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Transcript
DENS 521 Clinical Dental Therapeutics 5th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected] Other Beta Lactam Drugs, Overview These are important therapeutic agents with a b-lactam structure that are neither penicillins nor cephalosporins This group of inhibitors of cell wall synthesis includes: Monobactams Carbapenems Beta-Lactamase Inhibitors (such as clavulanic acid, sulbactam and tazobactam) These agents were developed to deal with β-lactamase-producing organisms Monobactams Monobactams are drugs with a monocyclic blactam ring They are relatively resistant to b-lactamases and active against G-ve bacteria (including pseudomonas) They have no activity against G+ve bacteria or anaerobes The main monobactam is aztreonam, which is resistant to many of the β-lactamases that are produced by most G-ve bacteria Aztreonam is isolated from Chromobacterium violaceum Aztreonam is effective only against G-ve aerobic organisms such as pseudomonads, Neisseria meningitidis and Haemophilus influenzae. Its activity against Enterobacteriaceae is excellent It is given parenterally and has a plasma half-life of 2 hours, and most of the drug is recovered unaltered in the urine It generally is well tolerated. Patients who are allergic to penicillins or cephalosporins appear not to react to aztreonam, with the exception of ceftazidime Carbapenems Carbapenems are β-lactams that contain a fused βlactam ring and a five-membered ring system that differs from the penicillins in being unsaturated and containing a carbon atom instead of the sulfur atom This class of antibiotics has a broader spectrum of activity than do most other β-lactam antibiotics Imipenem, a carbapenem, is very resistant to hydrolysis by most β-lactamases It has a very broad spectrum of antimicrobial activity, being active against many aerobic and anaerobic G+ve and G-ve (including P. aeruginosa) organisms It is sometimes given together with cilastatin, which inhibits its inactivation by renal enzymes Meropenem is similar to imipenem but is not metabolized by the kidney Imipenem is not absorbed orally. Both imipenem and cilastatin have a t1/2 of about 1h. When administered concurrently with cilastatin, about 70% of it is recovered in the urine as the active drug. Dosage should be modified for patients with renal insufficiency Nausea and vomiting are the most common adverse reactions. Neurotoxicity can occur with high doses Patients who are allergic to other b-lactam antibiotics may have hypersensitivity reactions when given imipenem Beta-Lactamase Inhibitors These drugs can inactivate b-lactamases, thus prevent the destruction of b-lactam antibiotics that are substrates for these enzymes An important example is clavulanic acid It is produced by Streptomyces clavuligerus Clavulanic acid It has poor intrinsic antimicrobial activity, but it is a "suicide" inhibitor that irreversibly binds b-lactamases produced by many G+ve and G-ve microorganisms It is well absorbed by mouth and also can be given parenterally It is combined with amoxicillin as an oral preparation (Augmentin®) and with ticarcillin as a parenteral preparation (Timentin®) Amoxicillin plus clavulanate is effective against b-lactamase-producing strains of staphylococci, H. influenzae, gonococci and E. coli It is also used for treatment of acute otitis media in children, sinusitis & animal bite wounds The addition of clavulanate to ticarcillin extends its spectrum such that it resembles imipenem to include aerobic G-ve bacilli, S. aureus and Bacteroides spp. Sulbactam is similar in structure to clavulanic acid. It is given orally or parenterally along with a b-lactam antibiotic. It is available for IV or IM use combined with ampicillin (Unasyn®), which has good activity against G+ve cocci, including b-lactamase-producing strains of S. aureus, G-ve aerobes (but not Pseudomonas) and anaerobes It is also effective for the treatment of mixed intra-abdominal and pelvic infections Other Cell Wall or Membrane-active Agents Vancomycin Vancomycin is an antibiotic produced by Streptococcus orientalis Vancomycin is primarily active against G+ve bacteria (e.g., S. pyogenes, S. pneumoniae) MOA: It inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of the cell wall precursor unit attached to its lipid carrier This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis The cell membrane is also damaged, which contributes to the antibacterial effect It is thus bactericidal for dividing microorganisms Resistance: Vancomycin resistance is due to expression of enzymes that modify cell wall precursor by substituting a terminal D-lactate for D-alanine, reducing vancomycin binding affinity by 1000 times Other Cell Wall or Membrane-active Agents, Vancomycin, Its structure The transpeptidation reaction in that is inhibited by b-lactam antibiotics Θ b-Lactam antibiotics Mechanism of Action, In motion Inhibition of bacterial cell wall synthesis, MOA of Vancomycin Other Cell Wall or Membrane-active Agents, Vancomycin Vancomycin is poorly absorbed from the GIT It can be administered orally to patients with pseudomembranous colitis, although metronidazole is preferred Parenteral doses must be administered intravenously Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, unusual accumulation may occur It should be used only to treat serious infections: Management of infections due to methicillin-resistant staphylococci, including pneumonia & endocarditis Management of severe staphylococcal infections in patients who are allergic to penicillins and cephalosporins Management of known or suspected penicillin-resistant pneumococcal infections Other Cell Wall or Membrane-active Agents, Vancomycin Side Effects: Hypersensitivity reactions e.g., macular skin rashes and anaphylaxis Rapid I.V. infusion may cause erythematous or urticarial reactions, flushing, tachycardia and hypotension The extreme flushing that can occur is sometimes called "red-neck" or "redman" syndrome This is not an allergic reaction but a direct toxic effect of vancomycin on mast cells, causing them to release histamine Auditory impairment, sometimes permanent, may follow the use of this drug. Ototoxicity is associated with excessively high concentrations of the drug in plasma The "peak" concentration should remain below 60 mg/ml to avoid ototoxicity Nephrotoxicity has become an unusual side effect when appropriate doses are used, as judged by renal function and determinations of blood levels of the drug Caution must be exercised when ototoxic or nephrotoxic drugs, such as aminoglycosides, are administered concurrently or in patients with impaired renal function