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Antibiotic classification

The document discusses antibiotic classification and modes of action. It begins by explaining the objectives of the document, which are to explain antibiotic classification schemes, modes of action, and why susceptibility testing is performed. It then covers topics like the definition of antibiotics, sources of antibacterial agents, their role in inhibiting or destroying bacteria, and how they work through various mechanisms of action. The goal of susceptibility testing is outlined as providing guidance for appropriate therapy selection to help patients currently and in the future, as well as monitor resistance evolution. Interpretation of susceptibility test results is discussed alongside factors that can influence clinical outcomes.

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Customer Education Antibiotic Classification 1 © bioMérieux, Inc., Customer Education March 2008 Antibiotic ClassificationAntibiotic Classification andand Modes of ActionModes of Action Part # 60-00415-0
Customer Education Antibiotic Classification 2 © bioMérieux, Inc., Customer Education March 2008 bioMérieux, the blue logo and VITEK are used, pending and/or registered trademarks belonging 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.
Customer Education Antibiotic Classification 3 © bioMérieux, Inc., Customer Education March 2008 Module Objectives Antibiotic ClassificationAntibiotic Classification 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 cell • Explain the modes of action for the antibiotics in each of the five functional antibiotic classes • List examples of natural resistance in each of the five functional antibiotic classes • Explain why it is not necessary to perform susceptibility testing for certain organism / antibiotic combinations
Customer Education Antibiotic Classification 4 © bioMérieux, Inc., Customer Education March 2008 AntibioticsAntibiotics && Susceptibility TestingSusceptibility Testing Microbiologists work with antibiotics every day. Antimicrobial Susceptibility Testing (AST) is one of the primary functions of the 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.
Customer Education Antibiotic Classification 5 © bioMérieux, Inc., Customer Education March 2008 What is an Antibiotic?What is an Antibiotic? Antibiotic is a chemical substance produced by a microorganism that inhibits the growth of or kills other microorganisms. Antimicrobial agent is a chemical substance derived from a biological source or produced by chemical synthesis that kills or inhibits the growth of microorganisms. The noun “antibiotic” was first used in 1942 by Dr. Selman A. Waksman, soil microbiologist. Dr. Waksman and his colleagues discovered several actinomycetes derived antibiotics. The two terms are usually used synonymously and that practice will continue throughout this presentation. The word “antibiotic” will be used to describe: a chemical substance derivable from a microorganism or produced by chemical synthesis that kills or inhibits microorganisms and cures infections.
Customer Education Antibiotic Classification 6 © bioMérieux, Inc., Customer Education March 2008 Sources of Antibacterial AgentsSources of Antibacterial Agents • Natural - mainly fungal sources • Semi-synthetic - chemically-altered natural compound • Synthetic - chemically designed in the lab Toxicity Effectiveness Natural Semi-synthetic Synthetic • The original antibiotics were derived from fungal sources. These can be referred to as “natural” antibiotics • Organisms develop resistance faster to the natural antimicrobials because they have been pre-exposed to these compounds in nature. Natural antibiotics are often more toxic than synthetic antibiotics. • Benzylpenicillin and Gentamicin are natural antibiotics • Semi-synthetic drugs were developed to decrease toxicity and increase effectiveness • Ampicillin and Amikacin are semi-synthetic antibiotics • Synthetic drugs have an advantage that the bacteria are not exposed to the compounds until they are released. They are also designed to have even greater effectiveness and less toxicity. • Moxifloxacin and Norfloxacin are synthetic antibiotics • There is an inverse relationship between toxicity and effectiveness as you move from natural to synthetic antibiotics
Customer Education Antibiotic Classification 7 © bioMérieux, Inc., Customer Education March 2008 Role of AntibioticsRole of Antibiotics What is the role of antibiotics? • To inhibit multiplication Antibiotics have a bacteriostatic effect. At which drug concentration is the bacterial population inhibited? • Minimal Inhibitory Concentration = MIC Bacteriostatic = inhibits bacterial growth
Customer Education Antibiotic Classification 8 © bioMérieux, Inc., Customer Education March 2008 MICMIC –– Broth Dilution Reference TechniqueBroth Dilution Reference Technique Mueller Hinton 1 ml 1 ml 0 0.5 1 2 4 8 16 µg/ml 107 CFU 35°C - 16 - 20 h 0 0.5 1 2 MIC = 4 8 16 µg/ml 0 0.5 1 2 4 8 16 µg/ml Quantitative 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 of antibiotic in body fluids with the dosage given For treatment purposes, the dosage of antibiotic given should yield a peak body fluid concentration 3-5 times higher than the MIC or MIC x 4 = dosage to obtain peak achievable concentration
Customer Education Antibiotic Classification 9 © bioMérieux, Inc., Customer Education March 2008 Role of AntibioticsRole of Antibiotics What is the role of antibiotics? • To destroy the bacterial population Antibiotics have a bactericidal effect. At which drug concentration is the bacterial population killed? • Minimal Bactericidal Concentration = MBC Bactericidal = kills bacteria
Customer Education Antibiotic Classification 10 © bioMérieux, Inc., Customer Education March 2008 MBCMBC –– Reference TechniqueReference Technique 10 µl 0 µg/ml 4 µg/ml 8 µg/ml 16 µg/ml MBC = 16 µg/ml 0 0.5 1 2 MIC = 4 8 16 µg/ml Quantitative Measure • MBC = lowest concentration of antibiotic that kills bacteria
Customer Education Antibiotic Classification 11 © bioMérieux, Inc., Customer Education March 2008 Relationship of MIC/MBCRelationship of MIC/MBC MIC MBC Bactericidal MIC MBC Bacteriostatic 1 2 8 16 32 64 1284 1 2 8 16 32 64 128411 There is a much closer relationship between the MIC and MBC values for bactericidal drugs than for bacteriostatic drugs.
Customer Education Antibiotic Classification 12 © bioMérieux, Inc., Customer Education March 2008 How Do Antibiotics Work?How Do Antibiotics Work? Mechanisms of Action -Antibiotics operate by inhibiting crucial life sustaining processes in the organism: the synthesis of cell wall material the synthesis of DNA, RNA, ribosomes and proteins. Target –The target of the antibiotic should be selective to minimize toxicity…but all antibiotics are toxic to some degree! The targets of antibiotics should be selective to minimize toxicity. • Selective Toxicity Harm the bacteria, not the host
Customer Education Antibiotic Classification 13 © bioMérieux, Inc., Customer Education March 2008 • Help patients today - To provide guidance to the physician in selection of antimicrobial therapy with the expectation of optimizing outcome • Help patients tomorrow - Build an antibiogram to guide physicians in selecting empiric therapy for future patients with the expectation of optimizing outcome • Help patients next decade - Drive new drug research - Monitor the evolution of resistance Why Do Susceptibility Testing?Why Do Susceptibility Testing? We do this testing: • To provide a guide for therapy • Allows selection of the most appropriate agent Least expensive Narrowest spectrum Most effective • To monitor the evolution of resistance Antibiotic 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
Customer Education Antibiotic Classification 14 © bioMérieux, Inc., Customer Education March 2008 Why Do Antimicrobials Fail?Why Do Antimicrobials Fail? In Vitro Testing MIC & S/R Host Factors Immune System Underlying Diseases Barrier Status Foreign Bodies Site of Infection CNS Intravascular Pulmonary Surgical Intervention Antibiotic Properties PK and PD Metabolism & Elimination Tissue Penetration Adverse Event Profile Pathogen Species Virulence Factors Resistance Mechanisms There are many possible reasons antimicrobials may fail. Selection of the appropriate antibiotic depends on: knowledge of organism’s natural resistance pharmacological properties of the antibiotic toxicity, binding, distribution, absorption achievable levels in blood, urine previous experience with same species nature of patients underlying pathology patient’s immune status Susceptibility testing focuses primarily on the interaction of antimicrobial agents, the organisms and their resistance mechanisms.
Customer Education Antibiotic Classification 15 © bioMérieux, Inc., Customer Education March 2008 • MICs are not physical measurements • There are many factors that play a role in determining clinical outcome • Susceptibility in vitro does not uniformly predict clinical success in vivo • Resistance will often, but not always, correlate with treatment failure Interpreting Susceptibility ResultsInterpreting Susceptibility Results Susceptibility tests are essentially artificial measurements. in vitro response approximate range of effective inhibitory action possible error equivalent to one tube dilution The only true measure of bacterial response to an antibiotic is the clinical response of the patient. outcome or in vivo response One of the real values of AST is to predict resistance S = success likely, but no guarantee R = correlates well with treatment failure Is Resistance Testing a better name for what we do than Susceptibility Testing?
Customer Education Antibiotic Classification 16 © bioMérieux, Inc., Customer Education March 2008 What is the Ideal Antibacterial?What is the Ideal Antibacterial? • Selective target – target unique • Bactericidal – kills • Narrow spectrum – does not kill normal flora • High therapeutic index – ratio of toxic level to therapeutic level • Few adverse reactions – toxicity, allergy • Various routes of administration – IV, IM, oral • Good absorption • Good distribution to site of infection • Emergence of resistance is slow
Customer Education Antibiotic Classification 17 © bioMérieux, Inc., Customer Education March 2008 Antibiotic ClassificationAntibiotic Classification andand Modes of ActionModes of Action In the AES Knowledge Base, phenotypes are organized by drug class. The AES decision process attempts to identify a phenotype for each drug class tested. In order to understand and use the software effectively, it is 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 antibiotics and their modes of action.
Customer Education Antibiotic Classification 18 © bioMérieux, Inc., Customer Education March 2008 Antibiotic ClassificationAntibiotic Classification Grouped by Structure and Function Five functional groups cover most antibiotics 1. Inhibitors of cell wall synthesis 2. Inhibitors of protein synthesis 3. Inhibitors of membrane function 4. Anti-metabolites 5. Inhibitors of nucleic acid synthesis Antibiotics are usually classified based on their structure and/or function. 1. Structure - molecular structure. ß-Lactams - Beta-lactam ring Aminoglycosides - vary only by side chains attached to basic structure 2. Function - how the drug works, its mode of action. 5 functional groups These are all components or functions necessary for bacterial growth Targets for antibiotics In these discussions, we will primarily use the functional classification, but will point out where structural similarities also exist.
Customer Education Antibiotic Classification 19 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins Inhibitors of Cell Wall Synthesis Beta-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
Customer Education Antibiotic Classification 20 © bioMérieux, Inc., Customer Education March 2008 R’--CONH COOH OO B-lactam ring Beta-lactams 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-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-produced enzymes called beta-lactamases Some more common Beta-lactamase enzymes include: Penicillinases Cephalosporinases ESBL’s Cephamycinases Carbapenemases
Customer Education Antibiotic Classification 21 © bioMérieux, Inc., Customer Education March 2008 Beta-lactams (Penicillins) International Common Name Penicillins (pen G)* Penicillin G Penicillinase-stable penicillins (pen M) Oxacillin Methicillin Aminopenicillins* (pen A) Ampicillin Amoxicillin Carboxypenicillins* (pen C) Ticarcillin Ureidopenicillins* (pen U) Piperacillin β-lactam / β-lactamase inhibitor combinations Amoxicillin + clavulanic acid Ampicillin + sulbactam Ticarcillin + clavulanic acid Piperacillin + tazobactam Amidinopenicillin Mecillinam * Penicillinase labile: hydrolyzed by staphylococcal penicillinase 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-lactams - Penicillins Spectrum of Action 1. Natural penicillins • Penicillin G: Active against Gram-positive organisms that do not produce beta-lactamases, Neisseria and some anaerobes 2. Penicillinase-resistant penicillins • Penicillin M: Active against penicillinase-producing Staphylococci 3. Extended-spectrum penicillins • Aminopenicillins: Slightly less active than Penicillin G against Pneumococci, Streptococci and Meningococci, but active against many strains of Salmonella, Shigella, and P.mirabilis, H.influenzae) • Carboxypenicillins: More stable than aminopenicillins to hydrolysis by the ß-lactamases of most Enterobacteriaceae and Pseudomonas aeruginosa • Ureidopenicillins: Greater activity than carboxypenicillins against Gram-positives, enterics and P.aeruginosa 4. Co-Drugs (Beta-lactam + beta-lactamase inhibitor) • ß-lactamase inhibitors (BLI) combinations: Additional activity against beta-lactamase producing organisms, including Staphylococcus spp., some enterics, H.influenzae and Bacterioides spp 5. Amidinopenicillins • Mecillinam: Restricted use to urinary infection with E.coli. Active against penicillinase and low-level cephalosporinase.
Customer Education Antibiotic Classification 22 © bioMérieux, Inc., Customer Education March 2008 These enzymatic inhibitors have weak or poor antibacterial activity alone, but a strong affinity for β- lactamases: Clavulanic Acid Sulbactam Tazobactam Beta-lactamase Inhibitors (BLI) Aim: to block β-lactamases Combination β-lactams - β-lactamase inhibitor: Amoxicillin + Clavulanic Acid Ampicillin + Sulbactam Ticarcillin + Clavulanic Acid Piperacillin + Tazobactam Never Alone! 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactamase inhibitors (BLI) have a beta(ß)-lactam ring, but have weak or poor 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 penicillinase Penicillinase of K. pneumoniae ESBL (to a greater or lesser degree) - if the penicillinase is being overproduced, the inhibitor effect may be diluted (Inoculum Effect) In the case of penicillinase production, where: Amoxicillin R Amoxicillin + Clavulanic acid usually S • Inhibitors are active against all penicillinase (PASE and ESBL) but never on cephalosporinase NEW ISSUE - BLI can act as inducers and actually stimulate enzyme (beta- lactamase) production. It is possible to see the following: Pseudo monas Ticarcillin = S Ticarcillin/Clavulanic = R Enterobacteriaceae Piperacillin = S Piperacillin/Tazobactam = R
Customer Education Antibiotic Classification 23 © bioMérieux, Inc., Customer Education March 2008 Beta-lactams (Cephems) International Common Name 1st Generation Cephalosporins C1G Cephalothin Cefazolin 2nd Generation Cephalosporins C2G Cefuroxime Cefamandole Cephamycin (new C2G) Cefoxitin Cefotetan – removed 3rd Generation Cephalosporins C3G Cefotaxime Ceftazidime Ceftriaxone 4th Generation Cephalosporins C4G Cefepime Oral C3G Cefixime Cefpodoxime Next Generation Cephalosporins Ceftobiprole Ceftaroline 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-lactams - Cephems Spectrum of Action • 1st generation cephalosporins (C1G): Narrow spectrum; good Gram-positive activity and relatively modest Gram-negative activity. Inactivated by Gram-neg beta-lactamases (Derived from Cephalosporium acremonium). • 2nd generation cephalosporins (C2G): Better Gram-negative coverage (more beta-lactamase stability), but less Staphylococcal activity. • Cephamycins: Remain susceptible in presence of Extended Spectrum ß-lactamase (ESBL) because they are not a substrate for the enzyme. Can be used as an indicator for ESBL (Derived from Streptomyces lactamdurans). - AstraZeneca discontinued its Cefotetan products in June 2006. Currently available from other manufacturers. • 3rd generation cephalosporins (C3G): Wider spectrum of action when compared to C1G and C2G. Less active than narrow spectrum agents against Gram-positive cocci, but much more active against the Enterobacteriaceae and Pseudomonas aeruginosa (better beta- lactamase stability). • 4th generation cephalosporins (C4G): Broadest spectrum of action. Active against high level cephalosporinases of Enterobacteriaceae and Pseudomonas aeruginosa (not usually used with ESBL producing organisms). None have activity to MRSA or Enterococcus spp.
