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

Targets of Antibiotic

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

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

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

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

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

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

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

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

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

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

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

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