Pharma - Glycopeptides (MQ) Principles of Antimicrobial Therapy PDF 2024

Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Glycopeptides/Fosfomycin Fall 2024 Glycopeptides  Considered bactericidal against Gram-positive bacteria  Due to their large molecular weight and hydrophilic nature, glycopeptides don’t permeate the cell membr...

Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Glycopeptides/Fosfomycin Fall 2024 Glycopeptides  Considered bactericidal against Gram-positive bacteria  Due to their large molecular weight and hydrophilic nature, glycopeptides don’t permeate the cell membrane of Gram-negative cell membranes Mechanism of Actions:  Inhibit cell wall synthesis by binding (via hydrogen bonds) firmly to D-Ala-D-Ala terminus of a growing peptidoglycan pentapeptide to inhibit the transglycosylase enzyme, which is responsible for linking adjacent disaccharide units. This prevents further elongation of the peptidoglycan and cross-linking.  Increase membrane permeability and disrupts the bacterial cell membrane potential Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Glycopeptides/Fosfomycin Fall 2024 Antibacterial spectrum:  Mainly Gram (+) cocci such as staphylococci (including MRSA), streptococci, and enterococci (E. faecium and E. faecalis)  Synergistic with gentamicin & streptomycin against E. faecium and E. faecalis  Gram (+) anaerobes including C. difficile  Not active against Gram (-) bacteria Includes: Vancomycin, teicoplanin, and telavancin A. Vancomycin Indications: (Mainly intravenous route)  Septicemia or endocarditis caused by methicillin-resistant staphylococci (MRSA)  Endocarditis caused by enterococci in patients with serious penicillin allergy (usually combined with gentamicin)  Meningitis due to penicillin-resistant S. pneumoniae (In combination)  Enterocolitis caused by C. difficile (Given orally) Resistance:  Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan, such that the terminal D-Ala is replaced by D-lactate  This results in the loss of a critical hydrogen bond that facilitates high affinity binding of vancomycin to its target and loss of activity  This mechanism is also present in rare vancomycin resistant S. aureus strains, which have acquired a similar enterococcal resistance mechanism Adverse Effects:  Phlebitis at site of injection  Nephrotoxicity (requires monitoring) and ototoxicity (rare)  “Red man” syndrome – prevented by slow infusion over 1-2 hours or pretreatment with oral antihistamine Principles of Antimicrobial Therapy (PH 1100-116) Dr. Qaddoumi Notes – Glycopeptides/Fosfomycin Fall 2024 B. Teicoplanin  Like vancomycin in terms of antibacterial spectrum and clinical indications but is active against vancomycin-resistant S. aureus  Has higher activity against enterococci than vancomycin C. Telavancin  Like vancomycin in terms of antibacterial spectrum but differs in clinical uses  Approved only for complicated skin and soft tissue infections and hospital-acquired pneumonia Fosfomycin  Broad spectrum antibiotic that is even active against extended spectrum β-lactamase- producing (ESBL) E. coli  Despite this, its use in severe infection is limited due to resistance related to lack of transport of the drug into the cell Antibacterial spectrum:  Active against both Gram (+) & Gram (-) organisms including E. coli & E. faecalis Mechanism of Action:  It inhibits a very early stage of bacterial cell wall synthesis  Since it’s an analog of phosphoenolpyruvate, it inhibits the enzyme enolpyruvate transferase, which is responsible for the formation of N-acetylmuramic acid; one of the main peptidoglycan saccharide building units Indication:  Uncomplicated lower urinary tract infection in women (safe in pregnancy) given as a single 3-g dose tablet