Antimicrobial Drugs PDF

Antimicrobial drugs DR INDRAN BALAKRISHNAN CONSULTANT/HON. ASSOC. PROFESSOR IN MEDICAL MICROBIOLOGY ROYAL FREE HOSPITAL AND UNIVERSITY COLLEGE LONDON Content  Concept of selective toxicity  Main groups of antibiotics and examples  Pharmacokinetic and pharmacodynamic concepts rele...

Antimicrobial drugs DR INDRAN BALAKRISHNAN CONSULTANT/HON. ASSOC. PROFESSOR IN MEDICAL MICROBIOLOGY ROYAL FREE HOSPITAL AND UNIVERSITY COLLEGE LONDON Content  Concept of selective toxicity  Main groups of antibiotics and examples  Pharmacokinetic and pharmacodynamic concepts relevant to antibiotic use  Safety concerns around antibiotics  Antibiotic resistance  Rational use of antibiotics ILO  To gain a broad overview of the mechanisms of action of antibiotics  To gain an overview of the various considerations involved in antibiotic use  To appreciate the significance of the spectre of antibiotic resistance Antimicrobial Drugs Antibiotic: Substance produced by a microorganism that in small amounts inhibits the growth of another microbe. Antibiotic producing microbes include:  Gram-Positive Rods:  Bacillus subtilis: Bacitracin  Bacillus polymyxa: Polymyxin  Fungi:  Penicillium notatum: Penicillin  Cephalosporium spp.: Cephalothin  Actinomycetes:  Streptomyces venezuelae: Chloramphenicol  Streptomyces griseus: Streptomycin  Streptomyces nodosus: Amphotericin B  Micromonospora purpurea: Gentamicin Antimicrobial Mechanisms of Action Selective Toxicity  Inhibition of Cell Wall Synthesis: Interfere with peptidoglycan synthesis.  Result in cell lysis.  Low toxicity. E.g. B-lactams (Penicillin) Glycopeptides (Vancomycin) Β-Lactams  3 groups  Penicillins  Cephalosporins  Carbapenems  Inhibit enzymes involved in cell wall assembly  No activity against atypical organisms  Mycoplasma  Legionella  Chlamydia Glycopeptides Antimicrobial Mechanisms of Action  Inhibition of Protein Synthesis: Interfere with procaryotic (70S) ribosomes, also found in mitochondria.  Most have broad spectrum of activity E.g. Tetracyclines Macrolides (erythromycin) Aminoglycosides (gentamicin) Macrolides - Action & Resistance Quiz 1  The site of action of B-lactam antibiotics is:  A) Cell membrane  B) Cell wall  C) DNA  D) Mitochondria  E) Ribosome Quiz 1  Cell wall – transglycosylases and transpeptidases involved in peptidoglycan biosynthesis Antimicrobial Mechanisms of Action Selective Toxicity  Injury to the Plasma Membrane: Cause changes in membrane permeability.  Result in loss of metabolites and/or cell lysis.  Many polypeptide antibiotics. E.g. Polymyxin B (antibacterial) or fluconazole (antifungal).  Inhibition of Nucleic Acid (DNA/RNA) Synthesis: Interfere with DNA replication and transcription. E.g. Quinolones (Ciprofloxacin) Quinolones - Mode of Action Antimicrobial Mechanisms of Action  Selective Toxicity  Inhibition of Synthesis of Essential Metabolites: Involve competitive inhibition of key enzymes.  Closely resemble substrate of enzyme. E.g. Trimethoprim inhibits the synthesis of folic acid. Antifolates – Mode of Action Influences on drug efficacy  Distribution (pharmacodynamics) in body (membrane permeability lipid soluble/active transport)  Concentrations in tissues, bone, CSF, bile etc  Metabolism (pharmacokinetics)- can the antibiotic be broken down and rendered ineffective?  Excretion (liver, kidneys)- Does renal/liver impairment lead to toxicity?  Dosing Regimens Appropriate therapy  Administration either external (topical) or systemic (blood stream)  Systemic drugs can be administered intravenously, intramuscularly or orally  Frequency of doses can vary Safety Concerns with the Use of Antimicrobials: Toxicity Kidney and ear damage (aminoglycosides) Liver damage Pseudomembranous colitis  Interactions with other medications May neutralize effectiveness of contraceptive pills  Hypersensitivity reactions Anaphylactic reactions to penicillin  Foetal damage/risk to pregnant women Tetracycline causes discoloration of teeth in children and may cause liver damage in pregnant women Fluoroquinolones may cause cartilage damage.  