Basic Pharmacology Mod 5: Glycopeptides & Cell Wall Inhibitors PDF

BASIC PHARMACOLOGY 09/04/2024. MOD 5: GLYCOPEPTIDES AND OTHER CELL WALL...

BASIC PHARMACOLOGY 09/04/2024. MOD 5: GLYCOPEPTIDES AND OTHER CELL WALL SYNTHESIS INHIBITORS Deo L. Panganiban, M.D., FPSECP Trans Group/s: 6A, 7A I. CLASSIFICATION D-alanine residue from one of the peptidoglycan precursors. Glycosyltransferases create covalent bonds between CLASSIFICATION OF CELL WALL SYNTHESIS adjacent sugar molecules (e.g., NAM, NAG). INHIBITORS The net result of covalent bonds between the peptides and sugar chains creates a rigid cell wall that protects Vancomycin the bacterial cell from osmotic forces that will result in Glycopeptides Teicoplanin cell rupture. Beta-lactam antibiotics bear a structural resemblance to Telavancin the natural D-ala-D-ala substrate for the transpeptidases Lipoglycopeptides Dalbavancin and exert their inhibitory effects on cell wall synthesis by Oritavancin tightly binding to the active binding site of PBP. Glycosides inhibit the late stages of cell wall Lipopeptides Daptomycin peptidoglycan synthesis by binding to the D-ala-D-ala peptide terminus of the pentapeptide ending precursors, Cyclic Lipopeptide Bacitracin localized at the altered surfaces of the cytoplasmic membranes. Anti-TB Drug Cycloserine Lipoglycosides show stronger inhibition of transglycosylases and membrane destabilization effects, causing rapid bacterial cell death due to their membrane-anchoring properties and dimerization of molecules. 1. WHY ARE GLYCOPEPTIDES NOT EFFECTIVE AGAINST GRAM NEGATIVE BACTERIA? Gram negative bacteria contain an outer membrane unique to that kind of bacteria that typically contains porins that facilitate the diffusion of small hydrophilic molecules. Penicillin and cephalosporins can also diffuse to reach their sites of action. However, glycopeptides have a molecular mass that is too large to allow them to permeate through the boardings to reach the peptidoglycan cell wall → ineffective against gram negative bacteria. Classification and Timeline of Cell Wall Synthesis Inhibitors. A. VANCOMYCIN II. GLYCOPEPTIDES Forms of Vancomycin: Injectable (L) and Oral (R). 1. MECHANISM OF ACTION AND BASIS OF RESISTANCE Vancomycin binds avidly to the D-ala-D-ala peptide terminus of the growing peptide chains and prevents transpeptidase interaction with the substrate. In the absence of a drug, transpeptidases or PBPs in the Inhibits cell wall synthesis by interfering with the second cell wall catalyze cross-links between adjacent glycan stage of peptidoglycan synthesis chains which involves the removal of a terminal Inhibits cell wall synthesis by binding firmly to the D-alanyl-alanine (D-ala-D-ala) terminus of nascent peptidoglycan pentapeptide. Pharmacology - Mod 5 Glycopeptides and Other Cell Wall Synthesis Inhibitors 1 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ This inhibits the transglycosidase, preventing NO significant activity against gram-negative (-) further elongation of peptidoglycan and bacteria cross-linking. ○ The peptidoglycan is thus weakened → the cell 5. MECHANISMS OF RESISTANCE becomes susceptible to lysis. ○ Cell membrane is also damaged → contributing to The permeability barrier provided by the outer the antibacterial effect. membrane of bacteria Altered target site in gram-negative (-) bacteria 2. MODE OF ACTION: BACTERICIDAL No cross-resistance with other antibiotics ○ Resistance to Vancomycin in Enterococci is due to modification of the D-ala-D-ala binding site of the peptidoglycan building block in which the terminal D-ala is replaced by D-lactate i. This results in the loss of a clinical hydrogen bond that facilitates high affinity binding of Vancomycin to the target and leads to a loss of activity ii. This mechanism is also present in Vancomycin-resistant Staphylococcus aureus strains, which have acquired the enterococcal system determinants ○ The underlying mechanism for reduced Vancomycin susceptibility in Vancomycin Schematic diagram of the mechanism of action of intermediate strains, with MICs of 4-8 mcg/mL of Vancomycin and Glycopeptides in general. Staphylococcus aureus, is not known i. However, these strains have altered cell wall 3. PHARMACOKINETICS (ADME) metabolism that results in a thickened cell Poorly absorbed in GIT wall with increased numbers of D-Ala-D-Ala Administered orally – only for the tx of residues, which then serve as dead-end antibiotic-associated enterocolitis caused by binding sites for Vancomycin Clostridium difficile ○ Vancomycin is sequestered within the cell wall by Parenteral doses must be administered IV. ○ 1 hour IV infusion of 1g produces blood levels of these false targets and is thus prevented from 15-30 mcg/L for 1-2 hours reaching its sites of action ○ The drug is widely distributed throughout the body 55% bound to plasma proteins 6. CLINICAL USES Diffuses widely EXCEPT in non-inflamed meninges ○ CSF levels occur in 7-30% of simultaneous serum Alternative drug in: concentrations, which is achieved if there is a. Staphylococcal endocarditis inflammation of the meninges. b. Methicillin-resistant infections Excreted unchanged through the kidneys c. Enterococcal infections ○ 90% of the drug is excreted in the kidneys via d. Diphtheroid infections glomerular filtration. e. Clostridium difficile colitis ○ In the presence of renal insufficiency, striking Synergistic effect with an Aminoglycoside in hard-to accumulation may occur. ○ In functionally anephric patients, the half-life of treat infections vancomycin is 6-10 days. ○ A significant amount (~50%) of vancomycin is 7. ADVERSE REACTIONS removed during a standard hemodialysis-run when a modern high flux membrane is used. Adverse reactions are encountered in about 10% of cases 4. SPECTRUM OF ACTIVITY Most reactions are minor Vancomycin is irritating to tissue, resulting in phlebitis Virtually ALL gram-positive (+) organisms at the site of injection ○ Vancomycin is bactericidal for gram-positive (+) bacteria in 0.5-10 mcg/mL concentrations Chills and fever may occur ○ Most pathogenic staphylococci, including those Ototoxicity is rare, and nephrotoxicity is uncommon with producing lactamases and those resistant to current preparations nafcillin and methicillin, are killed by 2 mcg/mL or ○ However, administering Vancomycin with less another ototoxic or nephrotoxic drug, such as an ○ Vancomycin kills staphylococci relatively slowly aminoglycoside, increases the risk of these and only if cells are actively dividing toxicities i. The rate is less than that of the penicillin’s, both in vitro and in vivo ○ Ototoxicity can be minimized by maintaining peak ○ Vancomycin is synergistic in vitro with serum concentrations below 60 mcg/mL gentamicin and streptomycin against ○ Increased risk in patients greater than 53 years Enterococcus faecium and Enterococcus faecalis old with preexisting hearing problems or that do not exhibit high levels of aminoglycoside underlying renal impairment. resistance Pharmacology - Mod 5 🏠 Glycopeptides and Other Cell Wall Synthesis Inhibitors 2 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  III. LIPOGLYCOPEPTIDES ADVERSE REACTIONS “Red man” syndrome after rapid IV (4 to 10 mins) SPECTRUM OF ANTIBACTERIAL ACTIVITY infusion Gram-positive bacteria (+), including: ○ MRSA (Methicillin-resistant S. aureus) Ototoxicity most important & irreversible ○ VISA (Vancomycin-intermediate S. aureus) ○ VRSA (Vancomycin-resistant S. aureus) Nephrotoxicity in impure preparations ○ Daptomycin (non-susceptible S. aureus) ○ VRE (Vancomycin-resistant Enterococci) 7.1 “Red Man” Syndrome — after rapid IV infusion A. TELAVANCIN Among the more common reactions is the so called red man or red neck syndrome This infusion-related flushing is caused by the release of histamine from mast cells. More likely to happen if the patient is taking other drugs that enhances mast cells degranulation (e.g., opioids) Can be largely prevented by prolonging the infusion period to 1-2 hours or via premedication with H1 antihistamines Telavancin. Semi-synthetic lipoglycopeptide derived from Vancomycin Active against gram-positive (+) bacteria Has in vitro activity against many strains, with reduced susceptibility to Vancomycin “Red Man” Syndrome. B. TEICOPLANIN Telavancin: Mechanism of Action. Teicoplanin as an Injectable Drug. A glycopeptide antibiotic that is very similar to 1. MECHANISM OF ACTION Vancomycin Can be given IM as well as IV. Has 2 