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Oxytetracycline

Oxytetracycline is a tetracycline analog isolated from the actinomycete Streptomyces rimosus. It was first found near Pfizer laboratories in a soil sample by Finlay et al. In 1950, Robert B Woodward, worked out the chemical structure of oxytetracycline, enabling Pfizer to mass produce the drug under the trade name, Terramycin. This discovery by Woodward was a major advancement in tetracycline research and paved the way for the discovery of an oxytetracycline derivative, doxycycline, which is one of the most popularly used antibiotics today. Oxytetracycline is a broad-spectrum antibiotic, active against a wide variety of bacteria. However, some strains of bacteria have developed resistance to this antibiotic, which has reduced its effectiveness for treating some types of infections.

Therapeutic use

Oxytetracycline is indicated for treatment of infections caused by a variety of Gram positive and Gram negative microorganisms including Mycoplasma pneumoniae, Pasteurella pestis, Escherichia coli, Haemophilus influenzae (respiratory infections), and Diplococcus pneumoniae. Its better absorption profile makes it preferable to tetracycline for moderately severe acne at a dosage of 250500 mg four times a day for usually six to eight weeks at a time, but alternatives should be sought if no improvement occurs by three months. It is sometimes used to treat spirochaetal infections, clostridial wound infection and anthrax in patients sensitive to penicillin. Oxytetracycline is used to treat infections of the respiratory and urinary tracts, skin, ear, eye and gonorrhoea, although its use for such purposes has declined in recent years due to large increases in bacterial resistance to this class of drugs. The drug is particularly useful when penicillins and/or macrolides cannot be used due to allergy. It may be used to treat Legionnaire's disease as a substitute for a macrolide or quinolone. Oxytetracycline is especially valuable in treating nonspecific urethritis, Lyme disease, brucellosis, cholera, typhus, tularaemia. and infections caused by Chlamydia, Mycoplasma and Rickettsia. Doxycycline is now preferred to oxytetracycline for many of these indications because it has improved pharmacologic features.

Infections caused by oxytetracycline-sensitive organisms include:

1) Respiratory tract infections: Pneumonia, whooping cough and other lower respiratory tract infections due to susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae and other organisms. Mycoplasma pneumoniae pneumonia. Treatment of chronic bronchitis (including the prophylaxis of acute exacerbations).

2) Urinary tract infections: caused by susceptible strains of the Klebsiella species. Enterobacter species, Escherichia coli, Streptococcus faecalis and other organisms.

3) Sexually transmitted diseases: Infections due to Chlamydia trachomatis including uncomplicated urethral, endocervical or rectal infections. Non-gonococcal urethritis caused by Ureaplasma urealyticum. Oxytetracycline is also indicated in chancroid, granuloma inguinale and lymphogranuloma venereum. Oxytetracycline is an alternative drug in the treatment of gonorrhoea and syphilis.

4) Skin Infections: Acne vulgaris when antibiotic therapy is considered necessary and severe rosacea.

5) Ophthalmic infections: Trachoma, although the infectious agent, as judged by immunofluorescence, is not always eliminated. Inclusion conjunctivitis may be treated with oral oxytetracycline alone or in combination with topical agents.

6) Rickettsial infections: Rocky Mountain spotted fever, typhus group, Q fever and Coxiella endocarditis and tick fevers.

7) Other infections: Stagnant loop syndrome. Psittacosis, brucellosis (in combination with streptomycin), cholera, bubonic plague, louse and tick-borne relapsing fever, tularaemia, glanders, melioidosis and acute intestinal amoebiasis (as an adjunct to amoebicides).

Oxytetracycline is an alternative drug in the treatment of leptospirosis, gas-gangrene and tetanus.

Dosage and Administration

The standard dose is 250500 mg six-hourly by mouth. In particularly severe infections, this dose may be increased accordingly. Occasionally, oxytetracycline is given by intramuscular injection or topically in the form of creams, ophthalmic ointments or eye drops.

Oxytetracycline should be given one hour before or two hours after meals, since food and some dairy products interfere with absorption. Therapy should be continued for up to three days after symptoms have subsided.

