tetracyclines

1. Antibiotics inhibiting protein synthesis:
Tetracyclines
Dr Ravi Kant Agrawal, MVSc, PhD
Senior Scientist (Veterinary Microbiology)
Food Microbiology Laboratory
Division of Livestock Products Technology
ICAR-Indian Veterinary Research Institute
Izatnagar 243122 (UP) India

2. Tetracyclines
The structure of
tetracycline
 Produced from Soil microorganism
 Chlortetracycin is first member
derived from Streptomyces aureofaciens
in 1948
 This was followed by oxytetracyclin
 Removal of chlorine atom from
Chlortetracyclin produced semisynthetic
tetracyclin like Methacyclin, Doxycyclin
and Minocyclin

3. Structure
• Name "tetracycline" refers to a number of antibiotics of either
natural, or semi-synthetic origin
• They are so named for their four (“tetra-”) hydrocarbon rings (“-
cycl-”) derivation (“-ine”).
• To be specific, they are defined as "a subclass of polyketides
having an octahydrotetracene-2-carboxamide skeleton".
• They are collectively known as "derivatives of polycyclic
naphthacene carboxamide".
• Acidic and hygroscopic compounds

4. Classification
• Short acting (t1/2 < 8 hrs): Oxytetracyclin, Tetracyclin, Chlortetracyclin
• Intermediate acting (t1/2 = 8-16 hrs): Demeclocyclin, Methacyclin
• Long acting tetracyclin (t1/2>16hrs): Doxycyclin, Minocyclin

5. Properties of Tetracyclines
• Bacteriostatic (almost always)
• Broad spectrum: Wide range of aerobic and anaerobic Gram
positive and Gram negative bacteria including Chlamydia,
Rickettsiae, Mycoplasma spp.
• Selectivity results from transfer into bacterial cells but not
mammalian cells
• Active against multiplying bacteria
• Effect is reversible
• Low toxicity

6. Tetracycline Antibiotics
Tetracycline Tigecycline
Doxycycline

7. Mechanism of Action
• Enter microorganisms in part by passive diffusion and in part by
an energy dependent process of active transport.
• They reversibly bind to the 30S ribosomal subunit of bacteria,
blocking the binding of aminoacyl-tRNA to the site A on the
mRNA ribosome complex.
• This prevents addition of amino acids to the growing peptide,
resulting in inhibition of protein synthesis
• Quickly bacteriostatic drugs, but at high dosage they are also
bactericidal.
• http://pharmaxchange.info/press/2011/05/mechanism-of-
action-of-tetracyclines/

8. P A
mRNA
30S
50S
tRNA
aa-tRNA
X
Tetracyclines: Mode of Action
Reversible binding to 30S ribosome subunit blocking
aminoacyl-tRNA access to acceptor site (A site)

9. Pharmacological properties
• All Tetracylines are administered orally.
• Oral absorption variable with drug.
• Recent lipid soluble Minocyclin, Doxycyclin are 100%
bioavailable
• Absorption occurs mainly in the upper small intestine and is
impaired by food (except Doxycycline and Minocycline).
• Tetracycline, in particular, is chelated and inactivated by calcium
(milk), magnesium, aluminum (antacids) and iron
• Should be taken when the stomach is empty and Must not be
taken with milk or antacids
• Doxycycline is less avidly chelated and can be taken with a meal
• Longer plasma half life (16-18 hrs)
• Carbamazepine, phenytoin, barbiturates, and chronic alcohol
ingestion may shorten the half life of doxycycline
• Excreted by glomerular filtration

10. Pharmacological properties
• Widely distributed in body
• Limited CNS penetration: Minocycline best CSF penetration
• Cross placenta, excreted in milk
• All cross placenta and concentrate in fetal bones and teeth
• Bind in tissues undergoing calcification (teeth, bones) or tumors
with high calcium content (gastric carcinoma)
• Concentrated in saliva and gingival fluid
• Concentrate in liver and partially metabolized
• Secreted into bile and excreted in urine
• Doxycycline and Minocycline largely excreted in feces; can be
used in renal failure

11. Toxicity
 Gastrointestinal discomfort/distress: Anorexia, epigastric pain,
abdominal distention, nausea, vomiting, diarrhea, sore mouth,
perianal irritation
 Hepatotoxicity (Liver toxicity): Hepatic injury- Increased during
pregnancy
 Renal toxicity (Nephrotoxicity)
 Teeth and depression of bone growth
 Discoloration enamel (teeth) and hypoplasia of teeth
Deposition in fetal and growing bones, inhibits bone growth in
children (stunted growth)
 Photosensitization
 Severe sunburn in sun; doxy/demeclocycline
 Local tissue toxicity
 Potentially teratogencic
 Vestibular toxicity

