Cephalosporins & B-lactamase Inhibitors PDF

1 Lecture 7 B-lactamase inhibitors & Cephalosporins Dr. Noura Sayed  2 Course Learning outcomes 1.Outline the relation between the chemical structure and the biological activity studied in the...

1 Lecture 7 B-lactamase inhibitors & Cephalosporins Dr. Noura Sayed  2 Course Learning outcomes 1.Outline the relation between the chemical structure and the biological activity studied in the designing process of chemotherapeutic agents. (1-1-3-3) 2.Identify the pharmacological properties of the studied chemotherapeutic agents including mechanisms of action, uses, adverse reactions in addition to their physicochemical properties.(1-1-4-1)  11 2-Cephalosporins The first cephalosporin (cephalosporin C) was derived from a fungus (Acremonium chrysogenum) obtained in the mid 1945 from sewer waters on the island of Sardinia. Its structure was not determined not until 1961. Biosynthetic precursors of cephalosporin C are valine & cysteine. Its use is limited due to weak activity. First commercial cephalosporin is cephalothin.  12 2-Cephalosporins S O N O C CH3 O Penem COOH Penam Cephalosporanic acid H2N S O N O C CH3 O Cepham COOH Cephem 7-Amino Cephalosporanic acid [7-ACA]  13 2-Cephalosporins Structure of cephalosporin C B-lactam ring is less strained than in penicillin but it’s still reactive due to: 1-Olifenic linkage at C3. 2-Acetoxymethyl group (EWG = activating group).  14 2-Cephalosporins  15 2-Cephalosporins Advantage & Disadvantage Advantages: Disadvantages: 1. It has activity against Gram-ve 1. It has 1/1000 the activity of and Gram+ve bacteria. penicillin G. 2. It has greater resistance to acid 2. (3-acetoxymethyl) group hydrolysis and β-lactamase undergoes lactonization in GIT enzymes. (inactivation). 3. It is less likely to cause allergic 3. High polarity of the side chain: reactions. Difficult to isolate & purify & Poor GIT absorption.  16 2-Cephalosporins Mechanism of action  17 2-Cephalosporins Lactonization R R R O O O HN HN HN S S esterase S spontaneous N O H+ N OH N O lactonization O O COONa O COONa O O Active Less active Inactive Good leaving group  18 2-Cephalosporins SAR  19 Classes of Cephalosporins 1) Based on route of administration: Oral cephalosporins. Parentral cephalosporins. 2) Based on Generation system: 1st generation 2nd generation 3rd generation 4th generation 5th generation  20 Classes of Cephalosporins 5th G (MRSA) 4th Generation (broader strain- CNS pseudomonas) 3rd Generation anaerobic 2nd Generation (G-ve- Hemophilus influenza) 1st Generation (G+ve, G-ve (some derivative))  21 First generation cephalosporin They have a lower activity than comparable penicillins, but with better range. Most are poorly absorbed through the gut wall and have to be injected. The appearance of resistant Gram–ve organisms. Uses: Uncomplicated skin and soft-tissue infections Uncomplicated urinary tract infections Streptococcal pharyngitis (strep throat)  22 First generation cephalosporin Cephalothin Parentral (why?) Cephalexin [Ceporex®] Cefadroxil [Duricef®] O HO HC C HN S NH2 N O CH3 Oral oral COOH Side effect: Diarrhea G+ve and Some G-ve bacilli Less potent than cephalothin???  23 Second generation cephalosporin Introduced since 1970 till the present. Spectrum as 1st generation, but more active ≠ G-ve with exception to anaerobes. More resistant to ß-lactamase. They are effective against Hemophilus influenza Uses: They are effective against the upper and lower respiratory tract infections, acute sinusitis and Otitis media. They are not effective against the Central nervous system infections as they cannot cross the blood-brain barrier.  24 Second generation cephalosporin It include: Cephamycins & Oximinocephalosporins Cephamycins are very similar to cephalosporins and were isolated from a culture of Streptomyces clavuligerus (bacteria). e.g.: Cefoxitin is Broad spectrum & more active against G-ve and more resistant to ß-lactamase.  