Français Antibiotic Drugs
Doxycycline
Doxycycline is a broad spectrum semisynthetic tetracyclines.
Chemical structure
The molecular formula is C22H24N2O8, HCl, ½ C2H6O, ½ H2O and molecular weight is 512.9
Mechanism of action
Tetracycline is a bacteriostatic drug acts by binding reversibly to the 30S subunit of the bacterial ribosome. This inhibits addition of amino acids to the growing peptide resulting in inhibition of protein synthesis.
Site of action
Pharmacokinetics
Absorption of doxycycline is not significantly affected by milk or food, but co-administration of antacids or mineral supplements should be avoided. Its long half-life permits once daily dosing.
Antimicrobial spectrum
Doxycycline has static action against a varied range of aerobic and anaerobic gram-positive and gram-negative bacteria. Doxycycline is effective against sensitive strains of staphylococci, bacteroides spp., propionibacterium, peptococcus, asexual erythrocytic forms of plasmodium falciparum, mycoplasma pneumonia, chlymadia pneumonia, c.trachomatis and many more.
Indications and uses
Doxycycline is drug of choice for treatment of suspected or proven Rocky Mountain spotted fever. Doxycycline is used for treatment of falciparum malaria resistant to chloroquine, acne vulgaris, community-acquired pneumonia, lymphogranuloma venereum etc. Doxycycline can also be used for prophylaxis of malaria and leptospirosis.
Administration and dosage
| Condition | Dosage | |
| Adults& children > 45 kg | Children> 8 years | |
| Non-serious infection | 100 mg 12 hourly followed by a maintenance dose of 100 mg/day | 4.4 mg/kg, divided into 2 doses on 1st day, followed by 2.2 mg/kg as single daily dose or divided into 2 doses on subsequent days. |
| Serious /chronic infection | 100 mg 12 hourly | 4.4 mg/kg daily |
Precautions, contraindications and warnings
Caution in patients with liver impairment. Doxycycline should be taken with glass of water to reduce risk of oesophageal injury. Contraindicated in children <8 years, pregnancy and lactation, patients suffering from porphyria, severe hepatic dysfunction and with known hypersensitivity to doxycycline.
Adverse effects
Nausea, vomiting, and diarrhea are most common side effects of tetracycline. Other side effects are brown discoloration of the teeth, anorexia, epigastric distress, stomatitis, sore throat, glossitis, black hairy tongue, dysphagia, esophagitis, esophageal ulcers, pancreatitis, liver toxicity, kidney toxicity, photosensitization.
Technical Description on Doxycycline
Doxycycline is a semisynthetic tetracycline – class antibiotic.
Chemical structure
Doxycycline is a synthetic antibiotic produced from oxytetracycline. Molecular formula of doxycycline is C22H24N2O8, HCl, ½ C2H6O, ½ H2O and MW is 512.9.The structure of doxycycline is:
Preparations available
Doxycycline is available as different salts: Doxycycline HCl (hyclate), doxycycline carrageenate, doxycycline phosphate and doxycycline monohydrate.
Oral: 20, 50, 75, 100 mg tablets and capsules; powder to reconstitute for 25 mg/5 mL suspension; 50 mg/5 mL syrup
Parenteral: 100, 200 mg powder to reconstitute for injection
Mechanism of action
Like other tetracyclines doxycycline is primarily bacteriostatic. They enter gram negative bacteria by passive diffusion through the porin channels and gram positive bacteria and other organisms by energy-dependent active transport. It is concentrated intracellularly by vulnerable cells. Tetracyclines after entering the cell are bound reversibly to the 30S subunit of the ribosomes of bacteria. Here the aminoacyl-tRNA is prevented from attaching to the acceptor site which is present on the ribosomal complex of mRNA. This leads to inhibition of the process of adding amino acids to the emerging peptide.
The carrier involved in the active transport is absent in the mammalian cells and also tetracyclines do not bind to mammalian 60S or 30S ribosomes. These two factors are responsible for the selective toxicity of tetracyclines to the microbes.
In vitro studies have reported that doxycycline inhibits collagenase activity. Other studies have also reported that doxycycline decreases the raised collagenase activity in the gingival crevicular fluid of patients with adult periodontitis. The clinical significance of these findings is not known.
Site of action
Antimicrobial Action
Like other tetracyclines doxycycline is bacteriostatic with action against a varied range of aerobic and anaerobic gram-positive and gram-negative bacteria.
Antimicrobial activity specific to doxycycline:
- Doxycycline has retained excellent levels of activity against staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA).
- A number of anaerobes (Bacteroides, Propionibacterium, Peptococcus) are sensitive to doxycycline.
