Cephalosporins

 

Cephalosporins

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Chemical structure: The Cephalosporins are derived as semi-synthetically from Cephalosporin-C, obtained from a fungus Cephalosporium acremonium (initially isolated by Brotzu in 1948).

 All Cephalosporins contain the basic structure of a dihydrothiazine ring fused to a β-lactam ring to form 7-aminocephalosporanic acid (the basic nucleus of Cephalosporins), thus they are chemically related to Penicillins which also contain the β-lactam ring. By the addition of different side chains to position 7 of the β-lactam ring (R₁) and position 3 of dihydrothiazine ring (R₂), a large number of semi-synthetic antibiotics have been prepared. The modifications at position 7 are generally associated with alterations in the spectrum of antibacterial activity and substitutions at position 3 lead to change in pharmacokinetic profile. The physical and chemical properties of Cephalosporins are generally similar to those of Penicillins, although Cephalosporins are more water soluble and acid-stable.

Mechanism of action: All Cephalosporins are bactericidal and they inhibit the bacterial cell wall synthesis in a manner similar to that of Penicillins. However they bind to different proteins than those required by Penicillins.

Pharmacokinetics: Cephalosporins are widely distributed in body tissues (including lungs, kidneys, bones and soft tissues) and fluids (such as pleural, pericardial and synovial fluids). They are also capable to cross placental barrier. Some 3^rd generation Cephalosporins also cross the blood brain barrier and thus can be used to treat bacterial meningitis (caused by gram negative bacteria). Cephalosporins enter the milk in low concentrations. Most Cephalosporins do not undergo significant biotransformation and are excreted unchanged in the urine. Like Penicillins, Probenicid increases the half-lives of Cephalosporins.

Classification: Cephalosporins are commonly classified in terms of their chronological sequence of development into four groups- 1^st, 2^nd, 3^rd and 4^th generation Cephalosporins.

Classification of Cephalosporins
Generation	Examples
1st	Cephalothin, Cephradine
2nd	Cefuroxime, Cefaclor
3rd	Cefotaxime, Ceftiofur
4th	Cefpirome, Cefquinome

Antimicrobial spectrum: Like other β-lactam antibiotics, Cephaolsporins are generally considered to be more effective against actively growing bacteria. The 1^st generation Cephaolsporins have stronger activity against gram positive bacteria but weaker activity against gram negative bacteria. The 2^nd generation agents have greater activity against gram negative bacteria, but somewhat lesser action against gram positive bacteria. The 3^rd generation Cephaolsporins are most active of the Cephalosporins against gram negative bacteria, especially enteric bacteria but are less active against gram positive cocci. The recently introduced 4^th generation Cephalosporins have a very broad spectrum of acivity, which includes gram positive cocci, gram negative bacilli and pseudomonas.

Mechanisms of bacterial resistance: Acquisition of β-lactamases/cephalosporinases (that cause the destruction of Cephalosporins) and alteration in target sites/ribosomal structure (that reduces affinity for Cephalosporins) are the most common mechanisms by which bacteria can become resistant to Cephalosporins.

Clinical uses: Owing to their high cost, the Cephalosporins have limited use in large animal therapeutics, however they are sometimes used (either parentrally or in the form of intra-mammary preparations) for the treatment of mastitis. They are mostly used in human medicine and small animal (pet animals) practice. Out of Cephalosporins, the 3^rd generation Cephalosporins are most frequently used in human as well as in veterinary medicine. Cephalothin is mainly indicated for the treatment of infections caused by β-lactamase producing staphylococci. Cefuroxime is primarily used in human patients for the treatment of meningitis caused by meningococci and pneumococci. Gram negative meningitis in small animals is an indication for the use of Cefotaxime. Ceftiofur is oftenly used to treat bovine respiratory diseases (such as pneumonia and hemorrhagic septicemia), foot rot and small animal urinary tract infections.

Adverse effects: The Cephalosporins are relatively non-toxic antibiotics with low frequency of allergic reactions. Hypersensitivity reaction, if occurs, is similar to that caused by Penicillins with the manifestations of rashes, eosinophilia, lymphadenopathy and anaphylaxis. About 10% of the Penicillin hypersensitive individuals show some cross-reactivity to Cephalosporins. Other side effects associated with Cephalosporins in animals may include dysbiosis and superinfection. Although Cephalosporins possess nephrotoxic potential but their recommended therapeutic doses do not cause nephrotoxicity when used alone.

Drug interactions: Drug interactions of Cephalosporins are generally similar to those of Penicillins. Bacteriostatic agents (such as Tetracyclines, Amphenicols, Macrolides and Lincosamides) interfere with the bactericidal action of Cephalosporins and thus their concurrent administration should be avoided. Concomitant use of potentially nephrotoxic drugs (like Aminoglycosides and Loop diuretics) appears to enhance the nephrotoxic effect of Cephalosporins. Co-administration of Probenicid with Cephalosporins increases their plasma levels by competitively inhibiting their renal tubular excretion.