All infections due to Group A beta-haemolytic streptococci should be treated for at least 10 days.

Adults (including the elderly) and children over 12 years: The minimum recommended dosage is 250mg every six hours. Therapeutic levels are attained more rapidly by the administration of 500mg initially, followed by 250mg every six hours. For severe infections, the dosage may be increased to 500mg every six hours.

Children under 12 years: Contraindicated in this age group.

Elderly: Usual adult dose. Caution should be observed as subclinical renal insufficiency may lead to drug accumulation.

Renal impairment: In general, tetracyclines are contraindicated in renal impairment and the dosing recommendations only apply if use of this class of drug is deemed absolutely essential. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses.
 

Toxicology

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
dog LDLo intravenous 220mg/kg (220mg/kg) LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES

BEHAVIORAL: FOOD INTAKE (ANIMAL)

BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)
Antibiotics and Chemotherapy Vol. 3, Pg. 1015, 1953.
guinea pig LDLo intraperitoneal 2250mg/kg (2250mg/kg)   Antibiotiki. Vol. 20, Pg. 793, 1975.
infant TDLo parenteral 136mg/kg (136mg/kg) MUSCULOSKELETAL: CHANGES IN TEETH AND SUPPORTING STRUCTURES Lancet. Vol. 1, Pg. 827, 1962.
man TDLo oral 114mg/kg/4D (114mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE"

BLOOD: HEMORRHAGE
JAMA, Journal of the American Medical Association. Vol. 231, Pg. 734, 1975.
mouse LD50 intraperitoneal 5706mg/kg (5706mg/kg)   Antibiotiki. Vol. 20, Pg. 793, 1975.
mouse LD50 intravenous 140mg/kg (140mg/kg)   Arzneimittel-Forschung. Drug Research. Vol. 5, Pg. 1, 1955.
mouse LD50 oral 2240mg/kg (2240mg/kg)   Arzneimittel-Forschung. Drug Research. Vol. 5, Pg. 1, 1955.
mouse LD50 subcutaneous 700mg/kg (700mg/kg)   "CRC Handbook of Antibiotic Compounds," Vols.1- , Berdy, J., Boca Raton, FL, CRC Press, 1980Vol. 3, Pg. 44, 1980.
rat LD50 intravenous 260mg/kg (260mg/kg)   "Antibiotics: Origin, Nature, and Properties," Korzyoski, T., et al., eds., Washington, DC, American Soc. for Microbiology, 1978Vol. 1, Pg. 501, 1978.
rat LD50 oral 4800mg/kg (4800mg/kg)   "Antibiotics: Origin, Nature, and Properties," Korzyoski, T., et al., eds., Washington, DC, American Soc. for Microbiology, 1978Vol. 1, Pg. 501, 1978.
women TDLo oral 24mg/kg/6D-I (24mg/kg) BLOOD: THROMBOCYTOPENIA American Journal of Hematology. Vol. 43, Pg. 333, 1993.
 

 

Adverse Reactions

Adverse effects are mainly gastrointestinal and photosensitive allergic reactions common to the tetracycline antibiotics group. It can also damage calcium-rich organs, such as teeth and bones, although this is very rare. It sometimes causes nasal cavities to erode, quite commonly. Candidiasis (thrush) is not uncommon following treatment with broad-spectrum antibiotics. Very rarely severe headache and vision problems may be signs of dangerous intracranial hypertenion.

Tetracycline drugs may cause permanent tooth discoloration (yellow-grey-brown), if administered during tooth development, in the last half of pregnancy and in infancy up to twelve years of age. Enamel hypoplasia has also been reported. This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses.

The anti-anabolic action of tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of oxytetracycline may lead to azotaemia, hyperphosphataemia and acidosis.

When treating venereal disease, where co-existent syphilis is suspected, proper diagnostic procedures should be utilised. In all such cases, monthly serological tests should be made for at least four months.

The use of antibiotics may occasionally result in the overgrowth of nonsusceptible organisms including Candida. Constant observation of the patients is essential. If a resistant organism appears, the antibiotic should be discontinued and appropriate therapy instituted.