Customer Education Antibiotic Classification 24 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis New Anti- MRSA Cephalosporins New ! Ceftobiprole Ceftaroline A next generation cephalosporins? Inhibitors of Cell Wall Synthesis Beta-lactams - Cephems - Ceftobiprole Spectrum of Action • Next generation cephalosporin: Broad spectrum; active against the 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 approved • Has been added to CLSI® M100-S18, 2008 listing of antibiotics • No CLSI breakpoints • Once FDA approved, can no longer say if Staph is resistant to Oxacillin, report all beta-lactams as resistant.
Customer Education Antibiotic Classification 25 © bioMérieux, Inc., Customer Education March 2008 Beta-lactams International Common Name Monobactams Aztreonam Penems Carbapenems Penems Imipenem Meropenem Ertapenem Doripenem Faropenem 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-lactams: Monobactams Spectrum of Action • Aztreonam: Gram-negatives (Enterobacteriaceae and Pseudomonas). Not hydrolyzed by most commonly occurring plasmid and chromosomally mediated ß-lactamases, and does not induce the production of these enzymes. Beta-lactams: Penems Slightly different structure than the other ß-lactams, make the Penems much more resistant to beta-lactamase hydrolysis. Spectrum of Action • Carbapenems: ß-lactams with a broad spectrum of action. Gram- positives, except MRSA. Gram-negatives, Ps. aeruginosa (except Ertapenem) and anaerobes. Very efficient against high level cephalosporinase and ESBL. Wide diffusion in the body, especially in the cerebrospinal fluid. Doripenem (new) - Broad spectrum. Particularly good for Pseudomonas and other non-fermenters. • Penem: Oral. Primarily for respiratory tract infections. Poor activity with Serratia, Pseudomonas, Stenotrophomonas. Faropenem not yet FDA approved.
Customer Education Antibiotic Classification 26 © bioMérieux, Inc., Customer Education March 2008 From… the Bug To… the Drug Antibiotic Modes of ActionAntibiotic Modes of Action • Before we can understand the antibiotic modes of action, we need to review the structure and physiology of the bacterial cell
Customer Education Antibiotic Classification 27 © bioMérieux, Inc., Customer Education March 2008 Multiplication of BacteriaMultiplication of Bacteria • It is important to understand the growth cycle and physiology of bacteria to appreciate how it influences antimicrobial action • Bacteria are all around us. Given good growing conditions, a bacterium will divide. • A new cell wall forms at the center and the "bug" splits into two daughter cells, both of which carry the same genetic information as the parent • If the environment is perfect, the two daughter cells can split into four within 20 minutes • 1, 2, 4, 8, 16, 32, 64... • Typical bacterial growth cycle includes: Lag phase Exponential (log) phase Stationary phase Death phase
Customer Education Antibiotic Classification 28 © bioMérieux, Inc., Customer Education March 2008 Bacterial StructureBacterial Structure 1 µ 1 µ 2.5 µ Bacterial wall (peptidoglycan) Cytoplasm Cytoplasmic membrane Ribosomes DNA Typical Structure of a Bacterial Cell (from inside to outside) DNA bacterial genetic material Ribosomes (protein-making factories), energy-generating systems, digestive system, and everything else are located in the cytoplasm. Cytoplasmic Membrane or Inner Membrane a. Consists of phospholipids and other membrane proteins b. Semi-permeable c. Regulates pH, osmotic pressure and availability of essential nutrients Bacterial Cell Wall or Peptidoglycan a. Cross-linked mesh that gives a cell its shape, strength and osmotic stability, a protective suit of armour b. Porous up to 100,000 Da The outer layer of lipopolysaccharide (LPS) and phospholipid material helps protect 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
Customer Education Antibiotic Classification 29 © bioMérieux, Inc., Customer Education March 2008 GramGram--Positive Cell StructurePositive Cell Structure Teichoic acids Peptido - glycan Inner membrane PBP Protein Gram-Positive Cell Structure • The Gram-positive cell wall is thick and consists of 90% peptidoglycan • Teichoic acids link various layers of peptidoglycan together. Teichoic acids 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 involved in respiration and transmembrane transport) • extrinsic proteins which are hydrophilic • Penicillin-Binding Proteins (PBPs): periplasmic space proteins involved in peptidoglycan synthesis (glycosyltransferase, transpeptidase and carboxypeptidase activities)
Customer Education Antibiotic Classification 30 © bioMérieux, Inc., Customer Education March 2008 GramGram--Positive Cell StructurePositive Cell Structure
Customer Education Antibiotic Classification 31 © bioMérieux, Inc., Customer Education March 2008 PBP Protein Peptidoglycan Cytoplasmic membrane Outer membrane Porin Protein β−lactamase Endotoxin = LPS GramGram--Negative Cell StructureNegative Cell Structure Gram-Negative Cell Structure • The outer membrane is made up of: • phospholipids • endotoxin or lipopolysaccharide (LPS) - plays an important role in the antibiotic entry into the cell • proteins including the porins (complexes of three proteins) form aqueous channels that provide a route across the outer membrane for all the water-soluble compounds needed by the bacterium • 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 involved in respiration and transmembrane transport) • extrinsic proteins which are hydrophilic • Penicillin-Binding Proteins (PBPs) - periplasmic space proteins involved in peptidoglycan synthesis (glycosyltransferase, transpeptidase and carboxypeptidase activities)
Customer Education Antibiotic Classification 32 © bioMérieux, Inc., Customer Education March 2008 GramGram--Negative Cell Wall StructureNegative Cell Wall Structure
Customer Education Antibiotic Classification 33 © bioMérieux, Inc., Customer Education March 2008 glyD-ala D-ala gly gly gly gly D-ala N-acetyl m ura m ic acid N-acetyl glucosam ine L-ala D-gluNH2 L-lys D-ala L-lys D-gluNH2 L-ala N-acetyl glucosa m ine N-acetyl m uram ic acid Peptidoglycan StructurePeptidoglycan Structure Peptidoglycan • is a very high molecular weight polymer composed of many identical subunits • is a 3-D polymeric macromolecule • determines cell shape and prevents osmotic lysis, porous up to 100,000 daltons • contains N-acetylglucosamine (NAG), N-acetylmuramic acid (NAMA), and several different amino acids • involves 2 types of covalent chemical bonds: 1. B-1, 4 glycosidic bond between hexose sugars 2. Petide bond between amino acids • In Gram-positive bacteria, peptidoglycan accounts for as much as 90% of the cell wall (approximately 40 layers), with the rest consisting of the teichoic acids. • Gram-negative bacteria have a thin peptidoglycan layer (accounting for only 5-20% of the cell wall). However, in addition to the cytoplasmic membrane, they have a second phospholipid bilayer external to the peptidoglycan called the outer membrane.
Customer Education Antibiotic Classification 34 © bioMérieux, Inc., Customer Education March 2008 Mode of ActionMode of Action ofof BetaBeta--lactamslactams 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Humans have no cell wall (no peptioglycan), so this is a good selective target for the antibiotic.
Customer Education Antibiotic Classification 35 © bioMérieux, Inc., Customer Education March 2008 Entry of β-lactams in Gram-Positive Bacteria Peptido - glycan Cytoplasmic membrane Protein PBP β-lactam 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams are mostly water soluble. Differences in cell wall composition (more or less lipids) between different bacterial species partially account for their differential susceptibility to ß- lactams. The target of the ß-lactam antibiotics for all bacteria is the PBP (Penicillin Binding Protein) in the cytoplasmic membrane. Gram-Positives: In Gram-positive bacteria, there is no barrier to the entry of ß-lactams antibiotics. The peptidogylcan layers allow the diffusion of small molecules. However, ß-lactams cross the membranes with great difficulty due to high lipid content but, since their target PBP’s are found on the outer surface of the cytoplasmic membrane, they only have to cross the cell wall. Natural Resistance Enterococcus - PBP’s are different from other Gram-positives (also higher lipid content in cell wall), which causes a low level resistance to penicillins and resistance to C1G.
Customer Education Antibiotic Classification 36 © bioMérieux, Inc., Customer Education March 2008 Endotoxin = LPS Outer membrane Porin Peptidoglycan Cytoplasmic membrane PBP Protein β−lactamase 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Entry of β-lactams in Gram-Negative Bacteria Gram-Negatives: 1. Outer membrane entry through the: Porins: Hydrophilic ß-lactams tend to gain access into the periplasmic space using these watery funnels (i.e., E. coli organism has about 100,000 of these porins). Porins are transmembrane proteins. They complex together to form water-filled channels through which low molecular weight (<600 daltons) hydrophilic substances readily diffuse. Such diffusion is passive and the concentration in the periplasmic space can reach the level that prevails in the external environment as long as there are no mechanisms to pump the drug back out or which inactivate it. Phospholipids: This mode of entry is less common, but it seems to play a significant part in the case of certain ß-lactams. Lipid bilayers support the diffusion of lipophilic compounds (certain ß-lactams are lipophilic). However, if the organism’s LPS (endotoxin) is branched (e.g., as in the case of Pseudomonas aeruginosa), such diffusion is blocked. This is called impermeability. 2. Peptidoglycan entry 3. Periplasmic space entry: ß-lactams may encounter ß-lactamases 4. Cytoplasmic membrane PBP - bound Natural Resistance - Many Gram-negative organisms are naturally resistant to penicillin G and oxacillin because the drug is prevented from entering the cell by the LPS which blocks the porins.
Customer Education Antibiotic Classification 37 © bioMérieux, Inc., Customer Education March 2008 Cytoplasmic membrane PBP ⌦PBP = glycosyltransferases: generate peptidoglycan chains ⌦PBP = transpeptidases: cross-link different chains ⌦PBP = carboxypeptidases: regulate peptidoglycan production AutolysinsAutolysins: mediate chain maturation - activity inhibited by teichoic acidsteichoic acids in the cell wall. 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Interactions between β-lactams and PBPs • 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 synthesis and 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 peptidoglycan synthesis is stopped, the autolysins remain active. Autolysin activity is progressively potentiated. The peptidoglycan network begins to become disorganized and teichoic acid (which normally regulates autolysin activity by natural inhibition) tends to leak out. • Without a peptidoglycan layer, the bacterium bursts and eventually all cells die NOTE: Ceftobiprole and Ceftaroline (the next generation cephalosporins) have the ability to inactivate PBP2a which is primarily responsible for oxacillin resistance in Staphylococci.
Customer Education Antibiotic Classification 38 © bioMérieux, Inc., Customer Education March 2008 The efficacy of the antibiotic hangs on 2 parameters: •The rapidity of the drug entrance •The rate of enzymatic hydrolysis 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis β-lactamase and β-lactams Periplasmic Space Entry • The periplasmic space represents a “mine field” for ß-lactams due to the presence of ß-lactamase enzymes (defense enzymes) • ß-lactamases are found in all bacteria, although in variable amounts and with varying levels of activity (they can even be found in wild-type E. coli although at such a low concentration that their effect is insignificant). • ß-lactamases hydrolyze the ß-lactam ring. The rate of this hydrolysis depends on the rate on entry of the drug and the level of ß-lactamase activity. • In many cases, the rate of entry is sufficient to guarantee a consistently high enough concentration of the drug to interact with the PBP’s, even if a certain proportion is constantly being enzymatically hydrolyzed.
Customer Education Antibiotic Classification 39 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins Inhibitors of Cell Wall Synthesis Glycopeptides • The term ‘Glycopeptide’ included two main compounds with very similar structures and modes of action: Vancomycin and Teicoplanin • Teicoplanin not FDA approved in the U.S. • Both are of high molecular weight (1500-2000 daltons) • Glycopeptides have a complex chemical structure • Inhibit cell wall synthesis at a site different than the beta-lactams • All are bactericidal • All used for Gram-positive infections. (No Gram-negative activity) • Pharmaceutical research and development has been very active in this area recently resulting in new antimicrobials and classification
Customer Education Antibiotic Classification 40 © bioMérieux, Inc., Customer Education March 2008 Glycopeptide: Vancomycin Lipoglycopeptide: Dalbavancin Oritavancin Telavancin Teicoplanin Glycopeptides 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis New Inhibitors of Cell Wall Synthesis Glycopeptides: Glycopeptide Spectrum of Action • Vancomycin: MRSA (Methicillin Resistant Staph. aureus), C.difficile, Streptococci including Strep pneumoniae. Alternative to Penicillin G in serious infections. Good diffusion in all tissues (except CSF). High toxic effects: ears and kidneys. Glycopeptides: Lipoglycopeptide Spectrum of Action • Dalbavancin: (Vicuron) 2nd generation lipoglycopeptide. Bactericidal for MRSA and MRSE.1/week IV dosing – long acting. Not yet FDA approved. • Oritavancin: (Targanta) 2nd generation glycopeptide. Actually a lipoglycopeptide. IV – once per day dosing. For skin and skin structure infections. Activity similar to Vancomycin – better for Staphyloccus and Enterococcus. Not yet FDA approved. Bactericidal • Telavancin: (Theravance) bactericidal for all Gram-positive. Inhibits cell wall synthesis and inhibits bacterial phospholipid membrane synthesis. Single dose injectable. Not yet FDA approved. • Teicoplanin: Not FDA approved in the US. Widespread use in Europe.
Customer Education Antibiotic Classification 41 © bioMérieux, Inc., Customer Education March 2008 Mode of Action of Glycopeptides Vancomycin 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis
Customer Education Antibiotic Classification 42 © bioMérieux, Inc., Customer Education March 2008 Peptidoglycan Cytoplasmic membrane Protein PBP Glycopeptide 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Entry of Glycopeptides in Gram-Positive Bacteria In Gram-Positives: The drugs enter without any problem because peptidoglycan does not act as a barrier for the diffusion of these molecules.
