Tetracyclines

• History:
o Chlortetracycline, introduced in 1948, was the first tetracycline.
o Broad-spectrum antibiotics due to their effectiveness against:
▪ Rickettsia
▪ Gram-positive bacteria
▪ Gram-negative bacteria
▪ Aerobes and anaerobes
▪ Chlamydia
• Source and Chemistry:
o Oxytetracycline: A natural antibiotic produced by Streptomyces rimosus.
o Tetracycline: A semisynthetic derivative of chlortetracycline.
o Demeclocycline, Methacycline,Doxycycline and Minocycline are other
semisynthetic tetracyclines.
o Tetracyclines are analog of polycyclic naphthacenecarboxamide.

Effects on Pathogenic Microorganisms

• Bacteriostatic Nature:
o Tetracyclines are bacteriostatic antibiotics, meaning they inhibit bacterial
growth rather than killing bacteria directly.
o Minocycline and doxycycline, due to their lipophilic nature, are the most
potent by weight.
• Effective Against a Wide Range of Microorganisms:
o Active against both aerobic and anaerobic gram-positive and gram-
negative bacteria.
o Effective against organisms resistant to cell-wall-active agents, including:
▪ Rickettsia
▪ Mycoplasma pneumoniae
▪ Chlamydia spp.
▪ Some atypical mycobacteria
▪ Plasmodium spp. Etc.
o Not effective against fungi.
• Bacterial Resistance:
o Resistance to one tetracycline can lead to cross-resistance with other
members of the class.

o Resistant bacteria:
▪ Enterobacteriaceae (many strains have acquired resistance)
▪ Pseudomonas aeruginosa (all strains resistant)
Mechanism of Action

• Inhibition of Protein Synthesis:

o Tetracyclines inhibit bacterial protein synthesis by binding to the 30S
ribosomal subunit.
o This binding prevents the attachment of aminoacyl tRNA to the acceptor (A)
site on the mRNA-ribosome complex, disrupting protein production.
• Entry into Gram-Negative Bacteria:
o Tetracyclines enter via two mechanisms:
1. Passive diffusion through hydrophilic channels formed by porin
proteins in the outer membrane.
2. Active transport via an energy-dependent system that pumps
tetracyclines across the cytoplasmic membrane.
• Entry into Gram-Positive Bacteria:
o Entry requires metabolic energy, but the exact mechanism is not as well
understood as in gram-negative bacteria.

Absorption, Distribution, and Excretion of Tetracyclines

Absorption

• Oral absorption is incomplete, and Occurs in the stomach and upper small intestine,
and absorption is better in the fasting state.
• Interference with absorption:
o Impaired by ingestion of dairy products, antacids (containing calcium,
magnesium, or aluminum), and iron or zinc supplements.
o These interactions result from the chelation of tetracyclines with divalent and
trivalent cations.
• Doxycycline is safe for use in patients with renal failure because it does not
significantly accumulate, and is excreted in the feces.
Distribution

• Tetracyclines distribute widely into body tissues and fluids.

• Accumulate in liver, spleen, bone marrow and enamel of unerupted teeth.
• They can penetrate the cerebrospinal fluid (CSF), even without meningitis, and
reach high concentrations in synovial fluid and sinus mucosa.
• Cross the placenta and enter the fetal circulation.
• High concentrations are found in breast milk.

Excretion

• Most tetracyclines are eliminated primarily through the kidneys, with biliary
excretion .
• Minocycline is metabolized significantly by the liver.

Therapeutic Uses of Tetracyclines

• Extensive Use:
o Tetracyclines have been widely used to treat infectious diseases and as
additives in animal feeds to promote growth, leading to increased bacterial
resistance.
o Despite resistance, they remain effective against rickettsiae, mycoplasmas,
and chlamydiae.

Respiratory Tract Infections:

o Doxycycline is effective for respiratory tract infections.

Rickettsial Infections

• Tetracyclines are life-saving in rickettsial infections, including:

o Rocky Mountain spotted fever.
o Epidemic typhus (Brill’s disease), and Q fever.
• Doxycycline is the drug of choice for treating Rocky Mountain spotted fever in
adults and children.

Mycoplasma Infections

• Mycoplasma pneumoniae is sensitive to tetracyclines.

o Treatment with tetracyclines reduces the duration of symptoms (fever,
cough, malaise, fatigue, pulmonary rales, and radiological abnormalities).

Other uses

• Urinary Tract Infections: No longer recommended due to resistance.

• Actinomycosis: Tetracyclines may be an alternative to penicillin G.
• : Low doses are effective by inhibiting propionibacteria in sebaceous follicles.

Beside these tetra cyclines are used for given diseases:

Sexually Transmitted Diseases, Pelvic Inflammatory Disease & Epididymitis, Anthrax,
Bacillary Infections, Acne

Untoward Effects of Tetracyclines

Gastrointestinal Effects

• Common symptoms include nausea, vomiting, and diarrhea. Severe effects include
esophagitis, pancreatitis.

