Antimicrobial Pharmacology II PDF

antimicrobial pharmacology ii Altaf Darvesh, M. Pharm., Ph.D. 11-13-2024  Recommended Reading Katzung’s Basic and Clinical Pharmacology 16th edition, Vanderah, McGraw Hill Goodman and Gilman’s The Pharmacologic Basis of Therapeutics 14th edition, Brunton, Knollm...

antimicrobial pharmacology ii Altaf Darvesh, M. Pharm., Ph.D. 11-13-2024  Recommended Reading Katzung’s Basic and Clinical Pharmacology 16th edition, Vanderah, McGraw Hill Goodman and Gilman’s The Pharmacologic Basis of Therapeutics 14th edition, Brunton, Knollman, McGraw Hill (Available online on Access Medicine & Access Pharmacy) cell wall- or membrane-active agents  Objectives Describe the chemistry, pharmacology, mechanism of action, mechanisms of resistance, pharmacokinetics, adverse effects, toxicity, indications and uses of the following cell wall/cell membrane-active antimicrobial agents: daptomycin fosfomycin bacitracin  Daptomycin ▪ Novel cyclic lipopeptide antibiotic with a fatty acid “lipid tail”  Daptomycin – Mechanism of Action Step 1: Daptomycin binds to the cytoplasmic membrane. Step 2: Daptomycin forms complexes in a calcium-dependent manner. Step 3: Complex formation causes a rapid loss of cellular potassium, possibly by pore formation, membrane depolarization.  Daptomycin – Mechanism of action ▪ Distinct mechanism of action. ▪ Binding to cell membrane causes rapid depolarization and results in loss of membrane potential. ▪ Inhibition of protein, and DNA and RNA synthesis. ▪ Multiple aspects of bacterial cell membrane function are disrupted ▪ Only disruptive to the membrane but not the cell-wall. ▪ Thus, cell-lysis does not occur. ▪ Activity is concentration-dependent. ▪ Due to its unique mechanism of action, cross-resistance with other antibiotic classes seems not to occur readily, and there are no known resistance mechanisms. ▪ BACTERICIDAL D D no cell lysis but the cendoes die !  Daptomycin Pharmacokinetics ▪ Only administered IV ▪ Good penetration into vascular tissues and plasma ▪ Half-life = 8 to 9 h Adverse effects ▪ Myopathy ▪ Rhabdomyolysis ▪ Increases in creatine phosphokinase Uses ▪ Effective alternative to vancomycin D ▪ Not indicated for pulmonary infections (e.g. pneumonia) since it is inactivated by pulmonary surfactants  Fosfomycin Mechanism of Action substrate of MurA ▪ It Is an antimetabolite (analog) of phosphoenolpyruvate. ▪ It inhibits the cytoplasmic enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). ↳ helps with synthesis of NAG - get NAM from NAG ▪ The epoxide ring covalently binds to the cysteine residue of the enzyme active site – irreversible inhibition. INAG) ▪ This blocks the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine. INAM) [ ▪ This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precursor of N-acetylmuramic acid – the first step in peptidoglycan synthesis. J ▪ The drug is transported into the bacterial cell by glycerophosphate / glucose 6- phosphate transport system. ▪ BACTERICIDAL * * Inhibits the 1st * step in Synthesis *  Fosfomycin Mechanism of Resistance ▪ Decreased affinity to the MurA enzyme. ▪ Decreased transport into the bacterial cell through the glycerophosphate / glucose 6-phosphate transport system. Uses ▪ Active against both Gram-positive and Gram-negative organisms  Bacitracin ▪ Bacitracin is a cyclic polypeptide mixture first obtained from the Tracy strain of Bacillus subtilis in 1943. ▪ Major constituent is Bacitracin A  Bacitracin Mechanism of Action ▪ Bacitracin interferes with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. ▪ Bacitracin inhibits the enzyme protein disulfide isomerase – an enzyme that catalyzes the formation and breakage of disulfide bonds during protein folding. ▪ There is no cross-resistance between bacitracin and other antimicrobial drugs. ▪ BACTERICIDAL D * Uses ▪ Active against gram-positive bacteria. D * ▪ Bacitracin is highly nephrotoxic when administered systemically and thus is only used topically.  