Customer Education Antibiotic Classification 43 © bioMérieux, Inc., Customer Education March 2008 Outer membrane Porin Peptido - glycan Cytoplasmic membrane PBP Glycopeptide 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Entry of Glycopeptides in Gram-Negative Bacteria In Gram-Negatives: Glycopeptides are of high molecular weight (1500-2000 daltons), stopping them from passing through the porins of gram-negative bacteria (i.e., glycopeptides have no activity against Gram-negatives). Gram-negatives are naturally resistant. Use this property in Microbiology in several ways: Check Gram reaction - growth around Vancomycin disk would indicate a Gram-negative organism (resistant to Vancomycin). KVC disks/media - for anaerobe ID’s.
Customer Education Antibiotic Classification 44 © bioMérieux, Inc., Customer Education March 2008 L-ala N-acetyl glucosamine L-lys D-ala D-ala Glycopeptide EnzymesEnzymes N-acetyl muramic acid D-gluNH2 gly gly gly gly gly PentaglycinePentaglycine 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Mode of Action of Glycopeptides • Glycopeptides inhibit the final cell wall stage of the peptidoglycan synthesis process • The ‘pocket-shaped’ glycopeptide binds the D-ala-D-ala terminal of the basic sub-unit theoretically waiting to be incorporated into the growing peptidoglycan • Because it is so bulky, the glycopeptide inhibits the action of the glycosyltransferases and transpeptidases (which act as a kind of “cement”) - blocks pentaglycine from joining molecules, thereby blocking peptidoglycan growth. • Glycopeptides are bactericidal, but slow-acting
Customer Education Antibiotic Classification 45 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins Inhibitors of Cell Wall Synthesis Fosfomycins Spectrum of Action Fosfomycin: Acts to inhibit cell wall synthesis at a stage earlier than the penicillins or cephalosporins. FDA approved 1996. While it is a broad spectrum agent, CLSI ® only provides breakpoints for urinary tract infections due to E.coli and E.faecalis. Reference Method: Preferred reference method is agar dilution. Broth dilution should not be performed. Mode of Action: Inhibits the first step of the peptidoglycan synthesis process
Customer Education Antibiotic Classification 46 © bioMérieux, Inc., Customer Education March 2008 Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis Aminoglycosides - Gentamicin (Bactericidal) Tobramycin Amikacin MLSK - Erythromycin (Bacteriostatic) Clindamycin Quinupristin-Dalfopristin (Synercid) Clarithromycin Azithromycin Telithromycin Tetracyclines - Tetracycline (Bacteriostatic) Doxycycline Minocycline Glycylcyclines - Tigecycline Phenocols - Chloramphenicol (Bacteriostatic) Oxazolidinones - Linezolid (Bactericidal for Streptococci; Bacteriostatic for Enterococcus and Staphylococci) Ansamycins - Rifampin (Bacteriostatic or Bactericidal depending on organism and concentration)
Customer Education Antibiotic Classification 47 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Aminoglycosides • Humans do synthesize proteins, but at a much slower rate than bacteria • Drug can act on bacteria before it does damage to man • But, since it is a common process, we do tend to see more toxic side effects • Need to do therapeutic drug monitoring • All bactericidal
Customer Education Antibiotic Classification 48 © bioMérieux, Inc., Customer Education March 2008 O O O O OH OH OH 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides Inhibitors of Protein Synthesis Aminoglycosides: • Related in structure and function • Drugs differ based on location of radical groups attached to the 3 ring basic structure
Customer Education Antibiotic Classification 49 © bioMérieux, Inc., Customer Education March 2008 AMINOGLYCOSIDES International Common Name Amikacin Gentamicin Tobramycin Streptomycin Kanamycin Netilmicin 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides Inhibitors of Protein Synthesis Aminoglycosides: Spectrum of Action • Rapid bactericidal effect • Broad spectrum of action Gram-negative nosocomial infections and severe systemic infections Gram-positives, except Streptococus and Enterococcus. Must combine an aminoglycoside (Gentamicin or Streptomycin) with a penicillin, ampicillin or vancomycin for severe enterococcal infections (Synergy Testing). • In serious infection, used in association with beta-lactams or fluoroquinolones • Kanamycin develops resistance quickly • Hospital use only • Nephrotoxic and toxic for ears Drug Dosage Adjustment: Monitoring aminoglycosides is mandatory. It is important to control the serum level for peak and trough to ensure the bactericidal effect and avoid side effects.
Customer Education Antibiotic Classification 50 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis O O O O OH OH OH Mode of ActionMode of Action ofof AminoglycosidesAminoglycosides
Customer Education Antibiotic Classification 51 © bioMérieux, Inc., Customer Education March 2008 Protein SynthesisProtein Synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis A quick review of protein synthesis before we begin.
Customer Education Antibiotic Classification 52 © bioMérieux, Inc., Customer Education March 2008 Protein Synthesis Proteins are made up of at least 20 different amino acids Thousands of different proteins exist, each with its own function (enzymes, etc.). Each protein is manufactured in the cell using a code contained in the DNADNA. AA AAAA AA AA AAAA AA 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis • The code for the 20 essential amino acids consists of at least a 3-base set (triplet) of the 4 bases • If one considers the possibilities of arranging four things 3 at a time (4X4X4), we get 64 possible code words, or codons (a 3-base sequence on the mRNA that codes for either a specific amino acid or a control sequence).
Customer Education Antibiotic Classification 53 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Protein Synthesis Pathway • Proteins are manufactured in the cell using a code in the DNA • DNA is transcribed into RNA by an enzyme called RNA polymerase • The RNA strand is translated into proteins by the ribosomes
Customer Education Antibiotic Classification 54 © bioMérieux, Inc., Customer Education March 2008 50s subunit 30s subunit Protein RNA 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Protein Synthesis Role of Ribosome • Each ribosome consists of one small sub-unit (30S) and a larger one (50S) • The ribosome crawls along the messenger-RNA molecule translating the code and assembling the amino acids in the correct order before chemically joining them to create the protein
Customer Education Antibiotic Classification 55 © bioMérieux, Inc., Customer Education March 2008 - Outer Membrane Peptidoglycan Cytoplasmic Membrane Aminoglycoside Respiratory Enzymes + ++ - -- - - - -- 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Entry of Aminoglycosides Aminoglycoside Mode of Action Target = Ribosome in cytoplasm 1. Outer Membrane entry: Aminoglycosides are positively charged molecules which means they rapidly enter bacteria (negatively charged) since the two charges attract each other. The negative charge of bacteria is due to LPS in the outer membrane and the peptidoglycan (notably the teichoic acid). 2. Cytoplasmic Membrane entry: The drugs cross the cytoplasmic membrane via respiratory enzymes (involved in aerobic respiration). This is why bacteria without respiratory enzymes (strict anaerobes or facultative anaerobes like streptococci) are naturally resistant to aminoglycosides.
Customer Education Antibiotic Classification 56 © bioMérieux, Inc., Customer Education March 2008 Ribosome Abnormal protein RNA + aminoglycoside 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Mode of Action - Aminoglycosides Aminoglycosides bind to the RNA of the 30S ribosomal sub-unit. The resulting change in ribosome structure affects all stages of normal protein synthesis. • Initiation step of translation • Blocks elongation of peptide bond formation • Release of incomplete, toxic proteins Translational errors are frequent and many non-functional or toxic proteins are produced. The incorporation of such abnormal proteins into the cytoplasmic membrane compromises its function. The bactericidal activity of aminoglycosides ultimately stops protein synthesis and dramatically damages the cytoplasmic membrane.
Customer Education Antibiotic Classification 57 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis MLSK: (Macrolides, Lincosamides, Streptogramins, Ketolides) Bacteriostatic Their spectrum of activity is limited to Gram-positive cocci such as Streptococci and Staphylococci. These antibiotics are also active against anaerobes.
Customer Education Antibiotic Classification 58 © bioMérieux, Inc., Customer Education March 2008 MLSK Erythromycin Clindamycin Quinupristin-Dalfopristin 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Telithromycin Inhibitors of Protein Synthesis MLSK: (Macrolides, Lincosamides, Streptogramins, Ketolides) Four different classes of antibiotics which are unrelated in terms of structure but which have a similar mode of action and spectrum of activity.
Customer Education Antibiotic Classification 59 © bioMérieux, Inc., Customer Education March 2008 Macrolides, Lincosamides, Streptogramins, Ketolides MLSK International Common Name Macrolides Erythromycin Lincosamides Lincomycin Clindamycin Streptogramins Quinupristin / Dalfopristin Pristinamycin Ketolides Telithromycin NEW 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis Spectrum of Action Macrolides: Respiratory infections due to S. pneumoniae and S. pyogenes, Mycoplasma, Legionella, less serious Staphylococcal infections. Lincosamides: Gram-positive skin infections and anaerobe infections. Oral administration appropriate for out patient settings. Streptogramins: Quinupristin/Dalfopristin (Synercid): consists of an A and B component (Synergistic). A - prevents peptide bond formation and changes the ribosome to attract the B component. B - causes early release of incomplete peptide chains. Used for E. faecalis (VRE) and MRSA. Ketolides: Telithromycin: Represents a novel class that has received much attention recently due to their excellent activity against resistant organisms. Ketolides are semi-synthetic derivatives of erythromycin. FDA approved for bronchitis, sinusitis, community acquired pneumonia due to S.pneumoniae (including Macrolide Resistant strains), H. influenza, M.catarrhalis, S.aureus (sinusitis), M.pneumoniae, and C.pneumoniae Side effects – possible liver damage.
Customer Education Antibiotic Classification 60 © bioMérieux, Inc., Customer Education March 2008 Mode of Action of MLSK Erythromycin Clindamycin Quinupristin-Dalfopristin 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Telithromycin
Customer Education Antibiotic Classification 61 © bioMérieux, Inc., Customer Education March 2008 Peptidoglycan Cytoplasmic Membrane Protein PBP MLSK 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Entry of MLSK in Gram-Positive Bacteria The drugs enter a Gram-positive cell without any problem because peptidoglycan does not act as a barrier for the diffusion of these molecules nor does the cytoplasmic membrane. Target = Ribosome in cytoplasm
Customer Education Antibiotic Classification 62 © bioMérieux, Inc., Customer Education March 2008 Endotoxin = LPS Outer Membrane Porin Peptido - glycan Cytoplasmic Membrane PBP β-lactamase MLSK 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Entry of MLSK in Gram-Negative Bacteria • In Gram-negative bacteria there is no entry because MLSK are lipophilic molecules. They cannot cross the outer membrane which is hydrophilic. “Oil and water don’t mix”. • MLSK are also large molecules that cannot pass through the porins (which are also aqueous channels) – impermeability. • Most Gram-negatives are naturally resistant to MLSK
Customer Education Antibiotic Classification 63 © bioMérieux, Inc., Customer Education March 2008 Polypeptide release MLSK binds Peptide bonds Free amino acids Peptide bond initiation Translation: Initiation Elongation Termination 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Mode of Action - The MLSK Group • Antibiotics in the MLSK group are structurally distinct but have a similar mode of action by binding the 50S ribosomal subunit • During translation, it blocks the initiation step, elongation step or peptide release step of protein synthesis • Unfinished or toxic protein is released
Customer Education Antibiotic Classification 64 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins NEW Inhibitors of Protein Synthesis Tetracyclines: • Bacteriostatic • Chlortetracycline – 1948, the original tetracycline derived from a Streptomyces spp Glyclycyclines: • New class • Developed to overcome some of the more common tetracycline resistance mechanisms • Bacteriostatic • Broad spectrum
Customer Education Antibiotic Classification 65 © bioMérieux, Inc., Customer Education March 2008 Tetracyclines International Common Name Glycylcyclines Tetracycline Minocycline Doxycycline Tigecycline Tetracyclines Glycylcyclines 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis Tetracyclines: Spectrum of Action: Broad spectrum, but resistance is common which limits its use. Primarily for treatment of genital infections (chlamydiae) and atypicals (Rickettsiae, Mycoplasma). Growth promotor in animal husbandry. Toxicity: Diffuse well in cells and bones. Not recommended for pregnant women and children (less than 2 years old) because of the toxicity on bones and teeth of the fetus. Tetracycline = Short acting Minocycline and Doxycycline = Long acting Minocycline and Doxycycline are more active than Tetracycline. if Tetra = S, then Mino and Doxy = S if Tetra = R, must test Mino and Doxy (may be S) Glycylcyclines: Tigecycline Spectrum of Action: Same as the tetracyclines; may have activity against multi-drug resistant organisms. Derivative of Minocycline. (VT2 - available for Gram Negs. Must add breakpoints in 2.01 PC software. Breakpoints are included in 3.01 PC software. FDA Gram-negative breakpoints = 2/4/8.)
Customer Education Antibiotic Classification 66 © bioMérieux, Inc., Customer Education March 2008 Mode of Action Effect Tetracyclines Irreversibly binds to the 30S ribosomal sub-unit Inhibits elongation step of protein synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Mode of Action - Tetracycline Tetracycline exists as a mixture of two forms - lipophillic and hydrophillic. • Helps the antibiotic gain entry into the Gram-pos and neg cell • Once inside the cell it complexes with Mg++ ions, making the molecule bigger and trapping it inside the bacterial cell • It can then go on to reach it’s target - the 30s ribosome • There it inhibits the elongation step of protein synthesis Gram-positives have no natural resistance to the tetracyclines. Of the Gram-negative organisms only Proteus mirabilis is naturally resistant.
Customer Education Antibiotic Classification 67 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis Phenicols: • Bacteriostatic • Broad spectrum
Customer Education Antibiotic Classification 68 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Phenicols Chloramphenicol Inhibitors of Protein Synthesis Phenicols: Chloramphenicol Spectrum of Action: Very active against many Gram-positive and Gram-negative bacteria, Chlamydia, Mycoplasma and Rickettsiae. Restricted use for extra-intestinal severe salmonella infection. Empiric treatment of meningitis, crosses blood/brain barrier well. Toxicity: High toxicity, causes bone marrow aplasia and other hematological abnormalities.
