Antimicrobial Therapy Cell Wall Vancomycin Penicillins Cephalosporins Bacitracin Cycloserine Dolly Mehta 5 0236 dmehta uic edu Aztreonam Imipenem Cell memb Polymyxin Nystatin Colistin Amphotericin B Drugs Aminoglycosides Spectinomycin Protein syn Tetracyclines Clindamycin Dr Radulovacki Nucleic acid syn Chloramphenicol Erythromycin Rifampin Sulphonamides Sulfones Ciprofloxacin Trimethoprim Nalidixic acid Pyrimethamine Norfloxacin 1 Gram Gram Lipopolysachrides and proteins Proteoglycan PG Membrane PG Membrane periplasm DAP Peptide bond D Ala L Glu acid L Ala PG 15 50 nm thick charge 5 10 proteins and polysachharides memb penicillin binding proteins Image courtesy of the University of TexasHouston Medical School complex polysaccaride constitute endotoxin which trigger inflammatory reaction via TOLL receptors Cell wall PG 2 nm thick Periplasmic space lactamase PBP PBP hard to penetrate Anbtics such as Penicillin G methicillin 2 Layer of Peptidoglycan UDP MurNAc UDP GlcNAc UDP MurNAc UDP MurNAc L Ala Backbone of amino sugars alternating NAG NMGA cross linked with peptide chain UDP MurNAc L Ala D Glu M UDP L Ala D Glu DAP carrier NAG N acetylglucosamine NAMG N acetylmuramic acid Peptide chains From Rang et al From Rang et al 3 Minor drugs interfering peptidoglycan synthesis Cycloserine IV Administration and Elimination I structural analog of D Ala therefore competitive inhibitor isolated from fermentation broths of Streptomyces sps II Mechanism Prevents addition of 2 terminal alanines by inhibiting alanine racemase and D alaninyl D alanine synthetase V Oral rapidly absorbed and distributed through out the tissues and body fluids Eliminated via urine and partially metabolized Adverse Reaction mostly neurological delirium confusion and convulsions interferes with a variety of transaminase III Spectrum mycobacterium tuberculosis 2nd line mycobacterium kansii mycobacterium intracellulare 4 Bacitracin Vancomycin I obtained from Streptomyces orientalis or Nocardia orientalis I produced by Bacillus subtilis II Mechanism forms a complex with isoprenyl phosphate the lipid carrier that transport the sugar from the cytoplasm to the cell membrane dephosphorylate it and inhibits the release of carrier III Spectrum Gram including strains of staphylococcus that are resistant to penicillin IV Use Restricted to topical use such as for skin and eye infections II Mechanism prevents the cleavage of the sugar peptide from the lipid carrier Also inhibits RNA synthesis III Spectrum Ist choice for methicillin resistant staphylococcus and for antibiotic associated pseudomembranous colitis clostridium overgrowth alternate drug for Gram in a penicillin sensitive patient or for multiply resistant staphylococcus or streptococcus IV Administration intravenously oral administration in some GI infections such as pseudomembranous colitis 5 V Excretion mainly by glomerular filtration Penicillin Lactam antibiotics Discovered by Alexander Flemming 1928 Produced by penicillium VI Adverse Reaction i ii Hearing loss red man syndrome flushing and a maculopapullar rash on the face neck trunk and extremities occurs shortly after I V injection and is thought to be due to histamine release May lead to hypotension tachycardia shock and cardiac arrest 6 I Isolated from Penicillium chrysogenum II Mechanism Penicillin covalently bind to a heterologous group of proteins called penicillin binding proteins PBPs PBPs may number 7 or more in any given bacteria binding to PBPs results in i Inhibition of transpeptidase transpeptidase cross links pentaglycine bridge with the fourth residue D Ala of the pentapeptide The fifth residue also D Ala is released during this reaction Spheroblasts are formed ii Structural irregularities binding to PBPs may result in abnormal elongation abnormal shape cell wall defects iii Activation of autolytic enzymes binding to PBPs results in disinhibition of autolytic enzymes and thus lysis of cell wall 7 III International units of activity Activity contained in 0 6 g of the crystalline sodium salt of penicillin G One mg 1667 units The dosage of the semi synthetic penicillin s is expressed in terms of weight IV Mechanisms of Resistance i Production of lactamase Hydrolyses the lactam ring of penicillin s resulting in inactive antibiotic Different lactamases exists which are coded by genes on plasmids In Gram lactamase is secreted extracellularly in Gram lactamase is located in the periplasmic space This is the primary mechanism of acquired resistance V Susceptibility depend on structural differences in the cell wall i amount of peptidoglycan ii presence of autolytic enzymes iii presence of pores iv presence of lipopolysaccharide capsules etc For example Gram outer phospholipid membrane hinders the passage of these drugs But amoxacillin can pass through porins and therefore have increased activity against Gram ii Elaboration of altered PBPs with decreased affinity for lactams 8 VI Classification Based on their antimicrobial spectrum a Natural Penicillins or narrow spectrum Penicillins penicillin G benzyl penicillin and penicillin V phenoxymethyl penicillin Spectrum Gram cocci Streptococcus pyrogens and pneumonia for viridans and agalactiae combine with an aminoglycoside Gram positive rods Bacillus anthracis Cornybacterium diptheriae most Clostridium perfringens tetani but not difficile b lactamase Resistant Penicillins Have large R groups which sterically hinder access to the lactam bond includes nafcillin methicillin and the isoxazolyl penicillins oxacillin cloxicillin dicloxacillin and flucloxacillin Spectrum for lactase producing Staphylococcus Spirochetes Treponema palladium limited Gram negative coverage Neisseria species and Bacteroides species excluding fragilis 9 c Aminopenicillins or modern spectrum ampicillin and amoxacillin Acid resistant so administered orally Spectrum Gram i e Hemophillus influenzae Escherichia coli and the indole negative Proteus mirabilis Good activity against Neissaria species Decreased activity against most of Gram covered by the natural penicillins d Carboxypenicillins carbenicillin and ticarcillin e Ureidopenicillins or extended Spectrum Penicillins azliocillin mezlocillin and piperacillin Spectrum Superior activity against Pseudomonas aziocillin and piperacillin have 10 times greater activity than the carboxypenicillins Mezlocillin and piperacillin is extended to include Klebsiella species Spectrum Gram coverage of the aminopenicillins extended to include Pseudomonas
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