1. أ. م. د. وحدة اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul-2014 Cephalosporins 3

2. Objectives At end of this lecture, the students will be able to: 1- Identify the chemical structure and the classes of cephalosporin. 2- Discuss the clinically important features of each individual class of cephalosporin (Its pharmacokinetic properties, antibacterial activities, clinical uses and side effects). 3- Clarify the differences between different classes of cephalosporin. 4- State other agents affecting the cell wall. - At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.

3. Cephalosporin - They are B-lactam antibiotics that are closely related both structurally and functionally to the penicillin. - The chemical nucleus of the cephalosporin is 7- amino cephalosporanic acid bears a close resemblance to 6-amino penicillanic acid of penicillin. - Both penicillin and cephalosporin are safe during pregnancy.

4. Cephalosporin Chemical structure -The chemical nucleus of the cephalosporin is 7- amino cephalosporanic acid. - Most cephalosporin are produced semi- synthetically by the chemical attachment of side chains to 7- aminocephalospora-nic acid.

5. Mechanism of action of cephalosporin - Cephalosporin inhibit cell wall synthesis in a way similar to that of penicillin. - The cephalosporin are bactericidal drugs with both gram positive and gram negative activity. - They are more stable than penicillin to many bacterial Beta Lactamases and therefore usually have a broader spectrum of activity.

6. Classification of Cephalosporin - Cephalosporins have been classified as 1st, 2nd, 3rd, 4th or 5th generation on the basis of bacterial susceptibility pattern & resistance to B-lactimase: 1- First Generation: Orally: Cefadroxil, Cephalaxin, Cephalothin. Prenterally: Cefazolin. 2- Second Generation: Prenterally: Cefoxitin, Cefotetan, Cefonicid, Cefamandole. Oral: Cefuroxime axetil, Cefprozil.

7. Classification of Cephalosporin 3- Third Generation : Oral: Cefixime, Ceftibuten. Prenterally: Cefotaxime, Ceftriaxone, Ceftizoxime, Ceftazidime. 4- Forth Generation : Cefepime is the most clinically useful. Must be administered parenterally. 5- Fifth Generation: Ceftobiprole : New drug.

8. First Generation Cephalosporin Antibacterial Activity: - - These are highly effective against gram - positive (G+) bacteria including strep., pneumococcus & staph.---(as penicillin G). - - Also They have low activity against gram negative organisms including: Proteus mirabilis, E coli & Klebsiella pneumonia (PEcK)

9. Clinical Uses of First Generation Cephalosporin - They are not used for serious systemic infection. So used in: - Oral : widely used for the treatment of RTI, uncomplicated UTI & soft tissue infection (cellulites) & soft tissue abscess (minor staph. Infection). - Prenterally: Cephazolin penetrate well into most tissues mainly bone (not CNS). It is the drug of choice for surgical prophylaxis & also for the biliary tract & endocarditis.

10. Second Generation Cephalosporin Antibacterial Activity: - In general they are active against organisms affected by first generation drugs (slightly less activity against gram positive organisms). - It has also activity against three additional G- negative microorganism: Haemophilus influenzae, some Enterobacter aerogenes & some Neisseria species (in addition to Proteus mirabilis, E coli & Klebsiella pneumonia) (HEN PEcK).

11. Clinical Uses of Second Generation Cephalosporin Oral agents are used for : 1- The lower RTI such as sinusitis, otitis media & acute bronchitis (against B-lactimase producing H.Influenzae). 2- Because Cefoxitin & Cefotetan, pocess activity against anaerobic bacteroid, including bacteroid fragilis, can be useful in the treatment of mixed anaerobic infection (peritonitis & Diverticulitis). 3- Used for community acquired pneumonia.

12. Clinical Uses of Second Generation Cephalosporin Prenteral Agents: - Used for the treatment of mixed anaerobic infection such as abdominal & pelvic infection as peritonitis.