Customer Education Antibiotic Classification 69 © bioMérieux, Inc., Customer Education March 2008 Mode of Action Effect Chloramphenicol Binds to the 50S ribosomal sub-unit Inhibits elongation step of protein synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Chloramphenicol • Relatively small molecule, easily enters Gram-positive and Gram-negative bacteria • Target is Ribosome • Binds to 50S subunit where it inhibits elongation step of protein synthesis
Customer Education Antibiotic Classification 70 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis Oxazolidinones: • Bacteriostatic • Narrow spectrum
Customer Education Antibiotic Classification 71 © bioMérieux, Inc., Customer Education March 2008 NEW 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Oxazolidinones Linezolid Inhibitors of Protein Synthesis Oxazolidinones: Linezolid • Spectrum of Action: Gram-positive infections. Effective for E. faecium VRE, MRSA and multi-drug resistant S. pneumoniae. • Trade Name = Zyvox®
Customer Education Antibiotic Classification 72 © bioMérieux, Inc., Customer Education March 2008 MODEOFACTION EFFECT Linezolid Binds to the 50Sribosomal sub-unit Inhibits initiation process of protein synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Linezolid • Relatively small molecule, easily enters Gram-positive bacteria • Target is Ribosome • Linezolid disrupts bacterial growth by inhibiting the initiation process in protein synthesis • This site of inhibition occurs earlier in the initiation process than other protein synthesis inhibitors (e.g., chloramphenicol, clindamycin, aminoglycosides, and macrolides) that interfere with the elongation process • Because the site of inhibition is unique to linezolid, cross-resistance to other protein synthesis inhibitors has not yet been reported • Linezolid may also inhibit virulence factor expression and decrease toxin production in Gram-positive pathogens • It has been demonstrated that linezolid is bacteriostatic against Enterococci and Staphylococci, and bactericidal for the majority of Streptococci • Gram-negative bacteria appear to be naturally resistant
Customer Education Antibiotic Classification 73 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis Ansamycins Rifamycins Rifampin (Rifamipicin): • Bacteriostatic or bactericidal – depending on organism and concentration • Broad spectrum • Discovered in 1959 • Natural or semi-synthetic derivitive of Amycolatopsis rifamycinica (previously Streptomyces mediterranei)
Customer Education Antibiotic Classification 74 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Ansamycins Rifampin (Rifampicin) Inhibitors of Protein Synthesis Ansamycins Rifamycins Rifampin (Rifamipicin): Spectrum of Action: • Primarily Gram-positive organisms and some Gram-negatives • Used in combinations with other drugs to treat tuberculosis • Used to treat carriers of N.meningitidis (prophylaxsis) • Used in combination with other antibiotics for severe Staphycoccal infections (including MRSA) • Oral or IV administration Mode of Action: Forms a stable complex with RNA polymerase and prevents DNA from being transcribed into RNA, thus inhibiting protein synthesis
Customer Education Antibiotic Classification 75 © bioMérieux, Inc., Customer Education March 2008 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Lipopeptides Polymyxins Cyclic Lipopeptides NEW CLASS Inhibitors of Membrane Function Lipopeptides: (previously Polypeptides) Polymyxins have been around since 1940’s and 1950’s. Polymyxin A,B,C,D,E • Polymyxin B and E can be used therapeutically • Polymyxin B – derived from Bacillus polymyxa var. aerosporus • Polymyxin E – derived from Bacillus polymyxa var. colistinus = Colistin Colistin exsists as two forms: • Colistin sulfate – intestinal infections, topical, powders, media • Colistimethate sodium – most active, effective form • All Bactericidal
Customer Education Antibiotic Classification 76 © bioMérieux, Inc., Customer Education March 2008 Polymyxin B 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Polymyxins Colistin Inhibitors of Membrane Function Lipopeptides: Polymyxins Polymyxin B Spectrum of Action: Narrow spectrum for Gram-negative UTI, blood, CSF and eye infections. Can be used in combination against very resistant Pseudomonas, KPC. • High toxicity – neurotoxic and nephrotoxic • IV, IM and topical for infected wounds Colistin (Colistimethate Sulfate) Spectrum of Action: Narrow spectrum for Gram-negatives, especially Pseudomonas aeruginosa infections in cystic fibrosis patients. It has come into recent use for treating multi-drug resistant Acinetobacter infections. Ineffective for Proteus and Burkholderia. • High toxicity – neurotoxic and nephrotoxic • PO, IV and topical
Customer Education Antibiotic Classification 77 © bioMérieux, Inc., Customer Education March 2008 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Mode of ActionMode of Action ofof PolymyxinsPolymyxins Lipopeptides • Polymyxins • Polymyxin B • Colistin • Cyclic Lipopeptides • Daptomycin
Customer Education Antibiotic Classification 78 © bioMérieux, Inc., Customer Education March 2008 Outer Membrane Peptidoglycan Cytoplasmic Membrane Polymyxin Respiratory Enzymes + ++ - -- - - - -- Entry of Polymyxins 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function + + + LPS Polymyxin Mode of Action Target =Membrane phospholipids (lipopolysaccharides (LPS) and lipoproteins) 1. Outer and Cytoplasmic Membrane Effect: Polymyxins are positively charged molecules (cationic) which are attracted to the negatively charged bacteria. The negative charge of bacteria is due to LPS in the outer membrane and the peptidoglycan (notably the teichoic acid). The antibiotic binds to the cell membrane, alters its structure and makes it more permeable. This disrupts osmotic balance causing leakage of cellular molecules, inhibition of respiration and increased water uptake leading to cell death. The antibiotic acts much like a cationic detergent and effects all membranes similarly. Toxic side effects are common. Little or no effect on Gram-positives since the cell wall is too thick to permit access to the membrane. Gram-positives are naturally resistant.
Customer Education Antibiotic Classification 79 © bioMérieux, Inc., Customer Education March 2008 Daptomycin 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Cyclic Lipopeptides Inhibitors of Membrane Function Lipopeptides: Cyclic Lipopeptide Daptomycin (Cubicin) • Cubicin from CUBIST Pharmaceutical got FDA approval on September 12, 2003 • Bactericidal • Resistance rate appears to be low - requires multiple mutations • Only ‘Sensitive’ CLSI® breakpoints
Customer Education Antibiotic Classification 80 © bioMérieux, Inc., Customer Education March 2008 Daptomycin FDA approval for skin/skin structure infections S.aureus (MSSA and MRSA) Beta-hemolytic Streptococci (A,B,C,G) E.faecalis (Vanco sensitive) Cyclic Lipopeptides 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Inhibitors of Membrane Function Lipopeptides: Cyclic Lipopeptide Daptomycin (Cubicin) Spectrum of Action: Daptomycin: Daptomycin is bactericidal. Active against Gram-positive bacteria (MRSA, MSSA) including those resistant to methicillin, vancomycin and linezolid. • 1/day IV dosing • Requires Ca++ in the media Mode of Action: Binds to components (calcium ions) of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein. Gram-negatives appear to be naturally resistant.
Customer Education Antibiotic Classification 81 © bioMérieux, Inc., Customer Education March 2008 4. Anti4. Anti--MetabolitesMetabolites Sulfonamides Trimethoprim/Sulfamethoxazole (Folate Pathway Inhibitors) Anti-Metabolites • Called folate pathway inhibitors or anti-metabolites Folic acid is essential for the synthesis of adenine and thymine, two of the four nucleic acids that make up our genes, DNA and chromosomes. Humans do not synthesize folic acid. Good selective target. Sulfonamides • Bacteriostatic • Introduced in 1930’s – first effective systemic antimicrobial agent • Used for treatment of acute, uncomplicated UTI’s Trimethoprim/Sulfamethoxazole • TMP/SXT is bactericidal • Broad spectrum • Synergistic action
Customer Education Antibiotic Classification 82 © bioMérieux, Inc., Customer Education March 2008 Trimethoprim/Sulfamethoxazole 4. Anti4. Anti--MetabolitesMetabolites (Folate Pathway Inhibitors) Anti-Metabolites Trimethoprim/Sulfamethoxazole: Spectrum of Action: Prescribed for treatment of certain UTI’s, otitis media in children, chronic bronchitis in adults, enteritis and Travelers’ Diarrhea.
Customer Education Antibiotic Classification 83 © bioMérieux, Inc., Customer Education March 2008 Mode of ActionMode of Action ofof AntiAnti--metabolitesmetabolites 4. Anti4. Anti--MetabolitesMetabolites
Customer Education Antibiotic Classification 84 © bioMérieux, Inc., Customer Education March 2008 Competitive Antagonism 4. Anti4. Anti--MetabolitesMetabolites TMP/SXT Mode of Action • The drug resembles a microbial substrate and competes with that substrate for the limited microbial enzyme • The drug ties up the enzyme and blocks a step in metabolism
Customer Education Antibiotic Classification 85 © bioMérieux, Inc., Customer Education March 2008 Pathway for the Synthesis of Tetrahydrofolic Acid, a Cofactor needed for the Synthesis of DNA and RNA Synthesis of Tetrahydrofolic Acid 4. Anti4. Anti--MetabolitesMetabolites • Sulfonamides such as sulfamethoxazole tie up the enzyme pteridine synthetase while trimethoprim ties up the enzyme dihydrofolic acid reductase. As a result, tetrahydrofolic acid is not produced by the bacterium. • Sulfonamides, trimethoprim alone and in combination block folic acid essential for the synthesis of adenine and thymidine that make up the DNA, RNA. Therefore, folate pathway inhibitors do not have direct antibiotic activity but the end result is the same, the bacteria is unable to multiply. • The combination SXT (thrimethoprim-sulfamethoxazol) is synergistic and the association provides a bactericidal effect • Natural Resistance Enterococcus – low level and poorly expressed S. pneumoniae Ps. aeruginosa (impermeability)
Customer Education Antibiotic Classification 86 © bioMérieux, Inc., Customer Education March 2008 Quinolones Furanes 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis
Customer Education Antibiotic Classification 87 © bioMérieux, Inc., Customer Education March 2008 Ciprofloxacin Levofloxacin MoxifloxacinGatifloxacin 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Quinolones Inhibitors of Nucleic Acid Synthesis Quinolones: • Humans do synthesize DNA - shared process with bacteria • Do tend to see some side effects with Quinolones • Some drugs withdrawn from market quickly • All are bactericidal
Customer Education Antibiotic Classification 88 © bioMérieux, Inc., Customer Education March 2008 International Common Name Quinolones 1st Generation – Narrow Spectrum Nalidixic Acid Cinoxacin Fluoroquinolones Ciprofloxacin Enoxacin Garenoxacin Levofloxacin Lomefloxacin Norfloxacin Ofloxacin Sparfloxacin Gatifloxacin Moxifloxacin Trovafloxacin 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Quinolones Inhibitors of Nucleic Acid Synthesis Quinolones: • 1st Generation Quinolones: Only for Gram-negatives, used to treat urinary tract infections because they reach high concentrations in the site of infection. • Fluoroquinolones: Garenoxacin Gram-negative and Gram-positive coverage including Anaerobes, Atypicals, S.pneumoniae and Pseudomonas. In development for VT2 cards, not yet approved. • Fluoroquinolones: Ciprofloxacin, Levofloxacin, Norfloxacin, Ofloxacin) More effective (lower MIC values). Spectrum extended to cover Staphylococci, Streptococci and Pneumococci (sparfloxacin). More widespread tissue distribution (they reach the intestine and the lungs). Ciprofloxacin and Ofloxacin used for systemic infections. • Fluoroquinolones: Sparfloxacin, Gatifloxacin, Moxifloxacin Trovafloxacin removed from market very quickly after release cardiac arrhythmias, liver destruction, phototoxicity. Gatifloxacin (Tequin® ) removed from market 05/01/06 - diabetes.
Customer Education Antibiotic Classification 89 © bioMérieux, Inc., Customer Education March 2008 Mode of ActionMode of Action ofof QuinolonesQuinolones 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis
Customer Education Antibiotic Classification 90 © bioMérieux, Inc., Customer Education March 2008 Outer Membrane Peptido - glycan Cytoplasmic Membrane Quinolones 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Entry of Quinolones Quinolone Mode of Action • Small and hydrophilic, quinolones have no problem crossing the outer membrane. • They easily diffuse through the peptidoglycan and the cytoplasmic membrane and rapidly reach their target. • Target = Topoisomerases, e.g., DNA-gyrase • Rapid bactericidal activity
Customer Education Antibiotic Classification 91 © bioMérieux, Inc., Customer Education March 2008 Circular Bacterial DNA Coiled by DNA Gyrase Fits inside the bacterial cell 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Supercoiling of DNA • The bacterial chromosome is supercoiled by the enzyme DNA gyrase • A fully supercoiled chromosome will be about 1 micron in diameter - small enough to fit in the bacteria • The bacterial chromosome consists of a single circle of DNA • DNA is double-stranded forming a left-handed double helix • A typical E. coli’s chromosome is 1400 microns long • The E. coli’s bacterial cells are 2-3 microns long
Customer Education Antibiotic Classification 92 © bioMérieux, Inc., Customer Education March 2008 DNA Gyrase DNA Gyrase+QUINOLONE DNA Gyrase cuts DNA to regulate supercoiling. The Quinolone - DNA Gyrase complex blocks the supercoiling process. enzyme DNA 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Quinolones • Quinolones inhibit DNA synthesis • All topoisomerases can relax DNA but only gyrase can also carry out DNA supercoiling (‘supercoiling’ process is necessary to compact the bacterial chromosome which is 1000 times longer than the bacterial cell). Topoisomerases are also involved in DNA replication, transcription and recombination. • The main quinolone target is the DNA gyrase which is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process. The nick is only introduced temporarily and later the two ends are joined back together (i.e., repaired). • The quinolone molecule forms a stable complex with DNA gyrase thereby inhibiting its activity and preventing the repair of DNA cuts • Natural Resistance Gram Positives – 1st generation quinolones S.pneumoniae – decreased activity to Ofloxacin and Ciprofloxacin Ps. aeruginosa – decreased activity to Norfloxacin and Ofloxacin
Customer Education Antibiotic Classification 93 © bioMérieux, Inc., Customer Education March 2008 Quinolones Furanes 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis
Customer Education Antibiotic Classification 94 © bioMérieux, Inc., Customer Education March 2008 Furanes Nitrofurantoin 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Nitrofurans: Nitrofurantoin • Spectrum of Action: Urinary Tract Infections caused by Gram-negative and Gram-positive organisms • Broad spectrum • Bactericidal • Oral Mode of Action: The drug works by damaging bacterial DNA. In the bacterial cell, nitrofurantoin is reduced by flavoproteins (nitrofuran reductase). These reduced products are are highly active and attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal acitivity. Natural Resistance: Pseudomonas and most Proteus spp. are naturally resistant.
Customer Education Antibiotic Classification 95 © bioMérieux, Inc., Customer Education March 2008 Antibiotics and Modes of ActionAntibiotics and Modes of Action Questions?

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Antibiotic classification

  • 1.
    Customer Education AntibioticClassification 1 © bioMérieux, Inc., Customer Education March 2008 Antibiotic ClassificationAntibiotic Classification andand Modes of ActionModes of Action Part # 60-00415-0
  • 2.
    Customer Education AntibioticClassification 2 © bioMérieux, Inc., Customer Education March 2008 bioMérieux, the blue logo and VITEK are used, pending and/or registered trademarks belonging 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.
  • 3.
    Customer Education AntibioticClassification 3 © bioMérieux, Inc., Customer Education March 2008 Module Objectives Antibiotic ClassificationAntibiotic Classification 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 cell • Explain the modes of action for the antibiotics in each of the five functional antibiotic classes • List examples of natural resistance in each of the five functional antibiotic classes • Explain why it is not necessary to perform susceptibility testing for certain organism / antibiotic combinations
  • 4.
