Antibiotic Classification And Modes Of Action - WordPress
Customer EducationAntibiotic ClassificationAntibiotic ClassificationandModes of ActionPart # 60-00415-0 bioMérieux, Inc., Customer EducationMarch 20081
Customer EducationAntibiotic ClassificationbioMérieux, the blue logo and VITEK are used, pending and/or registered trademarksbelonging to bioMérieux SA or one of its subsidiaries.CLSI is a registered trademark of Clinical Laboratory and Standards Institute, Inc.Zyvox is a registered trademark of Pfizer Caribe Limited.Tequin is a registered trademark of Bristol-Myers Squibb Company. bioMérieux, Inc., Customer EducationMarch 20082
Customer EducationAntibiotic ClassificationAntibiotic ClassificationModuleObjectivesUpon completion of this module you will be able to: Explain why susceptibility testing is done Define the terms, bacteriostatic and bactericidal Describe the functional antibiotic classification scheme and listthe 5 main groups Name at least one antibiotic in each class Describe the structure of a Gram-positive and negative cell Explain the modes of action for the antibiotics in each of the fivefunctional antibiotic classes List examples of natural resistance in each of the five functionalantibiotic classes Explain why it is not necessary to perform susceptibility testingfor certain organism / antibiotic combinations bioMérieux, Inc., Customer EducationMarch 20083
Customer EducationAntibiotic ClassificationAntibiotics&Susceptibility TestingMicrobiologists work with antibiotics every day.Antimicrobial Susceptibility Testing (AST) is one of the primary functions ofthe Microbiology Lab.But, how much do Microbiologists really know about antibiotics?Let’s review some basic information and see how it can be applied daily. bioMérieux, Inc., Customer EducationMarch 20084
Customer EducationAntibiotic ClassificationWhat is an Antibiotic?Antibiotic is a chemical substance produced bya microorganism that inhibits the growth of orkills other microorganisms.Antimicrobial agent is a chemical substancederived from a biological source or producedby chemical synthesis that kills or inhibits thegrowth of microorganisms.The noun “antibiotic” was first used in 1942 by Dr. Selman A.Waksman, soil microbiologist. Dr. Waksman and his colleaguesdiscovered several actinomycetes derived antibiotics.The two terms are usually used synonymously and that practice willcontinue throughout this presentation.The word “antibiotic” will be used to describe:a chemical substance derivable from a microorganism orproduced by chemical synthesis that kills or inhibitsmicroorganisms and cures infections. bioMérieux, Inc., Customer EducationMarch 20085
Customer EducationAntibiotic ClassificationSources of Antibacterial Agents Natural - mainly fungal sources Semi-synthetic - chemically-altered natural compound Synthetic - chemically designed in the ness The original antibiotics were derived from fungal sources. These canbe referred to as “natural” antibiotics Organisms develop resistance faster to the natural antimicrobialsbecause they have been pre-exposed to these compounds innature. Natural antibiotics are often more toxic than syntheticantibiotics. Benzylpenicillin and Gentamicin are natural antibiotics Semi-synthetic drugs were developed to decrease toxicity and increaseeffectiveness Ampicillin and Amikacin are semi-synthetic antibiotics Synthetic drugs have an advantage that the bacteria are not exposed tothe compounds until they are released. They are also designed to haveeven greater effectiveness and less toxicity. Moxifloxacin and Norfloxacin are synthetic antibiotics There is an inverse relationship between toxicity and effectiveness asyou move from natural to synthetic antibiotics bioMérieux, Inc., Customer EducationMarch 20086
Customer EducationAntibiotic ClassificationRole of AntibioticsWhat is the role of antibiotics? To inhibit multiplicationAntibiotics have a bacteriostatic effect.At which drug concentration is thebacterial population inhibited? Minimal Inhibitory Concentration MICBacteriostatic inhibits bacterial growth bioMérieux, Inc., Customer EducationMarch 20087
Customer EducationAntibiotic ClassificationMIC – Broth Dilution Reference Technique1 ml107 CFUMuellerHinton 1 ml00µg/ml0.50.51 1224488 1616µg/ml35 C - 16 - 20 h0µg/ml0.512MIC 4816Quantitative Measure MIC lowest concentration of antibiotic that inhibits growth(measured visually) Interpretation of quantitative susceptibility tests is based on:relationship of the MIC to the achievable concentration ofantibiotic in body fluids with the dosage givenFor treatment purposes, the dosage of antibiotic given shouldyield a peak body fluid concentration 3-5 times higher than theMICorMIC x 4 dosage to obtain peak achievable concentration bioMérieux, Inc., Customer EducationMarch 20088
