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Antibacterial Agents Doç Dr Nevriye Gönüllü Antibacterial Agents Mechanisms of action Antibacterial spectrum Common mechanisms of resistance Antibacterial agents Sulfonamide – the year 1935 (protosil) Penicillin (Flemming) Streptomycin Tetracyclin ................and many others Despite the rapidity of the introduction of new chemotherapeutics Development of resistance!!! In vitro antimicrobial susceptibility testing Selects the active chemotherapeutic agent Antibacterial spectrum Range of activity of an antimicrobial against bacteria Broad spectrum: inhibits a wide variety of gram-positive and gram-negative bacteria Narrow spectrum: active against a limited variety of bacteria Antibiotic combinations To broaden the spectrum for empirical therapy or treatment of polymicrobial infections To prevent the emergence of resistant microorganisms To achieve a synergistic killing effect Bacteriostatic activity: inhibition of growth Bacteriocidal activity:killing of microrganisms Antibiotic synergism Antibiotic antagonism Inhibition of cell wall synthesis Beta-lactam antibiotics Vancomycin Bacitracin Inhibition of cell wall synthesis Antimycobacterial agents: Isoniazid Ethambutol Cycloserine Ethionamide Beta-lactam antibiotics Penicillins Cephalosporins Cephamycins Carbapenems Monobactams Beta-lactam antibiotics Major structural component of bacterial cell wall is peptidoglycan Basic structure : alternating molecules of N-acetylglucosamine and Nacetylmuramic acid cross-linked with peptide bridges Peptidoglycan Building of this chain and cross-links catalized by spesific enzmes: transpeptidases, carboxypeptidases and endopeptidases These enzymes are called penicillinbinding proteins (PBPs) because they can be bound by beta-lactam antibiotics Beta-lactam antibiotics Bind to PBPs in the growing bacterial cell wall Bactericidal Resistance to beta-lactam antibiotics Prevention of interaction between the antibiotic and the target PBP Decreased binding of the antibiotic to the PBP Hydrolysis of the antibiotic by betalactamases Resistance to beta-lactam antibiotics Prevention of interaction between the antibiotic and the target PBP: Only in gram-negative bacteria (Pseudomonas species) Size or charge change in the outer membrane pores Resistance to beta-lactam antibiotics Decreased binding of the antibiotic to the PBP: Modified PBP that fails to bind beta-lactam antibiotic but contributes to the synthesis of peptidoglycan Streptococcus pneumoniae: modification of an existing PBP through recombination – resistant to penicillins Staphylococcus aureus : acquisition of a new PBP (e.g., methicillin resistance in Staphylococcus aureus Resistance to beta-lactam antibiotics Beta-lactamase production: More than 200 Some are spesific( penisillinases, cephalosporinases) Some have broad range of activity (extendedspectrum beta-lactamases (ESBLs): commonly encoded on plasmids, easily transferred, limit the empirical use of betalactam antibiotics Penicillins Highly effective antibiotics with extremely low toxicity Obtained from culture of the mold Penicillium Penicillins Natural penicillins Penicillin G (IV), penicillin V(oral) Active against all beta-hemolytic and most other streptococci, meningococci,most gram-positive anaerobes Penicillins Penicillinases resistant penicillins Nafcillin Methicillin Oxacillin Cloxacillin Dicloxacillin +enhanced activity against staphylococci Penicillins Extended spectrum penicillins Ampicillin Amoxicillin Carbenicillin Ticarcillin Mezlocillin Piperacillin Penicillins Extended spectrum penicillins Ampicillin:spectrum activity limited to Escherichia, Proteus and Haemophilus Carbenicillin Ticarcillin Piperacillin: Klebsiella, Enterobacter, Pseudomonas Beta-lactamase inhibitors Clavulanic acid Sulbactam Tazobactam Relatively inactivate by themselves Combined with penicillins are effective against beta-lactamase producing bacteria Beta-lactamase inhibitors Amoxicillin/Clavulanic acid Ampicillin/Sulbactam Ticarcillin/Clavulanic acid Piperacillin/Tazobactam Cephalosporins and Cephamycins Beta-lactam antibiotic Isolated first from a mold Cephalosporium Cephamycins more stable to hydrolysis by beta-lactamase Same mechanism as penicillins Wider antibacterial spectrum Resistant to many beta-lactamases Improved pharmacokinetic properties Cephalosporins Narrow spectrum Expanded spectrum Broad spectrum Extended spectrum Cephalosporins Narrow spectrum:1. generation Cephalexin, cephalothin, cefazolin, cephapirin, cephradine) Equivalent activity as oxacillin against gram-positive some gram-negative activity (E. coli, Klebsiella, P. mirabilis) Cephalosporins Expanded spectrum: 2. generation Cefaclor, cefamandole,cefuroxime, cefotetan, cefoxitin) Equivalent activity as oxacillin against gram-positive Improved gram negative activity including Enterobacter, Citrobacter, Proteus species Cephalosporins Broad spectrum: 3. generation Cefixime, cefotaxime, ceftazidime, ceftriaxone Equivalent activity as oxacillin against gram-positive Improved gram negative activity including Pseudomonas Cephalosporins Extended spectrum: 4.generation Cefepime,cefpirome Equivalent activity as oxacillin against gram-positive Improved gram negative activity Other beta-lactam antibiotics Carbapenems Monobactams Carbapenems Imipenem Meropenem Broad spectrum