Dolly Mehta 5-0236 [email protected]. Non-beta Lactam Antibiotics Vancomycin Cycloserine Bacitracin Beta Lactam Antibiotics Penicilin Cephalosporins Monobactum.

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Dolly Mehta 5-0236 [email protected] Slide 2 Non-beta Lactam Antibiotics Vancomycin Cycloserine Bacitracin Beta Lactam Antibiotics Penicilin Cephalosporins Monobactum Carbepenams Beta-lactam inhibitors Tazobactum Slide 3 3 Gram positiveGram negative Slide 4 Peptidoglycan N acetylmuramic acid (NAM) N acetylglucosamine (NAG) Penta peptide (Glycine residues) NAG NAM L-Ala D-Glu L-Lys Slide 5 5 NAMNAGNAMNAG NAMNAGNAM NAG NAM periplasm Peptide cross linkGlycosidic bond BPBP P Transglycolase (TG) Transpeptidase (TP) Bactoprenol (C55-carrier) Slide 6 6 UdP NAMNAGNAMNAG NAMNAGNAM NAG NAM periplasm BPBP P NAM cycloserine P bacitracin Beta-lactams Inhibits TP vancomycin D-ala L-ala D-ala alanine racemase D-ala-D- ala-ligase Slide 7 Elaboration of normal penicillin binding proteins (PBPs) Mechanism of Resistance Inability of agents to penetrate to site of action Production of -lactamase Increased expression of efflux pumps Slide 8 8 Classification Penicillins Natural Penicillins i.e. PenV Extended-Spectrum Penicillins i.e. (Ampicillin/Amoxycillin) Antistaphylococcal Penicillins i.e. Piperacillin Cephalosporins Ist generation i.e. Ceftazolin IInd generation i.e. Cefactor IIIrd generation i.e. Cephaoxime IV generation i.e. Cefapime V generation i.e. Cefrazoline Slide 9 9 Untoward Effects Hypersensitivity ~(0.7%-4%) Allergy to one penicillin risk to other penicillins/cephalosporins Penicilloic acid Haptens IgE Abs Slide 10 10 Beta-Lactam & Other Cell Wall- Active Antibiotics SubclassClinical Applications/toxicity PENICILLINS Ampicillin, amoxicillin, ticarcillin, piperacillin Aumentin, Zosyn CEPHALOSPORINS Cephalexin Cefepime Ceftaroline CARBAPENEMS Imipenem-cilastatin MONOBACTAMS Aztreonam Beta-lactamase Inhibitors (suicidal inhibitor) Clavulanic Acid, Sulbactam, & Tazobactam GLYCOPEPTIDE Vancomycin Telavancin Streptococcal and Staph lycoccal infections, meningococcal infections, neurosyphilis, UTI, RTI, addition of beta-lactamase inhibitor restores activity against many -lactamase-producing bacteria Skin and soft tissue infections, urinary tract infections, surgical prophylaxis, improved stability to chromosomal lactamase, active against methicillin-resistant staphylococci, broad gram-negative activity Serious infections such as pneumonia and sepsis Infections caused by aerobic, gram-negative bacteria in patients with immediate hypersensitivity to enicillins No cross-allergenicity with penicillins Infections caused by gram-positive bacteria including sepsis, endocarditis, and meningitis C difficile colitis (oral formulation), Red man syndrome Slide 11 Antibiotics Protein Synthesis Aminoglycosides Macrolides Teteracycline Chloramphenicol Slide 12 Protein Synthesizing Machinery Ribosome mRNA tRNA bacteria has 50S and 30 S subunit which forms 70 S polysome that slides on mRNA has A, P and E sites for binding with tRNA forms template for protein synthesis transcribed from DNA attaches to 30s ribosomes brings amino acids attaches to A, P and E sites of ribosomes Slide 13 13 E A P uuu cca cau cca aug cca cau MET uac 30s 50s Aminoglycosides Binds 30S Slide 14 14 E A P uuu cca cau cca aug cca cau Met uac Pro uac Tetracycline Binds reversibly at 30 S ribosomal RNA Compete with tRNA Slide 15 15 E A P uuu cca cau cca aug cca cau Met Pro Macrolides, Lincosamide Binds 50S ribosomal RNA Blocks peptide translocation to P site Slide 16 16 E A P uuu cca cau cca aug cca cau Met Pro gga Chloramphenicol Binds 50S ribosomal RNA Inhibit peptidyltransferase Slide 17 17 Oxazolidinones E A P uuu cca cau cca aug cca cau 30s 50s Inhibits ribosomal complex formation Slide 18 Mechanisms of Resistance Intracellular penetration Modification of the ribosomal binding site (Tet) Low affinity of drug