Customer EducationAntibiotic ClassificationRole of AntibioticsWhat is the role of antibiotics? To destroy the bacterial populationAntibiotics have a bactericidal effect.At which drug concentration is thebacterial population killed? Minimal Bactericidal Concentration MBCBactericidal kills bacteria bioMérieux, Inc., Customer EducationMarch 20089
Customer EducationAntibiotic ClassificationMBC – Reference Technique0µg/ml0.512MIC 481610 µl0 µg/ml4 µg/ml8 µg/ml16 µg/mlMBC 16µg/mlQuantitative Measure MBC lowest concentration of antibiotic that kills bacteria bioMérieux, Inc., Customer EducationMarch 200810
Customer EducationAntibiotic ClassificationRelationship of 163264128BacteriostaticThere is a much closer relationship between the MIC and MBC valuesfor bactericidal drugs than for bacteriostatic drugs. bioMérieux, Inc., Customer EducationMarch 200811
Customer EducationAntibiotic ClassificationHow Do Antibiotics Work?Mechanisms of Action-Antibiotics operate by inhibiting crucial lifesustaining processes in the organism:the synthesis of cell wall materialthe synthesis of DNA, RNA, ribosomesand proteins.Target–The target of the antibiotic should beselective to minimize toxicity but allantibiotics are toxic to some degree!The targets of antibiotics should be selective to minimize toxicity. Selective ToxicityHarm the bacteria, not the host bioMérieux, Inc., Customer EducationMarch 200812
Customer EducationAntibiotic ClassificationWhy Do Susceptibility Testing? Help patients today- To provide guidance to the physician inselection of antimicrobial therapy with theexpectation of optimizing outcome Help patients tomorrow- Build an antibiogram to guide physicians inselecting empiric therapy for future patientswith the expectation of optimizing outcome Help patients next decade- Drive new drug research- Monitor the evolution of resistanceWe do this testing: To provide a guide for therapy Allows selection of the most appropriate agentLeast expensiveNarrowest spectrumMost effective To monitor the evolution of resistanceAntibiotic resistance has an impact on individual health and public health. Types of resistance seen and frequency Which drugs you can expect to be successful Emerging and new resistance seen in the community bioMérieux, Inc., Customer EducationMarch 200813
Customer EducationAntibiotic ClassificationWhy Do Antimicrobials Fail?Host FactorsAntibiotic PropertiesImmune SystemUnderlying DiseasesBarrier StatusForeign BodiesPK and PDMetabolism & EliminationTissue PenetrationAdverse Event ProfileIn VitroTestingMIC & S/RSite of InfectionPathogenCNSIntravascularPulmonarySurgical InterventionSpeciesVirulence FactorsResistance MechanismsThere are many possible reasons antimicrobials may fail.Selection of the appropriate antibiotic depends on:knowledge of organism’s natural resistancepharmacological properties of the antibiotic toxicity, binding,distribution, absorption achievable levels in blood, urineprevious experience with same speciesnature of patients underlying pathologypatient’s immune statusSusceptibility testing focuses primarily on the interaction of antimicrobialagents, the organisms and their resistance mechanisms. bioMérieux, Inc., Customer EducationMarch 200814
Customer EducationAntibiotic ClassificationInterpreting Susceptibility Results MICs are not physical measurements There are many factors that play a rolein determining clinical outcome Susceptibility in vitro does not uniformlypredict clinical success in vivo Resistance will often, but not always,correlate with treatment failureSusceptibility tests are essentially artificial measurements.in vitro responseapproximate range of effective inhibitory actionpossible error equivalent to one tube dilutionThe only true measure of bacterial response to an antibiotic is the clinicalresponse of the patient.outcome or in vivo responseOne of the real values of AST is to predict resistanceS success likely, but no guaranteeR correlates well with treatment failureIs Resistance Testing a better name for what we do than SusceptibilityTesting? bioMérieux, Inc., Customer EducationMarch 200815
