Antimicrobial Drugs and Resistance PDF

Lecture Overview: Antimicrobial Drugs  Overview of Antimicrobial  Norman-McKay assigned drugs readings:  Antibiotics classes  Chapter 15  Mechanisms for bacterial resistance  The spread of bacterial...

Lecture Overview: Antimicrobial Drugs  Overview of Antimicrobial  Norman-McKay assigned drugs readings:  Antibiotics classes  Chapter 15  Mechanisms for bacterial resistance  The spread of bacterial resistance  Acquired resistance  Antibiotic Stewardship  Resistant microbes of greatest concern 1 MMG1650 2024 Antimicrobial drugs radically changed modern medicine  Antimicrobial drugs: therapeutic compounds that kill microbes or inhibit their growth  Categorized based on the type of pathogen they target:  Antibacterial drugs (antibiotics) – treat bacterial infections  Antiviral drugs – target viral infections  Antifungal drugs – target fungal infections  Antiparasitic drugs – treat protozoan and helminthic (worm) infections  Prophylaxis: process that prevents infection or disease in a person at risk 2 MMG1650 2024 Where do antibiotics exist in nature?  Alexander Fleming (1928) determined that the mold excreted a compound that could inhibit the bacteria  Penicillin (from mold species Penicillium rubens)  Penicillin was mass-produced by the 1940s Figure 15.1 Norman-McKay. Microbiology: Basic and Clinical Principles. 2019 3 MMG1650 2024 Modifying Antibiotic Drugs  Antimicrobial compounds can be chemically modified  Semisynthetic  First-generation drugs  First round of chemical modification  Second-generation drugs  Second round of chemical modification  Drugs in later generations have expanded capabilities Figure 15.3 Norman-McKay. Microbiology: Basic and Clinical Principles. 2019 4 MMG1650 2024 If you know what type of bacteria is causing the infection you can choose the best antibiotic Empiric therapy is commonly started to protect the patient https://en.wikipedia.org/wiki/Antimicrobial_spectrum 5 MMG1650 2024 Know the classes of antibiotics and their cellular targets (mode of action) Daptomycin 6 MMG1650 2024  Norman-McKay. Microbiology: Basic and Clinical Principles. 2019 Beta-Lactams target cell walls  Beta-lactam antibiotics  Contain a four-sided beta-lactam ring  Prevent cross-linking of peptidoglycan Figure 15.6  Includes:  Penicillins  Names end in “cillin”  Cephalosporins (esp. 2nd-5th gen.)  Names begin with “cef-” or “ceph”  Carbapenems  Names end in “-penem”  Effective against multidrug-resistant (MDR) bacteria  CRE = Carbapenem resistant Enterobacteriaceae 7 MMG1650 2024 Importance of Peptidoglycan cross-linking Figure 15.5 Norman-McKay. Microbiology: Basic and Clinical Principles. 2019 8 MMG1650 2024 Vancomycin  Mode of action (MOA):  Considerations  Disrupt cell wall synthesis  Super toxic  Glycopeptide class – not β-  Monitor infusion rate to lactam avoid Red Man’s syndrome  Indications:  Growing resistance  Methicillin-resistant  Vancomycin-resistant S. Staphylococcus aureus aureus (VRSA)  Vancomycin-resistant enterococci (VRE) Red man syndrome Journal of Clinical Neuroscience Volume 50, April 2018, Pages 149- 150 https://doi.org/10.1016/j.jocn.2018.0 1.044 9 MMG1650 2024 Tetracyclines  Mode of action (MOA):  Considerations  Inhibit protein synthesis →  Take without food inhibition of bacterial cell  Avoid sun exposure growth  Common Key Generics  Indications: (Brands):  Skin infections  Ending in “-cycline”  Dental infections  Minocycline (Minocin)  Atypical infections  Doxycycline (Doryx, Periostat)  Tetracycline  Tigecycline 10 MMG1650 2024 Macrolides  Mode of action (MOA):  Considerations  Inhibit protein synthesis →  Take without food inhibition of bacterial cell  Common Key Generics growth (Brands):  Indications:  Ending in “-mycin”  Respiratory infections  Azithromycin (Zithromax)  STI  Clarithromycin (Biaxin)  Otitis media  Erythromycin (Ery-Tab)  Atypical infections  Note: * not every “-mycin” is a macrolide!