Prof Maged S. Abdel-Kader

Prof Maged S. Abdel-Kader
Cephalosporins Antibiotics, also known as antibacterials, are types of medications that destroy or slow down the growth of bacteria. The Greek word anti means "against", and the Greek word bios means "life" (bacteria are life forms).Antibiotics are used to treat infections caused by bacteria. β-LACTAMS A lactam is an internal amide, just like a lactone is an internal ester. A β-lactams indicates that the amine is in the β-position in relation to the carboxylic acid. All β-lactams will have similar mechanisms of action and many general properties. PENICILLINS They are the first group of antibiotics discovered. Source: Fermentation of Penicillium sp., which would lead to a mixture of compounds, Scientists tried to find other agents, that are: 1. Broad spectrum in action, 2. Orally active and 3. Builds up less or no resistance. Prof Maged S. Abdel-Kader Prof Maged S. Abdel-Kader

First isolated Cephalosporium aeremonium fungus. They separated by chromatography into three compounds as following: Cephalosporin P active only against gram (+ve) bacteria and structurally similar to fusidic acid (steroidal nucleus), highly toxic (hepato-toxic), used topically on wound. Cephalosporin N (Penicillin N), was not potent as antibiotic and not used clinically. Cephalosporin C structurally consists of 4-membered β-lactam and dihydrothiazine (6- member ring) rings. Both rings are known as cepham which is less strain than that penam of penicillin G. The first isolated agent, Cephalosporin C exhibited low antibacterial activity. Penicillium chrysogenum Prof Maged S. Abdel-Kader Prof Maged S. Abdel-Kader

Adding different substrates to produce other Cephalosporins did not work Using 7-ACA (7-amino cephalosporanic acid) produced enzymatically or chemically, led to production of very useful drugs with broad spectrum and resistance to ß-lactamases. Prof Maged S. Abdel-Kader

The six-member ring dihdrothiazine in cephalosporins exerts less stress on the b-lactam ring, leads to less susceptibility to act as a substrate for PBP. In general, Cephalosporins are more resistant to ß-lactamases and have a broader spectrum. However Penicillins are more potent against non ß-lactamase producing bacteria. They show less allergenicity than penicillin, where cross sensitivity occurs in about 10% of the cases. Should be especially careful with patients that develop severe reactions to penicillin. Prof Maged S. Abdel-Kader

Semi-synthetic derivatives
In the preparation of semisynthetic cephalosporins the following improvements are required: Increased acid stability. Increased activity against resistant micro-organisms through: Resistance to enzymatic destruction. Improvement penetration. Increased receptor affinity. Prof Maged S. Abdel-Kader

Semi-synthetic Cephalosporins
95% of cephalosporins are semi synthetic, 5% are fully synthetic and there is no natural cephalosporin used clinically. Cephalosporins are classified into 5 different generations according to: Spectrum and potency. Resistance toward β-lactamase enzymes. Pharmacokinetic properties. Prof Maged S. Abdel-Kader

General common properties of cephalosporins
They are effective against Proteus, E.coli and klebseilla. They are less allergic than penicillins. Prof Maged S. Abdel-Kader

Structure Activity Relationship
Changes in R-1 may cause changes in spectrum and ß-lactamase resistance, similar to Penicillins. An electron withdrawing group (NO2, Cl, CN,..) will give the compound better acid stability, A bulky group (phenyl, diphenyl, ..) close to the ring, gives it better resistance to ß-lactamases A polar group (NH2, COOH, OH, ..) extends its spectrum. Prof Maged S. Abdel-Kader

Changes in R2 will affect the pharmacokinetic properties of the drug: Using a non-metabolized group (Cl, CH3,..) can lead to oral activity and less metabolism. 1-Methyl-5-thiotetrazole (MTT) group leads to an extended spectrum, higher potency and a longer half-life. Prof Maged S. Abdel-Kader

It does however come with a price, a serious side effect, as it may cause bleeding due to hypoprothrombonemia. It will inhibit certain vitamin K-based enzymes that produce various clotting factors which can be reversed by using Vitamin K. These compounds also inhibit aldehyde dehydrogenase, causing alcohol intolerance. Addition of a methoxy group at the 7-alpha position led to compounds that are very effective against ß-lactamase producing organisms Hypoprothrombinemia is a blood disorder in which a deficiency of prothrombin (Factor II) results in impaired blood clotting, leading to an increased physiological risk for bleeding, especially in the gastrointestinal system Prof Maged S. Abdel-Kader Prof Maged S. Abdel-Kader