Customer EducationAntibiotic ClassificationWhat is the Ideal Antibacterial? Selective target – target uniqueBactericidal – killsNarrow spectrum – does not kill normal floraHigh therapeutic index – ratio of toxic level totherapeutic levelFew adverse reactions – toxicity, allergyVarious routes of administration – IV, IM, oralGood absorptionGood distribution to site of infectionEmergence of resistance is slow bioMérieux, Inc., Customer EducationMarch 200816
Customer EducationAntibiotic ClassificationAntibiotic ClassificationandModes of ActionIn the AES Knowledge Base, phenotypes are organized by drug class.The AES decision process attempts to identify a phenotype for eachdrug class tested. In order to understand and use the software effectively, itis important to have a solid working knowledge of antibiotic classification.In addition, each drug class typically has a unique mode of action.Bacteria in turn, direct their defenses against these specific modes of action.Understanding why antibiotics fail begins with the classification of antibioticsand their modes of action. bioMérieux, Inc., Customer EducationMarch 200817
Customer EducationAntibiotic ClassificationAntibiotic ClassificationGrouped by Structure and FunctionFive functional groups cover most antibiotics1. Inhibitors of cell wall synthesis2. Inhibitors of protein synthesis3. Inhibitors of membrane function4. Anti-metabolites5. Inhibitors of nucleic acid synthesisAntibiotics are usually classified based on their structure and/orfunction.1. Structure - molecular structure.ß-Lactams - Beta-lactam ringAminoglycosides - vary only by side chains attached to basicstructure2. Function - how the drug works, its mode of action.5 functional groupsThese are all components or functions necessary for bacterialgrowthTargets for antibioticsIn these discussions, we will primarily use the functional classification, butwill point out where structural similarities also exist. bioMérieux, Inc., Customer EducationMarch 200818
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall rs of Cell Wall SynthesisBeta-lactams There are about 50 different Beta (ß)-lactams currently on the market They are all bactericidal They are non-toxic (i.e., they can be administered at high doses) They are relatively inexpensive Beta-lactams are organic acids and most are soluble in water bioMérieux, Inc., Customer EducationMarch 200819
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall hibitors of Cell Wall SynthesisBeta-lactams Similar in structure, as well as, function All have a common structural ß-lactam ring Antibiotics vary by side chains attached All beta-lactams are subject to inactivation by bacterial-producedenzymes called beta-lactamasesSome more common Beta-lactamase enzymes hamycinasesCarbapenemases bioMérieux, Inc., Customer EducationMarch 200820
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisBeta-lactams (Penicillins)Penicillins(pen G)*Penicillinase-stable penicillins(pen M)Aminopenicillins*(pen A)Carboxypenicillins*(pen C)Ureidopenicillins*(pen U)β-lactam / β-lactamase l Common NamePenicillin linPiperacillinAmoxicillin clavulanic acidAmpicillin sulbactamTicarcillin clavulanic acidPiperacillin tazobactamMecillinam* Penicillinase labile: hydrolyzed by staphylococcal penicillinaseInhibitors of Cell Wall SynthesisBeta-lactams - PenicillinsSpectrum of Action1. Natural penicillins Penicillin G: Active against Gram-positive organisms that do notproduce beta-lactamases, Neisseria and some anaerobes2. Penicillinase-resistant penicillins Penicillin M: Active against penicillinase-producing Staphylococci3. Extended-spectrum penicillins Aminopenicillins: Slightly less active than Penicillin G againstPneumococci, Streptococci and Meningococci, but active against manystrains of Salmonella, Shigella, and P.mirabilis, H.influenzae) Carboxypenicillins: More stable than aminopenicillins to hydrolysis bythe ß-lactamases of most Enterobacteriaceae and Pseudomonasaeruginosa Ureidopenicillins: Greater activity than carboxypenicillins againstGram-positives, enterics and P.aeruginosa4. Co-Drugs (Beta-lactam beta-lactamase inhibitor) ß-lactamase inhibitors (BLI) combinations: Additional activityagainst beta-lactamase producing organisms, including Staphylococcusspp., some enterics, H.influenzae and Bacterioides spp5. Amidinopenicillins Mecillinam: Restricted use to urinary infection with E.coli. Activeagainst penicillinase and low-level cephalosporinase. bioMérieux, Inc., Customer EducationMarch 200821