- Asexual erythrocytic forms of P. falciparum are sensitive to doxycycline whereas the gametocytes are not sensitive.
- Doxycycline can be active against some tetracycline-resistant isolates.
Similar to tetracycline, doxycycline is highly efficacious against:
- Mycoplasma pneumoniae, Ureaplasma urealyticum, Actinomyces, Chlymadia pneumonia, C.trachomatis, C.psittaci, Rickettsia, Coxiella burnetii, Legionella species, spirochetes like Treponema pallidum, Borrelia recurrentis and burgdorferi.
It is also effective against:
- Some atypical mycobacteria and some non-tubercular strains and plasmodium.
It is active against the following gram negative bacteria:
- H. ducreyi, H. influenzae, Campylobacter jejuni, Vibrio cholerae, Legionella pneumophila, Francisella tularensis, and Pasteurella multocida.
- Calymmatobacterium granulomatis, Brucella abortus, Helicobacter pylori, Propionobacterium acnes, Burkholderia pseudomallei, Y. pestis and enterocolitica, Enterobacteriaceae are resistant.
- Pseudomona aeroginosa, Kleibsella, Proteus, Salmonella, Shigella, Bacteroids fragilis are not inhibited
Following gram positive bacteria are also susceptible:
- Bacillus anthracis and Listeria monocytogens
- Clostridium perfringens and C.tetani
Resistance
Resistance to tetracycline is generally inducible and mainly mediated by plasmids. Resistance to tetracycline occurs due to any of the three mechanisms:
- Enhanced efflux or diminished influx of tetracycline due to an dynamic pump which transports protein;
- Ribosome fortification due to formation of proteins that hinders attachment of tetracycline to the ribosome.
- Enzymatic inhibition.
Pharmacokinetics
Doxycycline is absorbed well after oral administration and food does not interfere with the absorption. But co-administration of antacids or mineral supplements should be avoided. Maximal concentration is achieved after two hours. Concentrations in plasma are equivalent whether doxycycline is given orally or parenterally. Plasma protein binding is about 80 to 90%. Its t1/2 is ranges from 12 to 24 hours. Lipid solubility of doxycycline is greater than tetracycline. Doxycycline has extensive tissue distribution.
Doxycycline is largely excreted unchanged both in the bile and urine. Unlike other tetracyclines doxycycline is excreted from thebody by organs other than the kidney.
Therapeutic Uses
It can be prescribed over other tetracyclines as it has a prolonged t1/2 and good oral absorption and it can be given in persons with kidney dysfunction.
The specific uses of doxycycline are:
- Doxycycline's decent activity against S. pneumoniae and H. influenzae and excellent activity against atypical pathogens such as Mycoplasma and Chlamydophilia pneumoniae make it an effective single agent for empirical therapy of community-acquired pneumonia in the outpatient setting or as an adjunct to cephalosporin-based therapy for inpatients.
- Doxycycline (300 mg as single administration) is effective in decreasing stool volume and eradicating Vibrio cholerae from the stool within 48 hours.
- Doxycycline (100 mg BD for 21 days) is first-line therapy for treatment of lymphogranuloma venereum.
- Doxycycline is preferred over other tetracyclines for venereal diseases in males and females caused by Chlamydia trachomatis.
- Non-pregnant females allergic to penicillin who have primary, secondary, or latent syphilis can be treated with doxycycline, 100 mg orally twice daily for 2 weeks
- Doxycycline is the drug of choice for treatment of suspected or proven Rocky Mountain spotted fever in adults and in children, including those <9 years of age, in whom the risk of staining of permanent teeth is outweighed by the seriousness of this potentially fatal infection.
- Doxycycline has better antiprotozoal activity and can be given with quinine in the management of falciparum malaria resistant to chloroquine.
- It is used in non-endemic areas for the treatment of chloroquine-resistant falciparum malaria in an oral dose of 200 mg daily for at least 7 days after treatment with quinine.
- Doxycycline 100 mg daily may be used for prophylaxis of malaria in areas of high risk or where multidrug resistance exists, and can be used prophylactically for up to 2 years.
- For the prophylaxis of leptospirosis, 200 mg may be given orally once a week throughout exposure for up to 21 days and 200 mg is also given when leaving the area of infection risk.
- Doxycycline, 100 mg every 12 hours (2.2 mg/kg every 12 hours for children weighing <45 kg), is indicated for prevention or treatment of anthrax.
- Doxycycline in combination with rifampin or streptomycin is effective for acute and chronic infections caused by Brucella melitensis, Brucella suis, and Brucella abortus.