mechanisms of action Has a long half-life (45-70 hours), permitting its ○ Like Vancomycin, it inhibits cell wall synthesis by once-daily dosing binding the D-Ala-D-Ala terminus of Poorly absorbed when administered orally peptidoglycan in the growing cell wall Around 90% bioavailable when administered ○ It also has a second mechanism of action, which is intramuscularly the disruption of cell membrane barrier function, thereby increasing membrane permeability It has a more specific action at the division septum–the site of cell wall synthesis due to its avid binding to lipids 2. PHARMACOKINETICS (ADME) Half-life: Approximately 8 hours ○ Supports a once-daily IV in soft tissue infections and hospital-acquired pneumonia at a dose of 120 mg/kg IV daily Unlike vancomycin, monitoring of serum Telavancin levels is NOT required 3. CONTRAINDICATIONS Teicoplanin. Potentially teratogenic → administration to pregnant women must be avoided ○ Pregnancy Category C: Telavancin has a boxed warning which is a potential risk of fetal Pharmacology - Mod 5 🏠 Glycopeptides and Other Cell Wall Synthesis Inhibitors 3 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  development toxicity in pregnant female exposed to 1. MECHANISM OF ACTION the drug ○ Women should avoid the use of telavancin during 4 SEPARATE MECHANISMS THAT ORITAVANCIN pregnancy unless the potential benefit to the patient UTILIZES AGAINST SUSCEPTIBLE GRAM-POSITIVE outweighs the potential risk for the fetus (+) ORGANISMS B. DALBAVANCIN 1 It binds to the stem peptide of peptidoglycan precursors, inhibiting transglycosylation or polymerization This process normally occurs during cell wall synthesis. 2 It inhibits crosslinking during bacterial cell wall biosynthesis via binding to cell wall pentaglycine peptide bridging segments Dalbavancin. 3 It disrupts the bacterial cell membrane permeability, interfering with its integrity, which A semi-synthetic lipoglycopeptide derived from eventually leads to cell death by various Teicoplanin mechanisms 4 Inhibits RNA synthesis Has in vitro activity against VRE Oritavancin interferes with bacterial wall synthesis and integrity, treating susceptible skin and subcutaneous tissue infections with gram-positive bacteria This drug is known to artificially increase the INR (internal normalized ratio) and aPTT (activated partial thromboplastin time), interfering with the coagulation testing Cases of infusion reactions have also been reported 2. DOSAGE FORMS Dalbavancin. Oritavancin injection comes as a powder, that is to be 1. MECHANISM OF ACTION mixed with liquid, and given through a needle or catheter placed in your vein Also has a lipophilic side chain but does not appear to It is usually injected slowly, over 3 hours, as a destabilize bacterial membranes. one-time dose by a healthcare provider Dalbavancin shares the same mechanism of action as vancomycin and teicoplanin 3. ADVERSE REACTIONS ○ But it has improved activity against many gram-positive bacteria, including Symptoms include: methicillin-resistant S. aureus (MRSA) and ○ Sudden reddening of the face, the neck, upper vancomycin-intermediate S. aureus (VISA) chest, or other body part It is NOT active against most strains of ○ Itching, rashes, and hives vancomycin-resistant Enterococci (VRE) You may slow or stop the infusion until your symptoms improve. 2. PHARMACOKINETICS (ADME) IV. LIPOPEPTIDES Dalbavancin has an extremely long half-life of 6-11 days ○ Allows for once-weekly IV over 30 minutes A. DAPTOMYCIN administration Daptomycin is a prototype of the lipopeptides It has been studied to treat skin and soft tissue subgroup infections and catheter-associated bloodstream infections 1. MECHANISM OF ACTION Off-label treatment for osteomyelitis The precise mechanism of action of Daptomycin is NOT C. ORITAVANCIN fully understood BUT it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail ○ This results in depolarization of the cell membrane with potassium efflux and rapid cell death Oritavancin. Pharmacology - Mod 5 🏠 Glycopeptides and Other Cell Wall Synthesis Inhibitors 4 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 2. MODE OF ACTION: BACTERICIDAL ii. Every other day in patients with creatinine clearance of less than 