13. 3- Third Generation Cephalosporin Antibacterial Activity: - Their activity against gram positive organisms is less than that of the first generation. - They have greater activity against gram negative bacteria than first or second generations plus other enteric organisms & Serratia marcescens. - Ceftazidime has activity against pseudomonas aeroginosa.

14. Clinical Uses of Third Generation Cephalosporin - They are used to treat serious infections caused by organisms that are resistant to most other drugs: - Parenteral: Used for the treatment of: Brain abscess, Meningitis, Gonorrhoea, Peritonitis, Pneumonia, Surgical prophylaxis, Septicemia, syphilis, Biliary tract infections, Skin infections. - Oral Preparations: used for : Gonorrhoea, Otitis media, pharyngitis, bronchitis and UTIs.

15. Forth Generation Cephalosporin -Cefepime is the most clinically useful. Must be administered parenterally. - It has a wide antibacterial activity being active against streptococci & staphylococci (only those Methicillin susceptible). - It has a wide antibacterial activity being active against streptococci & staphylococci (only those Methicillin susceptible). - It is also effective against aerobic G-ve organisms such as Enterobacter, E coli, K pneumoniae, Proteus mirabilis & pseudomonas aeroginosa.

16. Fifth Generation Cephalosporin Ceftobiprole: - New drug with activity against methicillin- resistant Staphylococcus aureus, penicillin- resistant Streptococcus pneumoniae and Enterococci. - Ceftobiprole cannot be given by mouth. Given parentrally. - Ceftobiprole is not licensed to be used in children - - Ceftobiprole has been approved for use in Canada and Switzerland (after Feb 2008), and is under review by regulatory authorities in the United States, the European Union, Australia, Russia and South Africa.

17. Side effects of Cephalosporin 1- Allergic Reactions of the penicillin type such as rash, urticaria and anaphylaxis. -There is cross allergy between penicillin and cephalosporins involving about 10% of patients. 2- Pain at the site of IM injection and thrombophlebitis after IV use can occur.

18. 3- All cephalosporins can produce pseudomembranous colitis caused by Clostridium difficile. 4- If cephalosporins are continued for more than 2 weeks, thrombocytopenia, leucopenia, interstitial nephritis or abnormal liver function tests may occur especially at high dosage. These reversed on stopping the drug.

19. Other agents affecting the cell wall 1- Vancomycin: Vancomycin is a tricyclic glycopeptide that has become increasingly important because of its effectiveness against multiple drug resistant organisms such as methicillin-resistant staphylococci.

20. Mechanism of action Vancomycin Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan layer at a site earlier than that inhibited by the B-lactam antibiotics. Antibacterial spectrum: - In order to limit the increase in vancomycin- resistant bacteria, it is important to restrict its use to the treatment of serious infections caused by B-lactam-resistant gram-positive microorganisms, or for patients with gram-positive infections who have a serious allergy to the B-lactams.

21. Clinical uses of Vancomycin 1-It is also used for potentially life-threatening antibiotic-associated colitis due to Clostridium difficile (pseudomembranous colitis) or staphylococci. 2- Vancomycin is used in individuals with prosthetic heart valves or in patients being implanted with prosthetic devices. 3- Vancomycin acts synergistically with the aminoglycosides and this combination can be used in the treatment of enterococcal endocarditis.

22. Side effects of Vancomycin - Side effects are a serious problem with vancomycin and include: 1- Fever, chills, and/or phlebitis at the infusion site. 2- Shock has occurred as a result of rapid administration. - 3- Flushing ("red man syndrome") and shock result due to histamine release caused by rapid infusion. - 4- Dose-related hearing loss has occurred in patients with renal failure who accumulate the drug.

23. Other agents affecting the cell wall 2- Bacitracin: - Bacitracin is a mixture of polypeptides that inhibits bacterial cell wall synthesis. - - It is active against a wide variety of gram-positive organisms. - - Its use is restricted to topical application because of its potential for nephrotoxicity.