Drugs

Tetracyclines (Broad Spectrum Antibiotics)

Tetracyclines

Introduction

  • Tetracyclines consist of four fused rings with a system of conjugated double bonds i.e. antibiotics having a nucleus of four cyclic rings.
  • Substitutions on these rings alter the individual pharmacokinetics and spectrum of antimicrobial activity

Classification

Tetracyclines
Demeclocycline
Doxycycline
Minocycline
Tetracycline
Oxytetracycline
Rolitetracycline
Chlortetracycline
Lymecycline

 
Mechanism of action
Tetracyclines enter susceptible organisms via passive diffusion & by an energy-dependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane.

  • In gram negative bacteria tetracyclines diffuse through porin channels as well.The more lipid-soluble members (doxycycline, minocycline) enter by passive diffusion also (this is partly responsible for their higher potency).

Tetracyclines concentrate intracellularly in susceptible organisms. The drugs bind reversibly to the 30S subunit of the bacterial ribosome. This action prevents binding of aminoacyl-t-RNA to the mRNA–ribosome complex, thereby inhibiting bacterial protein synthesis. The tetracyclines are primarily bacteriostatic.
Tetracyclines have selective toxicity for the microbes because :

  • The carrier involved in active transport of tetracyclines is absent in the host cells.
  • Moreover, protein synthesizing apparatus of host cells is less sensitive to tetracyclines.

Antibacterial spectrum
Tetracyclines are effective against a wide variety of organisms, including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. When originally introduced, tetracyclines inhibited practically all types of pathogenic microorganisms except fungi and viruses; hence the name ‘broad-spectrum antibiotic’. However, promiscous and often indiscriminate use has gradually narrowed the field of their usefulness.

  • Cocci : Tetracyclines (especially minocycline) are now active against few N. gonorrhoeae and N. meningitidis. All gram positive and gram negative cocci were originally sensitive, but now many Strep. pyogenes, Staph. aureus and enterococci have become resistant. Responsiveness of Strep. pneumoniae has decreased somewhat.
  • Most gram positive bacilli, e.g. Clostridia and other anaerobes, Listeria, Corynebacteria, Propionibacterium acnes, B. anthracis are inhibited but not Mycobacteria, except some atypical ones.
  • Sensitive gram-negative bacilli are H. ducreyi, Calymmatobacterium granulomatis, V. cholerae, Yersinia pestis, Y. enterocolitica, Campylobacter, Helicobacter pylori, Brucella, Pasteurella multocida, F. tularensis and many anaerobes; some H. influenzae have become insensitive. Enterobacteriaceae are now largely resistant. Notable bacilli that are not inhibited are Pseudomonas aeruginosa, Proteus, Klebsiella, Salmonella typhi and many Bact. fragilis. MIC against anaerobes is relatively higher.
  • Spirochetes, including T. pallidum and Borrelia are quite sensitive.
  • All rickettsiae (typhus, etc.) and chlamydiae are highly sensitive.
  • Mycoplasma and Actinomyces are moderately sensitive.
  • Entamoeba histolytica and Plasmodia are inhibited at high concentrations.

Therapeutic uses

Although tetracyclines are broad-spectrum antibiotics, they should be employed only for those infections for which a more selective and less toxic.
1. Empirical therapy : Tetracyclines are often employed when the nature and sensitivity of the infecting organism cannot be reasonably guessed, but they are not dependable for empirical treatment of serious/life-threatening infections.
They may also be used for initial treatment of mixed infections, although a combination of lactam and an aminoglycoside antibiotic or a third generation cephalosporin or a fluoroquinolone are now preferred.
2. Tetracyclines are the first choice drugs for following :

  • Venereal diseases
    – Chlamydial non specific urethritis/endocervivitis
    – Lymphogranulum venereum : resolves in 2-3 weeks.
    – Granuloma inguinale due to Calymm. granulomatis
  • Atypical Pneumonia due to Mycoplasma pneumoniae : duration of illness is reduced by tetracycline therapy. Psittacosis is treated in 2 weeks by tetracyclines.
  • Cholera : Tetracyclines have adjuvant value by reducing stool volume and limiting the duration of diarrhoea.
  • Brucellosis : Tetracyclines are highly efficacious; cause rapid symptomatic relief; therapy of choice is doxycycline 200 mg/ day + rifampin 600 mg/ day for 6 weeks. Gentamicin may be combined with doxycycline in acute cases.
  • Plague : Tetracyclines are highly effective in both bubonic and pneumonic plague. They are preferred for blind/ mass treatment of suspected cases during an epidemic, though streptomycin often acts faster.
  • Relapsing fever· due to Borrelia recurrentis responds adequately.
  • Rickettsial infections : typhus, rocky mountain spotted fever, Q fever, etc. respond dramatically. Chloramphenicol is an alternative.