30 mL/min In clinical trials, powered for non-inferiority, Daptomycin was equivalent in efficacy to Vancomycin ○ It can cause myopathy and creatine phosphokinase levels should be monitored 6. CONTRAINDICATIONS Pulmonary surfactant antagonizes Daptomycin → therefore, it should NOT be used to treat pneumonia ○ Treatment failures have been reported in association with an increase in Daptomycin MIC for Daptomycin: Mechanism of Action. clinical isolates obtained during treatment ○ The relation between an increase in MIC and treatment failure is unclear at this point STEPS 7. CLINICAL USES 1 Daptomycin first binds to the cytoplasmic membrane Daptomycin is an effective alternative to Vancomycin and its ultimate role continues to unfold 2 Then, it forms complexes in a calcium-dependent manner V. PHOSPHONIC ANTIBIOTICS Complex formation (Steps 2 and 3) causes a rapid loss of cellular potassium, possibly by A. FOSFOMYCIN pore formation and membrane depolarization Fosfomycin trometamol is a stable salt of phosphomycin or phosphonomycin 3 This is followed by arrest of DNA, RNA, and protein Inhibits a very early stage of bacterial cell wall synthesis, resulting in cell death synthesis Cell lysis does NOT occur. 1. MECHANISM OF ACTION 3. SPECTRUM OF ACTIVITY Daptomycin is a novel cyclic lipopeptide fermentation product of Streptomyces roseosporus It was discovered decades ago but has only recently been developed as the need for drugs that are active against resistant organisms has become more acute Its spectrum of activity is similar to that of Vancomycin ○ EXCEPT that it is more rapidly bactericidal in vitro and is active against vancomycin-resistant strains of Enterococci and Staphylococcus aureus (VRE and VRSA) Fosfomycin: Mechanism of Action. Phosphomycin is an analog of PEP ○ It is structurally unrelated to any other antimicrobial agent It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of Daptomycin: Spectrum of Activity. phosphoenolpyruvate to UDP N-acetylglucosamine ○ This reaction is the first step in the formation of 4. PHARMACOKINETICS (ADME) UDP N-acetylneuramic acid (the precursor of N-acetylneuramic acid) which is found only in Daptomycin is cleared through the kidneys bacterial cell walls ○ The drug is transported into the bacterial cell by 5. DOSAGE FORMS glycerophosphate or glucose 6-phosphate transport systems Recommended doses: Resistance to the drug is due to inadequate ○ 4mg/kg/dose for the treatment of skin and soft transport of drugs into the cell tissue infections, and ○ 6mg/kg/dose for treatment of bacteremia and 2. SPECTRUM OF ACTIVITY endocarditis i. Once daily in patients with normal renal Fosfomycin is active against both gram-positive (+) function; and and gram-negative (-) organisms at concentrations of 125 mcg/mL Pharmacology - Mod 5 🏠 Glycopeptides and Other Cell Wall Synthesis Inhibitors 5 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Susceptibility test should be performed in a growth A. CYCLOSERINE medium supplemented with Glucose-6-phosphate to minimize false positive indications of resistance In vitro synergism occurs when Fosfomycin is combined with Beta-lactam antibiotics, Aminoglycosides, or Fluoroquinolones 3. PHARMACOKINETICS (ADME) Fosfomycin trometamol is available in both oral and parenteral formulations ○ Oral bioavailability is approximately 40% ○ Peak serum concentrations are 10 mcg/mL and 30 mcg/mL, following a 2-gram or 4-gram oral dose respectively The half-life is approximately 4 hours. The active drug is excreted by the kidneys with urinary concentrations exceeding MICs for most urinary tract pathogens Cycloserine and its various dosage forms. 