Tetracyclines

Presented by:
Areeba Aziz (46)
• Tetracycline is produced by the Streptomyces genus of
actinobacteria.
• Tetracyclines are broad-spectrum bacteriostatic antibiotics that
inhibit protein synthesis.
• Acts on 30S ribosomal subunit.
• All tetracyclines are slightly bitter solids which are slightly water
soluble,
• They are available as hydrochlorides, which are more soluble.
• Aqueous solutions are unstable.
Tetracyclines available for clinical uses:

1. Tetracycline
2. Oxytetracycline
3. Demeclocycline
4. Doxycycline
5. Minocycline
(A new synthetic subclass ‘glycylcyclines’ represented by Tigecycline has
been added recently.)
6. Glycylcycline: Tigecycline (semisynthetic derivative of minocycline)
 Many others like Chlortetracycline, Methacycline, Rolitetracycline,
Lymecycline are no longer commercially available.
 Classification on basis of
Duration of Action
Short Acting (half life: 6-8 hrs.) Intermediate Acting (half life: 12 hrs.) Long Acting (half life: 16-18 hrs.)

Tetracycline Demeclocycline Doxycycline

Chlortetracycline Methacycline Minocycline

Oxytetracycline Tigecycline (half life: 36 hrs.)

Mechanism of Action:
• Tetracyclines enter microorganisms in part by:
1. Passive diffusion 2. energy-dependent process of active
transport.

• tetracyclines bind reversibly to the 30S subunit of the bacterial

ribosome
• blocking the binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex.
• This prevents addition of amino acids to the growing peptide.
• Polysome (complex of tRNA & mRNA: lead to translation) will not be
formed.
Antimicrobial Activity
1. Cocci: All gram-positive and gram-negative cocci were originally sensitive, but now
Strep. pyogenes, Staph. aureus (including MRSA) and enterococci respond. (only
few)
Strep. pneumoniae (responsiveness has decreased).
N. gonorrhoeae and N. meningitides (especially minocycline are active against few
of them)

2. Most gram-positive bacilli, e.g.

Clostridia
other anaerobes, Listeria, Corynebacteria, Propionibacterium acnes, B. anthracis
are inhibited
but not Mycobacteria, except M. leprae (to minocycline)
3. Sensitive gram-negative bacilli e.g—
V. cholerae, Y. enterocolitica, Campylobacter, Helicobacter pylori,
Brucella, 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.

4. Spirochetes, including
T. pallidum and Borrelia (quite sensitive).
5. All rickettsiae (typhus, etc.) and chlamydiae (highly sensitive).

6. Mycoplasma & Actinomyces (moderately sensitive).

7. Protozoa like
Entamoeba histolytica and Plasmodia (inhibited at high
concentrations).
Resistance:
• Three mechanisms of resistance have been described:
(1) impaired influx or increased efflux by an active transport protein pump;
I. Tet(AE) efflux pump efflux gram-negative species.
Resistant to:
older tetracyclines
doxycycline, and
minocycline.
Susceptible to:
tigecycline, which is not a substrate of these pumps.
II. Tet(K) efflux pump of staphylococci.
Resistance to:
Tetracycline
Susceptible to:
doxycycline, minocycline, or tigecycline, none of which are pump substrates.
(2) ribosome protection due to production of proteins that interfere with
tetracycline binding to the ribosome;
The Tet(M) ribosomal protection protein expressed by gram-positives produces
Resistance to:
Tetracycline
doxycycline
minocycline
Susceptible to:
Tigecycline (which, because of its bulky t-butylglycylamido substituent, has a
steric hindrance effect on Tet(M) binding to the ribosome).
(3) enzymatic inactivation.

