Pharmacology of Cephalosporins: General Overview Flavio Guzmán, M.D. http://pharmamotion.com.ar

β- lactams: cell wall inhibitors Penicillins Cephalosporins Carbapenems Monobactams

β-lactam ring The β-lactam ring is a common structure for: Penicillins Cephalosporins Monobactams Carbapenems Bacteria will target this ring to gain resistance.

Cell wall inhibitors: important features Cell wall inhibitors have bacericidal effect. They act sinergistically with amynoglycosides Time-dependent kinetics: the more time the drug binds the bacteria, the more effective it is. or instance, certain antibiotics, like beta-lactams (penicillins, cephalosporins, carbapenems, monobactams), clindamycin, macrolides (erythromycin, clarithromycin), oxazolidinones (linezolid), can be effective because of the extensive amount of time the antibiotic binds to the microorganism. The inhibitory effect can be effective because their concentration exceeds the MIC for the microorganism.

Mechanism of action 1 Beta-lactams bind PBP (Penicillin Binding Proteins). Some PBP have transpeptidase activity. Transpeptidase activity is essential in cell wall synthesis.

Mechanism of action 2 Transpeptidation inhibition Autolysins production Cell wall destruction

Cephalosporins 4th gen Cefepime 1st gen 2nd gen 3rd gen Cefadroxil Cefazolin Cephalexin Cephalothin 2nd gen Cefaclor Cefoxitin Cefuroxime sodium Cefuroxime axetil 3rd gen Cefnidir Cefixime Cefotaxime Ceftazidime Ceftibuten Ceftriaxone 4th gen Cefepime

Cephalosporins: characteristics As beta-lactams Mechanism of action Bactericidal ¿Bactericidal or bacteriostatic? Different, according to generations Antibiotic coverage

Chemical structure of cephalosporins Derived from 7-aminocephalosporanic acid. They suffer the “attack” of bacteria at their beta-lactam ring.

First gen. cephalosporins.: Cephalexin (prototype) Cefadroxil Parenteral Cephalotin Cefazolin

1st Generation cephalosporins: antibacterial coverage Active mainly against Gram positive cocci. Less active against Gram negative. Methicillin-sensitive Staphylococcus aureus Coagulase +,- Streptococcus Gram + PEcK: Proteus, E. Coli, Klebsiella Gram -

Clinical uses of first gen. cephalosporins Impetigo Caused by: Staphylococcus aureus and Streptococcus pyogenes Celullitis Group A streptococcus bacterium (Streptococcus pyogenes, GAS) and Staphylococcus aureus Prophylaxis of surgical wound infections Mainly produced by Gram positive bacteria

2nd generation cephalosporins Cefaclor Cefuroxime axetil Parenteral Cefoxitin Cefuroxime sodium

2nd generation cephalosporins. Antibiotic coverage Increased coverage against Gram negatives, while keeping coverage against Gram +. Methicillin-sensitive Staphylococcus aureus Streptococcus Gram + PEcK: Proteus, E. Coli, Klebsiella Haemophilus influenzae, Neisseria Gonorrhoeae, Enterobacter. Gram -

3rd generation cephalosporins Parenteral Ceftriaxone Cefotaxime Ceftazidime

3rd generation cephalosporins Coverage Increased coverage against Gram negatives. Decreased coverage against Gram + Methicillin-sensitive Staphylococcus aureus (less active than 1st gen cephalosporins). Streptococcus Gram + PEcK: Proteus, E. Coli, Klebsiella Haemophilus,Neisseria, Enterobacter. Serratia Gram -

3rd generation cephalosporins Clinical uses Bacterial meningitis: Gérmenes más frecuentes en adultos: S. Pneumoniae, N. meningitidis Gonorrhea Neisseria gonorrhoeae Pneumonia: only in some cases Only ceftazidime P. Aeruginosa infections.

Ceftriaxone and meningitis Pharmacokinetics Ceftiaxone crosses the Blood brain barrier and achieves good concentrations in CSF. Antibacterial coverage Active against Streptococcus y and Neisseria S. Pneumoniae and N. meningitidis are responsible for 80% of meningitis cases in adults.

4th generation cephalosporins Parenteral Cefepime

4th generation cephalosporins Antibacterial coverage Coverage against Gram + and Gram -, good activity against β-lactamase producing bacteria. Methicillin-sensitive Staphylococcus aureus Streptococcus Gram + PEcK: Proteus, E. Coli, Klebsiella Haemophilus,Neisseria, Enterobacter. Serratia Acinetobacter Pseudomonas aeruginosa Gram -

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