PRACTICE QUESTIONS 1. Which antimicrobial medication is an antimetabolite of phosphoenolpyruvate? A. Daptomycin > - forms pore and cause depolarization of Cel B. Bacitracin C. Fosfomycin 2. Which antimicrobial medication is a protein disulfide isomerase enzyme inhibitor? A. Daptomycin B. Bacitracin C. Fosfomycin  ribosomal antimicrobials the AA cone at a time) & transfer RNA tRNA-brings & to > attaches AA ribosome - peptide chain File:Peptide syn.png  Objectives ▪ Explain the steps in bacterial protein synthesis ▪ Discuss the chemistry of anti-ribosomals ▪ Describe the mechanism of action of anti-ribosomals ▪ Describe the mechanisms of resistance of anti-ribosomals ▪ Describe the pharmacokinetics of anti-ribosomals ▪ Describe the adverse effects of anti-ribosomals  Steps in bacterial protein synthesis Los ribosome tRNA brings AA and binds to Step 1 : Charged AA chain at the donor site binds growing the +RNA Step 2 Peptidyl : to the new AA Is released tRNA Step 3: uncharged Its Step 4 : AA chain with to Me tRNA shifts Peplidul site tRNA is recycled !  Steps in bacterial protein synthesis ▪ Amino acids are shown as numbered circles. ▪ The 70S ribosomal mRNA complex is shown with its 50S and 30S subunits. ▪ In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome. ▪ The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid 6 (peptide bond formation, step 2). ▪ The uncharged tRNA left at the donor site is released (step 3), and the new 6- amino acid chain with its tRNA shifts to the peptidyl site (translocation, step 4). ▪ The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). ▪ The tetracyclines (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit (step 1). Impairing Translation  Mechanism of action ▪ Ribosomal antimicrobial agents bind to ribosomal subunits and cause irreversible inhibition of bacterial protein synthesis. Anti-ribosomals that bind to Anti-ribosomals that bind to 30S ribosomal subunit 50S ribosomal subunit Aminoglycosides Macrolides Tetracyclines Chloramphenicol Lincosamide (Clindamycin) Oxazolidinone (Linezolid)  Aminoglycosides ▪ Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (in other aminoglycosides), to which various amino sugars are attached by glycosidic linkages. ▪ They are water-soluble, stable in solution, and more active at alkaline than at acid pH. ▪ Aminoglycosides are mostly used against aerobic gram-negative bacteria. Streptomycin Neomycin Amikacin Gentamicin Tobramycin Streptomycin Aminoglycosides – Mechanism of action  Aminoglycosides – Mechanism of action ▪ Binding to the 30S ribosomal subunit Protein synthesis is inhibited in the following three steps: ▪ Blocking of the initiation complex of peptide formation. -> no protein form. > abnormal protein - ▪ Misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional or toxic protein. > - shortened chains ▪ Blocking of translocation which causes premature termination. ▪ BACTERICIDAL D *  Aminoglycosides – Mechanisms of resistance ▪ Production of a transferase enzyme that inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation. This is the principal type of resistance encountered clinically. ▪ Deletion or alteration of the receptor protein on the 30S ribosomal subunit due to a mutation. ▪ There is impaired entry of aminoglycoside into the cell. Due to mutation or deletion of a porin transport protein Due to growth conditions under which the oxygen-dependent transport process is not functional.  Aminoglycosides – Pharmacokinetics ▪ Poorly absorbed very from the intact gastrointestinal tract. ▪ Aminoglycosides are usually administered intravenously as a 30–60- minute infusion. ▪ After intramuscular injection, aminoglycosides are well absorbed, giving peak concentrations in blood within 30–90 minutes. ▪ Aminoglycosides exhibit concentration-dependent killing. * D ▪ Better efficacy and less toxicity when administered as a single large dose than when administered as multiple smaller doses.  Aminoglycosides – Toxicity Ototoxicity and nephrotoxicity (high dose) Most likely to occur when therapy is continued for more than 5 days. Elderly patients Renal insufficiency Avoid use of loop diuretics (e.g. furosemide) Avoid use of other nephrotoxic antimicrobials (vancomycin, amphotericin B) Ototoxicity Tinnitus, vestibular damage, high-frequency hearing loss, vertigo, ataxia, loss of balance Nephrotoxicity Increased creatinine levels or reduced creatinine clearance  Tetracyclines ▪ All of the tetracyclines have the same basic structure  Tetracyclines ▪ Tigecycline is a glycylcycline and a semisynthetic derivative of minocycline. ▪ Eravacycline is a structural analog of tigecycline classified as a fluorocycline. ▪ Omadacycline is a synthetic aminomethylcycline derivative of minocycline.  