Antibiotics-Cell Wall Inhibitors PDF

Dr.SALEH KARAMAH AL-TAMIMI 1 Cell Wall Inhibitors Antibiotics Dr.SALEH KARAMAH AL-TAMIMI 2 β-LACTAM ANTIBIOTICS The β-lactam antibiotics include Penicillins Cephalosporins Carbapenems Monobactam (aztreonam). others (non-β-lactam):...

Dr.SALEH KARAMAH AL-TAMIMI 1 Cell Wall Inhibitors Antibiotics Dr.SALEH KARAMAH AL-TAMIMI 2 β-LACTAM ANTIBIOTICS The β-lactam antibiotics include Penicillins Cephalosporins Carbapenems Monobactam (aztreonam). others (non-β-lactam): Vancomycin, Bacitracin, Daptomycin, Fosfomycin Dr.SALEH KARAMAH AL-TAMIMI 3 Cell Wall Inhibitors Dr.SALEH KARAMAH AL-TAMIMI 4 I. Penicillins Dr.SALEH KARAMAH AL-TAMIMI 5 I. Penicillins Mechanism of action Bacterial cell wall is cross-linked polymer of polysaccharides and pentapeptides Penicillins interact with cytoplasmic membrane-Binding Proteins (PBPs) to inhibit transpeptidation reactions involved in cross-linking, the final steps in cell-wall synthesis. Dr.SALEH KARAMAH AL-TAMIMI 6 I. Penicillins: Mechanisms of resistance Dr.SALEH KARAMAH AL-TAMIMI 7 I. Penicillins Mechanisms of resistance: Penicillinases (beta-lactamases production) break lactam ring structure (e.g. Staphylococci) Structural change in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA], penicillin-resistant pneumococci) Decreased permeability to the drug (e.g., Pseudomonas) Dr.SALEH KARAMAH AL-TAMIMI 8 I. Penicillins Penicillins can be grouped according to their antimicrobial activity: Narrow-spectrum penicillins (Penicillin G and Penicillin V) are active against many gram-positive cocci. Penicillinase-resistant penicillins (Nafcillin, Oxacillin) are active against some strains of penicillinase-producing staphylococci, Extended-spectrum penicillins (Ampicillin, Piperacillin) are active against some gram-negative bacilli and anaerobic bacteria as well as gram-positive organisms. Dr.SALEH KARAMAH AL-TAMIMI 9 I. Penicillins General considerations: Activity enhanced if used in combination with beta- lactamase inhibitors (clavulanic acid, sulbactam) Synergy with aminoglycosides against pseudomonal and enterococcal species. Dr.SALEH KARAMAH AL-TAMIMI 10 Dr.SALEH KARAMAH AL-TAMIMI 11 Dr.SALEH KARAMAH AL-TAMIMI 12 Dr.SALEH KARAMAH AL-TAMIMI 13 Dr.SALEH KARAMAH AL-TAMIMI 14 Dr.SALEH KARAMAH AL-TAMIMI 15 Dr.SALEH KARAMAH AL-TAMIMI 16 Dr.SALEH KARAMAH AL-TAMIMI 17 Dr.SALEH KARAMAH AL-TAMIMI 18 Major Clinical Uses of Selected Penicillins Dr.SALEH KARAMAH AL-TAMIMI 19 I. Penicillins Pharmacokinetics: Most are eliminated via active tubular secretion with secretion blocked by probenecid; Probenecid has been used to slow the excretion and prolong the half- life of penicillin G Dose reduction needed only in major renal dysfunction: Nafcillin and oxacillin eliminated largely in bile; ampicillin undergoes enterohepatic cycling, but excreted by the kidney Benzathine penicillin G—repository form (half-life of 2-4 weeks) Dr.SALEH KARAMAH AL-TAMIMI 20 Pharmacokinetic Properties Dr.SALEH KARAMAH AL-TAMIMI 21 I. Penicillins-Adverse reactions Hypersensitivity - Incidence 5 to 7% with wide range of reactions (types I–IV). Urticarial, skin rash common, but severe reactions, including anaphylaxis, are possible GI distress (NVD), especially ampicillin Dr.SALEH KARAMAH AL-TAMIMI 22 I. Penicillins-Hypersensitivity Reaction Dr.SALEH KARAMAH AL-TAMIMI 23 Dr.SALEH KARAMAH AL-TAMIMI 24 Dr.SALEH KARAMAH AL-TAMIMI 25 II. Cephalosporins Dr.SALEH KARAMAH AL-TAMIMI 26 II. Cephalosporins Dr.SALEH KARAMAH AL-TAMIMI 27 II. Cephalosporins Mechanisms of action and resistance: identical to penicillins Subgroups and antimicrobial activity: First generation: cefazolin, cephalexin - Spectrum: gram-positive cocci (not MRSA), E. coli, Klebsiella pneumoniae, and some Proteus species -Common use in surgical prophylaxis - Pharmacokinetics: none enter CNS Dr.SALEH KARAMAH AL-TAMIMI 28 Dr.SALEH KARAMAH AL-TAMIMI 29 Cephalosporins Second generation: cefotetan, cefaclor, cefuroxime, cefoxitin - Spectrum: ↑ gram-negative coverage, including some anaerobes. Pharmacokinetics: no drugs enter the CNS, except cefuroxime. Cefuroxime is