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roselynnaranjo Cephalosporins • are B-Lactam antibiotics isolated from Cephalosporium spp. • inhibit wide variety of gram(+) and gram(-) bacteria • Abraham and Newton, the suppliers of fungi cultures isolated three principal antibiotic components: Cephalosporin PI- a steroid with minimal antibacterial property Cephalosporin N - Identical with synnematin N ( also called penicillin N Cephalosporin C -Resistant to S. aureus B-lactamase; antibacterial property is inferior to penicillin N. Cephalosporins • Cephalosporin N or Penicillin N - the amino acid in the chain confers more activity against gram(-) bacteria particularly Salmonella spp. - less active against gram(+) organism - contains thiazolidine ring NH2 O H HO H S NH CH3 N O CH3 O O OH Cephalosporins • Cephalosporin C - congener of Penicillin N - contains dihydrothiazide ring NH2 O H HO H NH S O N O O OH CH3 O O Nomenclature of Cephalosporins Chemical Abstracts > fused ring is named 5-thia, 1-azabicyclo[4.2.0]oct-2-ene > CEPHALOTHIN (is an antibiotic of the cephalosporin class. It is related to the penicillin drugs in how it kills bacteria, but cephalosporins have a much broader range of is 3-(acetoxymethyl)-7-[2(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene2-carboxylic acid. > saturated bicyclic ring system is named as cepham > all cephalosporins and cefamycins are named as 3-cephems, to designate the position of the double bond in the structure. activity against bacteria than penicillins. Degradation of Cephalosporins SOLV OL YS I S S S R1 – CONH – CH – CH l l CO ------ N CH2 R – CONH – CH – CH CH2 solvolysis l l l l C CO ------ N C C CH2 - - - R2 C CH2OH l l CO2H CO2H (Strong acidic solution) Desacetylcephalosporin Cephalosporin S R – CONH – CH – CH l l CO ------ N Desacetylcephalosporin Lactone ( In active form) CH2 l C C CH2 C ---- O O Lactonize Degradation of Cephalosporins B –LACTAMASE HYDROLYSIS OF S Hydrolysis of the ß-lactamase R1 – CONH – CH – CH l l CO ------ N R1 – CONH – CH – CH l l CO2H NH CH2 l C C CH2 - - - R2 l CO2H Cephalosporin S CH2 l C C CH2 - - - R2 l CO2H Cephalosporoic acid S R1 – CONH – CH – CH l l CO2H N CH2 l C C CH2 l CO2H Anhydrodesacetylphalosporoic acid Degradation of Cephalosporins ACYLASES Cephalosporin Aminocephalosporanic acid Desactyl-7Aminocephalosporanic acid Lactone CEPHALOSPORIN STRUCTURE increases the acid stability of the betalactam ring. O ll R1 – C - NH --R2 O OR3 Spectrum of Activity CEPHALOSPORINS > are considered broad-spectrum antibiotics with similar activities to that of ampicillin. > more resistant to the inactivation by the beta-lactamases, particularly those produced by gram(+) bacteria. > exhibit potent activity against most species of Klebsiella Different potencies are due to: 1. Different bacterial strains 2. Characteristics of individual bacterial species 3. Resistance to the inactivation of the beta-lactamases 4. Permeability of the bacterial cell 5. Intrinsic activity against bacterial enzymes involved in cell wall synthesis and cross linking. Antipseudomonal Cephalosporins cefotaxime Ceftriaxone Ceftriaxone Cefoperazone Moxalactam ceftazidime contain the polar functionalities such as (carboxy and Nacylureido) Adverse Reactions and Drug Interactions > non-toxic compound and exhibit selective toxicity towards bacteria > Allergy and hypersensitivity are most common reactions cefamandole, cefotetan, cefmetazole, moxalactam, cefoperazone have higher incidence of hypoprothrombinemia >poor nutritional status, debilitation, GIT surgery, hepatic disease or renal failure may lead to severe bleeding >vitamin K supplement is given to high risk patients undergoing cephalosporin therapy >react with alcohol due to the accumulation of acetaldehyde Classification of Cephalosporin 1. First generation Cephalosporins are moderate spectrum agents, with a spectrum of activity or treatable range of bacteria that includes penicillinase-producing, methicillin-susceptible staphylococci and streptococci They also have activity against some Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, but have no activity against Bacteroides fragilis, enterococci, methicillin-resistant staphylococci, Pseudomonas, Acinetobacter, Enterobacter, indolepositive Proteus, or Serratia. Classification of Cephalosporin Cefaclor 1. First generation Cephalosporins Cefprosil Loracarbef Cefazolin Cephradine Cephalexin Cefadroxil Cefoxitin Na Cefoperazone Cefuroxime Na Cefixime Cefotetan Disodium Classification of Cephalosporin 2. Second generation Cephalosporins > have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase. Cefaclor (Ceclor, Distaclor, Keflor, Raniclor) Cefonicid (Monocid) Cefprozil (cefproxil; Cefzil) Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym) Cefuzonam Classification of Cephalosporin 2. Second generation Cephalosporins > with antianaerobe activity Cefmetazole Cefoxitin Cefotetan > The following cephems are also sometimes grouped with second-generation cephalosporins: A. Carbacephems: - loracarbef (Lorabid) B. Cephamycins: - cefbuperazone, cefmetazole (Zefazone), cefminox, cefotetan (Cefotan), cefoxitin (Mefoxin) Classification of Cephalosporin 3. Third generation Cephalosporins Third-generation cephalosporins have a broad spectrum of activity and further increased activity against Gram-negative organisms. They may be particularly useful in treating hospital-acquired infections, although increasing levels of extended-spectrum beta-lactamases are reducing the clinical utility of this class of antibiotics. They are also able to penetrate the CNS, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillinresistant N. gonorrhoeae. Classification of Cephalosporin 3. Third generation Cephalosporins Cefcapene Cefdaloxime Cefdinir (Omnicef, Cefdiel) Cefditoren Cefetamet Cefpodoxime (Vantin,) Cefteram Ceftibuten (Cedax) Ceftiofur Cefixime (Suprax) Cefmenoxime Cefodizime Cefotaxime (Claforan) Cefpimizole Ceftiolene Ceftizoxime (Cefizox) Ceftriaxone (Rocephin) Classification of Cephalosporin 4. Fourth generation Cephalosporins Fourth-generation cephalosporins are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. Cefozopran Cefpirome (Cefrom) Cefquinome They also have a greater resistance to beta-lactamases than the thirdgeneration cephalosporins. Cefclidine Cefepime (Maxipime) Cefluprenam Cefoselis Many can cross the blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa. Classification of Cephalosporin 5. Fifth generation Cephalosporins Ceftobiprole has been described as "fifth generation" though acceptance for this terminology is not universal. Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance. PREPARE ½ CROSSWISE OR A SHORT QUIZ GOOD LUCK!