• Some bacteria show chromosomal mediated resistance :

Proteus sp
Pseudomonas aeruginosa,
 intrinsic resistance to
 all tetracyclines
 including tigecycline.
Pharmacokinetics:

• Absorption after oral administration is approximately:

30% for chlortetracycline;
60–70% for tetracycline, oxytetracycline, demeclocycline,
methacycline; and
95–100% for doxycycline and minocycline

• Tigecycline is poorly absorbed orally and must be administered

intravenously
• Absorption occurs mainly in the upper small intestine.
• Absorption is impaired by:
food (except doxycycline and minocycline)
multivalent cations (Ca 2+ , Mg 2+ , Fe 2+ , Al 3+ )
dairy products and antacids
alkaline pH
• Tetracyclines are 40–80% bound by serum proteins.
• Tetracycline hydrochloride or Oxytetracycline:
Oral dosages of 500 mg every 6 hours

produce peak blood levels of 4–6 mcg/mL.

• Doxycycline or Minocycline:
200 mg dose

produce peak blood levels of 2–4 mcg/mL.

• Tigecycline:
at standard dosage

produce peak blood levels of 0.6 mcg/mL

• Poor CSF penetration.
• Minocycline reaches very high concentrations in tears and saliva,

useful for eradication of the meningococcal carrier state.

• Tetracyclines cross the placenta, reach the fetus and are also excreted
in breast milk.
ADR major:
As a result of chelation with calcium, damage—growing bones and
teeth.
• Tetracyclines are excreted mainly in bile and urine (mostly by
glomerular filtration).
• Doxycycline and tigecycline, in contrast to other tetracyclines, are
eliminated by nonrenal mechanisms.
 Clinical Uses:
Tetracyclines
1. are excellent drugs for the treatment of:
• Mycoplasma pneumonia,
• Chlamydiae, and
• some spirochetes.
2. used in combination to treat gastric and duodenal ulcer disease caused by
Helicobacter pylori.
3. vibrio infections- In cholera but tetracycline resistance has appeared during
epidemics.
4. effective in most chlamydial infections, including sexually transmitted infections.
5. gonococcal disease, Doxycycline is used in combination with ceftriaxone
6. in the treatment or prophylaxis of protozoal infections, eg, those due to
Plasmodium falciparum
7. treatment of acne,
8. exacerbations of bronchitis,
9. community-acquired pneumonia,
10. Lyme disease,
11. relapsing fever,
12. leptospirosis, and
13. some nontuberculous mycobacterial infections (e.g, Mycobacterium
marinum).
14. bacterial gastroenteritis and urinary tract infections.
1. A Tetracycline is the drug of choice in the treatment of infections
caused by rickettsiae. Including:
o Rocky Mountain Spotted Fever
o Typhus group infection
o Rickettsial pox
o Q fever
in combination with other antibiotics—is indicated for:
 plague,
 tularemia, and
 brucellosis
2. Minocycline
• Dose: 200 mg orally daily for 5 days,
• can eradicate the meningococcal carrier state (but because of side
effects and resistance of many meningococcal strains, ciprofloxacin or
rifampin is preferred).

3. Demeclocycline
• inhibits the action of antidiuretic hormone in the renal tubule
• used in the treatment of inappropriate secretion of antidiuretic
hormone.
4. Tigecycline, the first glycylcycline to reach clinical practice.
- Susceptible:
- Many tetracycline-resistant strains are susceptible to tigecycline
Its spectrum is very broad.
1. Coagulase-negative staphylococci and
2. Staphylococcus aureus, including:
 methicillin-resistant
 vancomycin-intermediate, and
 vancomycin-resistant strains
3. Streptococci
 penicillin-susceptible
 penicillin-resistant
4. Enterococci, including vancomycin-resistant strains
5. Gram-positive rods
6. Enterobacteriaceae
7. Multidrug-resistant strains of Acinetobacter sp
8. Anaerobes, both gram-positive and gram-negative
9. Rickettsiae
10. Chlamydia sp
11. Legionella pneumophila; and
12. Rapidly growing Mycobacteria all are susceptible.
- Intrinsically Resistant;
 Proteus sp and
 P aeruginosa
- Dose:
Tigecycline, formulated for IV administration only, is given as a 100 mg
loading dose, then 50 mg every 12 hours.
volume of distribution is quite large
peak serum concentrations are low
Elimination is primarily biliary
no dosage adjustment is needed for patients with renal insufficiency
• Chief adverse effect of tigecycline is nausea, which occurs in up to
one third of patients, and occasionally vomiting.
• Tigecycline Used in treatment of:
skin and skin-structure infection
intra-abdominal infections
community-acquired pneumonia.
(associated with a small but significant increase in the risk of death
compared with other antibiotics used to treat these infection)
A. Oral Dosage
• For rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride is
for adults for children (8 years of age and older)
0.25–0.5 g four times daily 20–40 mg/kg/d