    Customer Education AntibioticClassification 4 © bioMérieux, Inc., Customer Education March 2008 AntibioticsAntibiotics && Susceptibility TestingSusceptibility Testing Microbiologists work with antibiotics every day. Antimicrobial Susceptibility Testing (AST) is one of the primary functions of the 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.
  • 5.
    Customer Education AntibioticClassification 5 © bioMérieux, Inc., Customer Education March 2008 What is an Antibiotic?What is an Antibiotic? Antibiotic is a chemical substance produced by a microorganism that inhibits the growth of or kills other microorganisms. Antimicrobial agent is a chemical substance derived from a biological source or produced by chemical synthesis that kills or inhibits the growth of microorganisms. The noun “antibiotic” was first used in 1942 by Dr. Selman A. Waksman, soil microbiologist. Dr. Waksman and his colleagues discovered several actinomycetes derived antibiotics. The two terms are usually used synonymously and that practice will continue throughout this presentation. The word “antibiotic” will be used to describe: a chemical substance derivable from a microorganism or produced by chemical synthesis that kills or inhibits microorganisms and cures infections.
  • 6.
    Customer Education AntibioticClassification 6 © bioMérieux, Inc., Customer Education March 2008 Sources of Antibacterial AgentsSources of Antibacterial Agents • Natural - mainly fungal sources • Semi-synthetic - chemically-altered natural compound • Synthetic - chemically designed in the lab Toxicity Effectiveness Natural Semi-synthetic Synthetic • The original antibiotics were derived from fungal sources. These can be referred to as “natural” antibiotics • Organisms develop resistance faster to the natural antimicrobials because they have been pre-exposed to these compounds in nature. Natural antibiotics are often more toxic than synthetic antibiotics. • Benzylpenicillin and Gentamicin are natural antibiotics • Semi-synthetic drugs were developed to decrease toxicity and increase effectiveness • Ampicillin and Amikacin are semi-synthetic antibiotics • Synthetic drugs have an advantage that the bacteria are not exposed to the compounds until they are released. They are also designed to have even greater effectiveness and less toxicity. • Moxifloxacin and Norfloxacin are synthetic antibiotics • There is an inverse relationship between toxicity and effectiveness as you move from natural to synthetic antibiotics
  • 7.
    Customer Education AntibioticClassification 7 © bioMérieux, Inc., Customer Education March 2008 Role of AntibioticsRole of Antibiotics What is the role of antibiotics? • To inhibit multiplication Antibiotics have a bacteriostatic effect. At which drug concentration is the bacterial population inhibited? • Minimal Inhibitory Concentration = MIC Bacteriostatic = inhibits bacterial growth
  • 8.
    Customer Education AntibioticClassification 8 © bioMérieux, Inc., Customer Education March 2008 MICMIC –– Broth Dilution Reference TechniqueBroth Dilution Reference Technique Mueller Hinton 1 ml 1 ml 0 0.5 1 2 4 8 16 µg/ml 107 CFU 35°C - 16 - 20 h 0 0.5 1 2 MIC = 4 8 16 µg/ml 0 0.5 1 2 4 8 16 µg/ml Quantitative 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 of antibiotic in body fluids with the dosage given For treatment purposes, the dosage of antibiotic given should yield a peak body fluid concentration 3-5 times higher than the MIC or MIC x 4 = dosage to obtain peak achievable concentration
  • 9.
    Customer Education AntibioticClassification 9 © bioMérieux, Inc., Customer Education March 2008 Role of AntibioticsRole of Antibiotics What is the role of antibiotics? • To destroy the bacterial population Antibiotics have a bactericidal effect. At which drug concentration is the bacterial population killed? • Minimal Bactericidal Concentration = MBC Bactericidal = kills bacteria
  • 10.
    Customer Education AntibioticClassification 10 © bioMérieux, Inc., Customer Education March 2008 MBCMBC –– Reference TechniqueReference Technique 10 µl 0 µg/ml 4 µg/ml 8 µg/ml 16 µg/ml MBC = 16 µg/ml 0 0.5 1 2 MIC = 4 8 16 µg/ml Quantitative Measure • MBC = lowest concentration of antibiotic that kills bacteria
  • 11.
    Customer Education AntibioticClassification 11 © bioMérieux, Inc., Customer Education March 2008 Relationship of MIC/MBCRelationship of MIC/MBC MIC MBC Bactericidal MIC MBC Bacteriostatic 1 2 8 16 32 64 1284 1 2 8 16 32 64 128411 There is a much closer relationship between the MIC and MBC values for bactericidal drugs than for bacteriostatic drugs.
  • 12.
    Customer Education AntibioticClassification 12 © bioMérieux, Inc., Customer Education March 2008 How Do Antibiotics Work?How Do Antibiotics Work? Mechanisms of Action -Antibiotics operate by inhibiting crucial life sustaining processes in the organism: the synthesis of cell wall material the synthesis of DNA, RNA, ribosomes and proteins. Target –The target of the antibiotic should be selective to minimize toxicity…but all antibiotics are toxic to some degree! The targets of antibiotics should be selective to minimize toxicity. • Selective Toxicity Harm the bacteria, not the host
  • 13.
    Customer Education AntibioticClassification 13 © bioMérieux, Inc., Customer Education March 2008 • Help patients today - To provide guidance to the physician in selection of antimicrobial therapy with the expectation of optimizing outcome • Help patients tomorrow - Build an antibiogram to guide physicians in selecting empiric therapy for future patients with the expectation of optimizing outcome • Help patients next decade - Drive new drug research - Monitor the evolution of resistance Why Do Susceptibility Testing?Why Do Susceptibility Testing? We do this testing: • To provide a guide for therapy • Allows selection of the most appropriate agent Least expensive Narrowest spectrum Most effective • To monitor the evolution of resistance Antibiotic 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
  • 14.
    Customer Education AntibioticClassification 14 © bioMérieux, Inc., Customer Education March 2008 Why Do Antimicrobials Fail?Why Do Antimicrobials Fail? In Vitro Testing MIC & S/R Host Factors Immune System Underlying Diseases Barrier Status Foreign Bodies Site of Infection CNS Intravascular Pulmonary Surgical Intervention Antibiotic Properties PK and PD Metabolism & Elimination Tissue Penetration Adverse Event Profile Pathogen Species Virulence Factors Resistance Mechanisms There are many possible reasons antimicrobials may fail. Selection of the appropriate antibiotic depends on: knowledge of organism’s natural resistance pharmacological properties of the antibiotic toxicity, binding, distribution, absorption achievable levels in blood, urine previous experience with same species nature of patients underlying pathology patient’s immune status Susceptibility testing focuses primarily on the interaction of antimicrobial agents, the organisms and their resistance mechanisms.
  • 15.
    Customer Education AntibioticClassification 15 © bioMérieux, Inc., Customer Education March 2008 • MICs are not physical measurements • There are many factors that play a role in determining clinical outcome • Susceptibility in vitro does not uniformly predict clinical success in vivo • Resistance will often, but not always, correlate with treatment failure Interpreting Susceptibility ResultsInterpreting Susceptibility Results Susceptibility tests are essentially artificial measurements. in vitro response approximate range of effective inhibitory action possible error equivalent to one tube dilution The only true measure of bacterial response to an antibiotic is the clinical response of the patient. outcome or in vivo response One of the real values of AST is to predict resistance S = success likely, but no guarantee R = correlates well with treatment failure Is Resistance Testing a better name for what we do than Susceptibility Testing?
  • 16.
    Customer Education AntibioticClassification 16 © bioMérieux, Inc., Customer Education March 2008 What is the Ideal Antibacterial?What is the Ideal Antibacterial? • Selective target – target unique • Bactericidal – kills • Narrow spectrum – does not kill normal flora • High therapeutic index – ratio of toxic level to therapeutic level • Few adverse reactions – toxicity, allergy • Various routes of administration – IV, IM, oral • Good absorption • Good distribution to site of infection • Emergence of resistance is slow
  • 17.
    Customer Education AntibioticClassification 17 © bioMérieux, Inc., Customer Education March 2008 Antibiotic ClassificationAntibiotic Classification andand Modes of ActionModes of Action In the AES Knowledge Base, phenotypes are organized by drug class. The AES decision process attempts to identify a phenotype for each drug class tested. In order to understand and use the software effectively, it is 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 antibiotics and their modes of action.
  • 18.
    Customer Education AntibioticClassification 18 © bioMérieux, Inc., Customer Education March 2008 Antibiotic ClassificationAntibiotic Classification Grouped by Structure and Function Five functional groups cover most antibiotics 1. Inhibitors of cell wall synthesis 2. Inhibitors of protein synthesis 3. Inhibitors of membrane function 4. Anti-metabolites 5. Inhibitors of nucleic acid synthesis Antibiotics are usually classified based on their structure and/or function. 1. Structure - molecular structure. ß-Lactams - Beta-lactam ring Aminoglycosides - vary only by side chains attached to basic structure 2. Function - how the drug works, its mode of action. 5 functional groups These are all components or functions necessary for bacterial growth Targets for antibiotics In these discussions, we will primarily use the functional classification, but will point out where structural similarities also exist.
  • 19.
    Customer Education AntibioticClassification 19 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins Inhibitors of Cell Wall Synthesis Beta-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
  • 20.
    Customer Education AntibioticClassification 20 © bioMérieux, Inc., Customer Education March 2008 R’--CONH COOH OO B-lactam ring Beta-lactams 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-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-produced enzymes called beta-lactamases Some more common Beta-lactamase enzymes include: Penicillinases Cephalosporinases ESBL’s Cephamycinases Carbapenemases
  • 21.
    Customer Education AntibioticClassification 21 © bioMérieux, Inc., Customer Education March 2008 Beta-lactams (Penicillins) International Common Name Penicillins (pen G)* Penicillin G Penicillinase-stable penicillins (pen M) Oxacillin Methicillin Aminopenicillins* (pen A) Ampicillin Amoxicillin Carboxypenicillins* (pen C) Ticarcillin Ureidopenicillins* (pen U) Piperacillin β-lactam / β-lactamase inhibitor combinations Amoxicillin + clavulanic acid Ampicillin + sulbactam Ticarcillin + clavulanic acid Piperacillin + tazobactam Amidinopenicillin Mecillinam * Penicillinase labile: hydrolyzed by staphylococcal penicillinase 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-lactams - Penicillins Spectrum of Action 1. Natural penicillins • Penicillin G: Active against Gram-positive organisms that do not produce beta-lactamases, Neisseria and some anaerobes 2. Penicillinase-resistant penicillins • Penicillin M: Active against penicillinase-producing Staphylococci 3. Extended-spectrum penicillins • Aminopenicillins: Slightly less active than Penicillin G against Pneumococci, Streptococci and Meningococci, but active against many strains of Salmonella, Shigella, and P.mirabilis, H.influenzae) • Carboxypenicillins: More stable than aminopenicillins to hydrolysis by the ß-lactamases of most Enterobacteriaceae and Pseudomonas aeruginosa • Ureidopenicillins: Greater activity than carboxypenicillins against Gram-positives, enterics and P.aeruginosa 4. Co-Drugs (Beta-lactam + beta-lactamase inhibitor) • ß-lactamase inhibitors (BLI) combinations: Additional activity against beta-lactamase producing organisms, including Staphylococcus spp., some enterics, H.influenzae and Bacterioides spp 5. Amidinopenicillins • Mecillinam: Restricted use to urinary infection with E.coli. Active against penicillinase and low-level cephalosporinase.
  • 22.
    Customer Education AntibioticClassification 22 © bioMérieux, Inc., Customer Education March 2008 These enzymatic inhibitors have weak or poor antibacterial activity alone, but a strong affinity for β- lactamases: Clavulanic Acid Sulbactam Tazobactam Beta-lactamase Inhibitors (BLI) Aim: to block β-lactamases Combination β-lactams - β-lactamase inhibitor: Amoxicillin + Clavulanic Acid Ampicillin + Sulbactam Ticarcillin + Clavulanic Acid Piperacillin + Tazobactam Never Alone! 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactamase inhibitors (BLI) have a beta(ß)-lactam ring, but have weak or poor 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 penicillinase Penicillinase of K. pneumoniae ESBL (to a greater or lesser degree) - if the penicillinase is being overproduced, the inhibitor effect may be diluted (Inoculum Effect) In the case of penicillinase production, where: Amoxicillin R Amoxicillin + Clavulanic acid usually S • Inhibitors are active against all penicillinase (PASE and ESBL) but never on cephalosporinase NEW ISSUE - BLI can act as inducers and actually stimulate enzyme (beta- lactamase) production. It is possible to see the following: Pseudo monas Ticarcillin = S Ticarcillin/Clavulanic = R Enterobacteriaceae Piperacillin = S Piperacillin/Tazobactam = R
  • 23.
    Customer Education AntibioticClassification 23 © bioMérieux, Inc., Customer Education March 2008 Beta-lactams (Cephems) International Common Name 1st Generation Cephalosporins C1G Cephalothin Cefazolin 2nd Generation Cephalosporins C2G Cefuroxime Cefamandole Cephamycin (new C2G) Cefoxitin Cefotetan – removed 3rd Generation Cephalosporins C3G Cefotaxime Ceftazidime Ceftriaxone 4th Generation Cephalosporins C4G Cefepime Oral C3G Cefixime Cefpodoxime Next Generation Cephalosporins Ceftobiprole Ceftaroline 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-lactams - Cephems Spectrum of Action • 1st generation cephalosporins (C1G): Narrow spectrum; good Gram-positive activity and relatively modest Gram-negative activity. Inactivated by Gram-neg beta-lactamases (Derived from Cephalosporium acremonium). • 2nd generation cephalosporins (C2G): Better Gram-negative coverage (more beta-lactamase stability), but less Staphylococcal activity. • Cephamycins: Remain susceptible in presence of Extended Spectrum ß-lactamase (ESBL) because they are not a substrate for the enzyme. Can be used as an indicator for ESBL (Derived from Streptomyces lactamdurans). - AstraZeneca discontinued its Cefotetan products in June 2006. Currently available from other manufacturers. • 3rd generation cephalosporins (C3G): Wider spectrum of action when compared to C1G and C2G. Less active than narrow spectrum agents against Gram-positive cocci, but much more active against the Enterobacteriaceae and Pseudomonas aeruginosa (better beta- lactamase stability). • 4th generation cephalosporins (C4G): Broadest spectrum of action. Active against high level cephalosporinases of Enterobacteriaceae and Pseudomonas aeruginosa (not usually used with ESBL producing organisms). None have activity to MRSA or Enterococcus spp.
  • 24.