Tetracyclines Mechanism of action ▪ Tetracyclines bind to the 30S ribosomal subunit and prevent binding of the incoming charged tRNA unit DD ▪ BACTERIOSTATIC Mechanisms of resistance ▪ Impaired influx or increased efflux by an active transport protein pump ▪ Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome ▪ Enzymatic inactivation of tetracyclines  Tetracyclines Interactions Tetracyclines chelate divalent (iron, magnesium, calcium) and trivalent (aluminum) cations, which can interfere with their absorption and activity. * form chelates and cause decrease in absorption when taken with milk , aluminum containing compounds canything with a 2 + or 3t charge  Tetracyclines – Adverse effects and toxicity ▪ Gastrointestinal upset with food · ▪ Hepatotoxicity · liver failure ▪ Photosensitivity · sunburn ▪ Deposition in bone and teeth – young children > - discolor and slow growth ▪ Pregnancy – bone deformity, growth inhibition, enamel discoloration  Macrolides The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. Erythromycin Clarithromycin Azithromycin  Macrolides Mechanism of action ▪ Macrolides bind to the 50S ribosomal subunit and blocks transpeptidation. *▪ BACTERIOSTATIC D Mechanisms of resistance ▪ Drug efflux by an active pump ▪ Ribosomal protection by inducible or constitutive production of methylase enzymes, which modify the ribosomal target and decrease drug binding; (gram negative ▪ Macrolide hydrolysis by esterases produced by enterobacteriaceae; ▪ Chromosomal mutations that alter the 50S ribosomal protein  acid Stable Erythromycin > - not Oral, IV, topical Half-life is 1.5 hours – dosed every 6 hours Cytochrome P450 (CYP450) 3A4 inhibitor CYP inhibition: Results in increased levels of unmetabolized drugs Increased risk for drug TOXICITY Gastroprokinetic agent - > diarned Stimulates GI motility by activing on motilin receptors Tachyphylaxis develops with long-term use Toxicity: Gastrointestinal upset QTc prolongation Topical use for acne: Avoids CYP3A4 interactions & QTc prolongation  Clarithromycin onlydrug its a acid stable Oral Half-life is 3-4 hours – dosed every 12 hours QTc prolongation Strong cytochrome P450 inhibitor (3A4) Toxicity: Gastrointestinal upset QTc prolongation Dysgeusia – altered sense of taste – taste disorder in the Dile as the Azithromycin > - excreted active drug ; acid stable Oral, IV Very long half-life of 68 hours – once-daily dosing QTc prolongation Advantages Once daily dosing -> due to Til Less GI distress compared to other macrolides Does not inhibit CYP450 enzymes D *  Chloramphenicol MOA ▪ Chloramphenicol bind to the 50S ribosomal subunit and blocks transpeptidation. ▪ only used in life threatening infections dre to Use is rare in the developed world due to serious toxicities Toxicity: dose-related anemia Serious blood dyscrasias (aplastic anemia) – monitor CBC frequently Gray baby syndrome (rare but serious) Gray baby syndrome is due to a lack of glucuronidation in the baby, thus leading to an accumulation of toxic chloramphenicol metabolites (impaired neonatal secondary metabolism)  Lincosamides (Clindamycin) ▪ Clindamycin is a chlorine-substituted derivative of lincomycin Mechanism of action ▪ Binds to the 23S ribosomal RNA 50S ribosomal subunit ▪ Blocks transpeptidation. ▪ Inhibits ribosomal translocation DD ▪ BACTERIOSTATIC  Clindamycin Mechanisms of resistance > target mutation ▪ Mutation of the ribosomal site - ▪ Enzymatic inactivation of clindamycin. ▪ Gram-negative aerobic species are intrinsically resistant because of poor D permeability of the outer membrane. Pharmacokinetics ▪ Oral, IV ▪ Hepatic clearance (half-life 2.5 h) ▪ Dosed every 6–8 hours Adverse effects ▪ C. difficile colitis ▪ Esophageal irritation > - takewl full glass of water and be upright this for 30 minutes to avoid minimize Indications ▪ Skin and soft tissue infections ▪ Anaerobic infections  Oxazolidinones Linezolid ▪ Linezolid is a member of the oxazolidinone class of synthetic antimicrobials. Mechanism of action and mechanism of resistance ▪ Linezolid inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis. ▪ Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes. ▪ Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA. BACTERIOSTATIC – Staphylococci, Enterococci D D BACTERICIDAL - Streptococci D D G Idal for Strep !  