available for both oral and parenteral administration Dr.SALEH KARAMAH AL-TAMIMI 30 Dr.SALEH KARAMAH AL-TAMIMI 31 Cephalosporins Third generation: ceftriaxone and cefotaxime (parenteral), cefdinir and cefixime (oral) - Spectrum: gram-positive and gram-negative cocci (Neisseria gonorrhea), plus many gram-negative rods - Pharmacokinetics: most enter CNS; important in empiric management of meningitis and sepsis Dr.SALEH KARAMAH AL-TAMIMI 32 Dr.SALEH KARAMAH AL-TAMIMI 33 Third generation Cephalosporins Ceftazidime & Cefoperazone are the only 2 drug have antipseudomonal activity Dr.SALEH KARAMAH AL-TAMIMI 34 Cephalosporins Fourth generation: cefepime (IV) - Even wider spectrum - Resistant to most beta-lactamases - Enters CNS Dr.SALEH KARAMAH AL-TAMIMI 35 Dr.SALEH KARAMAH AL-TAMIMI 36 Major Clinical Uses of Selected Cephalosporins Dr.SALEH KARAMAH AL-TAMIMI 37 Cephalosporins-Pharmacokinetics Renal clearance similar to penicillins, with active tubular secretion blocked by probenecid Dose modification in renal dysfunction Ceftriaxone is largely eliminated in the bile with longer half life than other cephalosporins. The orally administered cephalosporins are well absorbed from the gut, and their bioavailability is not significantly affected by food. Dr.SALEH KARAMAH AL-TAMIMI 38 Pharmacokinetic Properties Dr.SALEH KARAMAH AL-TAMIMI 39 Cephalosporins Adverse Effects The cephalosporins cause little toxicity to the host and have an excellent safety record. Hypersensitivity: - Incidence: 2% - Wide range, but rashes and drug fever most common. - the incidence is lower than with penicillin - Cephalosporins exhibit some cross sensitivity with penicillins. - The highest rate of allergic cross-sensitivity is between penicillin and first-generation cephalosporins Dr.SALEH KARAMAH AL-TAMIMI 40 Dr.SALEH KARAMAH AL-TAMIMI 41 Dr.SALEH KARAMAH AL-TAMIMI 42 III. Carbapenems Imipenem and Meropenem Mechanism of action: - Same as penicillins and cephalosporins - Resistant to beta-lactamases Spectrum: - Gram-positive cocci, gram-negative rods (e.g., Enterobacter, Pseudomonas spp.), and anaerobes - Important in-hospital agents for empiric use in severe life threatening infections. Dr.SALEH KARAMAH AL-TAMIMI 43 III. Carbapenems Pharmacokinetics: Imipenem is given with cilastatin, (a renal dehydropeptidase inhibitor, which inhibits imipenem’s metabolism to a nephrotoxic metabolite): Both drugs undergo renal elimination— ↓ dose in renal dysfunction Side effects: - GI distress - Drug fever (partial cross-allergenicity with penicillins) - CNS effects, including seizures with imipenem in overdose or renal dysfunction. Dr.SALEH KARAMAH AL-TAMIMI 44 Dr.SALEH KARAMAH AL-TAMIMI 45 IV. Monobactams Aztreonam is a monocyclic β-lactam (monobactam) antibiotic. - Mechanism of action: - Same as for penicillins and cephalosporins - Resistant to beta-lactamases - Uses: - IV drug mainly active versus gram-negative rods - It lacks activity against Gram positive or anaerobes. - No cross-allergenicity with penicillins or cephalosporins Dr.SALEH KARAMAH AL-TAMIMI 46  Vancomycin Vancomycin is a glycopeptide antibiotic active against many gram-positive cocci and gram-positive bacilli including some strains of MRSA. Vancomycin is usually the first choice for treating skin and soft tissue infections and other MRSA infections. Pharmacokinetics: - Used IV and orally (not absorbed) in colitis - Enters most tissues (e.g., bone), but not CNS - Eliminated by renal filtration (important to decrease dose in renal dysfunction). Dr.SALEH KARAMAH AL-TAMIMI 47 Vancomycin Side effects: - “Red man syndrome” (histamine release) - Ototoxicity (usually permanent, additive with other drugs) - Nephrotoxicity (mild, but additive with other drugs). Dr.SALEH KARAMAH AL-TAMIMI 48  Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci Bacitracin is used topically for infections caused by gram-positive cocci. Fosfomycin is administered as a single-dose treatment for uncomplicated urinary tract infections caused by E. coli or enterococci. Dr.SALEH KARAMAH AL-TAMIMI 49 Pharmacokinetic Properties Dr.SALEH KARAMAH AL-TAMIMI 50