    Customer Education AntibioticClassification 24 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis New Anti- MRSA Cephalosporins New ! Ceftobiprole Ceftaroline A next generation cephalosporins? Inhibitors of Cell Wall Synthesis Beta-lactams - Cephems - Ceftobiprole Spectrum of Action • Next generation cephalosporin: Broad spectrum; active against the 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 approved • Has been added to CLSI® M100-S18, 2008 listing of antibiotics • No CLSI breakpoints • Once FDA approved, can no longer say if Staph is resistant to Oxacillin, report all beta-lactams as resistant.
  • 25.
    Customer Education AntibioticClassification 25 © bioMérieux, Inc., Customer Education March 2008 Beta-lactams International Common Name Monobactams Aztreonam Penems Carbapenems Penems Imipenem Meropenem Ertapenem Doripenem Faropenem 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis Beta-lactams: Monobactams Spectrum of Action • Aztreonam: Gram-negatives (Enterobacteriaceae and Pseudomonas). Not hydrolyzed by most commonly occurring plasmid and chromosomally mediated ß-lactamases, and does not induce the production of these enzymes. Beta-lactams: Penems Slightly different structure than the other ß-lactams, make the Penems much more resistant to beta-lactamase hydrolysis. Spectrum of Action • Carbapenems: ß-lactams with a broad spectrum of action. Gram- positives, except MRSA. Gram-negatives, Ps. aeruginosa (except Ertapenem) and anaerobes. Very efficient against high level cephalosporinase and ESBL. Wide diffusion in the body, especially in the cerebrospinal fluid. Doripenem (new) - Broad spectrum. Particularly good for Pseudomonas and other non-fermenters. • Penem: Oral. Primarily for respiratory tract infections. Poor activity with Serratia, Pseudomonas, Stenotrophomonas. Faropenem not yet FDA approved.
  • 26.
    Customer Education AntibioticClassification 26 © bioMérieux, Inc., Customer Education March 2008 From… the Bug To… the Drug Antibiotic Modes of ActionAntibiotic Modes of Action • Before we can understand the antibiotic modes of action, we need to review the structure and physiology of the bacterial cell
  • 27.
    Customer Education AntibioticClassification 27 © bioMérieux, Inc., Customer Education March 2008 Multiplication of BacteriaMultiplication of Bacteria • It is important to understand the growth cycle and physiology of bacteria to appreciate how it influences antimicrobial action • Bacteria are all around us. Given good growing conditions, a bacterium will divide. • A new cell wall forms at the center and the "bug" splits into two daughter cells, both of which carry the same genetic information as the parent • If the environment is perfect, the two daughter cells can split into four within 20 minutes • 1, 2, 4, 8, 16, 32, 64... • Typical bacterial growth cycle includes: Lag phase Exponential (log) phase Stationary phase Death phase
  • 28.
    Customer Education AntibioticClassification 28 © bioMérieux, Inc., Customer Education March 2008 Bacterial StructureBacterial Structure 1 µ 1 µ 2.5 µ Bacterial wall (peptidoglycan) Cytoplasm Cytoplasmic membrane Ribosomes DNA Typical Structure of a Bacterial Cell (from inside to outside) DNA bacterial genetic material Ribosomes (protein-making factories), energy-generating systems, digestive system, and everything else are located in the cytoplasm. Cytoplasmic Membrane or Inner Membrane a. Consists of phospholipids and other membrane proteins b. Semi-permeable c. Regulates pH, osmotic pressure and availability of essential nutrients Bacterial Cell Wall or Peptidoglycan a. Cross-linked mesh that gives a cell its shape, strength and osmotic stability, a protective suit of armour b. Porous up to 100,000 Da The outer layer of lipopolysaccharide (LPS) and phospholipid material helps protect 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
  • 29.
    Customer Education AntibioticClassification 29 © bioMérieux, Inc., Customer Education March 2008 GramGram--Positive Cell StructurePositive Cell Structure Teichoic acids Peptido - glycan Inner membrane PBP Protein Gram-Positive Cell Structure • The Gram-positive cell wall is thick and consists of 90% peptidoglycan • Teichoic acids link various layers of peptidoglycan together. Teichoic acids 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 involved in respiration and transmembrane transport) • extrinsic proteins which are hydrophilic • Penicillin-Binding Proteins (PBPs): periplasmic space proteins involved in peptidoglycan synthesis (glycosyltransferase, transpeptidase and carboxypeptidase activities)
  • 30.
    Customer Education AntibioticClassification 30 © bioMérieux, Inc., Customer Education March 2008 GramGram--Positive Cell StructurePositive Cell Structure
  • 31.
    Customer Education AntibioticClassification 31 © bioMérieux, Inc., Customer Education March 2008 PBP Protein Peptidoglycan Cytoplasmic membrane Outer membrane Porin Protein β−lactamase Endotoxin = LPS GramGram--Negative Cell StructureNegative Cell Structure Gram-Negative Cell Structure • The outer membrane is made up of: • phospholipids • endotoxin or lipopolysaccharide (LPS) - plays an important role in the antibiotic entry into the cell • proteins including the porins (complexes of three proteins) form aqueous channels that provide a route across the outer membrane for all the water-soluble compounds needed by the bacterium • 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 involved in respiration and transmembrane transport) • extrinsic proteins which are hydrophilic • Penicillin-Binding Proteins (PBPs) - periplasmic space proteins involved in peptidoglycan synthesis (glycosyltransferase, transpeptidase and carboxypeptidase activities)
  • 32.
    Customer Education AntibioticClassification 32 © bioMérieux, Inc., Customer Education March 2008 GramGram--Negative Cell Wall StructureNegative Cell Wall Structure
  • 33.
    Customer Education AntibioticClassification 33 © bioMérieux, Inc., Customer Education March 2008 glyD-ala D-ala gly gly gly gly D-ala N-acetyl m ura m ic acid N-acetyl glucosam ine L-ala D-gluNH2 L-lys D-ala L-lys D-gluNH2 L-ala N-acetyl glucosa m ine N-acetyl m uram ic acid Peptidoglycan StructurePeptidoglycan Structure Peptidoglycan • is a very high molecular weight polymer composed of many identical subunits • is a 3-D polymeric macromolecule • determines cell shape and prevents osmotic lysis, porous up to 100,000 daltons • contains N-acetylglucosamine (NAG), N-acetylmuramic acid (NAMA), and several different amino acids • involves 2 types of covalent chemical bonds: 1. B-1, 4 glycosidic bond between hexose sugars 2. Petide bond between amino acids • In Gram-positive bacteria, peptidoglycan accounts for as much as 90% of the cell wall (approximately 40 layers), with the rest consisting of the teichoic acids. • Gram-negative bacteria have a thin peptidoglycan layer (accounting for only 5-20% of the cell wall). However, in addition to the cytoplasmic membrane, they have a second phospholipid bilayer external to the peptidoglycan called the outer membrane.
  • 34.
    Customer Education AntibioticClassification 34 © bioMérieux, Inc., Customer Education March 2008 Mode of ActionMode of Action ofof BetaBeta--lactamslactams 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Humans have no cell wall (no peptioglycan), so this is a good selective target for the antibiotic.
  • 35.
    Customer Education AntibioticClassification 35 © bioMérieux, Inc., Customer Education March 2008 Entry of β-lactams in Gram-Positive Bacteria Peptido - glycan Cytoplasmic membrane Protein PBP β-lactam 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams are mostly water soluble. Differences in cell wall composition (more or less lipids) between different bacterial species partially account for their differential susceptibility to ß- lactams. The target of the ß-lactam antibiotics for all bacteria is the PBP (Penicillin Binding Protein) in the cytoplasmic membrane. Gram-Positives: In Gram-positive bacteria, there is no barrier to the entry of ß-lactams antibiotics. The peptidogylcan layers allow the diffusion of small molecules. However, ß-lactams cross the membranes with great difficulty due to high lipid content but, since their target PBP’s are found on the outer surface of the cytoplasmic membrane, they only have to cross the cell wall. Natural Resistance Enterococcus - PBP’s are different from other Gram-positives (also higher lipid content in cell wall), which causes a low level resistance to penicillins and resistance to C1G.
  • 36.
    Customer Education AntibioticClassification 36 © bioMérieux, Inc., Customer Education March 2008 Endotoxin = LPS Outer membrane Porin Peptidoglycan Cytoplasmic membrane PBP Protein β−lactamase 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Entry of β-lactams in Gram-Negative Bacteria Gram-Negatives: 1. Outer membrane entry through the: Porins: Hydrophilic ß-lactams tend to gain access into the periplasmic space using these watery funnels (i.e., E. coli organism has about 100,000 of these porins). Porins are transmembrane proteins. They complex together to form water-filled channels through which low molecular weight (<600 daltons) hydrophilic substances readily diffuse. Such diffusion is passive and the concentration in the periplasmic space can reach the level that prevails in the external environment as long as there are no mechanisms to pump the drug back out or which inactivate it. Phospholipids: This mode of entry is less common, but it seems to play a significant part in the case of certain ß-lactams. Lipid bilayers support the diffusion of lipophilic compounds (certain ß-lactams are lipophilic). However, if the organism’s LPS (endotoxin) is branched (e.g., as in the case of Pseudomonas aeruginosa), such diffusion is blocked. This is called impermeability. 2. Peptidoglycan entry 3. Periplasmic space entry: ß-lactams may encounter ß-lactamases 4. Cytoplasmic membrane PBP - bound Natural Resistance - Many Gram-negative organisms are naturally resistant to penicillin G and oxacillin because the drug is prevented from entering the cell by the LPS which blocks the porins.
  • 37.
    Customer Education AntibioticClassification 37 © bioMérieux, Inc., Customer Education March 2008 Cytoplasmic membrane PBP ⌦PBP = glycosyltransferases: generate peptidoglycan chains ⌦PBP = transpeptidases: cross-link different chains ⌦PBP = carboxypeptidases: regulate peptidoglycan production AutolysinsAutolysins: mediate chain maturation - activity inhibited by teichoic acidsteichoic acids in the cell wall. 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Interactions between β-lactams and PBPs • 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 synthesis and 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 peptidoglycan synthesis is stopped, the autolysins remain active. Autolysin activity is progressively potentiated. The peptidoglycan network begins to become disorganized and teichoic acid (which normally regulates autolysin activity by natural inhibition) tends to leak out. • Without a peptidoglycan layer, the bacterium bursts and eventually all cells die NOTE: Ceftobiprole and Ceftaroline (the next generation cephalosporins) have the ability to inactivate PBP2a which is primarily responsible for oxacillin resistance in Staphylococci.
  • 38.
    Customer Education AntibioticClassification 38 © bioMérieux, Inc., Customer Education March 2008 The efficacy of the antibiotic hangs on 2 parameters: •The rapidity of the drug entrance •The rate of enzymatic hydrolysis 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis β-lactamase and β-lactams Periplasmic Space Entry • The periplasmic space represents a “mine field” for ß-lactams due to the presence of ß-lactamase enzymes (defense enzymes) • ß-lactamases are found in all bacteria, although in variable amounts and with varying levels of activity (they can even be found in wild-type E. coli although at such a low concentration that their effect is insignificant). • ß-lactamases hydrolyze the ß-lactam ring. The rate of this hydrolysis depends on the rate on entry of the drug and the level of ß-lactamase activity. • In many cases, the rate of entry is sufficient to guarantee a consistently high enough concentration of the drug to interact with the PBP’s, even if a certain proportion is constantly being enzymatically hydrolyzed.
  • 39.
    Customer Education AntibioticClassification 39 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins Inhibitors of Cell Wall Synthesis Glycopeptides • The term ‘Glycopeptide’ included two main compounds with very similar structures and modes of action: Vancomycin and Teicoplanin • Teicoplanin not FDA approved in the U.S. • Both are of high molecular weight (1500-2000 daltons) • Glycopeptides have a complex chemical structure • Inhibit cell wall synthesis at a site different than the beta-lactams • All are bactericidal • All used for Gram-positive infections. (No Gram-negative activity) • Pharmaceutical research and development has been very active in this area recently resulting in new antimicrobials and classification
  • 40.
    Customer Education AntibioticClassification 40 © bioMérieux, Inc., Customer Education March 2008 Glycopeptide: Vancomycin Lipoglycopeptide: Dalbavancin Oritavancin Telavancin Teicoplanin Glycopeptides 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis New Inhibitors of Cell Wall Synthesis Glycopeptides: Glycopeptide Spectrum of Action • Vancomycin: MRSA (Methicillin Resistant Staph. aureus), C.difficile, Streptococci including Strep pneumoniae. Alternative to Penicillin G in serious infections. Good diffusion in all tissues (except CSF). High toxic effects: ears and kidneys. Glycopeptides: Lipoglycopeptide Spectrum of Action • Dalbavancin: (Vicuron) 2nd generation lipoglycopeptide. Bactericidal for MRSA and MRSE.1/week IV dosing – long acting. Not yet FDA approved. • Oritavancin: (Targanta) 2nd generation glycopeptide. Actually a lipoglycopeptide. IV – once per day dosing. For skin and skin structure infections. Activity similar to Vancomycin – better for Staphyloccus and Enterococcus. Not yet FDA approved. Bactericidal • Telavancin: (Theravance) bactericidal for all Gram-positive. Inhibits cell wall synthesis and inhibits bacterial phospholipid membrane synthesis. Single dose injectable. Not yet FDA approved. • Teicoplanin: Not FDA approved in the US. Widespread use in Europe.
  • 41.
    Customer Education AntibioticClassification 41 © bioMérieux, Inc., Customer Education March 2008 Mode of Action of Glycopeptides Vancomycin 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis
  • 42.
    Customer Education AntibioticClassification 42 © bioMérieux, Inc., Customer Education March 2008 Peptidoglycan Cytoplasmic membrane Protein PBP Glycopeptide 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Entry of Glycopeptides in Gram-Positive Bacteria In Gram-Positives: The drugs enter without any problem because peptidoglycan does not act as a barrier for the diffusion of these molecules.
  • 43.
    Customer Education AntibioticClassification 43 © bioMérieux, Inc., Customer Education March 2008 Outer membrane Porin Peptido - glycan Cytoplasmic membrane PBP Glycopeptide 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Entry of Glycopeptides in Gram-Negative Bacteria In Gram-Negatives: Glycopeptides are of high molecular weight (1500-2000 daltons), stopping them from passing through the porins of gram-negative bacteria (i.e., glycopeptides have no activity against Gram-negatives). Gram-negatives are naturally resistant. Use this property in Microbiology in several ways: Check Gram reaction - growth around Vancomycin disk would indicate a Gram-negative organism (resistant to Vancomycin). KVC disks/media - for anaerobe ID’s.
  • 44.
