1 Pharmacology II-Cell wall inhibitor I.ppt.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) 1) Enterococcus faecium [vancomycin-r...

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) 1) Enterococcus faecium [vancomycin-resistant E. faecium(VRE)] 2) Staphylococcus aureus [methicillin-resistant S. aureus (MRSA)] 3) Klebsiella pneumoniae (carbapenem-resistant Klebsiella species) 4) Acinetobacter baumanii 5) Pseudomonas aeruginosa (fluoroquinolone-resistant P. aeruginosa) (multidrug-resistant (MDR) P. aeruginosa) 6) Enterobacter species MDR Escherichia coli  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, water-filled channels (porins) permit 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 cross-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) 1. Bacterial cell wall consists of strands of repeating N-acetylglucosamine (NAG) and N- acetylmuramic acid (NAM) subunits. The NAM subunits have short peptide chains (used in cross-linking). 2. The penicillin binding protein (PBP) forms a crosslink with another strand of bacterial cell wall. 3. The PBP dissociates from the wall once the cross-link has been formed. 4. Penicillin is added to the system. It enters the active site of the PBP and reacts with the serine group. 5. The beta-lactam ring of penicillin covalently linked to the PBP and permanently blocks the active site.  Antibacterial spectrum 6 1) Natural penicillins 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 2) Antistaphylococcal penicillins (β-lactamase-resistant penicillins). : 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. 3) Extended-spectrum penicillins (Semisynthetic penicillins) : 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 4) Antipseudomonal penicillins : Piperacillin and ticarcillin : Effective towards many gram-negative bacilli, but not towards Kblesiella (contains penicillinase) Resistance I. inactivation of antibiotic by ß-lactamase (major cause) II. modification of target PBPs III. impaired penetration of drug to target PBPs IV. efflux  21 Pharmacokinetics of Penicillins 1.Administration Ampicillin + sulbactam ticarcillin + clavulanic acid piperacillin + tazobactam IV or IM nafcillin oxacillin Penicillin V Amoxicillin Oral dicloxacillin IM (Depot form: slowly 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! 1. Hypersensitivity (most prominent) 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. 2. Diarrhoea 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 !