to date are mostly based on short-term, first trimester exposure with doxycycline. No human data are available to evaluate its long-term effects on pregnant women.

Animal studies have noted no teratogenic effects of doxycycline. However, because tetracyclines have been reported to cross the placenta and enter the fetal tissues, they can have a detrimental effect on the fetal development. Pregnant animals treated with tetracyclines have also shown evidence of embryotoxicity.

Doxycycline should therefore be avoided in pregnant women unless the benefits of using it outweigh the risks.

The presence of tetracyclines has been found in the milk of breastfeeding women. However, little is known about the extent of their absorption by the breastfed infant. There are also no data on the effects of prolonged exposure to drugs of this class in breast milk. In general, tetracyclines are not recommended for lactating women due to the potential for adverse reactions in nursing babies. Physicians should make a decision to stop nursing or to discontinue doxycycline, considering its importance to a breastfeeding mother.

Doxycycline is generally well tolerated compared to its other tetracycline counterparts. Due to its excellent absorption, it also causes fewer side effects to the lower bowel, especially diarrhea. Serious adverse effects are rarely reported with doxycycline. The following are some of the common as well as rarely observed adverse reactions:

Gastrointestinal: Common adverse reactions include diarrhea, nausea, vomiting, anorexia, dysphagia, enterocolitis, abdominal pain and distention, stomach upset and acid indigestion. Rarely observed reactions include esophagitis and esophageal ulcerations.

Skin: Common adverse reactions include photosensitivity, maculopapular and erythematous rashes, pruritus, and skin erythema. Rarely exfoliative dermatitis may occur.

Renal Toxicity: Tetracyclines may cause an elevation in the blood urea nitrogen (BUN). The use of doxycycline, however, has not been reported to increase the BUN in patients with renal impairment.

Hypersensitivity Reactions: Common side effects include urticaria, anaphylactoid reactions, angioedema, and anaphylaxis.

Blood: Hemolytic anemia, leukopenia, thrombocytopenia, and neutropenia. Rarely a drug reaction with eosinophilia and systemic symptoms (DRESS) may occur.

Other: Intracranial hypertension (IH) in adults, oropharyngeal and vaginal candidiasis, and bulging fontanels (BF) in infants. Both IH and BF usually disappear upon cessation of doxycycline.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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