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Lecture 2
Cell Wall Antibacterial
| Question | Answer |
|---|---|
| Cell Wall Inhibitors | interfere with synthesis of bacterial cell wall |
| Cell Wall Inhibitors | bacterial cells have cell walls (made of peptidoglycan; glycan units joined together by peptide cross links) |
| Cell Wall Inhibitors | actively proliferating mircoorganisms |
| Cell Wall Inhibitors | B-lactam antibiotics |
| B-Lactam Antibiotics | B-lactam ring, R = side chains |
| B-Lactam Antibiotics Groups ** | penicillins, cephalosporins, carbapenems (imipenem), monobactams |
| Penicillins | chemistry: thiazolidine ring (A) attached to B-lactam ring (B) that has a secondary amino group (RNH-) |
| Penicillins | Side chains = antimicrobial spectrum, stability to stomach acid, cross hypersensitivity, susceptibility to beta-lactamases |
| Penicillins | structural integrity necessary for biologic activity; hydrolysis of B-lactam ring --> inactive |
| Penicillins Mechanism of Action ** | interfere bacterial cell wall synthesis transpeptidation |
| Penicillins Mechanism of Action | structurally similar to terminal portion of peptidoglycan strand, compete for and bind to BPB, PBPs catalyze transpeptidase and facilitate cross linking of the cell wall |
| Penicillins Mechanism of Action | cross links account for cell wall rigidity, beta-lactam antibiotics covalently bind to active site of PBP, binding prevents transpeptidase reaction and stops peptidoglycan synthesis |
| Penicillins Mechanism of Action ** | inhibit bacterial growth by interfering with transpeptidation reaction of bacterial cell wall synthesis |
| Penicillins Antibacterial Spectrum | determined by ability to cross bacterial peptidoglycan cell wall, factors affecting PBP susceptibility include size charge, hydrophobicity of the B-lactam antibiotic, typically gram positive bacteria cell walls are easily crossed by penicillins |
| Penicillins Antibacterial Spectrum | Gram negative organisms have outer lipopolysaccharide membrane acting as barrier to penicillins = porins (water filled channels) allow penicillins to enter |
| Penicillins Beta-Lactamase | enzyme produced by bacteria that inactivates antibiotic |
| Penicillins Beta-Lactamase Classification Groups | penicillin's, anti staphylococcal penicillins, extended spectrum penicillins |
| Penicillins | Example: penicillin G, V (fermentations of the fungus) |
| Penicillins | susceptible to B-lactamase hydrolysis = inactivates antibiotic |
| Penicillins | greatest activity against = gram positive organisms, gram negative cocci, non b-lactamase producing anaerobes |
| Penicillins | little activity against = gram negative rods |
| Penicillin G | treats streptococci, meningococci, some enterococci, penicillin-susceptible pneumococci, non b-lactamase producing staphylococci |
| Penicillin V | Indicated in minor infections = oral form of penicillin, poor bioavailability, QID dosing, narrow antibacterial spectrum, amoxicillin commonly used instead |
| Anti-Staphylcoccal Penicillins | examples: nafcillin, oxacillin, dicloxacillin, methicillin |
| Anti-Staphylcoccal Penicillins | activity against = staphylococci and streptococci |
| Anti-Staphylcoccal Penicillins | not active against = enterococci, anaerobic bacteria, gram negative cocci and rods |
| Anti-Staphylcoccal Penicillins | resistant to staphylococcal B-lactamases = useful in infections caused by b-lactamase producing staphylococci; indicated for MSSA |
| Methicillin | used in lab tests to identify resistant strains of S aureus (MRSA); removed from use because of its toxicity (interstitial nephritis) |
| Extended Spectrum Pencillins | examples=aminopenicillins, antipseudomonal penicillins; activity against=gram positive organisms, gram negative cocci, non b-lactamase producing anaerobes, improved activity against gram negative rods; susceptible to hydrolysis by B-lactamase |
| Aminopenicillins | ampicillin, amoxicillin; different R groups attached to 6-aminopenicillianic acid nucleus; R group addition extends gram negative activity |
| Aminopenicillins | amoxicillin better absorbed orally, most active oral B-lactams against pneumococci, ampicillin effective for shigellosis |
| Ureidopenicillins | piperacillin; active against many Gram negative bacilli; klebsiella pneumonia |
| Ureidopenicillins**: piperacillin referred to as ___ | antipseudomonal penicillin |
| Ureidopenicillins | co-formulation with b-lactamase inhibitor tazobactam (extends spectrum of activity to include penicillinase-producing organisms) |
| Beta-Lactamse Inhibitors | Inactivate beta-lactamases; prevent destruction of beta-lactam antibiotics; hav e little intrinsic antibacterial activity alone |
