Pharmacology II: Cell Wall Inhibitors I PDF

Pharmacology II CELL WALL INHIBITORS I Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  ???Bad Bugs, No Drugs ESKAPE” pathogens (escape the effects of antibacterial)“ Enterococcus faecium [vancomycin-res...

Pharmacology II CELL WALL INHIBITORS I Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  ???Bad Bugs, No Drugs ESKAPE” pathogens (escape the effects of antibacterial)“ Enterococcus faecium [vancomycin-resistant E. faecium(VRE)] (1 Staphylococcus aureus [methicillin-resistant S. aureus (MRSA)] (2 Klebsiella pneumoniae (carbapenem-resistant Klebsiella species) (3 Acinetobacter baumanii (4 Pseudomonas aeruginosa (fluoroquinolone-resistant P. aeruginosa) (5 (multidrug-resistant (MDR) P. aeruginosa) Enterobacter species (6 MDR Escherichia coli Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America Recent collapse of antibacterial new molecular entities.(NMEs)  Organizations contributing to antibacterial new molecular.entities (NMEs).The entry and exit of organizations is indicated The leading ten organizations  19 Gram-positive and gram-negative bacterium cell wall Gram-positive Gram-negative easily traversed by penicillins - have an outer lipopolysaccharide membrane which blocks water-soluble penicillins. However, w a t e r- f i l l e d c h a n n e l s ( p o r i n s ) p e r m i t transmembrane entry of these penicillin. The peptidoglycan layer is much thicker in gram-.positive than in gram-negative ones Penicillin-binding proteins (PBPs) are membrane.proteins that cross-link peptidoglycan Cell wall inhibitors antibiotics B-lactam  Penicillin (MOA) 4 Mechanism of action Penicillins interfere with c ross- linkage of peptidoglycan cell wall, resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or activation of autolysins Note: Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall (inactive against mycobacteria, protozoa,.fungi, and viruses) Penicillin (MOA) 3 Penicillin inhibits PBP (peptidoglycan cell wall) Bacterial cell wall consists of strands of.1 repeating N-acetylglucosamine (NAG) and N- acetylmuramic acid (NAM) subunits. The NAM subunits have short peptide chains (used in.cross-linking) The penicillin binding protein (PBP) forms a.2 crosslink with another strand of bacterial cell.wall The PBP dissociates from the wall once the.3.cross-link has been formed Penicillin is added to the system. It enters the.4 active site of the PBP and reacts with the serine.group The beta-lactam ring of penicillin covalently.5 linked to the PBP and permanently blocks the  Antibacterial spectrum 6 Natural penicillins (1 Penicillin G and penicillin V Susceptible to beta-lactamases Penicillin V : Poor oral absorption (not indicated for bacteremia) More acid stable than penicillin G :  Antibacterial spectrum 7.(Antistaphylococcal penicillins (β-lactamase-resistant penicillins (2 Methicillin, nafcillin, oxacillin and dicloxacillin : The use is restricted to the treatment of infections caused by penicillinase-producing :.staphylococci, including methicillin-sensitive Staphylococcus aureus (MSSA).Methicillin is toxic (Interstitial nephritis), not clinically used anymore :.no activity against gram-negative infections : Extended-spectrum penicillins (Semisynthetic penicillins) (3 Ampicillin and amoxicillin : Antibacterial spectrum similar to penicillin G but are more :.effective against gram negative bacilli Treat respiratory infections : Amoxicillin prevents bacterial endocarditis during dental :.surgery β-lactamase inhibitors (clavulanic acid/sulbactam), : protects amoxicillin or ampicillin from enzymatic hydrolysis. For example, without the β-lactamase inhibitor, MSSA is resistant to ampicillin and amoxicillin*. Note: MRSA can be treated with vancomycin  Antibacterial spectrum 7 Antipseudomonal penicillins (4 Piperacillin and ticarcillin : Effective towards many gram-negative bacilli, but not towards : Kblesiella (contains penicillinase) Resistance inactivation of antibiotic by ß-lactamase (major cause).I modification of target PBPs.II impaired penetration of drug to target PBPs.III efflux.IV  21 Pharmacokinetics of Penicillins Administration.1 Ampicillin + sulbactam ticarcillin + clavulanic acid piperacillin + tazobactam IV or IM nafcillin oxacillin Penicillin V Amoxicillin Oral dicloxacillin I M ( D e p o t fo r m : s l o w l y Procaine penicillin G absorbed into the circulation benzathine penicillin G and persist at low levels.Question: Beta-lactamase has antibacterial activity ?TRUE or FALSE  39 Adverse reaction !This drug is remarkably non-toxic Hypersensitivity (most prominent).1 Ranging from rashes to angioedema (marked swelling of.the lips, tongue, and periorbital area) and anaphylaxis Cross-allergic reactions occur among the β-lactam.antibiotics Diarrhoea.2.Disruption of the normal balance of intestinal flora Pseudomembranous colitis from Clostridium difficile.and other organisms may occur with penicillin use  42 T H A N K Y O U !