    Customer Education AntibioticClassification 44 © bioMérieux, Inc., Customer Education March 2008 L-ala N-acetyl glucosamine L-lys D-ala D-ala Glycopeptide EnzymesEnzymes N-acetyl muramic acid D-gluNH2 gly gly gly gly gly PentaglycinePentaglycine 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Mode of Action of Glycopeptides • Glycopeptides inhibit the final cell wall stage of the peptidoglycan synthesis process • The ‘pocket-shaped’ glycopeptide binds the D-ala-D-ala terminal of the basic sub-unit theoretically waiting to be incorporated into the growing peptidoglycan • Because it is so bulky, the glycopeptide inhibits the action of the glycosyltransferases and transpeptidases (which act as a kind of “cement”) - blocks pentaglycine from joining molecules, thereby blocking peptidoglycan growth. • Glycopeptides are bactericidal, but slow-acting
  • 45.
    Customer Education AntibioticClassification 45 © bioMérieux, Inc., Customer Education March 2008 1. Inhibitors of Cell Wall Synthesis1. Inhibitors of Cell Wall Synthesis Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins Inhibitors of Cell Wall Synthesis Fosfomycins Spectrum of Action Fosfomycin: Acts to inhibit cell wall synthesis at a stage earlier than the penicillins or cephalosporins. FDA approved 1996. While it is a broad spectrum agent, CLSI ® only provides breakpoints for urinary tract infections due to E.coli and E.faecalis. Reference Method: Preferred reference method is agar dilution. Broth dilution should not be performed. Mode of Action: Inhibits the first step of the peptidoglycan synthesis process
  • 46.
    Customer Education AntibioticClassification 46 © bioMérieux, Inc., Customer Education March 2008 Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis Aminoglycosides - Gentamicin (Bactericidal) Tobramycin Amikacin MLSK - Erythromycin (Bacteriostatic) Clindamycin Quinupristin-Dalfopristin (Synercid) Clarithromycin Azithromycin Telithromycin Tetracyclines - Tetracycline (Bacteriostatic) Doxycycline Minocycline Glycylcyclines - Tigecycline Phenocols - Chloramphenicol (Bacteriostatic) Oxazolidinones - Linezolid (Bactericidal for Streptococci; Bacteriostatic for Enterococcus and Staphylococci) Ansamycins - Rifampin (Bacteriostatic or Bactericidal depending on organism and concentration)
  • 47.
    Customer Education AntibioticClassification 47 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Aminoglycosides • Humans do synthesize proteins, but at a much slower rate than bacteria • Drug can act on bacteria before it does damage to man • But, since it is a common process, we do tend to see more toxic side effects • Need to do therapeutic drug monitoring • All bactericidal
  • 48.
    Customer Education AntibioticClassification 48 © bioMérieux, Inc., Customer Education March 2008 O O O O OH OH OH 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides Inhibitors of Protein Synthesis Aminoglycosides: • Related in structure and function • Drugs differ based on location of radical groups attached to the 3 ring basic structure
  • 49.
    Customer Education AntibioticClassification 49 © bioMérieux, Inc., Customer Education March 2008 AMINOGLYCOSIDES International Common Name Amikacin Gentamicin Tobramycin Streptomycin Kanamycin Netilmicin 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides Inhibitors of Protein Synthesis Aminoglycosides: Spectrum of Action • Rapid bactericidal effect • Broad spectrum of action Gram-negative nosocomial infections and severe systemic infections Gram-positives, except Streptococus and Enterococcus. Must combine an aminoglycoside (Gentamicin or Streptomycin) with a penicillin, ampicillin or vancomycin for severe enterococcal infections (Synergy Testing). • In serious infection, used in association with beta-lactams or fluoroquinolones • Kanamycin develops resistance quickly • Hospital use only • Nephrotoxic and toxic for ears Drug Dosage Adjustment: Monitoring aminoglycosides is mandatory. It is important to control the serum level for peak and trough to ensure the bactericidal effect and avoid side effects.
  • 50.
    Customer Education AntibioticClassification 50 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis O O O O OH OH OH Mode of ActionMode of Action ofof AminoglycosidesAminoglycosides
  • 51.
    Customer Education AntibioticClassification 51 © bioMérieux, Inc., Customer Education March 2008 Protein SynthesisProtein Synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis A quick review of protein synthesis before we begin.
  • 52.
    Customer Education AntibioticClassification 52 © bioMérieux, Inc., Customer Education March 2008 Protein Synthesis Proteins are made up of at least 20 different amino acids Thousands of different proteins exist, each with its own function (enzymes, etc.). Each protein is manufactured in the cell using a code contained in the DNADNA. AA AAAA AA AA AAAA AA 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis • The code for the 20 essential amino acids consists of at least a 3-base set (triplet) of the 4 bases • If one considers the possibilities of arranging four things 3 at a time (4X4X4), we get 64 possible code words, or codons (a 3-base sequence on the mRNA that codes for either a specific amino acid or a control sequence).
  • 53.
    Customer Education AntibioticClassification 53 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Protein Synthesis Pathway • Proteins are manufactured in the cell using a code in the DNA • DNA is transcribed into RNA by an enzyme called RNA polymerase • The RNA strand is translated into proteins by the ribosomes
  • 54.
    Customer Education AntibioticClassification 54 © bioMérieux, Inc., Customer Education March 2008 50s subunit 30s subunit Protein RNA 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Protein Synthesis Role of Ribosome • Each ribosome consists of one small sub-unit (30S) and a larger one (50S) • The ribosome crawls along the messenger-RNA molecule translating the code and assembling the amino acids in the correct order before chemically joining them to create the protein
  • 55.
    Customer Education AntibioticClassification 55 © bioMérieux, Inc., Customer Education March 2008 - Outer Membrane Peptidoglycan Cytoplasmic Membrane Aminoglycoside Respiratory Enzymes + ++ - -- - - - -- 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Entry of Aminoglycosides Aminoglycoside Mode of Action Target = Ribosome in cytoplasm 1. Outer Membrane entry: Aminoglycosides are positively charged molecules which means they rapidly enter bacteria (negatively charged) since the two charges attract each other. The negative charge of bacteria is due to LPS in the outer membrane and the peptidoglycan (notably the teichoic acid). 2. Cytoplasmic Membrane entry: The drugs cross the cytoplasmic membrane via respiratory enzymes (involved in aerobic respiration). This is why bacteria without respiratory enzymes (strict anaerobes or facultative anaerobes like streptococci) are naturally resistant to aminoglycosides.
  • 56.
    Customer Education AntibioticClassification 56 © bioMérieux, Inc., Customer Education March 2008 Ribosome Abnormal protein RNA + aminoglycoside 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Mode of Action - Aminoglycosides Aminoglycosides bind to the RNA of the 30S ribosomal sub-unit. The resulting change in ribosome structure affects all stages of normal protein synthesis. • Initiation step of translation • Blocks elongation of peptide bond formation • Release of incomplete, toxic proteins Translational errors are frequent and many non-functional or toxic proteins are produced. The incorporation of such abnormal proteins into the cytoplasmic membrane compromises its function. The bactericidal activity of aminoglycosides ultimately stops protein synthesis and dramatically damages the cytoplasmic membrane.
  • 57.
    Customer Education AntibioticClassification 57 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis MLSK: (Macrolides, Lincosamides, Streptogramins, Ketolides) Bacteriostatic Their spectrum of activity is limited to Gram-positive cocci such as Streptococci and Staphylococci. These antibiotics are also active against anaerobes.
  • 58.
    Customer Education AntibioticClassification 58 © bioMérieux, Inc., Customer Education March 2008 MLSK Erythromycin Clindamycin Quinupristin-Dalfopristin 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Telithromycin Inhibitors of Protein Synthesis MLSK: (Macrolides, Lincosamides, Streptogramins, Ketolides) Four different classes of antibiotics which are unrelated in terms of structure but which have a similar mode of action and spectrum of activity.
  • 59.
    Customer Education AntibioticClassification 59 © bioMérieux, Inc., Customer Education March 2008 Macrolides, Lincosamides, Streptogramins, Ketolides MLSK International Common Name Macrolides Erythromycin Lincosamides Lincomycin Clindamycin Streptogramins Quinupristin / Dalfopristin Pristinamycin Ketolides Telithromycin NEW 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis Spectrum of Action Macrolides: Respiratory infections due to S. pneumoniae and S. pyogenes, Mycoplasma, Legionella, less serious Staphylococcal infections. Lincosamides: Gram-positive skin infections and anaerobe infections. Oral administration appropriate for out patient settings. Streptogramins: Quinupristin/Dalfopristin (Synercid): consists of an A and B component (Synergistic). A - prevents peptide bond formation and changes the ribosome to attract the B component. B - causes early release of incomplete peptide chains. Used for E. faecalis (VRE) and MRSA. Ketolides: Telithromycin: Represents a novel class that has received much attention recently due to their excellent activity against resistant organisms. Ketolides are semi-synthetic derivatives of erythromycin. FDA approved for bronchitis, sinusitis, community acquired pneumonia due to S.pneumoniae (including Macrolide Resistant strains), H. influenza, M.catarrhalis, S.aureus (sinusitis), M.pneumoniae, and C.pneumoniae Side effects – possible liver damage.
  • 60.
    Customer Education AntibioticClassification 60 © bioMérieux, Inc., Customer Education March 2008 Mode of Action of MLSK Erythromycin Clindamycin Quinupristin-Dalfopristin 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Telithromycin
  • 61.
    Customer Education AntibioticClassification 61 © bioMérieux, Inc., Customer Education March 2008 Peptidoglycan Cytoplasmic Membrane Protein PBP MLSK 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Entry of MLSK in Gram-Positive Bacteria The drugs enter a Gram-positive cell without any problem because peptidoglycan does not act as a barrier for the diffusion of these molecules nor does the cytoplasmic membrane. Target = Ribosome in cytoplasm
  • 62.
    Customer Education AntibioticClassification 62 © bioMérieux, Inc., Customer Education March 2008 Endotoxin = LPS Outer Membrane Porin Peptido - glycan Cytoplasmic Membrane PBP β-lactamase MLSK 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Entry of MLSK in Gram-Negative Bacteria • In Gram-negative bacteria there is no entry because MLSK are lipophilic molecules. They cannot cross the outer membrane which is hydrophilic. “Oil and water don’t mix”. • MLSK are also large molecules that cannot pass through the porins (which are also aqueous channels) – impermeability. • Most Gram-negatives are naturally resistant to MLSK
  • 63.
    Customer Education AntibioticClassification 63 © bioMérieux, Inc., Customer Education March 2008 Polypeptide release MLSK binds Peptide bonds Free amino acids Peptide bond initiation Translation: Initiation Elongation Termination 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Mode of Action - The MLSK Group • Antibiotics in the MLSK group are structurally distinct but have a similar mode of action by binding the 50S ribosomal subunit • During translation, it blocks the initiation step, elongation step or peptide release step of protein synthesis • Unfinished or toxic protein is released
  • 64.
    Customer Education AntibioticClassification 64 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins NEW Inhibitors of Protein Synthesis Tetracyclines: • Bacteriostatic • Chlortetracycline – 1948, the original tetracycline derived from a Streptomyces spp Glyclycyclines: • New class • Developed to overcome some of the more common tetracycline resistance mechanisms • Bacteriostatic • Broad spectrum
  • 65.
    Customer Education AntibioticClassification 65 © bioMérieux, Inc., Customer Education March 2008 Tetracyclines International Common Name Glycylcyclines Tetracycline Minocycline Doxycycline Tigecycline Tetracyclines Glycylcyclines 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Inhibitors of Protein Synthesis Tetracyclines: Spectrum of Action: Broad spectrum, but resistance is common which limits its use. Primarily for treatment of genital infections (chlamydiae) and atypicals (Rickettsiae, Mycoplasma). Growth promotor in animal husbandry. Toxicity: Diffuse well in cells and bones. Not recommended for pregnant women and children (less than 2 years old) because of the toxicity on bones and teeth of the fetus. Tetracycline = Short acting Minocycline and Doxycycline = Long acting Minocycline and Doxycycline are more active than Tetracycline. if Tetra = S, then Mino and Doxy = S if Tetra = R, must test Mino and Doxy (may be S) Glycylcyclines: Tigecycline Spectrum of Action: Same as the tetracyclines; may have activity against multi-drug resistant organisms. Derivative of Minocycline. (VT2 - available for Gram Negs. Must add breakpoints in 2.01 PC software. Breakpoints are included in 3.01 PC software. FDA Gram-negative breakpoints = 2/4/8.)
  • 66.
    Customer Education AntibioticClassification 66 © bioMérieux, Inc., Customer Education March 2008 Mode of Action Effect Tetracyclines Irreversibly binds to the 30S ribosomal sub-unit Inhibits elongation step of protein synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Mode of Action - Tetracycline Tetracycline exists as a mixture of two forms - lipophillic and hydrophillic. • Helps the antibiotic gain entry into the Gram-pos and neg cell • Once inside the cell it complexes with Mg++ ions, making the molecule bigger and trapping it inside the bacterial cell • It can then go on to reach it’s target - the 30s ribosome • There it inhibits the elongation step of protein synthesis Gram-positives have no natural resistance to the tetracyclines. Of the Gram-negative organisms only Proteus mirabilis is naturally resistant.
  • 67.
    Customer Education AntibioticClassification 67 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis Phenicols: • Bacteriostatic • Broad spectrum
  • 68.
    Customer Education AntibioticClassification 68 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Phenicols Chloramphenicol Inhibitors of Protein Synthesis Phenicols: Chloramphenicol Spectrum of Action: Very active against many Gram-positive and Gram-negative bacteria, Chlamydia, Mycoplasma and Rickettsiae. Restricted use for extra-intestinal severe salmonella infection. Empiric treatment of meningitis, crosses blood/brain barrier well. Toxicity: High toxicity, causes bone marrow aplasia and other hematological abnormalities.
  • 69.
    Customer Education AntibioticClassification 69 © bioMérieux, Inc., Customer Education March 2008 Mode of Action Effect Chloramphenicol Binds to the 50S ribosomal sub-unit Inhibits elongation step of protein synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Chloramphenicol • Relatively small molecule, easily enters Gram-positive and Gram-negative bacteria • Target is Ribosome • Binds to 50S subunit where it inhibits elongation step of protein synthesis
  • 70.
    Customer Education AntibioticClassification 70 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis Oxazolidinones: • Bacteriostatic • Narrow spectrum
  • 71.
    Customer Education AntibioticClassification 71 © bioMérieux, Inc., Customer Education March 2008 NEW 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Oxazolidinones Linezolid Inhibitors of Protein Synthesis Oxazolidinones: Linezolid • Spectrum of Action: Gram-positive infections. Effective for E. faecium VRE, MRSA and multi-drug resistant S. pneumoniae. • Trade Name = Zyvox®
  • 72.
