12-13 Tetracycline, glycylcyclines, Aminoglycosides

Question 1

What is the mechanism of action of tetracyclines?

Answer 1

• Protein synthesis inhibition in bacteria:
  
  • They bind reversibly the 30S ribosomal subunit ==> inhibition protein elongation by preventing tRNA translocation to the “A” site
• Bacteriostatic drugs
• They are actively taken up by susceptible bacteria by an energy-dependent transport mechanism

Question 2

Which are the drugs and their characteristics for tetracyclcines?

Answer 2

Question 3

What are the pharmacokinetics of tertacyclines?

Answer 3

• Absorption:
  
  • Oral
  • Reduced absorption if taken with dairy products or anything containing divalent (Ca²⁺, Mg²⁺, Fe²⁺) or trivalent cations due to their chelator effect
• Distribution:
  
  • Concentration in bile, liver, kidney, gingival fluid and skin
  • Bind to tissues undergoing calcification (e.g. teeth and bone)
• Elimination:
  
  • Kidney for most (reduced dose in renal dysfunction)
  • Bile in the feces for long-acting ones

Question 4

What is the spectrum/clinical use of tetracyclines?

Resistance?

Answer 4

• Useful and important antibiotics in the treatment of infections caused by atypical pathogens
• Not recommended for empiric treatment
• “Broad-spectrum” antibiotics, with good activity against gram (+), gram (-) aerobes, anaerobes
  
  • MRSA
  • Chlamydia (Urethritis, cervicitis, PID, pneumonia)
  • Mycoplasma species
  • H. pylori (GI ulcers)
  • Tick-born infections: Rickettsia, Borrelia burgdorferi (Lyme disease), Francisella (Tularemia)
  • Brucella
  • Ureaplasma urealyticum
  • Coxella burnetti (Q-fever)
  • Spirochetes
  • Treponema (only in case of b-lactam sensitivity)
  • Cholera
  • H. Influenza
  • Some amoebas
• Ø activity against Proteus and Pseudomonas aeruginosa

Resistance: (in plasmid type)

• Alteration of permeability
• Efflux mechanism: expels drugs out of the cell ==> ø intracellular accumulation
• Enzymatic inactivation of the drug and production of bacterial proteins preventing tetracycline binding to ribosomes

Question 5

What are the side effects of tetracyclines?

Drug interactions?

Answer 5

• Tooth enamel dysplasia and possible reduced bone growth in children (avoid as it is teratogenic)
  
  • They are chelators; thus, they go to bones and teeth and, don’t work as an antibiotic anymore ==> changes of teeth enamel
  • Teratogenic in pregnant woman
• Photosensitivity (demeclocycline, doxycycline)
• GI distress
  
  • Irritation of gastric and esophageal mucosa
  • Superinfections leading to candidiasis or colitis
  • Nausea, vomiting, diarrhea
• Vestibular dysfunction (minocycline)
  
  • Vertigo, dizziness and tinnitus
• Hepatonephrotoxicity
• Vaginal candidiasis

Drug interaction:

• Retinoids (vitamin A derivatives): enhancement of intracranial pressure
• Coumarin derivatives: risk of bleeding

Question 6

Glycylcyclines!

Drugs

Mechanism of action

Spectrum?

Pharmacokinetics?

Indication?

Adverse effects?

Answer 6

Drugs:

• Tigecycline
  
  • It is a derivative of minocycline and is the 1^st available member of the glycylcycline antimicrobial class

Mechanism of action:

• Protein synthesis inhibition in bacteria:
  
  • They bind reversibly the 30S ribosomal subunit
• Bacteriostatic drugs

Antimicrobial spectrum:

• Very broad spectrum
  
  • MRSA
  • Vancomycin-resistant staphylococci and streptococci
  • Penicillin-resistant enterococci
  • Enterobacteriacae
  • Rickettsia
  • Chlamydia
  • Legionella
  • Rapidly growing mycobacteria
• Tetracycline-resistant trains are sensitive to it
• Not good for Proteus and Pseudomonas aeruginosa

Pharmacokinetics:

• IV infusion –> large Vd
• Elimination via biliary tract

Indication:

• Complicated skin and soft tissue (except diabetic foot)
• Intra-abdominal infection

Adverse effects:

• Nausea, vomiting
• Acute pancreatitis
• ­ liver enzymes and serum creatinine (hepatonephrotoxic)
• Other effects similar to tetracyclines

Question 7

What is the mechanism of action of aminoglycosides?

