Cephalosporins Cephalosporins and Macrolide 1 I Mechanism of Action Cephalosporins are composed of a dihydrothiazine ring and a lactam ring The mechanism of action is identical to penicillins III Classification The cephalosporins are classified as first second or third generation cephalosporins This classification is dependent on the antimicrobial activity II Mechanism of Resistance Same as penicillins Cephalosporins are less susceptible to Staphylococcus lactamase however they are not the drug of choice Other bacteria are resistant because they produce distinct lactamases Methicillin resistant Staphylococcus is resistant to most cephalosporins 2 a 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 arg b 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 3 c Third generation cephalosporins moxalactam cefaperazone ceftazidirne ceftriaxone Spectrum Gram more resistant to non Staphylococcus lactamase readily cross the blood brain barrier Enterobacter Pseudomonas ceftazidime and cefaperazone only Serratia lactamase producing Haemophillus influenza and Neisseria species 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 by the renal tubules Cefaperazone and ceftriaxone are eliminated through the biliary tract Only cetizoxime and moxalactam retain good activity against Bacteroides fragilis 4 V Uses Cephalosporin with or without an aminoglycoside is firstline 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 lactamase producing Neisseria gonorrhea VI Adverse Side Effects i Hypersensitivity The frequency of cross reactivity with penicillinsensitive individuals is 5 to 15 CONTRAINDICATED in patients with a history of anaphylaxis to a penicillin ii Renal Toxicity iii Hyperprothrombinemia Thrombocytopenia Platelet dysfunction iv Disulfiram like Effect cefamandole cefotetan moxalactam cefoperazone 5 OTHER LACTAMS AND THE MONOBACTAMS VII Drug drug Interactions Imipenem Carbepenems a new class of drugs structurally similar to the penicillins Imipenem most extensively studied Cephalosporins demonstrate synergistic activity when combined with an aminoglycoside to treat Klebsiella 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 lactamase including that produced by staphylococcus Methicillin resistant staphylococcus is usually resistant to imipenem Susceptible organisms include 6 III 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 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 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 7 Lactamase Inhibitors Clavulanic Acid and Sulbactam I Mechanism of action i Poor antimicrobial activity ii Inhibits lactamase iii Included in combination with amoxacillin Augmentum or with ticaricillin In particular clavulanic acid is an irreversible suicide inhibitor of lactamase 8 DRUGS 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 III Absorption Distribution Excretion Due to multiple positive charges not absorbed after oral administration Polymyxins They do cross membranes poorly and are not well distributed I Mechanism of Action Act on membranes which are rich in phosphatidlyethanolamine They are polycationic and act like detergents to disrupt the cell membrane They are eliminated via the kidneys II Spectrum Bactericidal for Gram rods including Pseudomonas Ineffective against Gram organisms Resistance is rare in susceptible bacteria 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 neurotoxicity 9 Genetic determinants of antibiotic resistance I Mutations within chromosomes rare Transfer of plasmid between genetic elements in bacteria Transposons II Extrachromosomal plasmids Plasmids genetic elements other than chromosomes can replicate on their own contains one several genes copy number may be different referred to as R plasmids for carrying resistant gene Gene cassettes and integrons Resistance gene attached to small recognition site 10 Protein Synthesizing machinery Drugs inhibiting Protein Synthesis Aminoglycosides and Macrolides Ribosome bacteria has 50S and 30 S subunit which forms 70 S polysome that slides on mRNA has A P and E sites for binding with tRNA Teteracycline
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