Cephradine is the only 1st generation cephalosporin that is used both orally and parentrally. Cephalosporins are considered as broad spectrum antibiotics comparing to Penicillins due to the following: Resistance to inactivation by β-lactamase. Permeability of the bacterial cells. Stronger activity against bacterial enzymes involved in cell wall synthesis and cross linkage. Prof Maged S. Abdel-Kader

Adverse Reactions Allergic and hypersensitivity reactions. Allergic reactions are believed to occur less frequently with cephalosporins. Cross sensitivity between penicillins and cephalosporins is complex and the incidence is very low. Cephalosporins containing N-methyl-5-thiotetrazole ring (MTT) at C-3 position have been implicated in: Inhibition of vitamin K requiring enzymes involved in clotting factors. Inhibition of aldehyde dehydrogenase Prof Maged S. Abdel-Kader

First Generation cephalosporins
Prof Maged S. Abdel-Kader

The first Generation cephalosporins do not have as broad spectrum of action against gram (-ve) bacteria as the newer cephalosporins but they have the greatest activity against gram positive bacteria. Most first generation cephalosporins have similar spectra and they differ in their pharmacokinetic. Prof Maged S. Abdel-Kader

General Characteristics
Highly active against gram (+ve) bacteria as: Staph.aureus penicillinase producing strain. Staph. Epidermidis, in case of massive burn, surgery, skin grafts. Used as prophylaxis. Against Streptococci (except group D and Entrococci). Gravits = a piece of skin transplanted to a new site on a patient's body or to a different individual. Prof Maged S. Abdel-Kader Prof Maged S. Abdel-Kader

Active against some gram (-ve) bacteria like E.coli, Klebsiella, pneumonia and Proteus mirabilis. Limited activity against aerobic gram(-ve) Bacilli. Active against most of anaerobes except Bacteroides fragilis. Inactive against H. influenzae (2 nd gen is) and Ps. aerugenosae (3 rd gen is). They do not cross blood brain barriers. They are cephalosporinase sensitive. Prof Maged S. Abdel-Kader

They are not used in the nosocomial infection (hospital acquired infection caused by the micro-organisms which are opportunists when: The immune system of the host has been impaired. They can bypass anatomic barriers following burns, wounds or surgery. They are implanted by contaminated catheters, syringes or respirators . They are not used in the nosocomial infection but used with community-acquired infection. انتهازي Opportunists = Anatomic = تشريحي Catheters = قسطرة Prof Maged S. Abdel-Kader Prof Maged S. Abdel-Kader

1970 Cephalothin, used only parentral. Cephaprin, used only parentral. 1973 Cephalexin, oral only. Cephradine, oral & Parentral. Cefazolin, parentral only. Cefadroxil, oral only. Prof Maged S. Abdel-Kader

Cephalothin (Keflin) Cephalothin has been in clinical use longer than other because it has greatest resistance to hydrolysis by b-lactamase enzymes Its injection i.m often painful and i.v. causes phlebitis (Thrombophlebitis is swelling (inflammation) of a vein caused by a blood clot. It has a short t1/2.

Cefazolin (Kefzol, Cefamezin, Totacef, Zinol)
It is preferred for parentral administration because other cephalosporins are inactivated in plasma by deacetylation while cefazolin remains unchanged. It has long serum t1/2 permits less frequent administration and lower doses because it has a lower rate of renal excretion. It is less painful when used i.m and it produces less phlebitis when used i.v. Long t1/2, so it is used at long time interval leading to lower incidence of thrombophlebitis. Expanded spectrum against E.coli. Prof Maged S. Abdel-Kader

Cephalexin (Keflex, Cephoxin, Ceporex, Neocef, Ospexin, Starcef)
The drug present as zwitter ion. It is used orally only. The cheapest first generation cephalosporins Cephalexin is acid-stable and % of a dose is absorbed from GIT. It is chemically similar to cephradine but cephalexin has been in use longer and is preferred. Prof Maged S. Abdel-Kader

Cephradine (Velosef, Cefatrexyl, Cefradine, Farcosef, Ultracef)
Dihydrocephalexin Present as zwitter ion, orally and parentrally used. Cephradine, cephalexin and cefazolin have the same spectrum against E. coli. Less lipophelic, less protein binding, increasing blood level of the antibiotic therefore it is used for treatment of serious infection (bacteraemia). Prof Maged S. Abdel-Kader

Cefadroxil (Duricef, Longicef, Biodroxil, Curisafe, Ibidroxil)
Hydroxylcephalexin Orally used antibiotic. The presence of hydroxyl group retards the renal excretion, increasing its t 1/2. Its spectrum as that of cephradine and cefazolin Prof Maged S. Abdel-Kader

2nd Generation Cephalosporins

They have expanded activity against gram negative organisms due to: Increased affinity to penetrate the envelope of gram negative bacteria. Increased resistance to hydrolysis by gram negative β-lactamase producing bacteria. Prof Maged S. Abdel-Kader

