Glycopeptide antibiotics

Vancomycin and Other Glycopeptides

• Glycopeptide antibiotics are actinomycete-derived antibiotics with unique tricyclic or tetracyclic heptapeptide cores that are usually glycosylated.
• bactericidal
• inhibits cell wall synthesis by inhibiting transglycosylase enzyme (involved in chain elongation).
• It has narrow spectrum
• effective against gram positive organisms including MRSA, penicillin resistant pneumococci and Clostridium difficile.
• drug of choice for MRSA, Corynebacterium jeikeium and for serious infections in penicillin allergic patients.

• Glycopeptides – most prevalent class of therapeutics against  severe infections caused by :
• Gram-positive pathogens:
• 1) Enterococci
• 2) Methicillin-resistant staphylococcus aureus (MRSA)
• 3) Clostridium difficile

• MRSA – Endemic in India à Hospital acquired infection

• A study showed overall prevalence of methicillin resistance  as 41 %. Isolation rates for MRSA from OPD, IPD and ICU were 27, 49 and 47 per cent in 2009.

• Classification of glycopeptide antibiotics

Mechanism of action

• The bacterial cell wall- peptidoglycan– structural support.
• Peptidoglycan monomers- sugar backbone with peptide and disaccharide units attached by glycosidic bonds into long chains via Transglycosidation.
• The glycopeptide antibiotics- cell membrane- noncovalent bonds with terminal carbohydrates- inhibition of cross-linking by the Transpeptidase.
• Subsequently, the weakened cell wall- cell cytolysis and death.

Vancomycin

• Primary target: D-Ala-D-Ala terminus of pentapeptidic precursors
• Vancomycin forms complex with the D-Ala-D-Ala residues by forming five hydrogen bonds with the peptide backbone of the glycopeptide.
• This complex prevents the transpeptidation reactions via steric hindrance.
• These are administered parenterally (vancomycin by i.v. route and teicoplanin by i.v. or i.m. route) and are excreted unchanged in urine.

Clinical uses

• Blood stream infections and endocarditis caused by MRSA.
• Enterococcal endocarditis in a patient with serious penicillin allergy (with gentamicin) .
• Meningitis suspected or known to be caused by a penicillin-resistant strain of pneumococcus (with cefotaxime, ceftriaxone, or rifampin)
• Other infections due to staphylococci – septicemias, LRTI, bone, skin and skin structure infections
•  Oral vancomycin, 0.125–0.25 g every 6 hours – antibiotic associated  pseudomembranous colitis by C. Difficile – because it is not absorbed from the gastrointestinal tract and higher concentration reaches the colon.

Adverse reactions

• Adverse reactions in about 10% of cases (most reactions are minor).
• “Red man” or “red neck” syndrome à Rapid i.v. infusion of high doses of vancomycin can cause RED MAN SYNDROME (diffuse flushing due to histamine release). It is the most common adverse

reaction to vancomycin.

• Phlebitis at the site of injection.
• Chills and fever
• Ototoxicity( rare)and nephrotoxicity uncommon with current  preparations.
• Its dose should be decreased in renal failure.

Mechanism of resistance

• Enterococci- mediated by acquirement of a gene à codes for enzymes: synthesis of low- affinity and removal of high- affinity peptidoglycan precursors                                      
• Nine types of vancomycin resistance (Van A to Van N)
• Van A enterococci- resistance induced by Vancomycin and Teicoplanin
• Van B enterococci – sensitive to Vancomycin, resistant to Teicoplanin.

Teicoplanin

• Teicoplanin is another glycopeptide with similar characteristics but can be given once daily due to long t1/2 (45-70 hours).
• The fatty-acid component increased lipophilicityà greater cellular and tissue penetration

• Mechanism
• It inhibits the synthesis of peptidoglycans in the bacterial cell wall by the nonspecific binding
• 2) The saturation of the outer layers of bacterial peptidoglycans.
• 3) Teicoplanin then binds to the D-Ala-D-Ala terminus of the   precursors, which fits into a cleft in the teicoplanin molecule

• Teicoplanin does not cause red man syndrome or nephrotoxicity.

• Indicated for treatment of serious infections by staphylococcus or streptococcus

      1) Bone- osteomyelitis

      2) joints- septic arthritis

      3) blood- non cardiac bacteremia, septicemia

• Unlike vancomycin, it can be given IM and IV
• Teicoplanin has a long half-life (45–70 hours), permitting once-daily dosing .

Semisynthetic glycopeptides

Telavancin, Oritavancin and Dalbavancin

 Advantages:

 1) Overcome the emergence of MRSA strains showing weaken sensitivity to Vancomycin

 2) To increase the penetration into tissues and into CSF

 3) Longer half-life in comparison with Vancomycin

 4) Improvements for infrequent dosing

 5) Greater potency

 6) Lower risk of development of resistant microorganisms.

Telavancin

• FDA approval in 2009
• A derivative of vancomycin:
  •  Lipophilic group: increased membrane interactions
• Phosphonate group: improved adsorption, distribution, metabolism and the excretion profile of telavancin.
• Dual mechanism of action– Inhibition of peptidoglycan biosynthesis and membrane depolarization.
• Apart from vancomycin like mechanism, it also disrupts membrane potential.
• approved à treatment of complicated skin and soft tissue infections à 10 mg/kg IV daily.
• Clinical use subsequently extended to include hospital-acquired and ventilator-associated bacterial pneumonia
• potentially teratogenic, so administration to pregnant women must be avoided
• The half-life of telavancin is approximately 8 hours, which supports once-daily intravenous dosing.

Dalbavancin

• Approved in May 2014.
• A semisynthetic derivative of the teicoplanin-like glycopeptide A40926 complex, derived from Nonomuraea sp.
• Three phase-III trials successfully completed between 2003 and 2005, but the FDA required additional non-inferiority data in 2007
• In 2009, two additional phase-III trials were initiated which met their primary endpoint of non-inferiority.
• Amidation of the C-terminal carboxyl group with a dimethylaminopropylamine group produced dalbavancin
• These modifications led to an extended half-life of over 300 h in human allowing for once weekly dosing.

Uses

• Approved for the treatment of adult patients with complicated skin and skin structure infections, including those caused by MRSA
• It is not active against most strains of vancomycin-resistant enterococci.
• Dalbavancin has an extremely long half-life of 6–11 days, which allows for once weekly intravenous administration

Oritavancin

• Approved in August 2014
• Two phase-III trials completed with results disclosed in 2001 and 2003, but the FDA rejected a new drug application (NDA) in 2008 for concerns over safety and effectiveness.
• In 2009, 2 more phase-III trials for Gram-positive ABSSSI completed. 

Use

• The injection form is approved for treatment of acute bacterial skin and skin structure infections (ABSSSI)
•  Dimer formation- residual activity against vancomycin-resistant bacteria.
•  Intrinsic bactericidal activity especially against streptococci
•  Effectiveness – not affected by the antibiotic-resistance mechanisms developed by staphylococci and enterococci, effective in VRSA and VRE

Spectrum of activity

• Aerobic gram-positive microorganisms
  • Listeria monocytogenes
  •  Streptococcus pyogenes
  • Streptococcus pneumoniae (including penicillin-resistant strains)
  • Streptococcus agalactiae
• Anaerobic gram-positive microorganisms
  • Actinomyces species
  •  Lactobacillus species

Drugs under trial