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisBeta-lactamase Inhibitors (BLI)Aim: to block β-lactamasesThese enzymatic inhibitors have weak or poorantibacterial activity alone, but a strong affinity for βlactamases: Clavulanic AcidSulbactamNeverTazobactamAlone!Combination β-lactams - β-lactamase inhibitor:Amoxicillin Ampicillin Ticarcillin Piperacillin Clavulanic AcidSulbactamClavulanic AcidTazobactamBeta-lactamase inhibitors (BLI) have a beta(ß)-lactam ring, but have weak orpoor antibacterial activity. They have a very high affinity for ß-lactamases They act as a trap, and are hydrolyzed in preference to the ß-lactam drug.The drug is left intact to act on the bacteria (cell wall). Should be called penicillinase inhibitors, because they are active against:Staph penicillinasePenicillinase of K. pneumoniaeESBL (to a greater or lesser degree) - if the penicillinase is beingoverproduced, the inhibitor effect may be diluted (Inoculum Effect)In the case of penicillinase production, where:AmoxicillinRAmoxicillin Clavulanic acidusually S Inhibitors are active against all penicillinase (PASE and ESBL) but never oncephalosporinaseNEW ISSUE - BLI can act as inducers and actually stimulate enzyme (betalactamase) production. It is possible to see the following:Pseudo monasEnterobacteriaceaeTicarcillin STicarcillin/Clavulanic RPiperacillin S Piperacillin/Tazobactam R bioMérieux, Inc., Customer EducationMarch 200822
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisBeta-lactams (Cephems)st1 Generation CephalosporinsC1G2nd Generation CephalosporinsC2GCephamycin (new C2G)3rd Generation CephalosporinsC3G4th Generation CephalosporinsC4GOral C3GNext GenerationCephalosporinsInternational Common itinCefotetan – iximeCefpodoximeCeftobiproleCeftarolineInhibitors of Cell Wall SynthesisBeta-lactams - CephemsSpectrum of Action 1st generation cephalosporins (C1G): Narrow spectrum; goodGram-positive activity and relatively modest Gram-negative activity.Inactivated by Gram-neg beta-lactamases (Derived fromCephalosporium acremonium). 2nd generation cephalosporins (C2G): Better Gram-negativecoverage (more beta-lactamase stability), but less Staphylococcalactivity. Cephamycins: Remain susceptible in presence of ExtendedSpectrum ß-lactamase (ESBL) because they are not a substrate forthe enzyme. Can be used as an indicator for ESBL (Derived fromStreptomyces lactamdurans).- AstraZeneca discontinued its Cefotetan products in June 2006.Currently available from other manufacturers. 3rd generation cephalosporins (C3G): Wider spectrum of actionwhen compared to C1G and C2G. Less active than narrow spectrumagents against Gram-positive cocci, but much more active against theEnterobacteriaceae and Pseudomonas aeruginosa (better betalactamase stability). 4th generation cephalosporins (C4G): Broadest spectrum ofaction. Active against high level cephalosporinases ofEnterobacteriaceae and Pseudomonas aeruginosa (not usually usedwith ESBL producing organisms).None have activity to MRSA or Enterococcus spp. bioMérieux, Inc., Customer EducationMarch 200823
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisNew Anti- MRSA CephalosporinsCeftobiproleNew !CeftarolineA next generation cephalosporins?Inhibitors of Cell Wall SynthesisBeta-lactams - Cephems - CeftobiproleSpectrum of Action Next generation cephalosporin: Broad spectrum; active againstthe common Gram-negative bacteria. Some Gram-positive activity(Drug Resistant S. pneumoniae). Notable for activity against MRSA,unlike any other beta-lactam antibiotic. Bactericidal. Not yet FDA approvedHas been added to CLSI M100-S18, 2008 listing of antibioticsNo CLSI breakpointsOnce FDA approved, can no longer say if Staph is resistant toOxacillin, report all beta-lactams as resistant. bioMérieux, Inc., Customer EducationMarch 200824
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisBeta-lactamsInternational Common s of Cell Wall SynthesisBeta-lactams: MonobactamsSpectrum of Action Aztreonam: Gram-negatives (Enterobacteriaceae andPseudomonas). Not hydrolyzed by most commonly occurringplasmid and chromosomally mediated ß-lactamases, and does notinduce the production of these enzymes.Beta-lactams: PenemsSlightly different structure than the other ß-lactams, make the Penemsmuch more resistant to beta-lactamase hydrolysis.Spectrum of Action Carbapenems: ß-lactams with a broad spectrum of action. Grampositives, except MRSA. Gram-negatives, Ps. aeruginosa (exceptErtapenem) and anaerobes. Very efficient against high levelcephalosporinase and ESBL. Wide diffusion in the body, especiallyin the cerebrospinal fluid.Doripenem (new) - Broad spectrum. Particularly good forPseudomonas and other non-fermenters. Penem: Oral. Primarily for respiratory tract infections. Poor activitywith Serratia, Pseudomonas, Stenotrophomonas.Faropenem not yet FDA approved. bioMérieux, Inc., Customer EducationMarch 200825