| Beta-Lactamse Inhibitors | ampicillin, amoxicillin, piperacillin combinations (clavulanic acid, sulbactam, tazobactam); extend activity of penicillins |
| Beta-Lactamse Inhibitors Clavulanic Acid | gram positive and negative microorganisms; PO and parenteral; combines with amoxicillin (augmentin) |
| Beta-Lactamse Inhibitors Sulbactam | similar structurally to clavulanic acid; IV or IM combines with ampicillin; some intrinsic activity against Acinetobacter sp |
| Beta-Lactamse Inhibitors Tazobactam | available as parental combination with piperacillin and ceftolozane |
| Methods of Resistance | inactivation of antibiotic by beta-lactamase, target PBP modification; altered penetration of drug to target PBP, antibiotic efflux |
| Resistance | important to choose antibiotic with appropriate spectrum and use shortest duration |
| Pharmacokinetics | food impairs absorption of most oral penicillins (except amoxicillin); administer at least 1 to 2 hours before or after a meal (amoxicillin can be taken with or without food); IV administrations of Pen G preferred over IM |
| Pharmacokinetics | highly protein-bound penicillins(nafcillin) vs less protein bound penicillins (G, ampicillin) |
| Pharmacokinetics | excreted in sputum and breast milk; poor penetration in eye, prostate, CNS |
| Pharmacokinetics | nafcillin cleared by biliary excretion; oxacillin, dicloxacillin, cloxacillin eliminated by both kidney and biliary (dose adjustments not necessary in renal failure); clearance of penicillins less efficient in newborns |
| Adverse Reactions | most serious adverse effects due to hypersensitivity; nafcillin = neutropenia and interstitial nephritis; oxacillin=hepatitis; ampicillin=pseudomembranous colitis |
| Cephalosporins | more stable to beta-lactamase than penicillins; broader spectrum of activity vs penicillins |
| Cephalosporins | classified based on spectrum of activity = first, second, third, fourth generations |
| Cephalosporins | MOA similar to penicillin antibiotics; antibiotics resistance; cross reactions between pens and cephalosporins |
| First Generation Cephalosporins (narrow spectrum) uses=cefazolin (surgical prophylaxis) | oral formulations=cephalexin, cefadroxil; parenteral formulation=cefazolin; spectrum of activity=active against gram positive cocci, modest activity against gram negative organisms; uses=oral formulations (UTI and staphyl/streptococcal infections) |
| Second Generation Cephalosporins | oral=cefaclor, cefuroxime, cefprozil; parenteral=cefoxitin, cefotetan; additional gram negative coverage, klebsiella sp |
| Second Generation Cephalosporins Clinical Uses | oral agents active against H influenza or Moraxella catarrhalis; used to treat sinusitis, otitis media, lower respiratory tract infections; cefoxitin & cefotetan have activity against anaerobes, cefuroxime used to treat community acquired pneumonia (CAP) |
| Third Generation Cephalosporins | Parenteral = cefotaxime (claforan); ceftazidime, ceftriaxone (rocephin); oral agents=cefpodoxime proxetil, cefdinir (omincef), cefditoren pivoxil, cefixime (suprax) |
| Third Generation Cephalosporins | Expanded gram negative coverage, some able to cross BBB, ceftazidime useful against P aeruginosa |
| Third Generation Cephalosporins Pharmacokinetics | penetrate body fluids and tissues well; IV cephalosporins reach levels in CSF sufficient enough to stop most susceptible pathogens; cefixime given orally for UTI, ceftriaxone excreted primarily thru biliary tract (others excreted renally) |
| Third Generation Cephalosporins Clinical Uses | resistant organisms; not susceptible to strains expressing extended-spectrum B-lactamases (ESBL); avoid in treatment of Enterobacter infections because of emerging resistance; ceftriaxone and cefotaxime approved for meningitis treatment |
| Fourth Generation Cephalosporins | cefepime (maxipime) = parenteral administration); good activity against P aeruginosa, enterobacteriaceae, methicillin-suspceible S aureus, S pneumonia; highly active against Haemophilus and Neisseria sp |
| Fourth Generation Cephalosporins-Cefepime | crosses into CSF; cleared renally; t1/2 2 hours; used empirically in febrile neutropenia, in combo with other agents |
| Fifth Generation Cephalosporins- MRSA and Ceftaroline** | Ceftaroline foasmil(teflaro)=increased binding to PBP 2a (confers resistance to MRSA) and PBP 2x (confers resistance to S pneumonia) --> benefits in MRSA and resistant S pneumonia |
| Fifth Generation Cephalosporins- MRSA and Ceftaroline** | Ceftaroline foasmil(teflaro)=I V fusion; normal t1/2 2.7 hours; primarily renally excreted |
