16 Clindamycin, Streptogramins, Oxazolidinones

Question 1

What is the mechanism of action of clindamycin?

Resistance mechanism?

Answer 1

• Protein synthesis inhibition
  
  • They irreversibly bind the 50S ribosomal subunit ==> inhibition of translocation of peptidyl-tRNA from acceptor to donor site
• Bacteriostatic
• Immunomodulatory effect

Resistance:

• Inability of the organism to take up the antibiotic
• Efflux pump
• Decreased affinity of the 50S ribosomal subunit for the antibiotic
• Presence of a plasmid-associated erythromycin esterase in gram (-) bacteria (e.g. Enterobacteriaceae)

Question 2

What is the antimicrobial spectrum of clindamycin?

Clinical use?

Answer 2

Antimicrobial spectrum:

• Narrow spectrum:
  
  • Gram (+) cocci (including community-acquired MRSA)
  • Gram (+) and (-) anaerobes, except Clostridium difficile
• Concentration in bone has clinical value in osteomyelitis due to gram (+) cocci

Clinical use:

• Staph infection and mixed aerobic + anaerobic infection:
  
  • Odontogenic infections
  • Osteomyelitis
  • Intraabdominal infections (gynecological)
  • Anaerobic lung infections (aspiration pneumonia, lung abscess)
  • Skin, soft tissue infection (diabetic foot)
  • Chronic upper respiratory tract infections
  • Pneumocysitis carinii, toxoplasma encephalitis in AIDS
  • Malaria in case of multiresistant Pl. falciparum
• Frequently used in combination with agents effective against gram (-) bacteria​
  
  • With gentamycin, used to treat female genital tract infections (e.g. chlamydia)

Question 3

What are the pharmacokinetics and administration of clindamycin?

Answer 3

• Good absorption
• Good penetration, high concentration in bone
• No penetration into CNS

Administration:

• IV infusion, IM or oral
• 3-4x/day

Question 4

What are the side effects of clindamycin?

Answer 4

• Pseudomembranous colitis (most likely cause due C. Difficile)
  
  • Treatment: metronidazole, vancomycin
• Rash, erythema
• Thrombocytopenia, neutropenia
• Neuromuscular blockade

Question 5

Which are the streptogramin drugs?

Answer 5

Mixture of 2 streptogramins in 70:30 (A:B) ratio

• Streptogramin A: Quinupristin
  
  • Binds to 23S rRNA
• Streptogramin B: Dalfopristin

Question 6

What is the mechanism of action of streptogramins?

Answer 6

• Protein synthesis inhibitors
  
  • They bind reversibly different sites of the 50S ribosomal subunit
    
    • Quinupristin prevents elongation similarly to macrolides (inhibition of translocation of peptidyl-tRNA from acceptor to donor site) and cause release of incomplete peptide chains
    • Dalfopristin disrupts elongation by interfering the addition of new amino acids to the peptide chain
  • They synergistically interrupt protein synthesis
• Bactericidal

Question 7

What is the antibacterial spectrum and clinical use of streptogramins?

Answer 7

Antibacterial spectrum:

• Gram (+) cocci (even against multiple-resistant strain except E. Fecalis)
  
  • Slow bactericidal action against E. Fecium

Clinical use:

• Vancomycin resistant E. Fecium
• Multiple drug resistant bacteremia

Question 8

What are the pharmacokinetics and administration of streptogramins?

Answer 8

• Long PAE
• Very short half-life:
  
  • Fast metabolism, elimination mainly by feces
• Inhibition of CYP 3A4 isoenzyme – Drug interaction

Administration:

• Parenteral (IV infusion 2-3x/day)
  
  • By central venous canula

Question 9

What are the adverse effects of streptogramins?

Answer 9

• Infusion related effects:
  
  • Phlebitis
  • Arthralgia-myalgia

Question 10

What is the drug and mechanism of action of oxazolidinones?

Answer 10

Drug:

• Linezolid

Mechanism of action:

• They are protein synthesis inhibitors
  
  • They irreversibly bind to 50S ribosomal subunit protein and inhibit the assembly of the 70S ribosomal complex thus the initiation of protein synthesis
    
    • Bacteriostatic
• Bactericidal against streptococci

Question 11

What is the spectrum and clinical use of oxazolidinones?

Answer 11

Antibacterial spectrum:

• Gram (+) cocci (both aerobe and anaerobe) and gram (+) rods
• No effect on gram (-) bacteria

Clinical use:

• Vancomycin resistant E. Fecium
• MRSA/E
• Multiple drug resistant infection

Question 12

What are the pharmacokinetics and administration of oxazolidinones?

Answer 12

Pharmacokinetics:

• Completely absorbed after oral administration
• Enters CNS
• Special binding on 23 S rRNA of 50S subunit

Administration:

• Oral or parenteral administration
• 2x/day

Question 13

What are the adverse effects of oxazolidinones?

Answer 13

• GI disturbance
• Thrombocytopenia
• Anemia
• Neutropenia (rare)
• Weak MAO inhibitor
• Drug interaction:
  
  • SSRI ==> serotonin syndrome!