Antibiotic Resistance Quiz 3 The main side effect of gentamicin is: a) Bone marrow suppression b) Nephrotoxicity c) Neurotoxicity d) Rash e) Tooth discoloration Quiz 3  Nephrotoxicity  Ototoxicity  Serum levels are monitored Evolution of Resistance Genetics  Random genetic event  Acquisition of DNA  Plasmids  Transposons  Naked DNA  Alteration of DNA  Mutation  Loss of DNA  Deletion Bacteria and Genes 2 2 IB  Antibiotics kill bacteria by inactivating or damaging bacterial proteins  All bacterial proteins are encoded by bacterial genes  These genes are being changed and exchanged continually  So the proteins they encode are also being changed and exchanged Resistance Mechanisms Quiz 2  The action of B-lactamases is to:  A) Break down B-lactam antibiotics  B) Inhibit fungal replication  C) Inhibit DNA supercoiling  D) Inhibit protein synthesis  E) Reduce the emergence of resistance Quiz 2  B-lactamases hydrolyse B-lactam antibiotics, rendering them inactive. Fitness Cost of Resistance 2  These resistance mechanisms impose a biological cost  Resistant bacteria grow more slowly than sensitive bacteria 6 IB ……….unless an effective antibiotic is present  The effective antibiotic exerts a selection pressure on the bacterial population  Susceptible bacteria will die  Resistant bacteria will survive and multiply  A resistant population will replace the susceptible one  The antibiotic transforms the biological disadvantage of resistance into an overwhelming selective advantage  Reducing Resistance 2 7 -Reduce Antibiotic Exposure IB  Does the patient need antibiotics?  Is there an infection?  Many non-infective illnesses can mimic infection  Acute asthma can look like pneumonia  Epilepsy can look like meningitis  Is the infection bacterial  Viral infections usually do not need treatment  Gastroenteritis  Pneumonia  Meningitis  Reducing Resistance 2 8 -Keep The Antibiotic Spectrum Narrow IB  Some antibiotics are active against many different bacteria (broad spectrum)  Meropenem  Cefotaxime  Ceftriaxone  Some antibiotics are active against only a few bacteria (narrow spectrum)  Flucloxacillin  Trimethoprim  Nitrofurantoin  Metronidazole  In order for the antibiotic to exert selection pressure, it must be active against the organism  The narrower the spectrum, the less the selection pressure for resistance Reducing Resistance 2 9 -Start Smart Then Focus IB  Sometimes, when you have a sick patient, and you are not sure what is wrong with them, you have to start broad spectrum antibiotics  The important thing is to send off all the lab tests before you start  Review in 48 hours  Clinical state  White cell count  Temperature  Any cultures  And then ask these questions:  Does the patient need antibiotics?  Is this the most appropriate antibiotic? Reducing Resistance 3 0 -Keep The Antibiotic Duration Short IB  Selection pressure is only exerted in the presence of the antibiotic  Every dose exerts additional pressure  Stop the antibiotic and the pressure disappears  If an antibiotic has been started, and tests subsequently show that there is no bacterial infection  STOP the antibiotic  There is no need to “complete the course”  Most infections resolve within 5D  Most antibiotics should be stopped within 5D Summary  Many derived from biological sources  Different sites of action – “target site”  Selective toxicity  PD/PK determine dosage and route of administration QR code  Toxicity for student feedback  Drug resistance of increasing concern