These drugs active against many cephalothin-resistant E.coli, Klebsiella and Proteus sp. Unlike first generation cephalosporins, the second and third generation cephalosporins drugs vary in their spectra of action. They are less active against gram positive than the first generation cephalosporins. Prof Maged S. Abdel-Kader

Cefaclor (Ceclor, Bacticlor, Cloracef, Misaclor, Serviclor)
Orally active. Presence of chlorine atom increases drug lipophilicity which increases its blood level and makes it long acting Tasteless therefore it is suitable as pediatric formulation. Active against H. influenzae. It is well absorbed from GIT even with full stomach Long acting Prof Maged S. Abdel-Kader

Cefprozil- Cefproxil (cefzil)
Orally used as Tablet or suspension. cis and trans isomeric mixture ( ≥ 90% cis). Used in bronchitis, ear infections, skin infections, and other bacterial infections. Side Effects: Gastrointestinal: Diarrhea (2.9%), nausea (3.5%), vomiting (1%), and abdominal pain (1%). Hypersensitivity: Rash (0.9%), urticaria (0.1%). CNS: Dizziness (1%), hyperactivity, headache, nervousness. Prof Maged S. Abdel-Kader

Cefuroxime (Zinnat, Zinacef)
oral second-generation Cefuroxime axetil is an acetoxyethyl-ester-prodrug of cefuroxime which is effective orally Unlike most other second-generation cephalosporins, cefuroxime can cross the blood-brain barrier have greater activity against Haemophilus influenzae, Neisseria gonorrhoeae Prof Maged S. Abdel-Kader

If ingested after food, this antibiotic is both better absorbed and less likely to cause its most common side effects. Side Effects: diarrhea, nausea, vomiting, headaches/migraines, dizziness, and abdominal pain Prof Maged S. Abdel-Kader

Cefoxitin (Mefoxin) It has 7-methoxy group which gives a limited resistance to some cephalosporinase producing strains. It is used as pareneteral, i.v. an i.m., the i.m. dosage form is very painful. It has an ester of carbamic acid in the side chain which hydrolyzed by esterase to gives inactive metabolite. It is particularly active against Bacteroides fragilis and other anaerobes. Cefoxitin and cefamandole were the first used second generation cephalosporins in USA. Prof Maged S. Abdel-Kader

Cefamandole (Mandole)
Formate ester of cefamandole is responsible for increase stability of the drug. N-methyl tetrazole leads to increases the resistance of the drug to cephalosporinase enzyme. Parenteral use only. It is active against many strains of H. influenzae, Enterobacter, indole-positive Proteus, Pr. mirabilis, Pr. vulgaris, B. fragilis, and Clostridium species Prof Maged S. Abdel-Kader

3rd Generation Cephalosporins

General Characteristics
Have substitution in basic ring structure which increase their affinity to PBP receptors, thereby enhancing activity. Out of them there are 5 parentrally administered including (cefotxamine, ceftriaxone and cefoperazone). And 3 are orally administered (cefpodoxime proxetil, cefixime, ceftibuten). Prof Maged S. Abdel-Kader

All are used for treatment of gram negative meningitis except cefoperazone. They are excreted by kidney except cefoperazone which excreted mainly by liver. Cefotaxime and ceftriaxone have been extensively used in treatment of gram negative meningitis. Ceftizoxime has the best activity for treatment of diabetic foot and mixed aerobic / anaerobic infections in the abdomen, female genital tract and They should be reserved for the treatment of severe infections due to gram negative Bacilli susceptible bacteria. Prof Maged S. Abdel-Kader

Cefotaxime is the only third generation cephalosporins that are metabolized to a biologically active form. They are very active in the treatment of nosocomial infections. All are active against Ps. aeruginosa and N. gonorrhea. They can cross BBB, therefore, they are used for treatment of meningitis (Parentrally). They have a high affinity to bind with PBP. Prof Maged S. Abdel-Kader

Spectrum Gram negative Bacilli and most Enterobacteriaceae including second generation cephalosporins resistant strains. Cefoperazone is active against Ps. auroginosa, in addition to Neisseria spp. and H. influenzae. Cefotaxime and cefoperazone have the greatest activity against Staph. aureus including MRSA. Most enteric gram negative Bacilli including E.coli, Klebsiella, Proteus, indole positive proteus, Citrobacter and Serratia species Prof Maged S. Abdel-Kader

