Glycopeptides PDF - Curtin University

Glycopeptides Dr Petra Czarniak Senior Lecturer, Curtin Medical School  WARNING This material has been reproduced and communicated to you by or on behalf of Curtin University in accordance with section 113P of the Copyright Act...

Glycopeptides Dr Petra Czarniak Senior Lecturer, Curtin Medical School  WARNING This material has been reproduced and communicated to you by or on behalf of Curtin University in accordance with section 113P of the Copyright Act 1968 (the Act) The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.  Learning Objectives At the end of this lecture, students should be able to: Discuss the mechanism of action, spectrum of activity, resistance, pharmacokinetics, indications, dosage, adverse effects and drug interactions of glycopeptides Name and briefly discuss 3 semi- synthetic lipoglycopeptides natural glycopeptides - group of chemically antibacterial Glycopeptides complex compounds obtained from original species of soil Vancomycin Produced by Streptomyces orientalis Vancocin 125mg Vancocin 125mg & 250mg caps Vancocin 500mg & 1g injection used for treatment or serious Teicoplanin infections caused by gram + Vancocin 250mg Produced by Actinoplanes teichomyetius bacteria Targocid 400mg injection New drugs 'lipo' - : lipoglycopeptides Semisynthetic glycopeptides Dalbavancin, oritavancin and telavancin Inhibits polymerisation - > specifically Glycopeptides , transglycosalation (elongation process of the NAM NAC chain. Mechanism of action Inhibit cell wall synthesis by binding with high affinity to the terminal 2 D-alanine residues (D-alanyl-D- alanine) at the free carboxyl end of the pentapeptide This sterically hinders the elongation of the peptidoglycan backbone In contrast, inhibit a later stage of cell wall synthesis by blocking the cross-linkage of pentapeptide side chains. by inhibiting transpeptidase enzymes Glycopeptides ↓ narrow spectrum or activity Antimicrobial activity Narrow: G+ve bacteria ONLY High molecular weight not able to penetrate the cell membrane of G-ve bacteria Activity confined to Staphylococci G+ve bacteria MRSA, coagulase –ve staph Streptococci S. pyogenes, S. pneumoniae, S. viridans Corynebacterium Clostridium spp Species of G-ve bacilli & mycobacteria are resistant Generally bactericidal Except for enterococci (bacteriostatic)  Glycopeptides S. aureus is commonly found on the skin & in the noses of healthy people Wound infections septicaemia & death. Methicillin-resistant strain - most antibiotics are ineffective against it. “Vancomycin-intermediate" S. aureus mutations have led to individual (VISA). ~ thicker cell wall with bacteria developing Resistant to many other AB low level resistence Emergence = major concern High-level vancomycin resistant S. aureus 2002  Glycopeptides In 2002, superbug - vancomycin resistant S. aureus (VRSA) Isolated from foot ulcers on a diabetic patient in Detroit, Michigan New antibiotic resistance gene MRSA was well known But newer strain developed resistance to vancomycin & most other AB It had a conjugative plasmid into which the Van A transposon was integrated as a result of an interspecies horizontal gene transfer from E. faecalis to a methicillin-resistant strain of S. aureus Genetic analysis: Patient’s own vancomycin-sensitive S. aureus acquired vancomycin resistance gene (vanA)from VRE through conjugation. Staphylococcus aureus  Resistance Strains of enterococci were once uniformly susceptible to glycopeptides Glycopeptide-resistant strains of enterococci (mainly Enterococcus faecium) have emerged as major nosocomial pathogens Vancomycin resistance determinants in E. faecium & E. faecalis are located on a transposon that is part of a conjugative plasmid This can be transferred to other enterococci & other G+ve mo These strains are then usually resistant to many antibiotics. But....... How can resistance occur?  