1Dolly [email protected] TherapyCell Wall Cell memb Protein syn Nucleic acid syn Bactericidal—kill Bacteriostatic---restricts growthWhat are the components of the bacterial cell wall??PeptidoglycanMN acetylmuramic acid (NAMA)GN acetylglucosamine (NAG)Penta peptide Glycine M G M G M GM G M G M GM G M G M GM2Proteoglycan (PG) (15-50 nm thick)MembraneGram +PG (2 nm thick)MembraneLipopolysachrides and proteinsperiplasmGram -Biosynthesis of Peptidoglycan30 enzymesMUDPUDPMP-C55 lipidP-P-C55MUMPGUDPUDPP-P-C55MGCYTOMEMBWALLP-P-C55MGGMM G M G M GP-P-C55 lipidtranspeptidasePI. structural analog of D-Ala (competitive inhibitor), stable in alkaline solution rapidly destroyed in neutral or alkaline pHIII. Antibacterial activity: M. tuberculosisused in conjunction with tuberculosis drugs for treating pulmonary or extrapulmonary tuberculosis WHEN PRIMARY Anti-Tuberculosis agents (such as Isoniazid, rifampin) failedCycloserine (Seromycin)II. Mechanism:MUDPcycloserineIV. Absorption, Distribution and excretion70-90% Orally absorbeddistributed throughout body fluids CSF conc. = plasmaMetabolism low, i.e.: 50% excreted UNCHANGED in urine in Ist 12 hrs may accumulate to toxic conc. in patients with renalinsufficiency and can be removed by dialysisV. Untoward EffectsCNS: headache, tremor, confusion etcCONTRAINDICATED: Epileptic patientsCaution: patients with history of depression or suicidal attempts3VancomycinIII. Antibacterial activity: Gram+, Essentially all Gram–are resistant due to alteration of D-ala-D-ala target to D-ala-D-ser or D-ala-D-lactateI. Tricyclic glycopeptide antibiotic from Streptomyces orientalis or Nocardia orientalisII. Mechanism: Inhibits polymerization P-P-C55MGMGP-P-C55MG()n+MG()nIV. Absorption, Distribution and excretion: poorly absorbed so given intravenously slowly NEVER INTRAMUSCULARLYappears in body fluids and CSF90% excreted by glomerular filtration V. Untoward Effects:Hypersensitive Reacn such as skin rashes, and anaphylaxisChills, rash and fever may occurRapid administration causes flushing, tachycardia, hypotension, erythematous or urticarial reac Extreme flushing “red-neck” or “red-man” syndrome is not due to allergy but direct toxicity of mast cellsI. produced by Bacillus subtilis.III. Antibacterial Activity: Gram (+) cocci and bacilli. Enterobacteriaceae, Pseudomonas, Candida spp and Nocardia are resistant IV. Use: Restricted to topical use such as for skin and eye infections BacitracinII. Mechanism:P-P-C55 lipidP-C55 lipidPenicillin: β-Lactam antibioticsDrug of choice for a large number of diseasesCCH COOHCH3CH3SCHNCHC=ONHCR=OBAAB β-lactum ringThiazolidine ringR decides:Penicillin subtypeantibacterial activityresistance to β-lactamasestability for stomach acidsDiscovered by Alexander Flemming 1928. Produced by penicillium4II. Mechanism: . M G M G M GM G M G M GM G M G M GMa. Inhibits cross linkingb. binds covalently with penicillin-binding proteins (PBPs). Number of PBPs varies. i.e. S aureus has 4 PBPs whereas E coli has 7Affinity of PBPs to antibiotics is variable PBPPBPbinding to PBPs results in:ii Structural irregularitiesi. Inhibition of transpeptidaseCell lysis PenicillinlyticNon-lytic (affect holin-like proteins in bacterial cell memb, altering memb potential)III. Mechanisms of Resistance:i. Elaboration of altered PBPsdecreased affinity for β-lactamsformed by homologous recombination between PBPs of different bact sp.by transposans from unknown org ii. Inability of agent to penetrate to site of action Gram-bact due to presence of outer layer composed of LPSSmall hydrophilic antibiotics can pass through channels porinsi.e. amoxicillin, ampicillin>Penicillin GP aeruginosa resistant to most Abts as lacks porins5iii. Presence of active efflux pumps i.e E. coliiv. Production of β-lactamase:Hydrolyse β lactam ring of penicillin's Different b-lactamases exists which are coded by genes on plasmids class A-D:Class A: degrade penicillin, some cephalosporin's, carbapenems Inhibited by clavulanate, tazobactumClass B: Zn dependent destroy all Antbts except aztreonamClass C: cephalosporin'sClass D: cloxacillinGram (+), b lactamase is secreted in large amts extracellularly;Gram (-), b lactamase is located in the periplasmic space, small amounts. Primary mechanism of acquired resistance!Gram (-) e.g. pseudomonas sp, enterobacter sp.Inferior to ampicillin against Gram + cocciCarboxypenicillinCabbenicillinticarcillinGram (+) cocci, hydrolyzed by penicillinase so ineffective against most strains of S. aureusNatural PenicillinsPenicillin G (benzyl penicillin)Penicillin V (phenoxymethyl penicillin)Pseudomonas sp, 10 times more effective than carboxypenicillinUreidopenicillins (extended penicillin) Mezlocillin, Azliocillin (discontinued in US), PiperacillinFirst choice for S aureus and S epidermidisβ-lacatamse resistant Penicillin; methicillin(discontinued in US), nafcillin, oxacilin, cloxacillinnot marketed in US)Gram (-) e.g Hemophillus influenzae, E.Coli, Neissaria sp. Aminopenicillins (or modern spectrum) Ampicillin, amoxicillinSpectrum Classification6VI. Absorption, Distribution, Metabolism, Excretioni. Acid stability. Acid-labile (penicillin G, methicillin. carbenicillin, ureidopenicillins). Acid-stable and can be administered orally (penicillin V, ampicillin, amoxacillin, and the isoxazolyl penicillins). ii. Distributed widely throughout body water after absorbtion. iii. do not achieve high levels in the CSF. Active transport process pumps penicillin's from CSF to the bloodstream. This mechanism is blocked by Probenecid.iv. meningitis, inflammation induced increase in the permeability leads to high levels of penicillin (i.e. ampicillin or amoxicillin is used to treat meningitis due to Haemophillus influenza). v. Not metabolized to any significant extent. Predominantly eliminated unchanged via the glomerular filtration (10%) and tubular secretion (90%). Active secretion can be blocked by probenecid.Therapeutic usesPenicillin G and V: Pneumococcal Pneumonia,Steptococcal infections, syphilis, meningococcal infectionsAminopenicillins: Upper respiratory infectionsUrinary tract infectionsBacterial meningitisAntiseudomonal penicillin's: bacteremias, pneumonias infections following burnsVII. Repository Forms of Penicillin G:i. Penicillin G procaine is more slowly absorbed after intramuscular injection than Penicillin G sodium salt. An injection of 300,000 units will maintain adequate plasma levels for 24 hours. ii.