Photosensitivity

• Tetracyclines, may cause photosensitivity reactions leading to onycholysis and nail

pigmentation.

Hepatic Toxicity

• High doses can induce hepatic damage, especially in pregnant women.

Tetracycline-induced liver toxicity can be severe.

Renal Toxicity

• Tetracyclines aggravate renal disease. Doxycycline has fewer renal side effects.

Effects on Teeth

• Tetracyclines cause permanent tooth discoloration, particularly in children receiving

the drug during tooth calcification (2 months to 5 years). Risks are higher in
pregnancy and children under 8 years.

Miscellaneous Effects

• Bone growth depression in infants, thrombophlebitis after IV use, vestibular

toxicity (dizziness and ataxia), and increased intracranial pressure in infants are
possible side effects.
• Hypersensitivity reactions include rash, angioedema, and anaphylaxis..

Precautions

• Avoid tetracyclines in pregnant women and children under 8 years.

 Chloramphenicol

History and Source

• Discovery: Chloramphenicol, an antibiotic originally produced by Streptomyces

venezuelae, was introduced into clinical practice in 1948.
• Initial Use: It was widely used across various infections due to its broad-spectrum
antimicrobial activity.

Mechanism of Action

Chloramphenicol primarily functions as an

antibiotic by inhibiting protein synthesis in
bacteria and, to a lesser extent, in eukaryotic
cells. Below are the key points detailing its
mechanism of action:

1. Cellular Penetration

• Transport Mechanism:
Chloramphenicol readily penetrates
bacterial cells through facilitated
diffusion, allowing it to reach its site
of action effectively.

2. Ribosomal Binding

• Target Site: The drug binds

reversibly to the 50S ribosomal
subunit of the bacterial ribosome.
• Competitive Inhibition:
Chloramphenicol binds near the site
where macrolide antibiotics and
clindamycin also attach, resulting in
competitive inhibition of these
drugs.

3. Inhibition of tRNA Binding

• The binding of tRNA to the codon recognition site on the 30S ribosomal subunit
remains unaffected.
• Aminoacyl tRNA Blockage: However, chloramphenicol prevents the binding of the
amino acid–containing end of the aminoacyl tRNA to the acceptor site on the 50S
ribosomal subunit.

4. Inhibition of Peptide Bond Formation

• The interaction between peptidyl transferase (the enzyme responsible for forming
peptide bonds) and its amino acid substrate is inhibited, leading to a halt in peptide
bond formation.
5. Effects on Eukaryotic Cells

• Mitochondrial Protein Synthesis: Chloramphenicol can also inhibit protein

synthesis in mammalian mitochondria, which contain 70S ribosomes resembling
those of bacteria, as opposed to the 80S ribosomes found in cytoplasmic cells.
• Sensitivity of Erythropoietic Cells: The erythropoietic cells (red blood cell
precursors) are particularly sensitive to chloramphenicol, which can lead to adverse
effects, such as bone marrow suppression.

Antimicrobial Actions of Chloramphenicol

Broad spectrum of antimicrobial activity against various bacteria. Here are the key points
regarding its antimicrobial actions:

. Bacteriostatic vs. Bactericidal Activity

• Bacteriostatic Effect: Chloramphenicol is primarily bacteriostatic against most

species.
• Bactericidal Effect: It may be bactericidal against:
o Haemophilus influenzae
o Neisseria meningitidis
o Streptococcus pneumoniae

Activity Against Specific Bacteria •

Gram-Negative Bacteria, Anaerobic Bacteria, Aerobic Gram-Positive Cocci, Staphylococcus

aureus, Mycoplasma, Chlamydia, Rickettsia, Enterobacteriaceae

Resistance to Chloramphenicol

1. Mechanisms of Resistance

• Plasmid-Encoded Acetyltransferase: The most common mechanism, where the

enzyme inactivates chloramphenicol by acetylation.
• Decreased Permeability: Some bacteria develop reduced permeability to the drug.
• Ribosomal Mutation: Changes in the ribosomal target can also confer resistance.

2. Effect of Resistance

• Acetylated Derivatives: These derivatives of chloramphenicol cannot bind

effectively to bacterial ribosomes, leading to reduced susceptibility.

Pharmacokinetics

Chloramphenicol (CHLOROMYCETIN) exhibits specific absorption, distribution,

metabolism, and excretion characteristics that influence its clinical use.

1. Absorption

• Route: Rapidly absorbed from the gastrointestinal tract.

 • Prodrug Formulation: The parenteral preparation is sodium succinate, an inactive
prodrug that achieves similar plasma concentrations as chloramphenicol itself through
hydrolysis by esterases.

2. Distribution

• Body Fluids: Chloramphenicol is widely distributed and reaches therapeutic

concentrations in body fluids.
• Cerebrospinal Fluid (CSF): Achieves concentrations approximately 60% of those in
plasma (range of 45% to 99%), regardless of the presence of meningitis. There is a
potential for accumulation in the brain.
• Chloramphenicol is present in bile, breast milk, placental fluid.
• About 50% of chloramphenicol is bound to plasma proteins, with reduced binding
observed in cirrhotic patients and neonates.