Most aerobic and anaerobic gram-positive and gram-negative bacteria Except oxacillin-resistant staphylococci, most Enterococcus faecium, selected gramnegative bacilli (Burkholderia, Stenotrophomonas, some Pseudomonas) Monobactam Aztreonam Narrow spectrum Active against gram negative bacteria Advantage: do not disturb patient’s normal flora Glycopeptides Vancomycin Obtained from Streptomyces Disrupts cell wall Active against oxacillin-resistant Staphylococci and other gram-positive bacteria resistant to beta-lactam antibiotics Vancomycin Inactive against gram-negative bacteria Too large to pass the outer membrane Intrinsic resistance: Leuconostoc, Lactobacillus, Pediococcus, Erysipelothrix and enterococci Enterococci resistance: plasmids Polypeptides Bacitracin Isolated from Bacillus Used in topically applied products skin infections caused by Staphylococcus and group A Streptococcus Gram negative are resistant Inhibits cell wall synthesis (inhibits peptidoglycan carrier), may also damage cytoplasmic membrane and inhibit RNA transcription Bacitracin Resistance is most likely due to failure of the antibiotic to penetrate into the bacterial cell Polymixins Derived from Bacillus Serious side effects: nephrotoxicity External treatment of localized infections Eye infections, external otitis, skin infections Inactive against gram-positive bacteria because they have no outer membrane Oral administration is used to sterilize the gut. Antimycobacterial agents: Isoniazid Ethambutol Cycloserine Ethionamide Resistance may be due to reduced drug uptake or alteration of the target cell Inhibition of Protein Synthesis Aminoglycoside Tetracycline Oxazolidinone Macrolide Clindamycin Streptogramin Aminoglycosides From Streptomyces species: Streptomycin, Neomycin, Kanamycin, Tobramycin From Micromonospora: Gentamycin, sisomicin Synthetic: Amikasin and Netilmicin Aminoglycosides Irreversibly bind to the 30S ribosomal proteins Bactericidal Anaerobes, streptococci and enterococci are resistant, aminoglycosides fail to penetrate through the cell wall Aminoglycosides Primarily used to treat infections with gram-negative bacilli,tobramicin slightly more active than gentamisin vs. Pseudomonas, amikacin most active Streptomycin : tuberculosis, tularemia Resistance to Aminoglycosides Mutation of the ribosomal binding site Decreased uptake Increased expulsion Enzymatic modification of the antibioticthe most common Tetracyclines Broad spectrum Inhibition of protein synthesis Tetracycline, doxycycline,minocycline Chlamydia, Mycoplasma and Rickettsia infections Macrolides Broad spectrum Erythromycin,Clarithromycin, Azithromycin Neisseria, Legionella, Mycoplasma, Chlamydia, Chlamydophila, Treponema, Rickettsia Binding to the 23S RNA of the 50S ribosomal subunit Oxazolidinone Protein synthesis inhibitor Narrow spectrum Linezolid Staphylococci,streptococci, enterococci( including resistant strains to penicillins,vancomycin,aminoglycosides) Chloramphenicol Protein synthesis inhibitor Broad antibacterial spectrum Drug of choice for typhoid fever Side effect: bone marrow supression Plasmid encoded resistance (producing of chloramphenicol acetyltransferase) Clindamycin Protein synthesis inhibitor (50S ribosome) From Streptomyces species Active against staphylococci and anaerobic gram-negative bacteria Cross resistance with erythromycin occurs Streptogramins From Streptomyces Protein synthesis inhibitor Quinupristin-dalfopristin (Synercid) Use is restricted to vancomycinresistant E faecium Inhibition of Nucleic Acid Synthesis Quinolones Rifampin and Rifabutin Metronidazole Quinolones Synthetic chemotherapeutics Inhibit bacterial DNA gyrases required for DNA replication, recombination and repair Narrow spectrum Broad spectrum Expanded spectrum Quinolones Narrow spectrum: Nalidixic acid: used in urinary tract infections Resistance developed Quinolones Broad spectrum: Ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin Quinolones Expanded spectrum: Gatifloxacin, grepafloxacin, clinafloxacin, moxifloxacin) Broad spectrum especially against gram-positive bacteria (streptococci and enterococci) Resistance to quinolones Chromosomally mediated: mutations in the structural genes for DNA gyrase and topoisomerase type IV Rifampin Bactericidal for Mycobacterium tuberculosis Resistance develops quickly Should be used as combination Rifabutin-a derivative: M. avium Metronidazole Amoebiasis Giardiasis Serious anaerobic bacterial infections (including Bacteroides fragilis) Antimetabolites Sulphonamides Competes with p-aminobenzoic acid Prevents folic acid synthesis required by certain microorganisms Broad spectrum: Nocardia, Chlamydia, Some protozoa Antimetabolites Trimethoprim: another antimetabolite +sulfamethoxazole: synergistic combination Broad spectrum Pneumocystis carinii Resistance to antimetabolites Pseudomonas-permeability barriers Enterocoocci-intrinsic resistance Other antibiotics Clofazidime: M tuberculosis Pyrazinamide (PZA): M. tuberculosis Resistance 1-Genetic bases of resistance 2-Biochemical mechanism of resistance 1-Genetic basis of resistance Mutation of cellular genes Acquisition of resistance genes Mutation of acquired genes Biochemical mechanism of resistance Modification of the antibiotic: such as beta-lactamases Modification of the target molecule Restricted access to the target Efflux pumps