1Cephalosporins and MacrolideCephalosporins2I. Mechanism of Action: Cephalosporins are composed of a dihydrothiazine ring and a β-lactam ring. The mechanism of action is identical to penicillins. II. Mechanism of Resistance: Same as penicillins. Cephalosporins are less susceptible to Staphylococcus β-lactamase; however they are not the drug of choice. Other bacteria are resistant, because they produce distinct β-lactamases. Methicillin-resistant Staphylococcus is resistant to most cephalosporins. III. Classification: The cephalosporins are classified as first, second, or third generation cephalosporins. This classification is dependent on the antimicrobial activity.3a. First generation cephalosporins: cephalothin, cefazolin, cefalexin.Spectrum: Gram (+) cocci (Streptococcus, pneumococcus but not or methicillin-resistant Staphylococcus). Gram (-) (Escherichia co1i, Kiebsiella pneumoniae, and the indole negative Proteus mirabilis).Some anaerobic cocci (Peptococcus and peptosteptococcus, but NOT Bacteroides fragilis). Ineffective against Pseudomonas argb. Second generation cephalosporins: cefuroxime, cefamandole, cefoxitin, cefaclor.Spectrum: Gram (-) Enterobacter species, Klebsiella species, and indole-positive Proteus species. Haemophilus influenza is covered by cefuroxime, cefamandole, cefaclor; Bacteroides fragilis by cefoxitin. These drugs do not achieve adequate levels in the CSF. Eruginosa, Enterobacter, and indole-positive Proteus species. These drugs do not cross the blood-brain barrier.4c. Third generation cephalosporins: moxalactam, cefaperazone, ceftazidirne, ceftriaxone.Spectrum: Gram (-), more resistant to non-Staphylococcus β-lactamase, readily cross the blood-brain barrier. Enterobacter, Pseudomonas (ceftazidime and cefaperazone only), Serratia, β-lactamase producing Haemophillus influenza and Neisseria species. Only cetizoxime and moxalactam retain good activity against Bacteroides fragilis. IV. Absorption. Distribution, Metabolism and Elimination:i. widely distributed throughout body water. Only the third generation achieves adequate levels in the CSF. ii. Primally eliminated via the kidneys and are actively secreted bythe renal tubules. Cefaperazone and ceftriaxone are eliminated through the biliary tract.5V. Uses: Cephalosporin with or without an aminoglycoside is first-line treatment of Klebsiella. First generation cephalosporins are used for surgical prophylaxis of wound infection. Third generation cephalosporins are used to treat meningitis due to pneumococci, meningococci, and Haemophillus influenza. Ceftriaxone is the drug of choice for treating β-lactamase producing Neisseria gonorrheaVI. Adverse Side Effects:i. Hypersensitivity: The frequency of cross-reactivity with penicillin-sensitive individuals is 5 to 15%. CONTRAINDICATED in patients with a history of anaphylaxis to a penicillin. ii. Renal Toxicityiii. Hyperprothrombinemia, Thrombocytopenia, Platelet dysfunctioniv. Disulfiram-like Effect: cefamandole, cefotetan, moxalactam, cefoperazone.6VII. Drug-drug Interactions:Cephalosporins demonstrate synergistic activity when combined with an aminoglycoside to treat Klebsiella. OTHER β-LACTAMS AND THE MONOBACTAMSImipenem: Carbepenems, a new class of drugs structurally similar to the penicillins. Imipenem most extensively studied. I. Mechanism of action: Binds to penicillin binding proteins. Hence it disrupts cell wall synthesis and is bactericidal. II. Spectrum: Broad-spectrum covers Gram (+) and Gram (-) I.e. Streptococci, Enterococci. Staphylococci, Lister, Enterobacteriaceae, Pseudomonas, Bacteroides, and Clostridium. Resistant to most forms of β-lactamase, including that produced by staphylococcus. Methicillin-resistant staphylococcus is usually resistant to imipenem. Susceptible organisms include:7III. Metabolism: Rapidly hydrolyzed by dipeptidase, found in the brush border of the proximal renal tubule. It is always administered with cilastatin, an inhibitor of dipeptidase. IV. Side effects: Individuals who are allergic to the penicillins may demonstrate cross-reactivity with imipenem. Imipemem may produce nausea and vomiting. Seizures have been reported with high doses. Aztreonam: A monocyclic β-lactam (a monobactam). I. Mechanism of action: Interacts with penicillin binding proteins and induces the formation of long filamentous bacteria. II. Spectrum: It more closely resembles the spectrum of the aminoglycosides. Gram (+) and anaerobic bacteria are resistant. include: Enterobacteriaceae, Pseudomonas, Hemophillus and Neisseria. Aztreonam is resistant to the β-lactamase produced by gram negative organisms. III. Side effects: Generally, the drug is well tolerated. Patients who are allergic to penicillins do not exhibit cross-reactions with aztreonam.8β-Lactamase Inhibitors: Clavulanic Acid and SulbactamI. Mechanism of action:i. Poor antimicrobial activity. ii. Inhibits β-lactamase. iii. Included in combination with amoxacillin (Augmentum) or with ticaricillin. In particular, clavulanic acid is an irreversible, "suicide" inhibitor of β-lactamase.9DRUGS WHICH INTERFERE WITH CELL MEMBRANES Includes antifungal drugs—amphotericin B, colistin, imidazoles,and nystatin. The polymyxins are the only drugs in this category which have antibacterial activity. Polymyxins I. Mechanism of Action: Act on membranes which are rich in phosphatidlyethanolamine. They are polycationic and act like detergents to disrupt the cell membrane. II. Spectrum : Bactericidal for Gram (-) rods, including Pseudomonas. Ineffective against Gram (+) organisms. Resistance is rare in susceptible bacteria. III. Absorption, Distribution, Excretion:Due to multiple positive charges not absorbed after oral administration. They do cross membranes poorly; and are not well distributed. They are eliminated via the kidneys. IV. Uses: Topical "triple antibiotic" lotions (with neomycin and bacitracin). Rarely used systemically alone (very toxic). Sometimes injected into body cavities (pleural cavity, joint spaces). VII. Adverse Reactions: Nephrotoxicity and neurotoxicity10Genetic determinants of antibiotic resistanceI. Mutations within chromosomes: rareII. Extrachromosomal: plasmids Plasmids: genetic elements other than chromosomescan replicate on their owncontains one-several genescopy number may be different referred to as R plasmids for carrying resistant geneTransfer of plasmid between genetic elements in bacteriaTransposons Gene cassettes and integrons Resistance gene attached
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