Answer 7

• They are protein synthesis inhibitors
  
  • They irreversibly bind to 30S ribosomal subunit protein and inhibit the assembly of the ribosomal complex thus the initiation of protein synthesis
    
    • Bacteriostatic
  • They can also cause the 30S ribosomal subunit to misread the genetic code (“frame-shift”)
    
    • Formation of the wrong amino acid and thus wrong protein –> Bactericidal
• They are actively transported across the cell membrane by an O₂-dependent process

Question 8

What is the spectrum and clinical used of aminoglycosides?

Answer 8

• Aerobe gram (-):
  
  • Excellent activity
  • E. coli, Klebsiella, Enterobacter,
  • Acinetobacter, Proteus, Ps. Aeruginosa-resistant
  • Neisseria
  • H. Influenza
• Aerobe gram (+):
  
  • Moderate activity
• Synergism with b-lactams:
  
  • Particularly in treatment of enterococcis fecalis and fecium infective endocarditis
• No activity: Anaerobes, intracellular pathogens, spirochetes

Question 9

What are the main indications of aminoglycosides?

Answer 9

• Monotherapy:
  
  • Gram negative aerobe infection
  • UTI
• Combination:
  
  • Sepsis
  • Intra-abdominal infection (perhaps with metronidazole)
  • Severe nosocomial infection (mainly with b-lactams)
  • Enterococcus (ampicillin + gentamycin)
  • Streptococci, staphylococci endocarditis
  • Ps. Aeruginosa (with b-lactam) tobramycin is more potent

Question 10

What are the pharmacokinetics of aminoglycosides?

Answer 10

• Administration: Parenteral
• Serum peak after in application is about 60min
• Poor tissue penetration:
  
  • Low concentrations in CNS, bronchial secretion and prostatic tissue
• Low protein binding
• Excretion via the kidneys:
  
  • Active uptake and accumulation in renal cortex
• Their kinetics are significantly influenced by any change of extracellular water space or renal elimination
  
  • Large dose 1x/day ==> reduced risk of nephrotoxicity and increases convenience.
• The dynamic effect of aminoglycosides is concentration-dependent. The efficacy is dependent on the MIC of the organism.
  
  • For the optimal eradication, serum concentration should exceed the MIC 8-10 times
  • The larger the dose, the longer the PAE

Administration:

• 1x/day administration (short infusion or IM injection)
  
  • Not bolus as they may cause NMJ blockade
• BUT, in endocarditis the daily dose in 2-3 parts
• Dosage:
  
  • Based on the bodyweight, or creatinine clearance
• Monitoring of serum concentration is required:
  
  • Rapidly changing renal function
  • Rapidly changing extravascular water volume
  • Burns
  • Higher dose or longer treatment than usual

Question 11

Which are the aminoglycoside drugs?

Answer 11

Question 12

Which are the adverse effects of aminoglycosides?

Answer 12

• Nephrotoxicity (6 to 7% incidence) includes:
  
  • Retention of aminoglycosides in the proximal tubular cells disrupts Ca²⁺-mediated transport processes causing reversible symptoms:
    
    • Proteinuria
    • Hypokalemia
    • Acidosis
    • Acute tubular necrosis:
      
      • Usually reversible, but enhanced by vancomycin, amphotericin B, cisplatin, and cyclosporine
• Ototoxicity (2% incidence):
  
  • Directly related to high peak plasma levels and duration of treatment
  • The antibiotic accumulates in the organ of corti of the inner ear ==> hair cell damage and causes:
    
    • Deafness (irreversible) and vestibular dysfunction (reversible)
  • Toxicity may be enhanced by loop diuretics
• Neuromuscular blockade with ↓ release of ACh:
  
  • Associated with a rapid increase in concentration or concurrent administration with neuromuscular blockers
  • Patients with myasthenia gravis are particularly at risk
    
    • Calcium gluconate or neostigmine can reverse the block that causes the neuromuscular paralysis
• Allergic reaction:
  
  • Contact dermatitis when applying topically neomycin