Resistance Enterococcal resistance results from alteration of D-alanyl-D-alanine To D-alanyl-D-lactate Or D-alanyl-D-serine These bind glycopeptide poorly due to the lack of a critical site for hydrogen bonding  Resistance 7 distinct resistance genotypes are recognized VanA Resistance to both vancomycin & teicoplanin. Associated with substitution of D-alanyl-D-alanine by D-alanyl-D-lactate loss of binding affinity Inducible: E. faecium & E. faecalis The first 2 are most prevalent, especially in VanB Enterococcus faecium Tends to be a lower level of resistance & resistance also results from a D-lac substitution It is inducible by vancomycin but not by teicoplanin so many strains still susceptible to teicoplanin VanC always expressed Is non-transferable, chromosomally mediated, expressed constitutively Associated with substitution of D-alanyl-D-alanine by D-alanyl-D-serine. Characterized by low-level resistance to vancomycin alone L alanine substituted with serine VanD Resistance has been found in a few strains of E. faecium. It results from a D-lac substitution, is usually expressed constitutively, and confers non-transferable resistance to vancomycin and reduced susceptibility to teicoplanin VanE , VanG & VanL  Pharmacokinetics Absorption Distribution Vancomycin Vancomycin Poorly absorbed after Widely distributed including oral admin CSF - When meninges are inflamed In Australia, only Teicoplanin used for CDAD More highly plasma protein bound (90-95%) Parenteral admin = Vancomycin bound 30% IV (not IM – painful) 7 Teicoplanin Elimination Can be admin IV or Vancomycin IM 90% of IV dose excreted by glomerular 125 my every oh filtration close adjustment Metabolism for 10-14 t1/2 6 hrs days is required Both drugs not Accumulates if impaired renal function metabolised Teicoplanin Excretion is through glomerular filtration t1/2 100 hrs  Indications Due to the incidence of clinical isolates resistant to vancomycin, eg vancomycin-resistant enterococci (VRE), Australia has adopted guidelines recommended by the Centers for Disease Control Hospital Infection Control Practices Advisory Committee (USA) for its use. Similar considerations apply to teicoplanin. These are: Tx of serious infections caused by susceptible organisms resistant to penicillins (MRSA and multi-resistant S. epidermidis, MRSE) or in people with serious allergy to penicillins usually with other agents Vancomycin - meningitis, endocarditis (with other agents), MRSA infections; Teicoplanin – septic arthritis  Indications Clostridioides difficile-associated disease (relapse or unresponsive to metronidazole treatment) Antibacterial prophylaxis for endocarditis before certain procedures in penicillin-hypersensitive people at high risk Surgical prophylaxis for major procedures involving implantation of prostheses (eg cardiac and vascular procedures) in institutions with a high rate of MRSA or MRSE Examples of combination therapy Osteomyelitis (MRSA) eg Vancomycin + fusidic acid + rifampicin Endocarditis eg Vancomycin + aminoglycoside (gentamicin) Dosage & Concentration concentration Monitoring is ensure that adequate and minimise development or resistance Higher vancomycin doses than used previously are often recommended Oral vancomycin 125mg every 6 hours for 10 – 14 days IV: 1-1.5g bd (not IM – too painful) Concentration monitoring of vancomycin allows the dose to be individualised loading dose may be required When given with nephrotoxic drugs eg aminoglycoside Where PK altered, eg Burns pts May need higher doses due to Obese* large Vd & drug clearance During high-dose &/or prolonged tx When treating infections due to MRSA with heterogeneous (hVISA) susceptibility Pts with unstable or impaired renal function After a dose change Dosage & Concentration Monitoring Concentration monitoring for teicoplanin not usually necessary since concn & toxicity not clearly related But for serious infections trough concns should be > 10mg/L to determine Therapeutic range of vancomycin trough level For twice daily dosing, trough level should be 10– 20 mg/L Take the 1st sample just before the 4th dose A trough >10 mg/L minimises resistance developing but may increase the risk of nephrotoxicity, especially if other nephrotoxic agents are being used, eg aminoglycosides.  