Antimicrobial Agents - CEU Cardenal Herrera

Chapter 3: Antimicrobial agents Dra Verónica Veses- Jimenez [email protected] Overview Introduction to antimicrobial agents History of antimicrobial discovery/development Antimicrobial action Targets of antimicrobial agents Antimicrobial resistance INTRODUCTION TO ANTIMICROBIAL...

Chapter 3: Antimicrobial agents Dra Verónica Veses- Jimenez [email protected] Overview Introduction to antimicrobial agents History of antimicrobial discovery/development Antimicrobial action Targets of antimicrobial agents Antimicrobial resistance INTRODUCTION TO ANTIMICROBIAL AGENTS Antimicrobial Chemotherapy Use of drugs to combat infectious agents – Antibacterial (antibiotics) – Antiviral – Antifungal – Antiparasitic Antimicrobial Chemotherapy Differential toxicity: based on the concept that the drug is more toxic to the infecting organism than to the host Majority of antimicrobials are substances produced by various species of microorganisms: bacteria, fungi, actinomycetes- to suppress the growth of other microorganisms and to destroy them, or may be semi- synthetic or synthetic What is the ideal antimicrobial Have the appropriate spectrum of activity for the clinical setting Have no toxicity to the host, be well tolerated Low propensity for development of resistance Not induce hypersensitivies in the host Have rapid and extensive tissue distribution Have a relatively long half-life Be free of interactions with other drugs Be convenient for administration Be relatively inexpensive HISTORY Fathers of Antimicrobial Therapy The German chemist Paul Ehrlich developed the idea of selective toxicity: that certain chemicals that would be toxic to some organisms, e.g., infectious bacteria, would be harmless to other organisms, e.g., humans. In 1928, Sir Alexander Fleming, a Scottish biologist, observed that Penicillium notatum, a common mold, had destroyed staphylococcus bacteria in culture. Sir Alexander Fleming Around the fungal colony is a clear zone where no bacteria are growing Zone of inhibition due to the diffusion of a substance with antibiotic properties from the fungus Timeline of antibiotic discovery ANTIMICROBIAL ACTION How do antimicrobial agents work must bind or interfere with an essential target may inhibit or interfere with essential metabolic process may cause irreparable damage to cell Definitions Spectrum of Activity: – Narrow spectrum - drug is effective against a limited number of species – Broad spectrum - drug is effective against a wide variety of species Definitions II Minimum Inhibitory Concentration (MIC) - minimum concentration of antibiotic required to inhibit the growth of the test organism. Minimum Bactericidal Concentration (MBC) - minimum concentration of antibiotic required to kill the test organism. Bacteriostatic Bactericidal Time dependent killing Concentration dependent killing Definitions III Treatment vs prophylaxis Prophylaxis - antimicrobial agents are administered to prevent infection Treatment - antimicrobial agents are administered to cure existing or suspected infection ANTIMICROBIAL TARGETS Targets of antibacterial agents Inhibit cell wall production Inhibit protein synthesis Inhibit nucleic acid synthesis Block biosynthetic pathways Disrupt bacterial membranes INHIBIT CELL WALL PRODUCTION Classes β-lactams: – Penicillins – Cephalosporins – Monobactams – Carbapenems Glycopeptides – Vancomycin – Teicoplanin Penicillins Penicillins contain a β-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-positive organisms) Penicillins are bactericidal but can act only on dividing cells They are not toxic to animal cells which have no cell wall β-lactams are produced by fungi, some ascomycetes, and several actinomycete bacteria PBP: transpeptidase The bacterial cell wall is a unique biopolymer in that it contains both D- and L-amino acids. Its basic structure is a carbohydrate backbone of alternating units of N- acetyl glucosamine and N-acetyl muramic acid. The NAM residues are cross-linked with oligopeptides Mode of action The β-lactam binds to Penicillin Binding Protein (PBP) PBP is unable to crosslink peptidoglycan chains The bacteria is unable to synthesize a stable cell wall The bacteria is lysed Examples Penicillin G / V - good gram positive (not Staphylococcus) -not useful from gram negatives or anaerobic bacteria Synthetic penicillins (Ampicillin) - good gram positive (not Staphylococcus) - moderate gram negative (not Pseudomonas) Anti-staphylococcal penicillins - Cloxacillin, Methicillin Anti-pseudomonal penicillins - Piperacillin Beta-lactamases Bacterial enzymes that inactivate the betalactamic antibiotics. More tan 200 different beta-lactamases have been described. There are four clases: – A: penicillases found in common gram-negative bacilli, with minimum activity against cephalosporins – B: zinc-dependent metalloenzymes that have a broad spectrum of activity against all beta-lactams – C: cephalosporinases encoded on the bacterial chromosome – D: penicillases found in common gram-negative bacilli Compounds such as clavulanic acid, sulbactam, or Cephalosporins History – Discovered in sewage in Sardinia in the mid 1940s. – Cephalosporium sp was recovered and proved a source of cephalosporin. – Subsequently, four generations of cephalosporins have emerged. Cephalosporins: mode of action and classification They have the same mechanism of action than penicillin (inhibition PBP) however they have a wider antibacterial spectrum, are resistant to many beta-lactamases, and have longer half-lives. CLASSIFICATION: – first generation are early compounds – second generation- resistant to β-lactamases – third generation- resistant to β-lactamases & increased spectrum