Customer EducationAntibiotic ClassificationAntibiotic Modes of ActionFrom the BugTo the Drug Before we can understand the antibiotic modes of action, we need toreview the structure and physiology of the bacterial cell bioMérieux, Inc., Customer EducationMarch 200826
Customer EducationAntibiotic ClassificationMultiplication of Bacteria It is important to understand the growth cycle and physiology of bacteria toappreciate how it influences antimicrobial action Bacteria are all around us. Given good growing conditions, a bacteriumwill divide. A new cell wall forms at the center and the "bug" splits into two daughtercells, both of which carry the same genetic information as the parent If the environment is perfect, the two daughter cells can split into fourwithin 20 minutes 1, 2, 4, 8, 16, 32, 64. Typical bacterial growth cycle includes:Lag phaseExponential (log) phaseStationary phaseDeath phase bioMérieux, Inc., Customer EducationMarch 200827
Customer EducationAntibiotic ClassificationBacterial StructureBacterial wall(peptidoglycan)2.5 µCytoplasm1µCytoplasmic membraneRibosomesDNA1µTypical Structure of a Bacterial Cell (from inside to outside)DNA bacterial genetic materialRibosomes (protein-making factories), energy-generating systems, digestivesystem, and everything else are located in the cytoplasm.Cytoplasmic Membrane or Inner Membranea. Consists of phospholipids and other membrane proteinsb. Semi-permeablec. Regulates pH, osmotic pressure and availability of essential nutrientsBacterial Cell Wall or Peptidoglycana. Cross-linked mesh that gives a cell its shape, strength and osmoticstability, a protective suit of armourb. Porous up to 100,000 DaThe outer layer of lipopolysaccharide (LPS) and phospholipid material helpsprotect bacteria from bacteriophages, pH, enzymes, phagocytosis. To multiply, the bacteria must be able to synthesize peptidoglycan,proteins and DNA The cell wall, the ribosomes and DNA are all potential antibiotic targets bioMérieux, Inc., Customer EducationMarch 200828
Customer EducationAntibiotic ClassificationGram-Positive Cell StructureTeichoicacidsPeptido glycanInnermembranePBPProteinGram-Positive Cell Structure The Gram-positive cell wall is thick and consists of 90% peptidoglycan Teichoic acids link various layers of peptidoglycan together. Teichoicacids also regulate the autolysin activity in this complex equilibrium. The cytoplasmic membrane (which defines the intracellular space)consist of: a lipid bilayer intrinsic proteins which are hydrophobic (mostly enzymes involvedin respiration and transmembrane transport) extrinsic proteins which are hydrophilic Penicillin-Binding Proteins (PBPs): periplasmic space proteinsinvolved in peptidoglycan synthesis (glycosyltransferase,transpeptidase and carboxypeptidase activities) bioMérieux, Inc., Customer EducationMarch 200829
Customer EducationAntibiotic ClassificationGram-Positive Cell Structure bioMérieux, Inc., Customer EducationMarch 200830
Customer EducationAntibiotic ClassificationGram-Negative Cell StructureEndotoxin LPSPorinProteinOutermembranePeptidoglycanβ e Cell Structure The outer membrane is made up of: phospholipids endotoxin or lipopolysaccharide (LPS) - plays an important role inthe antibiotic entry into the cell proteins including the porins (complexes of three proteins)form aqueous channels that provide a route across the outermembrane for all the water-soluble compounds needed by thebacterium The periplasmic space contains: peptidoglycan – 5-20% of cell wall various enzymes (in particular, ß-lactamases) The cytoplasmic membrane (which defines the intracellular space)consists of: a lipid bilayer intrinsic proteins which are hydrophobic (mostly enzymes involvedin respiration and transmembrane transport) extrinsic proteins which are hydrophilic Penicillin-Binding Proteins (PBPs) - periplasmic space proteinsinvolved in peptidoglycan synthesis (glycosyltransferase,transpeptidase and carboxypeptidase activities) bioMérieux, Inc., Customer EducationMarch 200831
Customer EducationAntibiotic ClassificationGram-Negative Cell Wall Structure bioMérieux, Inc., Customer EducationMarch 200832