for bacterial ribosomes acetylation, phosphorylation, adenylation of OH or NH2 gr (Macrolides, AG) Drug inactivation Metabolites can also compete with the drugs (Mac, AG) Efflux pumps (Tet, Mac) pH Anaerobic conditions (AG) Slide 19 a. Energy-Dependent Phase 1 (EDP1) Intracellular Penetration b. Create fissure inducing bacterial damage (EDP2 phase) Macrolides, Tetracyclines, chloramphenicol Aminoglycosides Slide 20 20 SubclassClinical Applications Toxicities AMINOGLYCOSIDES ( gentamicin, streptomycin ) TETRACYCLINES (doxyclines, micocyclines, tigecycline) useful in aerobic_Gram negative bacterial infections meningitis, Sepsis, pneumonia, endocardtis Infections caused by mycoplasma, chlamydiae, rickettsiae, some spirochetes malaria H pylori acne Nephrotoxic, ototoxicity, muscular blockade: of neuromuscular junction Gastrointestinal upset, hepatotoxicity, photosensitivity, deposition in bone and teeth MACROLIDES (erythromycin, clarithromycin, azrithromycin, Telithromycin ) LINCOSAMIDE Clindamycin STREPTOGRAMINS Quinupristin-dalfopristin CHLORAMPHENICOL OXAZOLIDINONES Linezolid Community-acquired pneumonia pertussis corynebacterial and Chlaydial infections Skin and soft tissue infections anaerobic infections Infections caused by staphylococci or vancomycin-resistant strains of E faecium Rarely used in developing Countries Infections caused by methicillin- resistant staphylococci and vancomycin-resistant enterococci Gastrointestinal upset, hepatotoxicity, QT c prolongation Gastrointestinal upset, C difficile colitis Severe infusion-related myalgias and arthralgias Dose-related anemia, idiosyncratic aplastic anemia, gray baby syndrome Duration-dependent bone marrow suppression, neuropathy, and optic neuritis, serotonin syndrome may occur when coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors) Slide 21 Drug Interactions Erythromycin, Chloramphenicol Cytochrome P450 Linezolid serotonin syndrome serotonins Slide 22 Anti-tubercular and Anti-leprosy agents Mycobacteria Tuberculosis leprosy Slide 23 Mycobacterial Cell Wall Mycolic acid Long fatty acids Allow the bacterium to grow dormantly Reside inside macrophages evading host's immune system Slide 24 24 Mechanism of Action of TB drugs Slide 25 25 Mechanism of Resistance of TB drugs Slide 26 26 SubclassClinical ApplicationsToxicities Isoniazid (INH) First-line agent for tuberculosis treatment of latent infection Hepatotoxic, peripheral neuropathy (give pyridoxine to prevent) Rifampin First-line agent for tuberculosis atypical mycobacterial infections eradication of meningococcal colonization, staphylococcal infections Rash, nephritis, thrombocytopenia, cholestasis, flu-like syndrome with intermittent dosing Pyrazinamide "Sterilizing" agent used during first 2 months of therapy allows total duration of therapy to be shortened to 6 months Hepatotoxic, hyperuricemia Ethambutol Given in four-drug initial combination therapy for tuberculosis until drug sensitivities are known also used for atypical mycobacterial infections Retrobulbar neuritis StreptomycinUsed in tuberculosis when an injectable drug is needed or desirable for drug-resistant strains Nephrotoxic, ototoxicity Slide 27 Drug Interactions of Rifampin induces Cytochrome P450 Increases elimination of several drugs i.e cyclosporineAnticonvulsants Protease inhibitors Slide 28 chronic ID skin, peripheral nerves and mucous membranes (eyes, respiratory tract). also known as Hansen's disease as bacillus causing it was discovered by G.A. Hansen in 1873. common in warm, wet areas in the tropics & subtropics. Leprosy Mycobacterium leprae Slide 29 Multidrug therapy Clofazimine binds GC rich DNA; anti-inflammatory inhibits the utilization of PABA folic acid metabolism Sulphones (Dapsones) Rifampin Slide 30 Sulphone syndrome: fever, jaundice, malaise exacerbation of lepromatos leprosy Untoward Effects Dapsone Clofazimine skin discoloration ranging from red-brown to nearly black