4. DOSAGE FORMS 1. MECHANISM OF ACTION Fosfomycin is approved for use as a single 3-gram dose for treatment of uncomplicated lower urinary tract infections in women The drug appears to be safe for use in pregnancy VI. CYCLIC POLYPEPTIDES A. BACITRACIN 1. MECHANISM OF ACTION Cycloserine: Mechanism of Action. An antibiotic produced by Streptomyces orchidaceous Bacitracin: Mechanism of Action. It is water-soluble and very unstable at an acid pH It inhibits many gram-positive (+) and gram-negative A cyclic peptide mixture first obtained from the Tracy (-) organisms strain of Bacillus subtilis in 1943 Used almost exclusively to treat tuberculosis caused It is active against gram-positive (+) microorganisms by strains of Mycobacterium tuberculosis resistant to the It inhibits cell wall formation by interfering with first-line agents dephosphorylation in cycling of the lipid carrier that A structural analog of D-alanine transfers peptidoglycan subunits to the growing cell ○ Inhibits the incorporation of D-alanine into wall peptidoglycan pentapeptide by inhibiting Alanine racemase, which converts L-alanine into D-alanine 2. SPECTRUM OF BACTERIAL ACTIVITY and D-alanyl-D-alanine ligase Bacitracin is highly nephrotoxic when administered 2. SPECTRUM OF ACTIVITY systemically and therefore is only used as a topical drug ACTIVE against Gram-negative (-) and Mycobacteria It is poorly absorbed After ingestion of 0.25g of Cycloserine, blood levels ○ Topical application results in local antibacterial reach 20-30 mcg/mL which is sufficient to inhibit many activity without systemic toxicity strains of gram-negative (-) bacteria and mycobacteria 3. CLINICAL USES 3. PHARMACOKINETICS (ADME) 500 units/g in an ointment base often combined with The drug is widely distributed in tissues, and most of the Polymyxin or Neomycin is indicated for the suppression drug is excreted in active form into the urine of mixed bacterial flora in surface lesions of the The dosage for treating tuberculosis is 0.5-1g per day skin, in wounds or on mucous membranes in 2 or 3 divided doses. Solutions of Bacitracin containing 100 to 200 units/mL in saline can be used for irrigation of joints, wounds, or 4. ADVERSE REACTIONS the pleural cavity Cycloserine causes serious dose-related CNS toxicity: headaches, tremors, acute psychosis, seizures (or VII. OTHER ANTI-TUBERCULAR DRUGS convulsions) Pharmacology - Mod 5 🏠 Glycopeptides and Other Cell Wall Synthesis Inhibitors 6 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ NOTE: If oral dosages are maintained BELOW 0.75 g/day, such effects can usually be avoided Benzodiazepines/other CNS depressants → exacerbate CNS effect → profound drowsiness, VIII. SUMMARY respiratory depression Antidepressants → psychiatric NOTABLE DRUG-DRUG INTERACTIONS effects DRUG INTERACTION NOTABLE ADVERSE EFFECTS Increased ototoxicity and Vancomycin nephrotoxicity with concomitant DRUG EFFECT administration of aminoglycosides Red man syndrome — flushing, Synergy or partial synergy with erythema, pruritus, hypotension Vancomycin beta-lactams versus Ototoxicity Teicoplanin oxacillin-resistant Staphylococcus Nephrotoxicity and vancomycin-resistant Enterococci Fever Pain Teicoplanin Cisplatin–Telavancin: decreased Skin reactions excretion rate May cause Red man syndrome Telavancin Telavancin–Amiodarone & Amitriptyline: prolonged QTc Risk of nausea interval Taste disturbances Telavancin Insomnia Insignificant CYP450 metabolism → QTc prolongation minimal drug interactions with other Dalbavancin CYP450 metabolized drugs Nausea NSAIDs and diuretics may reduce Diarrhea Dalbavancin renal function. Constipation Injection site reactions May affect CYP450 enzymes as an inducer (e.g., lower effectiveness of Fever Oritavancin Oritavancin CYP206 metabolized drugs) or Diarrhea inhibitor (e.g., increased effects of anticoagulants) May interact with Statin (muscle toxicity), Warfarin (increased risk of bleeding), Aminoglycosides and NSAIDs (increased risk of Daptomycin nephrotoxicity) Clearance may be inhibited by Probenecid With tobramycin (increased risk of renal toxicity) Synergism with aminoglycosides and beta-lactams Fosfomycin Antagonism with calcium supplements and antacids Addictive toxicity with Vancomycin Nephrotoxicity when given systemically → enhanced by aminoglycosides Prolonged muscle paralysis when Bacitracin given with neuromuscular blocker drugs Ototoxicity when given with loop diuretics Alcohol → CNS effects → dizziness, confusion, seizures Isoniazid → enhanced neurotoxic effects → peripheral neuropathy Cycloserine Ethionamide → increased risk of CNS toxicity → depression, seizures Phenytoin → increased serum levels Pharmacology - Mod 5 🏠 Glycopeptides and Other Cell Wall Synthesis Inhibitors 7 of 7 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.