Dolly [email protected] of Dr. Radulovacki’s lectureAntimicrobial TherapyCell Wall DrugsPenicillins CephalosporinsVancomycinBacitracinCycloserineAztreonamImipenemCell memb Protein syn Polymyxin ColistinNystatinAmphotericin BAminoglycosides SpectinomycinTetracyclinesChloramphenicolClindamycinErythromycinNucleic acid syn Sulphonamides SulfonesCiprofloxacin Trimethoprim Nalidixic acidRifampinPyrimethamineNorfloxacinProteoglycan (PG)MembraneGram +L-AlaL-Glu acidDAPD-AlaPeptide bondmembPG15-50 nm thick, - charge,5-10% proteinsand polysachharides(penicillin binding proteins)Image courtesy of the University of Texas-Houston Medical School.PGMembraneLipopolysachrides and proteinsperiplasmGram -Periplasmic space(β-lactamase)PG(2 nm thick)Cell wall(complex polysaccaride constitute endotoxin which trigger inflammatory reaction via TOLL receptors)hard to penetrate Anbticssuch as: PBPPBPPenicillin G, methicillinPeptide chainsNAG: N acetylglucosamineNAMG: N acetylmuramic acidLayer of PeptidoglycanBackbone of amino sugars alternating NAG, NMGA cross-linked with peptide chainFrom: Rang et alcarrierUDP-GlcNAcUDP-MurNAc UDP-MurNAcL-Ala L-AlaUDP-MurNAcD-GluL-AlaUDP-MurNAcD-GluDAPMFrom Rang et alUDPMinor drugs interfering peptidoglycan synthesisCycloserineI. 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 racemaseand D-alaninyl-D-alanine synthetaseIII. Spectrum: mycobacterium tuberculosis (2ndline); mycobacterium kansii; mycobacterium intracellulareIV. Administration and Elimination:•Oral • rapidly absorbed and distributed through out the tissues and body fluids. • Eliminated via urine and partially metabolized.V. Adverse Reaction: mostly neurological• delirium, confusion and convulsions• interferes with a variety of transaminaseBacitracinI. 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 carrierIII. Spectrum: Gram (+) including strains of staphylococcus that are resistant to penicillin IV. Use: Restricted to topical use such as for skin and eye infectionsVancomycinI. obtained from Streptomyces orientalis or Nocardia orientalisII. Mechanism: prevents the cleavage of the sugar peptide from the lipid carrier. Also inhibits RNA synthesis. III. Spectrum : Istchoice 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.V. Excretion: mainly by glomerular filtrationVI. Adverse Reaction:i. Hearing loss ii. "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.Penicillin: β-Lactam antibioticsDiscovered by Alexander Flemming 1928. Produced by penicilliumI. Isolated from Penicillium chrysogenumII. 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.III. International units of activity: Activity contained in 0.6 µg 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 β-lactamase:• Hydrolyses the β lactam ring of penicillin's resulting in inactive antibiotic. Different β-lactamases exists which are coded by genes on plasmids. • In Gram (+), β lactamase is secreted extracellularly; in Gram (-), β-lactamase is located in the periplasmic space. This is the primary mechanism of acquired resistance! ii. Elaboration of altered PBPs with decreased affinity for β-lactams.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 (-).VI. Classification: Based on their antimicrobial spectrum. a. Natural Penicillins or narrow spectrum Penicillinspenicillin 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); Spirochetes--Treponema palladium; limited Gram negative coverage– Neisseria species and Bacteroides species, excluding fragilis.b. β-lactamase Resistant Penicillins:Have large R groups which sterically hinder access to the β-lactam bond. includes:nafcillin, methicillin, and the isoxazolyl penicillins--oxacillin, cloxicillin, dicloxacillin, and flucloxacillin. Spectrum: for β- lactase-producing Staphylococcus!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.Spectrum: Gram (-) coverage of the aminopenicillins; extended to include: Pseudomonas species, Enterobacter species, and theindole-positive Proteus species (vulgaris,
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