12. Contraindication
• Oral administration in ruminant and horses not recommended as
they inhibit normal bacterial fermentation of plant fibres
• Should not be given with Milk
• Antacid, iron preparation, Saline purgative Sodium bicarbonate
decrease absorption

13. Resistance
• Emergence of resistance very common
• Plasmid mediated
• Resistance usually effect all tetracyclin
• But Minocyclin may retain some activity
• Bacterial resistance to tetracyclines is mainly due to the
following three mechanisms:
• ① Decreased intracellular accumulation owning to either
impaired influx or increased efflux by an active transport
protein pump; Production of novel cytoplasmic membrane
protein that mediates active efflux of drug so that inhibitory
levels are not maintained with in cells
• ② Ribosome protection owning to production of proteins
that interfere with tetracycline binding to the target site.
• ③ Enzymatic inactivation of tetracyclines

14. Antimicrobial Spectrum
• Antimicrobial Spectrum: Rickettsia, V. cholera, M. pneumonia,
Chlamydia, Shigella, H. pylori, P. tularensis, P. pseudomallei,
Brucella, Psittacosis, Borrelia
• Minocycline – carrier state of Meningococcal infections, N.
asteroides, N. gonorrhea
• Newer Tetracyclin like Tigecyclin effective against MRSA

15. Clinical uses
• First choice for rickettsial infections (typhus), chlamydial infections,
Mycoplasma pneumonia and Ureaplasma,.
• They are effective for many spirochetal infections, including relapsing fever
(first choice), leptospirosis, Lyme diseases (Borrelia burgdorfi), and syphilis.
• They are also effective for treatment of various G+ and G- bacterial infections.
• Brucellosis, cholera, and tularemia can be treated with tetracyclines as the
first choice.
• Other uses: Protozoal infections: intestinal amebiasis and atinomycosis
• Minocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal
carrier state
• Demeclocycline – inhibits the action of ADH in the renal tubule and has
been used in the treatment of inappropriate secretion of ADH or
similar peptides by certain tumors
• Tetracycline – 250-500 mg 4x/day adults
20-40 mg/kg/d – children above 8 y/0
• 600 mg daily dose for Demeclocycline and Methacycline
• 100 mg 1-2x/d for Doxycycline and Minocycline

16. Oxytetracyclin
• Oxytetracyclin (Teramycin) most commonly used in vety practice
• Streptomyces rimosus
• Readily absorbed after oral absorption
• Widely distributed in the body
• Broad spectrum
• Excretion via urine/bile
• Wide range of application

17. Tetracyclin
• Broad spectrum
• Streptomyces aureofasciens
• More stable
• Can be administered by any route

18. Doxycyclin
• Semisynthetic derived from Oxytetracyclin
• More Lipophilic
• Longer duration of action
• Rapidly and completely absorbed from GI tract
• Less effected by presence of Milk, Food and Calcium salt
• Penetrates better into many tissues of body Lungs/Brain/CSF
• Greater plasma protein binding capacity
• Significantly metabolized in the body and excreted as inactive
metabolite in faeces
• Not accumulate in patient with renal insufficiency
• Used for treatment of Canine ehrlichiosis, Psittacosis,
Anaplasmosis

19. Gram-positive
bacteria
Some Streptococcus
pneumoniae
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria meningitidis
Anaerobic
bacteria
Some Clostridia spp.
Borrelia burgdorferi,
Treponema pallidum
Atypical
bacteria
Rickettsia spp. Chlamydia
spp.
The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline
(parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral)

20. Tigecycline

21. 21
Tigecycline (Tygacil)
• Became available 2005
• Has very broad spectrum of activity including
– MRSA, VRSA, VISA, and coagulase-neg Staph
– Penicillin resistant and susceptible streptococci
– Enterococci (including VRE)
– Gram-positive rods
– Enterobacteriaceae
– Acinetobacter (multidrug resistant)
– Anaerobes (Gram + and -)
– Chlamydiae, rickettsiae, Legionella,
– fast growing mycobacteria
• NOT effective against Pseudomonas or Proteus where the efflux pump
is effective at removing it thereby causing intrinsic resistance.

22. Gram-positive
bacteria
Streptococcus pyogenes.
Viridans group streptococci,
Streptococcus pneumoniae,
Staphylococci, Enterococci,
Listeria monocytogenes
Gram-negative
bacteria
Haemophilus influenzae,
Neisseria spp.
Enterobacteriaceae
Anaerobic
bacteria
Bacteroides fragilis, Many
other anaerobes
Atypical
bacteria
Mycoplasma spp.
The antimicrobial activity of Tigecycline (parenteral)

23. Thanks
Acknowledgement: All the material/presentations available online on the
subject are duly acknowledged.
Disclaimer: The author bear no responsibility with regard to the source
and authenticity of the content.