Adverse Effects Reactions to vancomycin have due to product purity Adverse effects are more Common (> 1%) common with rapid IVI Thrombophlebitis - inflammation of N, V, D, indigestion & chills (oral vein vancomycin) Infrequent (0.1-1%) Nephrotoxicity Increased risk when Harvey RA. Pharmacology Fig 31.17 Concurrent use of aminoglycosides In renal impairment. Related to vancomycin serum concns. Teicoplanin - less nephrotoxic than vancomycin Thromobophlebitis = Inflammation of a vein https://www.nursingcenter.com/getattachment/NCBlog/February-2015-( - more common with vancomycin Complications-of-Peripheral-I-V-Therapy/phlebitis.PNG.aspx  Adverse Effects in the ringing Risk is higher with Rare ears prolonged use, in renal Superinfection impairment & when given everything Ototoxicity spinning around with other ototoxic drugs, - eg aminoglycosides, loop Dizziness, vertigo and tinnitus diuretics https://www.organicfacts.net/wp-content/uploads/thrombocytopenia.jpg Vancomycin alone rarely causes ototoxicity Ototoxicity is very rare with teicoplanin. Deafness may be permanent. Blood dyscrasias: ~ ↓ platelet count Thrombocytopenia (may be immune- mediated) neutrophil count ~↓ Neutropenia ↓ WBC count Leucopenia I cell count or Agranulocytosis ~ agranulocytes https://www.medindia.net/patientinfo/neutropenia.htm when Adverse vancomycin Effects administered too Red man syndrome (red neck quickly syndrome) Occurs less often with teicoplanin than vancomycin Usually due to infusion being given too quickly (< 60 min). Not an allergic reaction but a direct toxic effect of vancomycin on mast cells & basophils Causes them to release histamine Sx are partly due to histamine release & include Fever Chills ↓ blood pressure Erythema Facial & upper torso rash ↑ May be followed by hypotension, angioedema and itch. Management: Slow infusion - increasing the infusion time to >60 minutes Antihistamines eg promethazine Erythematous urticarial rash BMJ 2009  Precautions Allergy to vancomycin or teicoplanin Allergic cross-reactivity between vancomycin & teicoplanin has occurred Thrombocytopenia during Tx with either drug May recur because it may be immune mediated Hearing impairment May increase risk of ototoxicity Renal impairment Ototoxicity & nephrotoxicity may be more likely, esp vancomycin Tx with nephrotoxic drugs may increase risk of nephrotoxicity  Interactions Vancomycin Interaction + General General anaesthetics risk of vancomycin anaesthetics infusion-related adverse effects, including hypotension. Vancomycin infusion should be completed before induction of anaesthesia Colestyramine Colestyramine may bind vancomycin so oral vancomycin should be given 1 hour I before, or 4–6 hours after, colestyramine for those with4 cholesterol Currently not available in Australia L Semi-synthetic Lipoglycopeptides Dalbavancin Indicated for skin & soft tissue infections Is a teicoplanin-like lipoglycopeptide Similar MOA & activity to vancomycin Half-life = 6-11 days – allows once weekly dosing ~ long half-life Oritavancin Indicated for skin & soft tissue infections Active against many strains with reduced susceptibility or resistance to vancomycin or teicoplanin. Has extremely long half-life – single dose therapy for skin infections. Semi-synthetic Lipoglycopeptides Telavancin Indicated for skin & soft tissue infections Vancomycin-like lipoglycopeptide The half-life is 7–9 h, which allows once-daily dosing Was approved by the FDA in 2009 for tx of complicated skin & skin structure infections (cSSSI) caused by susceptible G+ve bacteria, including S. aureus, both MRSA & MSSA strains. Also indicated for pneumonia Higher nephrotoxicity to vancomycin Can cause QT prolongation  Quick Review Question Consider the following statements and indicate if the statement is TRUE or FALSE: Statement True False Glycopeptides are bactericidal ~ Glycopeptides have a narrow spectrum of activity (only Gram positive bacteria) ~ Glycopeptide have a narrow spectrum of activity (only Gram negative bacteria) w Glycopeptides inhibit bacterial cell wall synthesis by binding with high affinity to the terminal two alanine amino acids to sterically hinder the elongation of the peptidoglycan backbone ~ Glycopeptides are well absorbed after oral administration ~  References Australian Medicines Handbook 2023 Brunton L, Knollmann. Goodman and Gilman’s the Pharmacological Basis of Therapeutics 14th Ed. New York: McGraw-Hill, 2023 Finch RG, Greenwood D, Norrby SR, Whitely RJ. Antibiotic and Chemotherapy: Anti-infective agents and their use in therapy. 9th Ed. London: Elsevier, 2010 Katzung BG. Basic and Clinical Pharmacology 15th Ed. New York: Lange Medical Books/McGraw-Hill, 2021 Rang HP, Dale MM, Ritter JM, Flower R, Henderson G. Rang and Dale’s Pharmacology 9th Ed. Edinburgh; New York: Elsevier Churchill Livingstone, 2020. Ritter JM, Flower R, Henderson G, Loke YK, MacEwan D, Rang HP. Rang and Dale’s Pharmacology 9th Ed. Edinburgh; New York: Elsevier Churchill Livingstone, 2020.