3. Fate and Metabolism

• Hepatic Metabolism: The major route of elimination is hepatic metabolism to an

inactive glucuronide metabolite.
• Renal Clearance: Both the metabolite and chloramphenicol itself are excreted in
urine via filtration and secretion. Impaired hepatic function (e.g., cirrhosis) results in
decreased metabolic clearance, necessitating dosage adjustments.

4. Excretion

• Half-Life: The half-life of chloramphenicol is influenced by plasma bilirubin

concentrations and is not significantly altered by renal insufficiency or haemodialysis.
However, if dosage is reduced due to cirrhosis, clearance via haemodialysis can be
significant.

5. Special Considerations

• Neonates and Infants: Poor renal function and decreased esterase activity in
neonates can lead to increased plasma concentrations and prolonged time to peak
concentrations of active chloramphenicol (up to 4 hours). Adjustments to dosage may
be necessary based on these factors.

Therapeutic Uses of Chloramphenicol

Chloramphenicol is reserved for specific infections due to its potential toxicities, and therapy
should only be considered when the benefits outweigh the risks

1. Typhoid Fever

• Use: Chloramphenicol is less commonly used for typhoid fever due to the availability
of less toxic alternatives, such as third-generation cephalosporins and quinolones,
which are often more effective against resistant strains of Salmonella typhi.
2. Bacterial Meningitis

• Use: Although third-generation cephalosporins are the preferred treatment for

bacterial meningitis, chloramphenicol remains an alternative in cases of severe allergy
to β-lactams or in developing countries.

3. Anaerobic Infections

• Use: Chloramphenicol is effective against many anaerobic bacteria, including

Bacteroides spp., making it suitable for serious intra-abdominal infections and brain
abscesses.

4. Rickettsial Diseases

• Use: While tetracyclines are typically preferred for treating rickettsial diseases,
chloramphenicol can be used in patients with allergies, reduced renal function,
pregnant women, and children under 8 years who need prolonged therapy.

5. Brucellosis

• Use: Chloramphenicol is not the first-line treatment for brucellosis, where

tetracyclines are more effective. However, it can be used when tetracyclines are
contraindicated.

Untoward Effects of Chloramphenicol

Chloramphenicol is associated with several adverse effects, primarily due to its mechanism of
action, which inhibits protein synthesis in bacteria and affects human mitochondrial function.
Due to its potential to cause life-threatening blood dyscrasias, chloramphenicol is now only
used in specific, life-threatening infections where:

o Safer alternatives are unavailable, either due to antibiotic resistance or

allergies to other treatments.
o Examples include:
▪ Bacterial meningitis
▪ Rickettsial infections (e.g., Rocky Mountain spotted fever)

1. Mechanism of Toxicity

• Chloramphenicol inhibits the synthesis of proteins in the inner mitochondrial

membrane by affecting the ribosomal peptidyl transferase. This includes key
components like cytochrome c oxidase, which is crucial for aerobic metabolism.
Many of the drug's toxic effects can be traced back to this action.

2. Hypersensitivity Reactions

• Manifestations: Rarely, chloramphenicol can cause vesicular skin rashes, which may
occur alongside fever or as a singular symptom.
 • Jarisch-Herxheimer Reactions: These can occur following initiation of
chloramphenicol therapy for conditions like syphilis, brucellosis, and typhoid fever.

3. Hematological Toxicity (fatal blood disorders)

• Bone Marrow Effects: (A reversible condition related to the dose or duration of

therapy) The most critical adverse effect involves the hematopoietic system.
Chloramphenicol can cause:
o Dose-related toxicity: Presenting as anemia, leukopenia, or
thrombocytopenia.
• Aplastic anemia: (A rare but serious condition where the bone marrow fails to
produce enough blood cells). Aplastic anemia is more likely in patients undergoing
prolonged therapy or those with repeated exposures.

4. Toxic and Irritative Effects

• Gastrointestinal Reactions: Nausea, vomiting, diarrhea, unpleasant taste, and

perineal irritation may occur with oral administration.
• Neurological Effects: Rare toxic effects include blurred vision and digital
paresthesias. More serious effects like encephalopathy and cardiomyopathy can occur
due to mitochondrial enzyme system impairment, particularly in tissues with high
oxygen consumption.

5. Gray Baby Syndrome

• Risk in Neonates: Premature or low-birth-weight infants are at risk of developing

gray baby syndrome when exposed to excessive doses of chloramphenicol. Symptoms
typically manifest 2 to 9 days after treatment initiation and include:
o Vomiting, refusal to suck, rapid respiration, abdominal distention, cyanosis,
and loose green stools.
o The characteristic ashen-gray color and severe illness can progress rapidly,
with a mortality rate of around 40%.

6. Drug Interactions

• Cytochrome P450 Inhibition: Chloramphenicol inhibits hepatic CYPs, prolonging

the half-lives of drugs metabolized by this system, such as warfarin, phenytoin, and
certain antiretroviral agents.