1. Cephalosporin and Cell Wall Synthesis Inhibitors
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 3
September 24, 2011

2. Targets of Antibiotic

3. β-Lactam Antibiotic β-Lactam antibiotics have four classes Penicillins
Cephalosporins
Carbapenems
Monobactams

4. Why Cephalosporin Called β-Lactam Antibiotics?
Name of this antibiotic is because of the presence of β-lactam ring
This ring can be cleaved by β-lactamase enzymes produced by bacteria
This class of antibiotics kill bacteria by inhibiting bacterial cell wall synthesis

5. Structure of Cephalosporin
Nucleus of cephalosporin contains a β-lactam and a dihydrothiazine ring
β -lactam ring is the chemical group associated with antibacterial activity
Pharmacological, pharmacokinetic, and antibacterial properties of individual cephalosporins result from substitution of various
groups on the basic
molecule

6. Cephalosporin: Mechanism of Action
Inhibit the transpeptidation enzyme that cross-links the peptide chains of the bacterial cell wall peptidoglycan
Interfere autolytic enzymes (autolysin) in the cell wall, leads to lysis of the bacterium

7. Classification of Cephalosporin
Classification is based largely on their bacterial susceptibility patterns and resistance to β-lactamases activity:
1. First generation cephalosporins:
Cephalexin, cephazolin, cefadroxil. Effective against Strep. pyogenes and Strep. pneumoniae, E. coli
2. Second generation cephalosporins:
Cefuroxime, cefador, cefprozil. Efficacy of second generation cephalosporins has been increased, e.g., H. Influenzae.
3. Third generation cephalosporins:
Ceftriaxone, cefotaxime. Useful in severe sepsis, because they penetrate the blood-brain barrier well and are effective in meningitis
4. Fourth generation cephalosporins:
Cefepime

8. Cephalosporin: Pharmacokinetic Aspects
Administration:
Intravenous
Intramuscular
Oral
Distribution:
Distribute very well into body fluids
Cross the placenta
Excretion:
Excretion is mostly via the kidney, largely by tubular secretion

9. Clinical Use of Cephalosporin
1. First generation cephalosporins:
Have reasonable activity against Gram-(+)ve organisms and modest activity against Gram-(-)ve organisms
2. Second generation cephalosporins:
Show only moderate activity against most Gram-(+)ve organisms but reasonable potency against Gram-(-)ve organisms
3. Third generation cephalosporins:
Less active against Gram-(+)ve bacteria than those of the second generation but more active against Gram-(-)ve bacteria. Has some activity against pseudomonads
4. Fourth generation cephalosporins:
Comparable to 3rd generation but more resistant to some β-lactamase

10. Cephalosporin: Adverse Effects
Hypersensitivity reactions, very similar to those that occur with penicillin
Cross-reactions occur; about 10% of patients allergic to penicillins are allergic to cephalosporins also
Skin rashes as observed
Nephrotoxicity has been reported

11. Carbapenems Acts in the same way as the other β-lactams
Very broad spectrum of antimicrobial activity, being active against many aerobic and anaerobic Gram-(+)ve and Gram-(-)ve organisms

12. Carbapenems Few Carbapenems Antibacterial spectrum: Pharmacokinetics:
Imipenem, meropenem, ertopenem
Antibacterial spectrum:
Imipenem is the broadest-spectrum β-lactam antibiotic
Imipenem resists hydrolysis by most β-lactamases
Pharmacokinetics:
Administered intravenously and penetrate well into body tissues and fluids
Excreted by glomerular filtration
Adverse effects:
Cause nausea, vomiting, and diarrhea
High levels of imipenem may provoke seizures

13. Monobactams
Aztreonam contains a 5-monobactam ring and are resistant to β-lactamase degradation
It is used in severe sepsis, especially infections of the respiratory, urinary, biliary, gastrointestinal and female genital tracts
Mechanism of action:
Similar to penicillins
Pharmacokinetics:
Poorly absorbed after oral administration
Adverse effects: Rashes

14. Vancomycin Uses and antibacterial spectrum: Mechanism of action:
Valuable in resistant infections due to Staphylococcus and is given orally for the treatment of pseudomembranous colitis
Mechanism of action:
Inhibits bacterial cell wall synthesis as well as peptidoglycan polymerization
Adverse effects:
Hearing loss, hypersensitivity, rashes, nephrotoxicity