Linezolid Indications ▪ Infections caused by methicillin-resistant staphylococci (MRSA) and vancomycin-resistant enterococci (VRE) Adverse effects Pharmacokinetics ▪ Duration-dependent bone marrow suppression ▪ Oral, IV (generally greater than 2 weeks of treatment) ▪ hepatic clearance (half-life 6 h) ▪ Neuropathy and optic neuritis ▪ dosed twice-daily ▪ Thrombocytopenia ▪ Serotonin-syndrome Ccontraindicated with MAOI’s – caution with serotonergic antidepressants Tedizolid ▪ Does not possess MAO inhibition ▪ Safety trials conducted only for 6 days  PRACTICE QUESTIONS 1. Which anti-ribosomal agent can cause ototoxicity and nephrotoxicity? A. Clindamycin B. Streptomycin C. Erythromycin D. Clarithromycin 2. Which anti-ribosomal agent can cause gray baby syndrome? A. Amikacin B. Linezolid C. Tigecycline D. Chloramphenicol * musin e macrolide ! PRACTICE QUESTIONS 3. Which antimicrobial medication class prevents bacterial protein synthesis by binding to the 30S ribosomal subunit? A. Lincosamides B. Macrolides C. Oxazolidinones D. Tetracyclines - Aminoglycosides 4. Divalent and trivalent cations impair absorption of which class of antimicrobial agents? A. Aminoglycosides B. Macrolides C. Streptogramins D. Tetracyclines fluoroquinolones  Objectives ▪ Explain the mechanism of action of fluoroquinolones ▪ Explain the mechanism of resistance of fluoroquinolones ▪ Describe the pharmacokinetics of fluoroquinolones ▪ Describe the drug interactions of fluoroquinolones ▪ Describe the adverse effects of fluoroquinolones  Fluoroquinolones ▪ Fluoroquinolones are synthetic fluorinated analogs of nalidixic acid. ▪ They are active against a variety of gram-positive and gram-negative bacteria.  Mechanism of action ▪ Fluoroquinolones block bacterial DNA replication by inhibiting bacterial enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. ▪ Fluoroquinolones bind to the topoisomerase–DNA complex. ▪ The fluoroquinolone–topoisomerase–DNA complex inhibits DNA relaxation and separation. ▪ Inhibition of topoisomerase II prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. ▪ Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. ▪ DNA gyrase is the primary target for gram-negative bacteria and topoisomerase IV is the primary target for gram-positive bacteria. D ▪ BACTERICIDAL D target for topoisomerasesIs DNA for finoroquinolones topoisomerase-DNA complex target is 3 I↓· - - - - - : - --- - = - Topo > - IV ---- > - - ak/ - nellcate = - -- - - - - -- - - - - -- -- - - - -  Mechanisms of resistance ▪ Widespread usage has led to increased resistance. natant ▪ Reduced fluoroquinolone-binding to topoisomerase II / topoisomerase IV. and activity o ▪ Upregulation of efflux pump–mediated active transport of the drug out of the bacteria. ▪ Reduced expression of porin channels allowing quinolones to transit the outer membrane.  Pharmacokinetics Routes of Administration Oral Primary Generic Brand Bioavaila Route of Oral IV Ophthalmic Otic bility (%) Excretion Ciprofloxacin Cipro® ✓ ✓ ✓ ✓ 70% Renal Levofloxacin Levaquin® ✓ ✓ ✓ 99% Renal Moxifloxacin Avelox® ✓ ✓ 90% Non-renal Delafloxacin Baxdela® ✓ ✓ 59% Renal Gatifloxacin Zymaxid® ✓ n/a n/a Ofloxacin Floxin® ✓ ✓ ✓ n/a n/a (not used) Ciprofloxacin – poor oral bioavailability, oral doses higher than IV doses Moxifloxacin – excretion is non-renal, cannot be used for UTI’s since does not achieve adequate concentration in the urine -> choice if there is renal dysfxn Gatifloxacin – topical use only, eyedrops  Drug Interactions QTc prolongation Newer fluoroquinolones (levofloxacin, moxifloxacin) prolong the QTc interval and should be avoided in: ▪ patients with known QTc prolongation ▪ patients on certain antiarrhythmic drugs ▪ patients on other drugs that increase the QTc interval Seizure risk ▪ Fluoroquinolones increase plasma levels of methylxanthines such as theophylline and caffeine and increases risk for seizures. Cation interactions ▪ Oral absorption is impaired by divalent (Calcium, Magnesium, Iron) and trivalent (Aluminum, Iron) cations, including those in antacids. ▪ Thus, oral fluoroquinolones should be taken 2 hours before or 4 hours after any food (e.g., dairy) or pharmaceutical products containing these cations. ▪ The antibiotic will precipitate in presence of these cations causing reduced serum levels.  Adverse effects ▪D Not recommended for children or pregnant women (damage to growing cartilage and arthropathy, i.e. joint problems) ▪ QTc interval prolongation ▪ Disturbances in glucose regulation (hypoglycemia / hyperglycemia) ▪ Phototoxicity ▪ Tendinopathy / tendon rupture ▪ Peripheral neuropathy ▪ Myasthenia gravis  PRACTICE QUESTIONS 1. Fluoroquinolones target which of the following bacterial biochemical processes? A. Cell wall synthesis B. Cell membrane synthesis and function C. Ribosomal translation D. Nucleic acid metabolism 2. Which fluoroquinolone has a primarily non-renal route of excretion? A. Ciprofloxacin B. Levofloxacin C. Moxifloxacin D. Delafloxacin