In long-term therapy, periodic laboratory evaluation of organ systems, including haematopoietic, renal and hepatic studies should be performed.

High doses of tetracyclines have been associated with a syndrome involving fatty liver degeneration and pancreatitis.

The use of tetracyclines in general is contraindicated in renal impairment due to excessive systemic accumulation and used with caution in patients with hepatic impairment or those receiving drugs which may have hepatotoxic effects; high doses should be avoided.

Care is advised when administering to patients with myasthenia gravis.

Photosensitivity reactions may occur in hypersensitive persons and such patients should be warned to avoid direct exposure to natural or artificial sunlight and to discontinue therapy at the first sign of skin discomfort.

Pharmacokinetic

Bioavailability  
Metabolism  
Cmax (mg/ml)  
tmax (hrs)  
Half-life 6-8 hrs
Eliminiation rate Constant  
Excretion renal
Protein binding  

Absorption

Distribution

Elimination

Metabolism

Drug drug interaction

Antacids containing aluminium, calcium, iron, magnesium or zinc may impair absorption of oxytetracycline. Allow two to three hours between doses of oxytetracycline and antacids.

Since oxytetracycline has been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require a downward adjustment of their anticoagulant dosage. Oxytetracycline may prolong the action of coumarin anticoagulants.

Antidiarrhoeal preparations such as kaolin-pectin and bismuth subsalicylate hinder absorption of tetracyclines.

Combination of tetracyclines with diuretics may be detrimental to renal function.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving oxytetracycline in conjunction with penicillin.

A few cases of pregnancy or breakthrough bleeding have been attributed to the concurrent use of oxytetracycline with oral contraceptives and alternative contraceptive advice should be sought where necessary.

There have been reports of nephrotoxicity (increased blood urea nitrogen and serum creatinine) and death in some cases when oxytetracycline therapy has been combined with methoxyflurane.

Oxytetracycline may increase the hypoglycaemic effects of insulin and sulphonylureas in patients with diabetes mellitus.

Benign intracranial hypertension has been reported following the concomitant use of tetracyclines and vitamin A or retinoids and therefore concurrent use is contraindicated.
 

Mechanism of action

Oxytetracycline inhibits cell growth by inhibiting translation. It binds to the 30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome. The binding is reversible in nature. Oxytetracycline is lipophilic and can easily pass through the cell membrane or passively diffuses through porin channels in the bacterial membrane.

Microbiology

 

 


Medicinal Chemistry

CAS number: 79-57-2  EINECS: 201-212-8

Molecular Formula: C22H24N2O9

Average mass: 460.43399 Da

Monoisotopic mass:  460.148193 Da

Systematic name: (4S,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide

SMILES: CN(C)[C@@H]3C(\O)=C(\C(N)=O)C(=O)[C@@]4(O)C(/O)=C2/C(=O)c1c(cccc1O)[C@@](C)(O)[C@H]2[C@H](O)[C@@H]34

Std. InChI: 1S/C22H24N2O9/c1-21(32)7-5-4-6-8(25)9(7)15(26)10-12(21)17(28)13-14(24(2)3)16(27)11(20(23)31)19(30)22(13,33)18(10)29/h4-6,12-14,17,25,27-29,32-33H,1-3H3,(H2,23,31)/t12-,13-,14+,17+,21-,22+/m1/s1

ACD/LogP: -1.501 # of Rule of 5 Violations: 2
ACD/LogD (pH 5.5): -4.03 ACD/LogD (pH 7.4): -4.43
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 11 #H bond donors: 8
#Freely Rotating Bonds: 8 Polar Surface Area: 201.85 2
Index of Refraction: 1.762 Molar Refractivity: 110.6 cm3
Molar Volume: 268.172 cm3 Polarizability: 43.845 10-24cm3
Surface Tension: 111.305000305176 dyne/cm Density: 1.717 g/cm3
Flash Point: 461.601 C Enthalpy of Vaporization: 127.882 kJ/mol
Boiling Point: 839.646 C at 760 mmHg Vapour Pressure: 0 mmHg at 25C


Melting Point: 183C

log P (octanol-water): -0.9

Water Solubility:  313 mg/l

 

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