• For severe systemic infections, the higher dosage is indicated, at least for the first few days.
for demeclocycline or for doxycycline for minocycline.
methacycline

daily dose is 600 mg 100 mg once or twice daily 100 mg twice daily

• Oral tetracycline of choice : Doxycycline because it can be given twice daily, and its
absorption is not significantly affected by food.
Precautions:
All tetracyclines chelate with metals, and none should be orally administered with milk,
antacids, or ferrous sulfate.
To avoid deposition in growing bones or teeth, tetracyclines should be avoided in pregnant
women and children younger than 8 years.
B. Parenteral Dosage

Several tetracyclines are available for intravenous injection in doses of:

0.1–0.5 g every 6–12 hours (similar to oral doses)

Usual preferred agent: Doxycycline, at a dosage of:

 100 mg every 12–24 hours.

 IM injection is not recommended because of pain and inflammation

at the injection site
Adverse Effects:
• Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most
adverse effects are due to direct toxicity of the drug or to alteration of microbial flora.
A. Gastrointestinal Adverse Effects
 Nausea,
 vomiting, and
 diarrhea are the most common reasons for discontinuing tetracyclines.
Nausea, anorexia, and diarrhea can usually be controlled by
 administering the drug with food or carboxymethylcellulose,
 reducing drug dosage, or
 discontinuing the drug.
Tetracyclines alter the normal gastrointestinal flora. This can result in
 intestinal functional disturbances,
 anal pruritus,
 vaginal or oral candidiasis, or
 Clostridium difficile-associated colitis (the risk of C difficile colitis may be lower with tetracyclines
than with other antibiotics).
B. Bony Structures and Teeth
• Tetracyclines are readily bound to calcium deposited in newly formed bone or
teeth in young children.
• When given during pregnancy, it can be deposited in the fetal teeth, leading to:
fluorescence,
discoloration, and
enamel dysplasia
It can also be deposited in bone, where it may cause:
 deformity or
growth inhibition

(Because of these effects, tetracyclines are generally avoided in pregnancy. If

the drug is given for long periods to children younger than 8 years, similar
changes can result).
C. Other Toxicities
• can impair hepatic function,
especially during pregnancy,
in patients with preexisting hepatic insufficiency and
when high doses are given intravenously.
• Hepatic necrosis has been reported with daily doses of 4 g or more
intravenously.
• Renal tubular acidosis and Fanconi syndrome (administration of
outdated tetracycline preparations).
• Nephrotoxicity when given along with diuretics may cause
• May accumulate to toxic levels in patients with impaired kidney
function (all tetracyclines other than doxycycline).
• Venous thrombosis (lead by IV injection)
• Painful local irritation (produced by IM injection) should be avoided.
• Induce sensitivity to sunlight or UV light, particularly in fair-skinned
persons (by systemically administered tetracycline, especially
Demeclocycline)
• Particularly with Minocycline (with dosages of 200–400 mg/d, 35–70%
of patients will have these reactions) & with higher doses of
Doxycycline :
Dizziness,
vertigo,
nausea, and
Vomiting have been noted