* 11 MMG1650 2024 Fluoroquinolones  Mode of action (MOA):  Considerations  Interference with enzymes  Take without food for DNA replication  Avoid sun exposure  Indications:  Common Key Generics  Pneumonia (Brands):  Good option for resistant  Contain “-fl-” bacteria  Ciprofloxacin (Cipro)  Often reserved for empiric  Levofloxacin (Levaquin) use in severe infections  Mycobacterium tuberculosis  Enteric GN 12 MMG1650 2024 Aminoglycosides  Mode of action (MOA):  Considerations  Powerful inhibitors of  Super toxic! protein synthesis  Esp. for GN  Common Key Generics  Indications: (Brands):  GN infections  Ending in “-cin”  Eye infections  Not “-thromycin”  Ear infections  Not “-floxacin”  Endocarditis  Amikacin  Gentamicin  Neomycin  Tobramycin (Tobrex) 13 MMG1650 2024 Sulfonamides  Mode of action (MOA): https://basicmedicalkey.com/sulfonamides-trimethoprim-sulfamethoxazole-quinolones-and-agents-for-  Inhibition of folic acid synthesis → inhibiting bacterial cell growth  Folic acid needed for RNA/DNA and protein synthesis  Common Names/(Brands):  Sulfamethoxazole-Trimethoprim (Bactrim, Septra) urinary-tract-infections-2/ 14 MMG1650 2024 Daptomycin  Mode of action (MOA):  Considerations  Targets the plasma  IV or injection only (cytoplasmic membrane) → lysis  Effective against GN only; Cannot penetrate GP  Indications:  GN drug resistant infections 15 MMG1650 2024 16 MMG1650 2024 17 MMG1650 2024 Mechanisms of antimicrobial resistance: How does antibiotic resistance occur?  (1) Target Alteration  (2) Drug inactivation  (3) Reducing drug concentrations inside the cell International Journal of Molecular Sciences. 2020; 21(4):1363. https://doi.org/10.3390/ijms21041363 18 MMG1650 2024 Mechanisms of antimicrobial resistance  1. Target alterations  Bacterial protein changes (mutates); drug is no longer effective  β-lactam drugs bind the bacterial protein transpeptidase (PBP)  Some bacteria have a mutated form of PBP called PBP2a  β -lactam drugs will not bind PBP2a→ β -lactam resistance  2. Drug inactivation  Acquire new proteins (acquire new genes)  β -lactamases are enzymes that will cut (hydrolyze) the beta-lactams so they no longer work  Leads to β -lactam resistance 19 MMG1650 2024  Mechanisms of antimicrobial resistance  3. Reducing Drug Concentrations Inside the Cell  Limiting drug entry or pumping drugs out  Porins/transporters: mutated porins means certain drugs will not enter bacterial cell  Efflux pumps: pump drugs out; no effect intracellularly Mutated porins Efflux pumps 20 MMG1650 2024 How does antibiotic resistance spread? Horizontal gene transfer  Horizontal Gene Transfer  Genetic information passed between cells independent of cell division  HGT (acquisition of new genes) occurs in 3 ways:  Transformation  Take up new DNA from environment  Transduction  Genes transported between bacterial cells by bacteriophages (viruses)  Conjugation  Sharing DNA thru physical connection (sex pilus) 21 MMG1650 2024  Horizontal gene transfer: The spread of antimicrobial resistance Figure 15.5 Norman-McKay. Microbiology: Basic and Clinical Principles. 2019 22 MMG1650 2024 How do we respond to rise in antibiotic resistance?  Healthcare Settings as Incubators for Antimicrobial Resistance  Antimicrobial-resistant strains commonly found in clinical settings  ~32% healthcare workers have resistant strains on their hands, scrubs, and personal electronic devices  Antibiotic stewardship  a coordinated program that promotes the appropriate use of antibiotics,  microbial resistance, and  the spread MDR microbes  Without these efforts:  Estimate by 2050: 10 million/yr worldwide will die as a result of antimicrobial-resistant pathogens 23 MMG1650 2024 Resistant Microbes of greatest concern  According to CDC (2019): Urgent threats  Clostridium difficile (Clostridioides difficile)  Carbapenem-resistant Enterobacteriaceae (CRE)  Drug-resistant Neisseria gonorrhoeae  According to CDC (2019): Serious threats  Methicillin-resistant Staphylococcus aureus (MRSA)  Vancomycin-resistant Enterococcus (VRE)  and many more…  Check this out for more info:  https://www.cdc.gov/drugresistance/biggest-threats.html 24 MMG1650 2024 Learning Objectives:  After attending the lecture and completing the assigned readings the student will:  Define: empiric therapy and prophylaxis  For each drug class, identify: cellular target (mode of action) and whether they are bacteriostatic or bactericidal  Identify the 3 drug classes that are considered beta-lactam drugs  Explain the significance of MRSA, VRSA, and CRE  Describe the three mechanisms by which antibiotic resistance may develop  Define horizontal gene transfer and describe the 3 ways it occurs in bacteria 25 MMG1650 2024