Customer EducationAntibiotic ClassificationPeptidoglycan StructureN -a c e ty lm u ra m ic a c idN -a c e ty lg lu c o s a m in eD -a laD -a laL -a laD -g lu N H 2g lyL -ly sg lyD -g lu N H 2g lyD -a laL -ly sg lyg lyL -a laD -a laN -a c e ty lg lu c o sa m in eN -a c e ty lm u ra m ic a c idPeptidoglycan is a very high molecular weight polymer composed of many identicalsubunits is a 3-D polymeric macromolecule determines cell shape and prevents osmotic lysis, porous up to 100,000daltons contains N-acetylglucosamine (NAG), N-acetylmuramic acid (NAMA), andseveral different amino acids involves 2 types of covalent chemical bonds:1. B-1, 4 glycosidic bond between hexose sugars2. Petide bond between amino acids In Gram-positive bacteria, peptidoglycan accounts for as much as 90% ofthe cell wall (approximately 40 layers), with the rest consisting of theteichoic acids. Gram-negative bacteria have a thin peptidoglycan layer (accounting foronly 5-20% of the cell wall). However, in addition to the cytoplasmicmembrane, they have a second phospholipid bilayer external to thepeptidoglycan called the outer membrane. bioMérieux, Inc., Customer EducationMarch 200833
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisMode of ActionofBeta-lactamsHumans have no cell wall (no peptioglycan), so this is agood selective target for the antibiotic. bioMérieux, Inc., Customer EducationMarch 200834
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisEntry of β-lactams in Gram-Positive Bacteriaβ-lactamPeptido glycanCytoplasmicmembraneProteinPBPBeta-lactams are mostly water soluble.Differences in cell wall composition (more or less lipids) between differentbacterial species partially account for their differential susceptibility to ßlactams.The target of the ß-lactam antibiotics for all bacteria is the PBP (PenicillinBinding Protein) in the cytoplasmic membrane.Gram-Positives:In Gram-positive bacteria, there is no barrier to the entry of ß-lactamsantibiotics.The peptidogylcan layers allow the diffusion of small molecules.However, ß-lactams cross the membranes with great difficulty due tohigh lipid content but, since their target PBP’s are found on the outersurface of the cytoplasmic membrane, they only have to cross the cell wall.Natural ResistanceEnterococcus - PBP’s are different from other Gram-positives (also higherlipid content in cell wall), which causes a low level resistance to penicillinsand resistance to C1G. bioMérieux, Inc., Customer EducationMarch 200835
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisEntry of β-lactams in Gram-Negative BacteriaEndotoxin LPSPorinOutermembranePeptidoglycanβ es:1. Outer membrane entry through the:Porins: Hydrophilic ß-lactams tend to gain access into the periplasmicspace using these watery funnels (i.e., E. coli organism has about100,000 of these porins). Porins are transmembrane proteins. Theycomplex together to form water-filled channels through which lowmolecular weight ( 600 daltons) hydrophilic substances readily diffuse.Such diffusion is passive and the concentration in the periplasmicspace can reach the level that prevails in the external environment aslong as there are no mechanisms to pump the drug back out or whichinactivate it.Phospholipids: This mode of entry is less common, but it seems toplay a significant part in the case of certain ß-lactams. Lipid bilayerssupport the diffusion of lipophilic compounds (certain ß-lactams arelipophilic). However, if the organism’s LPS (endotoxin) is branched(e.g., as in the case of Pseudomonas aeruginosa), such diffusion isblocked. This is called impermeability.2. Peptidoglycan entry3. Periplasmic space entry: ß-lactams may encounter ß-lactamases4. Cytoplasmic membrane PBP - boundNatural Resistance - Many Gram-negative organisms are naturally resistantto penicillin G and oxacillin because the drug is prevented from entering thecell by the LPS which blocks the porins. bioMérieux, Inc., Customer EducationMarch 200836
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall SynthesisInteractions between β-lactams and PBPsCytoplasmicmembranePBP PBP glycosyltransferases: generate peptidoglycan chains PBP transpeptidases: cross-link different chains PBP carboxypeptidases: regulate peptidoglycan productionAutolysins:Autolysins mediate chain maturation - activity inhibited byteichoic acids in the cell wall. PBPs are enzymes involved in peptidoglycan synthesis(glycosyltransferases, transpeptidases and carboxypeptidases) There are many kinds of PBP’s - some essential, some not They are numbered by molecular weight Inhibition of these enzymes by ß-lactams inhibits peptidoglycan synthesisand therefore stops cell growth (bacteriostatic activity) ß-lactams form stable