25 Second generation cephalosporin Carbamate Not clinically used or urethane gp 1. greater resistance to β-lactamase 2. good metabolic stability to esterases  26 Second generation cephalosporin True cephalosporins: Oximinocephalosporins: Contains an imino-methoxy (methoxime) group at the α-position of the acyl side chain, which significantly increases the stability of cephalosporins against the β-lactamases. Cefaclor Oral with food or injection Oral agent  27 Third generation cephalosporin Replacement of furan ring with aminothiazole ring: increase the penetration through the outer membrane of G-ve bacteria. increase affinity for the transpeptidase enzyme. With good stability ≠ ß-lactamase. With broader spectrum than 2nd generation. Active against anaerobic bacteria Some of them active ≠ Pseudomonas (cephtazidime and cefoperazone). Taken I.M. or I.V.  28 Third generation cephalosporin Uses: They are effective in: 1. curing Gram negative bacillary meningitis(CNS), 2. serious infections of Enterobacteriaceae, 3. Upper Respiratory tract infections, 4. otitis media, 5. pyelonephritis 6. with added advantage against skin and soft-tissue infections.  Both 29 Used in TTT of Third generation cephalosporin meningitis Cefotaxime It is used parentrally due to its poor bioavailability (1% absorption). New special formula in physical complexation with a cationic analogue of bile acid for oral Ceftriaxone absorption. The highly acidic heterocyclic dioxotriazine ring on the thiomethyl gorup is believed to confer the unique pharmacokientic properties. Once daily.  30 Fourth generation cephalosporin They are oximinocephalosporins. They are zwitterionic compounds so have enhanced ability to penetrate the outer membrane of G-ve bacteria. True broad spectrum (have the broadest spectrum of activity, with similar activity against gram-positive organisms as first generation cephalosporins.) They are effective against CNS infections and can be used for treating meningitis, Also, against Pseudomonas. They also have a greater resistance to beta-lactamases than the third generation cephalosporins..  31 Fourth generation cephalosporin Cefepime is highly active against many resistant organisms that traditionally have been difficult to treat.  32 Fifth generation cephalosporin Has activity against various strains of MRSA and multi-resistant Streptococcus pneumonia (MDRSP). 1,3-thiazole ring is important for its activity against MRSA.  33 Fifth generation cephalosporin ceftolozane for treatment of Complicated Intra-abdominal Infections (cIAI), and Complicated Urinary Tract Infections (cUTI). ceftolozane/tazobactam (Zerbaxa) 7-aminothiadiazole = increased activity against gram-negative organisms. alkoximino group, provides stability against many β-lactamases. a dimethylacetic acid = enhanced activity against Pseudomonas aeruginosa. The addition of a bulky side chain (a pyrazole ring) at the 3-position prevents hydrolysis of the β-lactam ring via steric hindrance.  4 β-lactamase Inhibitors -lactamase inhibitors used in combination with -lactamase sensitive penicillins for infections caused by -lactamase-producing bacteria (e.g. Clavulanic acid, Sulbactam/Tazobactam, and Olivanic acids).  5 A-Clavulanic acid a strained β-lactam ring; the enol ether; the Z configuration for the double bond of the enol ether (activity is reduced but not eliminated if the double bond is E ); no substitution at C-6; ( R )-stereochemistry at positions 2 and 5; the carboxylic acid group. 1st natural -lactam without sulfur (oxapenam). Isolated from Streptomyces clavuligerus in 1976. With weak anti-bacterial activity but Potent irreversible inhibitor of most -lactamases. Called Suicide substrate for -lactamase.  6 β-lactamase inhibitors Amoxicillin and clavulanic acid (Augmentin®) Combination with Amoxicillin and Clavulanic acid: 1- Decrease dose of amoxicillin. 2- Increase spectrum of activity.  7 B-Sulbactam & Tazobactam O O O O S S N N N N N O COOH O Triazole ring COOH Sulbactam Tazobactam Penicillanic acid sulphone derivatives. Semisynthetic ß-lactamase inhibitors. Act as suicide substrates and have a broader spectrum of activity against β-lactamases than clavulanic acid but is less potent.  8 β-lactamase inhibitors To overcome the bioavailability issue: Formation of mutual prodrug sultamicillin Gives high serum levels of sulbactam and ampicillin. Has synergistic activity. a double ester of formaldehyde hydrate in which one of hydroxyl group is esterified with ampicillin and the other with sulbactam. Sultamicillin  9 β-lactamase inhibitors Piperacillin + Tazobactam (Tazocin®) enhances piperacillin's effectiveness by inhibiting many beta lactamases, but not MRSA. Used for the treatment of serious, hospital-acquired infections.  10 Olivanic acids Isolated from Streptomyces olivaceus. They are 1000 times more potent than Carbapenem ring clavulanic acid. Effective against the β-lactamases which break down cephalosporins lacks chemical stability. 34