| Cephalosporin Adverse Effects | allergy=documented anaphylaxis with penicillin - increased risk of reacting with cephalosporins; cross sensitivity most common among penicillin, aminopenicillins, and early generation cephalosporins; avoid using 1 & 2 generations w/history of anaphylaxis |
| Cephalosporin Adverse Effects** | Toxicity=local irritation after IM injection; thrombophlebitis after IV injection; cefotetan contains methylthiotetrazole group which may cause hypoprothrombinemia and bleeding disorders (may also cause disulfiram-like reaction-avoid alcohol) |
| Beta-lactamase Inhibitor Combinations | Generic: avibactam + ceftazidime = brand(avycaz); Tazobactam + ceftolozane = zerbaxa |
| First Generation Cephalosporins | cefacdroxil, cefazolin, cephalexin |
| Second Generation Cephalosporins | cefaclor, cefotetan, cefoxitin, cefprozil, cefurozime |
| Third Generation Cephalosporins | Cefdinir, cefditoren pivotal, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone |
| Fourth Generation Cephalosporins | cefepime |
| Fifth Generation Cephalosporins | Ceftaroline |
| Other Beta-Lactam Antibiotics: Monobactams | monocyclic B-lactam ring; activity limited to aerobic gram negative organisms (covers P aeruginosa) |
| Other Beta-Lactam Antibiotics: Monobactams | Aztreonam; penetrates CNS; administered IM/IV; accumulation possible in renal failure; relatively nontoxic (possible phlebitis, skin, rash, abnormal LFTs; use with caution in patients allergic to ceftazidime |
| Carbapenems | doripenem, ertapenem, imipenem, meropenem; penetrate body tissues and fluids well, CSF included; renally cleared |
| Imipenem | spectrum of activity against most gram negative rods, gram positive, anaerobes |
| Imipenem | resistant to b-lactamases but not to carbapenemases or metallo b-lactamases |
| Imipenem | inactivated by dehydropeptivdases in renal tubules causing low urinary concentrations = administered with cilastatin for clinical use |
| Carbapenem Indications | suspejibile organisms resistant to other available drugs; treatment of mixed aerobic and anaerobic infections; highly active in treating enterobacter infections |
| Carbapenem Adverse Effects | AE more common with imipenem; excess levels of imipenem in renal failure patients may lead to seizures; cross sensitivity possible with patients allergic to penicillin <1% |
| Glycopeptide Antibiotics: Gylcopeptide and Lipoglycopeptide Antibiotics | vancomycin, oritavancin, dalbavancin, telavancin |
| Vancomycin - mechanism of action | inhibits bacterial cell wall synthesis; cell wall is weakened and cell membrane is damaged |
| vancomycin antibacterial activity | bactericidal against gram positive bacteria; most pathogenic staphylococci killed in concentrations; staphylococci cells need to be actively dividing; active against many gram positive aerobes |
| Vancomycin pharmacokinetics | poorly absorbed from intestinal tract --> given PO for enterocolitis, C diff infections; administered parenterally for systemic infections; parenteral doses given IV (avoid IM administration); widely distributed |
| Vancomycin pharmacokinetics | primarily excreted by glomerular filtration; elimination t1/2 4 to 6 hours in normal renal function |
| Vancomycin indications | PO administration - c difficile; parenteral vancomycin-bloodstream infections and endocarditis caused by MRSA |
| Vancomycin Adverse Reactions | phlebitis at injection site; chills, fever; nephrotoxicity; red man syndrome (infusion related flushing caused by release of histamine) |
| Lipoglycopeptide antibiotics | telavancin (vibativ), oritavancin (kimyrsa, orbactive), dalbavancin (dalavance); bactericidal, concentration dependent, gram positive coverage, similar spectrum of activity to vancomycin, activity against some vancomycin resistant bacteria |
| Telavancin (Vibativ) | active against gram positive bacteria; two MOA=inhibits cell wall synthesis and disrupts bacterial cell membrane potential and increases membrane permeability |
| Telavancin (Vibativ) | half life 8 hours; once daily IV dosing; approved for treatment of complicated skin and soft tissue infections and hospital acquired pneumonia; adverse effects=substantial nephrotoxicity, increased mortality in clinical trials, potentially teratogenic |
| Dalbavancin and Oritavancin | MOA similar to vancomycin; extremely long half lives; once weekly IV administration; approved for treatment of skin and soft tissue infections; interfere with phospholipid reagents used in assessing coagulation; use alternative therapy with heparin use |
| Dalbavancin | administered over 30 min |
| Oritavancin | Kim infused over 1 hour; orbactiv infused over 3 hours |
| Other cell wall or membrane active agents | daptomycin, fosfomycin, bacitracin |
Created by:
bluedolphin7
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