3. Tetracyclines are second choice drugs:

  • To penicillin/ ampicillin for tetanus, anthrax, actinomycosis and Listeria infections.
  • To ceftriaxone, amoxicillin or azithromycin for gonorrhoea, especially for penicillin resistant nonPPNG; also in patients allergic to penicillin, but response rate has decreased.
  • To ceftriaxone for syphilis in patients allergic to penicillin; early syphilis can be treated in 2 weeks but late syphilis requires 1 month.
  • To penicillin for leptospirosis; doxycycline 100 mg BD for 7 days is curative. Weekly doxycycline (200 mg) has been used as prophylactic in subjects at risk during an epidemic.
  • To azithromycin for pneumonia due to Chlamydia pneumoniae. Oral as well as topical tetracycline has been used in trachoma.
  • To ceftriaxone/ azithromycin for chancroid.
  • To streptomycin for tularemia.

4. Other situations in which tetracyclines may be used are:

  • Urinary tract infections : Odd cases in which the organism has been found sensitive.
  • Community-acquired pneumonia, when a more selective antibiotic cannot be used.
  • Amoebiasis : along with other amoebicides for chronic intestinal amoebiasis.
  • As adjuvant to quinine or sulfadoxinepyrimethamine for chloroquine-resistant P. falciparum malaria.
  • Acne vulgaris : prolonged therapy with low doses may be used in severe cases (since Propionibacterium acnes is sensitive to tetracyclines), but simpler treatments are preferred in most cases.
  • Chronic obstructive lung disease : prophylactic use may reduce the frequency of exacerbations, but the risk : benefit ratio is controversial.

Resistance

Resistance to tetracyclines develops slowly in a graded manner. Mechanisms are as following :

  • An efflux pump that expels drug out of the cell, thus preventing intracellular accumulation. (most commonly encountered),
  • Elaboration of tetracycline inactivating enzymes,
  • Plasmid mediated production of a ‘protection’ protein which protects the ribosomal binding site from tetracycline.

Nearly complete cross resistance is seen among different members of the tetracycline group. However, some organisms not responding to other tetracyclines may be inhibited by therapeutically attained concentrations of minocycline (the most potent agent). Thus, resistance to one tetracycline does not confer universal resistance to all tetracyclines.
Partial cross resistance between tetracyclines and chloramphenicol has been noted.

Side effects

  • Gastric discomfort : Epigastric distress commonly results from irritation of the gastric mucosa and is often responsible for noncompliance with tetracyclines. Esophagitis may be minimized through coadministration with food (other than dairy products) or fluids and the use of capsules rather than tablets. [Note: Tetracycline should be taken on an empty stomach.]
  • Effects on calcified tissues : Deposition in the bone and primary dentition occurs during the calcification process in growing children. This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth. The use of tetracyclines is limited in pediatrics.
  • Hepatotoxicity : Rarely hepatotoxicity may occur with high doses, particularly in pregnant women and those with preexisting hepatic dysfunction or renal impairment.
  • Phototoxicity : Severe sunburn may occur in patients receiving a tetracycline who are exposed to sun or ultraviolet rays. This toxicity is encountered with any tetracycline, but more frequently with tetracycline and demeclocycline. Patients should be advised to wear adequate sun protection.
  • Vestibular dysfunction : Dizziness, vertigo, and tinnitus may occur particularly with minocycline, which concentrates in the endolymph of the ear and affects function. Doxycycline may also cause vestibular dysfunction.
  • Pseudotumor cerebri : Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. Although discontinuation of the drug reverses this condition, it is not clear whether permanent sequelae may occur.

Precautions

  • Tetracyclines should not be used during pregnancy, lactation and in children.
  • They should be avoided in patients on diuretics: blood urea may rise in such patients.
  • They should be used cautiously in renal or hepatic insufficiency.
  • Preparations should never be used beyond their expiry date.
  • Do not mix injectable tetracyclines with penicillin-inactivation occurs.
  • Do not inject tetracyclines intrathecally.
  • Tetracyclines are not recommended by IM route because it is painful and absorption from the injection site is poor. Slow i.v. injection may be given in severe cases, but is rarely required now.
  • A variety of topical preparations (ointment, cream, etc.) are available, but should not be usee because there is high risk of sensitization. However, ocular application is not contraindicated.

Drug Interactions 
Contraindications 

  • Tetracyclines should not be used in pregnant or breast-feeding women or in children less than 8 years of age.

For detailed query or in case of uncertainty, Always consult your doctor or pharmacist.

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