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Learning objective

• By the of this lecture the student will be able to: • Describe the mode of action of cephalosporins • Differentiate the spectrum of activity of the 4 classes of cephalosporins • State the side effects & therapeutic uses of cephalosporins • Describe the mechanism of action of vancomycin

Cephalosporins

Closely related in structure to penicillin

Cephalosporins:Mechanism of action

Cephalosporins inhibit the peptidoglycan synthesis of bacterial cell wall in a manner similar to that of penicillin and are considered bactericidal.

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Cephalosporins: Spectrum of Activity
All cephalosporins are active against most G+ cocci, including penicillinase-producing staphylococci and many strains of G- bacilli, Relatively ineffective against enterococci. Divided into 4 major groups called “Generations”

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Cephalosporins: Generations
- First-generation cephalosporins - Second-generation cephalosporins - Third-generation cephalosporins - Fouth-generation cephalosporins
•In general, 1st generation cephalosporins have better activity against gram-positive bacteria and less gram-negative activity, while 3rd generation agents, with a few exceptions, have better gram-negative activity and less gram-positive activity. The fourth generation agent has both gram-positive and gram-negative activity. •Elimination is primarily via the kidneys, though a few exceptions include ceftriaxone which have significant biliary elimination 6

First Generation Cephalosporins
• Examples: Cefazolin
① - They have a stronger antimicrobial action on G+ bacteria than that of the other generations.

② - Their action on G- bacteria is relatively poor.
③ - They have nephrotoxicity to a certain degree.

④ - They are NOT effective against pseudomonas.

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First Generation Cephalosporins
- Comparatively, they are stable for beta- lactamase (penicillinase ). ④ -They are chiefly used in treating infection of the penicillinase-productive aurococcus (S.aureus ) and surgical prophylaxis. ⑤ - Do not penetrate the central nervous system and can not be used to treat meningitis.

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Second Generation Cephalosporins
 Examples: cefaclor ① Action of this generation on G+ bacteria is the same or less than that of the first generation. ② Their antimicrobial action on G- bacteria is increased ③ Some of them are effective against anaerobes

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Second Generation Cephalosporins
④ - Ineffective against p.aeruginosa. ⑤ They are stable to many kinds of betalactamases. ⑥ Do not penetrate the central nervous system and can not be used to treat meningitis ⑦ - less nephrotoxic than the first generation.

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Third Generation Cephalosporins
 ① ② ③ ④

Ceftriaxone One of the broadest spectrum cephalosporins high activity against G- bacteria. low activity against G+ bacteria. The highest resistance to β-lactamase.

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Third Generation Cephalosporins
⑤ The best penetration into the CSF
⑥ Almost no nephrotoxicity ⑦ Some of them are effective against P.aeruginosa and enteric bacilli

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Fourth Generation Cephalosporins
• e.g Cefepime: • Similar to third generation agents but more resistant to hydrolysis by beta lactamase. • It is useful against many enterobacter resistant to other cephalosporins.

Cephalosporins: Side effects
Relatively few and low The most common ones are Allergyhypersensitivity reactions (5%-10%)
anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia. During treatment with third and fourth generation drugs, resistant bacteria, as well as fungi, often proliferate and may induce superinfections.
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Cephalosporins: Side effects
Nephrotoxicity:
 The first-generation cephalosporins have certain nephrotoxicity.  The second-generation have slight nephrotoxicity.

The third and fourth generation have no
nephrotoxicity.

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Clinical uses of cephalosporins
1. Infections resistant to penicillins 2. Patients sensitive to penicillins 3. Gram-ve urinary tract infections and meningitis 4. Respiratory tract infections

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Cephalosporins
NB: • Patients with history of penicillin allergy may tolerate cephalosporins. • But patients with history of anaphylaxis should never receive cephalosporins • Non of the cephalosporins is active against MRSA.

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Other inhibitors of cell wall synthesis

Vancomycin
• It is active only against gram-positive bacteria especially staphylococci. • Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization .

Vancomycin: Therapeutic indications
• 1. Infections caused by methicillin –resistant staphylococci (MRSA) • 2. Vancomycin is used in combination with: a) gentamycin for treatment of enterococcal endocarditis in penicillin allergic patient. b) 3rd generation cephalosporins for treatment of meningitis caused by penicillin resistant pneumococci.

Vancomycin: Adverse effects
1. Irritation leading to phetibitis at the site of infection. 2. Chills and fever. 3. Ototoxicity and nephrotoxicity especially if given with another ototoxic or nephrotoxic drug as aminoglylosides. 4. Histamine release . (red man syndrome)

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