of activity – fourth generation- increased spectrum of activity Cephalosporins: examples 1st generation- mainly gram positive, some gram negative (cefazolin) 2nd generation- weaker gram positive, better gram negative (cefuroxime) 3rd generation - excellent gram negative, some gram positive (ceftriaxone) 4th generation - excellent gram negative, good gram positive Other beta-lactams Monobactams: narrow spectrum Carbapenems: Most broad spectrum of activity of all antimicrobials Have activity against gram-positive and gram-negative aerobes and anaerobes except: – Methicillin Resistant Staphylococcus aureus and Methicillin Resistant Staphylococcus epidermidis – Enterococcus faecium – Stenotrophomonas maltophilia – Burkholderia cepacia Glycopeptides Inhibit bacterial cell wall synthesis by binding to the D- alanine-D-alanine termini of the pentapeptide chains, which interferes with the formation of bridges between the peptidoglycan chains. Narrow spectrum affecting only Gram-positive bacteria (they cannot cross the outer membrane of Gram- negatives) Bactericidal (except for Enterococcus) Examples: vancomycin; teicoplanin Vancomycin : “Last resort” drug in medicine INHIBITORS OF PROTEIN SYNTHESIS Inhibitors of protein synthesis Inhibit protein synthesis by binding to the ribosome; binding may be reversible or irreversible Includes – macrolides and ketolides – Chloramphenicol and lincosamides – Tetracyclines – Aminoglycosides – Streptogramins – Oxazolididones Macrolides Erythromycin, clarithromycin, azithromycin Mode of action - The macrolides inhibit translocation by binding to 50 S ribosomal subunit. Bacteriostatic Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella (intracellular bacteria) Chloramphenicol and Lincosamides Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. Spectrum of activity: – Chloramphenicol - Broad range – Lincomycin (first isolated from Streptococcus lincolnensis) and clindamycin - Moderate-spectrum; they are primarily active against Gram-positive bacteria, most anaerobic bacteria and some mycoplasma. Chloramphenicol : Adverse effects Chloramphenicol is toxic but is used in the treatment of bacterial meningitis It causes a rare anemia, probably immunological in origin but often fatal Reversible bone marrow depression caused by its effect on protein synthesis in humans Liver enzyme inhibition Aminoglycosides gentamicin, tobramycin, amikacin Mode of action: bind to 30S subunit of the ribosomes and inhibit transpeptidation and translocation processes, resulting in premature detachment of incomplete polypeptide chains. Are bactericidal Spectrum of action - excellent gram negative, moderate gram positive Tetracyclines tetracycline, minocycline and doxycycline Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome Spectrum of activity - Broad spectrum; Useful against intracellular bacteria Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. Streptogramins Streptogramins irreversibly bind to the 50S ribosomal subunit Narrow spectrum Example: Virginiamycin (banned in EU) Oxazolididones Protein synthesis inhibitor on the ribosomal 50S subunit of the bacteria. Seems to block initiation. Example: linezolid, useful for methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae INHIBITORS OF NUCLEIC ACID SYNTHESIS Inhibitors of nucleic acid synthesis Fluoroquinolones Ansamycins Metronidazol Fluoroquinolones nalidixic acid, ciprofloxacin, ofloxacin, levofloxacin, lomefloxacin, sparfloxacin, norfloxacin, moxifloxacin Mode of action: bind to two essential enzymes required for DNA replication (DNA gyrase and topoisomerase IV) Spectrum of activity - Gram-positive cocci and urinary tract infections Ansamycins Rifampin /Rifampicin Enters neutrophils and macrophages and inhibits DNA- dependent RNA polymerase. Spectrum of activity: – used for the treatment of tuberculosis – Meningitis prophylaxis The most serious adverse effect is hepatotoxicity Metronidazol Initially for the treatment of parasitic infections. It is effective against anaerobic bacterial infections. These bacteria reduce a nitro group in the molecule producing cytotoxic compounds which interfere with the bacterial DNA. It is not active against aerobic or facultative bacteria INHIBITORS OF METABOLIC PATHWAYS Sulfonamides (sulfamethoxazole) + trimethoprim Mode of action - sulfonamides are analogues of para- aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. Trimetoprim binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. Mechanism of action of TMP-SMX DISRUPT BACTERIAL MEMBRANES Disrupt bacterial membranes Lipopeptides Polymixins Lipopeptides Disrupt multiple aspects of bacterial cell membrane function Spectrum: Gram-positive organisms Example: Daptomycin Polymyxins Mode of action: binds to the lipid A portion of lipopolysaccharide and also to phospholipids, disrupting the outer membrane of gram negative bacteria Spectrum of action: gram negative, since the cell membrane is not exposed in gram positive Toxic in humans (highly nephrotoxic). Only used in topic applications Combination Therapy To prevent the emergence of resistance - M. tuberculosis To treat polymicrobial infections Initial empiric therapy Synergy Combination Therapy Why do not use two antibiotics all the time? Antagonism Cost Increased risk of side effects May actually enhance development of resistance inducible resistance Interactions between drugs of different classes Often unnecessary for maximal efficacy What influences the choice of antibiotic? Activity of agent against proven or suspected organism Site of infection Mode of administration Metabolism and excretion – renal and hepatic function Duration of treatment / frequency of dose Toxicity / cost Local rates of resistance