- Doxycyline hyclate is indicated specifically for use as an adjunct to scaling and root planing to promote attachment level gain and to reduce pocket depth in patients with adult periodontitis.
- Solutions of doxycycline are also used for malignant effusions.
Administration and dosage
- Doxycycline is typically given orally as the base or its numerous salts, usually the hyclate.
- Doses are expressed in terms of doxycycline; doxycycline hyclate 115 mg is equivalent to about 100 mg of anhydrous doxycycline.
- Doxycycline capsules and tablets should be given with plenty of fluid, with the patient in an upright position, and well before going to bed.
- If gastric irritation occurs, it can be given with food or milk.
- Dispersible tablets or liquid formulations are advisable in elderly patients.
- If oral therapy is not possible, doxycycline hyclate may be given by slow IV infusion of a solution containing 0.1 to 1 mg/mL, in equivalent doses over 1 to 4 hours.
Dosage
| Condition | Dosage | |
| Adults& children > 45 kg | Children> 8 years | |
| Non-serious infection | 100 mg 12 hourly followed by a maintenance dose of 100 mg/day | 4.4 mg/kg, divided into 2 doses on 1st day, followed by 2.2 mg/kg as single daily dose or divided into 2 doses on subsequent days. |
| Serious /chronic infection | 100 mg 12 hourly | 4.4 mg/kg daily |
Interactions
Specific interactions are:
- Unlike other tetracyclines, doxycycline binding to calcium is less but its absorption can be affected by Fe2+, aluminium, Zn, Mg2+ and bismuth.
- Chronic alcohol consumption, rifampicin, and anticonvulsants like phenytoin, phenobarbitone and carbamazepine enhance metabolism of doxycycline due to induction of hepatic microsomal enzymes.
Most of the interactions which are similar to other tetracyclines are:
- As it inhibits enterohepatic circulation, concurrent use may lead failure of oral contraceptive pills.
- Dose of anticoagulants should be reduced as tetracyclines may lead to a reduction in the prothrombin action in plasma.
- Simultaneous use of the anaesthetic methoxyflurane may lead to kidney toxicity which may result in death.
- Tetracyclines being bacteriostatic may hinder bactericidal activity of penicillin; hence avoid giving tetracyclines with penicillin.
- It should be avoided with diuretics as blood urea may increase.
- Tetracyclines inhibits intestinal flora that produces vitamin K, and therefore may potentiate the anticoagulant effects of warfarin.
- There have been reports of pseudotumor cerebri (benign intracranial hyper tension) associated with the concomitant use of isotretinoin and tetracyclines.
Contraindications
- Hypersensitivity to any of the tetracyclines.
- Children less than 8 years of age.
- Pregnancy and lactation
- Porphyria
- Severe hepatic dysfunction
Special Precautions
- Impaired hepatic function;
- History or predisposition to oral candidiasis.
- Should be taken with at least a glass of water in an upright position to reduce the risk of oesophageal injury.
Pregnancy: Doxycycline penetrates the placental barrier.
Lactation: Tetracyclines are found in breast milk.
Adverse Effects
Gastrointestinal
- Vomiting and loose stools are most commonly responsible for stoppage of tetracyclines.
- Other effects seen are: Anorexia, epigastric distress, stomatitis, sore throat, glossitis, black hairy tongue, dysphagia, esophagitis, oesophageal ulcers, and pancreatitis.
- Tetracyclines can lead to modification of the commensal flora in the intestines and lead to killing of the sensitive commensal microorganisms and it can lead to increased multiplication of clostridium, candidial species, pseudomonas, staphylococcal species.
Liver Toxicity
- It can cause deterioration of liver function, particularly in patients with pre-existing liver insufficiency and during pregnancy.
- Liver necrosis can be seen with large IV dose (greater than four gm).
- Also hepatic necrosis is more common in pregnancy and can be fatal.
Bony Structures and Teeth
- Tetracyclines bound readily to calcium in teeth or recently formed bone in young aged children.
- It results in permanent brown discoloration of the teeth.
- If a tetracycline is consumed in pregnancy, it gets deposited in the developing teeth of the foetus, which can result in development of dysplastic enamel, discoloured teeth and increased fluorescence.
- The developing bone in the foetus can also be deposited tetracycline leading to stunting of growth or other deformities.
Photosensitization
- Systemically administered tetracyclines, can induce sensitivity to sunlight or ultraviolet light.
- Onycholysis and pigmentation of the nails may develop.
Vestibular Reactions
- Giddiness, vertigo, and vomiting can be seen.
Other side effects
- Long-term therapy may produce increased WBC count, lymphocytes, and thrombocytopenic purpura.