complexes with PBPs Bind irreversibly to PBP by a covalent bond ß-lactams also have bactericidal activity. Although peptidoglycansynthesis is stopped, the autolysins remain active. Autolysin activity isprogressively potentiated. The peptidoglycan network begins to becomedisorganized and teichoic acid (which normally regulates autolysin activityby natural inhibition) tends to leak out. Without a peptidoglycan layer, the bacterium bursts and eventually all cellsdieNOTE: Ceftobiprole and Ceftaroline (the next generationcephalosporins) have the ability to inactivate PBP2a which is primarilyresponsible for oxacillin resistance in Staphylococci. bioMérieux, Inc., Customer EducationMarch 200837
Customer EducationAntibiotic Classification1. Inhibitors of Cell Wall Synthesisβ-lactamase and β-lactamsThe efficacy of the antibiotic hangs on 2 parameters: The rapidity of the drug entrance The rate of enzymatic hydrolysisPeriplasmic Space Entry The periplasmic space represents a “mine field” for ß-lactams due to thepresence of ß-lactamase enzymes (defense enzymes) ß-lactamases are found in all bacteria, although in variable amounts andwith varying levels of activity (they can even be found in wild-type E. colialthough at such a low concentration that their effect is insignificant). ß-lactamases hydrolyze the ß-lactam ring. The rate of this hydrolysisdepends on the rate on entry of the drug and the level of ß-lactamaseactivity. In many cases, the rate of entry is sufficient to guarantee a consistentlyhigh enough concentration of the drug to inte
Upon completion of this module you will be able to: Explain why susceptibility testing is done Define the terms, bacteriostatic and bactericidal Describe the functional antibiotic classification scheme and list the 5 main groups Name at least one antibiotic in each class Describe the structure of a Gram-positive and negative .
and the Core Elements of Antibiotic Stewardship for Nursing Homes (23). This 2016 report, Core Elements of Outpatient Antibiotic Stewardship, provides guidance for antibiotic stewardship in outpatient settings and is applicable to any entity interested in improving outpatient antibiotic prescribing and use.
R M AB ARP R R M APP B 3 Completeness of antibiotic prescribing documentation. Ongoing audits of antibiotic prescriptions for completeness of documentation, regardless of whether the antibiotic was initiated in the nursing home or at a transferring facility, should verify that the antibiotic prescribing
The four core elements of outpatient antibiotic stewardship are commitment, action for policy and practice, tracking and reporting, and education and expertise. Outpatient clinicians and facility leaders can commit to improving antibiotic prescribing and take action by implementing at least one policy or practice aimed at improving antibiotic
of all known ARGs in the full-microbial pan-genome is defined as the antibiotic resistome (132). What is most important conceptually about the antibiotic resistome is the potential accessibility of individual ARGs to all bacteria. In this review, we focus on our current knowledge of the evolution of antibiotic resistance in plant-pathogenic .
AirScan iR - Industrial Operation The AirScanTMiR has several modes of operation, including two normal run modes, two 4/20 mA loop check modes and five calibration modes. These will be explained in Operation, Section C, Modes of Operation. Modes are entered by properly activating pushbuttons located on the circuit board, shown in Figure 4.
classification has its own merits and demerits, but for the purpose of study the drugs are classified in the following different ways: Alphabetical classification Morphological classification Taxonomical classification Pharmacological classification Chemical classification
3. Severe onset (i.e. concurrent fever 39 /102.2 F) AND purulent nasal discharge for at least 3 days Mild-moderate symptoms AND Does not attend daycare AND No antibiotic treatment in past 30 days AND 2 years of age Mild-moderate symptoms AND Attends daycare OR Received antibiotic treatment in past 30 days OR 2 years of age Severe
2.15.20 Profit sharing transactions 28 2.15.21 Re-importation of goods after repair or processing abroad 29 2.15.22 Split shipments or split consignments 29 2.15.23 Sole distributors, concessionaires and agents 30 2.15.24 Tie-in sales 30 . Effective 24 January 2014 Valuation of Imports – External Directive SC-CR-A-03 Revision: 2 Page 3 of 52 2.15.25 Time element 30 2.15.26 Transfer pricing .