Neisseria and H. influenzae are susceptible to all third generation cephalosporins. Activity against Staph. and Sterpt. is less with the third generation cephalosporins than with first and second generations. Cefataxime and cefoperazone have the greatest activity against Staph. while MRSA is susceptible to all third generation cephalosporins except ceftazdime. Active against Strept. pyogenes and most Strept. pneumoniae Have their greatest impact in the treatment of meningitis caused by gram negative enteric bacteria Prof Maged S. Abdel-Kader

Cefotaxime (Claforan, Ceforan, Cefotax, Foxime, Hebitaxime, Rametax, Sigmataxim , Xorin) It is very active against N. gonorrhea Greatest activity against Staph. aureus including MRSA. It used for treatment of nosocomial infections Metabolized to a biologically active form. Parenteral use. It is short acting drug Prof Maged S. Abdel-Kader

Ceftriaxone (Rocepghin, Cefotrix, Cefaxone, Epicephin, Longacef, Triaxone, Xoraxon, Zoxon) It is active against all types of Gonorrhea. It’s a drug of choice for treatment of Gonorrhea, H. influenzae (meningitis in infants, otitis) Parenteral use. Used as a prophylaxis against meningitis Prof Maged S. Abdel-Kader

Cefoperazone (Cefobid, Cefazone, Cefrazon, Cefron, Cefozon)
The second more potent third generation cephalosporins against Ps. aeurginosea. Sulbactam and Cefoperazone combination is marketed under the names Sulperazone and Bacperazone Parenteral use. Prof Maged S. Abdel-Kader

Not used for treatment of gram negative meningitis. Excreted mainly by liver. Greatest activity against Staph. aureus including MRSA. Prof Maged S. Abdel-Kader

Cefdinir (Cedenir, Cefdin, Dinar, Cefzon, Omnicef)
Orally used as Capsules or Suspension. Broad spectrum against gram +ve and gram –ve bacteria. Omnicef was the top selling cephalosporin in the USA in 2008. Side Effects: Diarrhea, headache, nausea and abdominal pain Prof Maged S. Abdel-Kader

Ceftazidime (Cefidime, Cefzim, Cetazime, Fortum)
I.V. or I.M. injection every 8-12 hours. Broad spectrum Lower respiratory tract, Urinary tract, skin, blood stream, joint and Abdominal infections. Meningitis. Active against Pseudomonal infections. Resistant to b-lactamases. Prof Maged S. Abdel-Kader

Side Effects: Diarrhea, headache, nausea and abdominal pain Prof Maged S. Abdel-Kader

4th Generation Cephalosporins

They are dipolar ionic compounds diffuse more rapidly into gram negative bacterial envelope. They have a lower affinity for β-lactamases. They have a broad spectrum of antibacterial activity against Enterobacteriaceae more than third generation cephalosporins They have excellent activity against H. influenzea, N. gonorrhea and N. meningitis. They are active against Pseudomonas aurogenosa. Prof Maged S. Abdel-Kader

They are not active against Enterococci or MRSA. They are more resistant to β- lactamases enzymes due to some modification in both C-7 and C-3 positions. The side chain at C-3 is charged, highly polar, and this will increase the penetration power to cell envelope of gram negative bacteria. Prof Maged S. Abdel-Kader

Cefepime (Maxipime, Forcetex, Onsime, Wincep)
The only clinically used drug of the fourth generation. Used Parenteral only. It is poor β- lactamase inducers, this is an important factor to delay the resistance of some bacteria to the drug. It is more active than third generation cephalosporins against Enterobacter. It is active against Ps. aeurginosea and excellent activity against H. influenzae, N. gonorrhea and N. meningitis. Active against some gram positive bacteria but not active against Enterococci group D and MRSA. It is used in treatment of nosocomial infections. Prof Maged S. Abdel-Kader

5th Generation Cephalosporins
Fourth-generation cephalosporins as of March, 2007, were considered to be "a class of highly potent antibiotics that are among medicine's last defenses against several serious human infections" according to the Washington Post.[15] The mnemonic "LAME" is used to note organisms against which cephalosporins do not have activity: Listeria, Atypicals (including Mycoplasma and Chlamydia), MRSA, and enterococci. Fifth-generation cephalosporins are effective against MRSA, however. Prof Maged S. Abdel-Kader Prof Maged S. Abdel-Kader

Ceftolozane (Zerbaxa)
Developed for the treatment of infections with resistant gram-negative bacteria Mainly for urinary tract, intra-abdominal infections Ceftolozane is combined with the β-lactamase inhibitor tazobactam. Prof Maged S. Abdel-Kader

Useful for Hospital-acquired infections.Ninety percent of Pseudomonas aeruginosa were inhibited by a ceftolozane-tazobactam at a concentration of 4 μg/mL (MIC90, making it the most potent anti-pseudomonal antibiotic in clinical use. Prof Maged S. Abdel-Kader

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