    Customer Education AntibioticClassification 72 © bioMérieux, Inc., Customer Education March 2008 MODEOFACTION EFFECT Linezolid Binds to the 50Sribosomal sub-unit Inhibits initiation process of protein synthesis 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Linezolid • Relatively small molecule, easily enters Gram-positive bacteria • Target is Ribosome • Linezolid disrupts bacterial growth by inhibiting the initiation process in protein synthesis • This site of inhibition occurs earlier in the initiation process than other protein synthesis inhibitors (e.g., chloramphenicol, clindamycin, aminoglycosides, and macrolides) that interfere with the elongation process • Because the site of inhibition is unique to linezolid, cross-resistance to other protein synthesis inhibitors has not yet been reported • Linezolid may also inhibit virulence factor expression and decrease toxin production in Gram-positive pathogens • It has been demonstrated that linezolid is bacteriostatic against Enterococci and Staphylococci, and bactericidal for the majority of Streptococci • Gram-negative bacteria appear to be naturally resistant
  • 73.
    Customer Education AntibioticClassification 73 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Inhibitors of Protein Synthesis Ansamycins Rifamycins Rifampin (Rifamipicin): • Bacteriostatic or bactericidal – depending on organism and concentration • Broad spectrum • Discovered in 1959 • Natural or semi-synthetic derivitive of Amycolatopsis rifamycinica (previously Streptomyces mediterranei)
  • 74.
    Customer Education AntibioticClassification 74 © bioMérieux, Inc., Customer Education March 2008 2. Inhibitors of Protein Synthesis2. Inhibitors of Protein Synthesis Ansamycins Rifampin (Rifampicin) Inhibitors of Protein Synthesis Ansamycins Rifamycins Rifampin (Rifamipicin): Spectrum of Action: • Primarily Gram-positive organisms and some Gram-negatives • Used in combinations with other drugs to treat tuberculosis • Used to treat carriers of N.meningitidis (prophylaxsis) • Used in combination with other antibiotics for severe Staphycoccal infections (including MRSA) • Oral or IV administration Mode of Action: Forms a stable complex with RNA polymerase and prevents DNA from being transcribed into RNA, thus inhibiting protein synthesis
  • 75.
    Customer Education AntibioticClassification 75 © bioMérieux, Inc., Customer Education March 2008 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Lipopeptides Polymyxins Cyclic Lipopeptides NEW CLASS Inhibitors of Membrane Function Lipopeptides: (previously Polypeptides) Polymyxins have been around since 1940’s and 1950’s. Polymyxin A,B,C,D,E • Polymyxin B and E can be used therapeutically • Polymyxin B – derived from Bacillus polymyxa var. aerosporus • Polymyxin E – derived from Bacillus polymyxa var. colistinus = Colistin Colistin exsists as two forms: • Colistin sulfate – intestinal infections, topical, powders, media • Colistimethate sodium – most active, effective form • All Bactericidal
  • 76.
    Customer Education AntibioticClassification 76 © bioMérieux, Inc., Customer Education March 2008 Polymyxin B 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Polymyxins Colistin Inhibitors of Membrane Function Lipopeptides: Polymyxins Polymyxin B Spectrum of Action: Narrow spectrum for Gram-negative UTI, blood, CSF and eye infections. Can be used in combination against very resistant Pseudomonas, KPC. • High toxicity – neurotoxic and nephrotoxic • IV, IM and topical for infected wounds Colistin (Colistimethate Sulfate) Spectrum of Action: Narrow spectrum for Gram-negatives, especially Pseudomonas aeruginosa infections in cystic fibrosis patients. It has come into recent use for treating multi-drug resistant Acinetobacter infections. Ineffective for Proteus and Burkholderia. • High toxicity – neurotoxic and nephrotoxic • PO, IV and topical
  • 77.
    Customer Education AntibioticClassification 77 © bioMérieux, Inc., Customer Education March 2008 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Mode of ActionMode of Action ofof PolymyxinsPolymyxins Lipopeptides • Polymyxins • Polymyxin B • Colistin • Cyclic Lipopeptides • Daptomycin
  • 78.
    Customer Education AntibioticClassification 78 © bioMérieux, Inc., Customer Education March 2008 Outer Membrane Peptidoglycan Cytoplasmic Membrane Polymyxin Respiratory Enzymes + ++ - -- - - - -- Entry of Polymyxins 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function + + + LPS Polymyxin Mode of Action Target =Membrane phospholipids (lipopolysaccharides (LPS) and lipoproteins) 1. Outer and Cytoplasmic Membrane Effect: Polymyxins are positively charged molecules (cationic) which are attracted to the negatively charged bacteria. The negative charge of bacteria is due to LPS in the outer membrane and the peptidoglycan (notably the teichoic acid). The antibiotic binds to the cell membrane, alters its structure and makes it more permeable. This disrupts osmotic balance causing leakage of cellular molecules, inhibition of respiration and increased water uptake leading to cell death. The antibiotic acts much like a cationic detergent and effects all membranes similarly. Toxic side effects are common. Little or no effect on Gram-positives since the cell wall is too thick to permit access to the membrane. Gram-positives are naturally resistant.
  • 79.
    Customer Education AntibioticClassification 79 © bioMérieux, Inc., Customer Education March 2008 Daptomycin 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Cyclic Lipopeptides Inhibitors of Membrane Function Lipopeptides: Cyclic Lipopeptide Daptomycin (Cubicin) • Cubicin from CUBIST Pharmaceutical got FDA approval on September 12, 2003 • Bactericidal • Resistance rate appears to be low - requires multiple mutations • Only ‘Sensitive’ CLSI® breakpoints
  • 80.
    Customer Education AntibioticClassification 80 © bioMérieux, Inc., Customer Education March 2008 Daptomycin FDA approval for skin/skin structure infections S.aureus (MSSA and MRSA) Beta-hemolytic Streptococci (A,B,C,G) E.faecalis (Vanco sensitive) Cyclic Lipopeptides 3. Inhibitors of Membrane Function3. Inhibitors of Membrane Function Inhibitors of Membrane Function Lipopeptides: Cyclic Lipopeptide Daptomycin (Cubicin) Spectrum of Action: Daptomycin: Daptomycin is bactericidal. Active against Gram-positive bacteria (MRSA, MSSA) including those resistant to methicillin, vancomycin and linezolid. • 1/day IV dosing • Requires Ca++ in the media Mode of Action: Binds to components (calcium ions) of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein. Gram-negatives appear to be naturally resistant.
  • 81.
    Customer Education AntibioticClassification 81 © bioMérieux, Inc., Customer Education March 2008 4. Anti4. Anti--MetabolitesMetabolites Sulfonamides Trimethoprim/Sulfamethoxazole (Folate Pathway Inhibitors) Anti-Metabolites • Called folate pathway inhibitors or anti-metabolites Folic acid is essential for the synthesis of adenine and thymine, two of the four nucleic acids that make up our genes, DNA and chromosomes. Humans do not synthesize folic acid. Good selective target. Sulfonamides • Bacteriostatic • Introduced in 1930’s – first effective systemic antimicrobial agent • Used for treatment of acute, uncomplicated UTI’s Trimethoprim/Sulfamethoxazole • TMP/SXT is bactericidal • Broad spectrum • Synergistic action
  • 82.
    Customer Education AntibioticClassification 82 © bioMérieux, Inc., Customer Education March 2008 Trimethoprim/Sulfamethoxazole 4. Anti4. Anti--MetabolitesMetabolites (Folate Pathway Inhibitors) Anti-Metabolites Trimethoprim/Sulfamethoxazole: Spectrum of Action: Prescribed for treatment of certain UTI’s, otitis media in children, chronic bronchitis in adults, enteritis and Travelers’ Diarrhea.
  • 83.
    Customer Education AntibioticClassification 83 © bioMérieux, Inc., Customer Education March 2008 Mode of ActionMode of Action ofof AntiAnti--metabolitesmetabolites 4. Anti4. Anti--MetabolitesMetabolites
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    Customer Education AntibioticClassification 84 © bioMérieux, Inc., Customer Education March 2008 Competitive Antagonism 4. Anti4. Anti--MetabolitesMetabolites TMP/SXT Mode of Action • The drug resembles a microbial substrate and competes with that substrate for the limited microbial enzyme • The drug ties up the enzyme and blocks a step in metabolism
  • 85.
    Customer Education AntibioticClassification 85 © bioMérieux, Inc., Customer Education March 2008 Pathway for the Synthesis of Tetrahydrofolic Acid, a Cofactor needed for the Synthesis of DNA and RNA Synthesis of Tetrahydrofolic Acid 4. Anti4. Anti--MetabolitesMetabolites • Sulfonamides such as sulfamethoxazole tie up the enzyme pteridine synthetase while trimethoprim ties up the enzyme dihydrofolic acid reductase. As a result, tetrahydrofolic acid is not produced by the bacterium. • Sulfonamides, trimethoprim alone and in combination block folic acid essential for the synthesis of adenine and thymidine that make up the DNA, RNA. Therefore, folate pathway inhibitors do not have direct antibiotic activity but the end result is the same, the bacteria is unable to multiply. • The combination SXT (thrimethoprim-sulfamethoxazol) is synergistic and the association provides a bactericidal effect • Natural Resistance Enterococcus – low level and poorly expressed S. pneumoniae Ps. aeruginosa (impermeability)
  • 86.
    Customer Education AntibioticClassification 86 © bioMérieux, Inc., Customer Education March 2008 Quinolones Furanes 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis
  • 87.
    Customer Education AntibioticClassification 87 © bioMérieux, Inc., Customer Education March 2008 Ciprofloxacin Levofloxacin MoxifloxacinGatifloxacin 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Quinolones Inhibitors of Nucleic Acid Synthesis Quinolones: • Humans do synthesize DNA - shared process with bacteria • Do tend to see some side effects with Quinolones • Some drugs withdrawn from market quickly • All are bactericidal
  • 88.
    Customer Education AntibioticClassification 88 © bioMérieux, Inc., Customer Education March 2008 International Common Name Quinolones 1st Generation – Narrow Spectrum Nalidixic Acid Cinoxacin Fluoroquinolones Ciprofloxacin Enoxacin Garenoxacin Levofloxacin Lomefloxacin Norfloxacin Ofloxacin Sparfloxacin Gatifloxacin Moxifloxacin Trovafloxacin 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Quinolones Inhibitors of Nucleic Acid Synthesis Quinolones: • 1st Generation Quinolones: Only for Gram-negatives, used to treat urinary tract infections because they reach high concentrations in the site of infection. • Fluoroquinolones: Garenoxacin Gram-negative and Gram-positive coverage including Anaerobes, Atypicals, S.pneumoniae and Pseudomonas. In development for VT2 cards, not yet approved. • Fluoroquinolones: Ciprofloxacin, Levofloxacin, Norfloxacin, Ofloxacin) More effective (lower MIC values). Spectrum extended to cover Staphylococci, Streptococci and Pneumococci (sparfloxacin). More widespread tissue distribution (they reach the intestine and the lungs). Ciprofloxacin and Ofloxacin used for systemic infections. • Fluoroquinolones: Sparfloxacin, Gatifloxacin, Moxifloxacin Trovafloxacin removed from market very quickly after release cardiac arrhythmias, liver destruction, phototoxicity. Gatifloxacin (Tequin® ) removed from market 05/01/06 - diabetes.
  • 89.
    Customer Education AntibioticClassification 89 © bioMérieux, Inc., Customer Education March 2008 Mode of ActionMode of Action ofof QuinolonesQuinolones 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis
  • 90.
    Customer Education AntibioticClassification 90 © bioMérieux, Inc., Customer Education March 2008 Outer Membrane Peptido - glycan Cytoplasmic Membrane Quinolones 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Entry of Quinolones Quinolone Mode of Action • Small and hydrophilic, quinolones have no problem crossing the outer membrane. • They easily diffuse through the peptidoglycan and the cytoplasmic membrane and rapidly reach their target. • Target = Topoisomerases, e.g., DNA-gyrase • Rapid bactericidal activity
  • 91.
    Customer Education AntibioticClassification 91 © bioMérieux, Inc., Customer Education March 2008 Circular Bacterial DNA Coiled by DNA Gyrase Fits inside the bacterial cell 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Supercoiling of DNA • The bacterial chromosome is supercoiled by the enzyme DNA gyrase • A fully supercoiled chromosome will be about 1 micron in diameter - small enough to fit in the bacteria • The bacterial chromosome consists of a single circle of DNA • DNA is double-stranded forming a left-handed double helix • A typical E. coli’s chromosome is 1400 microns long • The E. coli’s bacterial cells are 2-3 microns long
  • 92.
    Customer Education AntibioticClassification 92 © bioMérieux, Inc., Customer Education March 2008 DNA Gyrase DNA Gyrase+QUINOLONE DNA Gyrase cuts DNA to regulate supercoiling. The Quinolone - DNA Gyrase complex blocks the supercoiling process. enzyme DNA 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Quinolones • Quinolones inhibit DNA synthesis • All topoisomerases can relax DNA but only gyrase can also carry out DNA supercoiling (‘supercoiling’ process is necessary to compact the bacterial chromosome which is 1000 times longer than the bacterial cell). Topoisomerases are also involved in DNA replication, transcription and recombination. • The main quinolone target is the DNA gyrase which is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process. The nick is only introduced temporarily and later the two ends are joined back together (i.e., repaired). • The quinolone molecule forms a stable complex with DNA gyrase thereby inhibiting its activity and preventing the repair of DNA cuts • Natural Resistance Gram Positives – 1st generation quinolones S.pneumoniae – decreased activity to Ofloxacin and Ciprofloxacin Ps. aeruginosa – decreased activity to Norfloxacin and Ofloxacin
  • 93.
    Customer Education AntibioticClassification 93 © bioMérieux, Inc., Customer Education March 2008 Quinolones Furanes 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis
  • 94.
    Customer Education AntibioticClassification 94 © bioMérieux, Inc., Customer Education March 2008 Furanes Nitrofurantoin 5. Inhibitors of Nucleic Acid Synthesis5. Inhibitors of Nucleic Acid Synthesis Nitrofurans: Nitrofurantoin • Spectrum of Action: Urinary Tract Infections caused by Gram-negative and Gram-positive organisms • Broad spectrum • Bactericidal • Oral Mode of Action: The drug works by damaging bacterial DNA. In the bacterial cell, nitrofurantoin is reduced by flavoproteins (nitrofuran reductase). These reduced products are are highly active and attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal acitivity. Natural Resistance: Pseudomonas and most Proteus spp. are naturally resistant.
  • 95.
    Customer Education AntibioticClassification 95 © bioMérieux, Inc., Customer Education March 2008 Antibiotics and Modes of ActionAntibiotics and Modes of Action Questions?