Cephalosporins Pharmacist Omar Abdulrahman Abdulqader B. SC. Pharmacy 17 September 2018 Cephalosporins Pharmacist Omar Abdulrahman Abdulqader B. SC. Pharmacy M. Sc. Pharmaceutical Chemistry

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as "Cephalosporium". They constitute a subgroup of β-lactam antibiotics called cephems. Cephalosporins were discovered in 1945.

Cephalosporins Naturally cephalosporin is cephalosporin C.

The more useful semi synthetic modification of the basic 7- Acylamino Cephalosporanic Acid (7-ACA) nucleus have resulted from acylation of the 7-amino group with different acids or nucleophilic substitution or reduction of the acetoxyl group.

Chemical degradation Cephalosporins undergo various hydrolytic degradation reactions whose specific nature depends on the individual structure. Among 7- acylamino cephalosporanic acid derivatives, the 3- acetoxylmethyl group is the most reactive site. In addition to its reactivity to nucleophilic displacement reactions, the acetoxyl function of this group readily undergoes solvolysis in strongly acidic solutions to form the desacetyl cephalosporin derivatives.

The latter lactonize to form the desacetylcephalosporin lactones, which are virtually inactive. The 7- acylamino group of some cephalosporins can also be hydrolyzed under enzymatic (acylases) and, possibly, non enzymatic conditions to give 7- ACA derivatives. Following hydrolysis or solvolysis of the 3- acetoxymethyl group, 7- ACA also lactonizes under acidic conditions.

The reactive functionality common to all cephalosporins is the - lactam. Hydrolysis of the - lactam of cephalosporins is believed to give initially cephalosporoic acid (in which the R’ group is stable, [e.g., R’= H or S heterocycle]) or possibly anhydrodesacetylcephalosporoic acid (7- ADCA)

Oral Cephalosporins The oral activity conferred by the phenylglycyl substituent is attributed to acid stability of the lactam ring, resulting from the prensence of a proronated amino group on the 7- acylamino portion of the molecule. Also important for high acid stability (and, therefore, good for oral activity) of the cephalosporins is the absence of the leaving group at the position 3.

Thus, despite the presence of the phenylglycyl side chain in its structure, the cephalosporanic acid derevative cephaloglycin is poorly absorbed orally, presumably because of solvolysis of the 3- acetoxyl group in the low pH of the stomach. The resulting 3- hydroxyl derivative undergoes lactonization under acidic conditions.

The 3- hydroxyl derivatives and, especially, the corresponding lactones are considerably less active in vitro than the parent cephalosporins. Generally, acyl derivatives of 7- ADCA show lower in vitro antibacterial potencies than the corresponding 7- ACA analogs.

Spectrum of activity The cephalosporins are considered broad spectrum antibiotics with patterns of antibacterial effectiveness comparable to that of ampicillin. Several significant differences exist, however, cephalosporins are much more resistant to inactivation by β- lactamases, particularly those produced by Gram +ve bacteria, than is ampicillin.

Ampicillin, however, is generally more active against non β- lactamase – producing strains of Gram +ve and Gram –ve bacteria, sensitive to both it and the cephalosporins.

β- Lactamase Resistance The susceptibility of cephalosporins to various lactamases varies considerably with the source and properties of these enzymes. Cephalosporins are significantly less sensitive than all but not more than β- lactamase – resistant penicillins to hydrolysis by the enzymes from S. aureus and Bacillus subtilis. The penicillinase resistance of cephalosporins appears to be a property of the bicyclic cephem ring system rather than of the acyl group.

Despite natural resistance to Staphylococcal β- lactamase, the different cephalosporins exhibit considerable variation in rates of hydrolysis by the enzyme. Thus, of several cephalosporins tested in vitro, cephalothin and cefoxitin are the most resistant, and cephaloridine and cefazolin are the least resistant.

The introduction of polar substituent in the aminoacyl moiety of cephalosporins appears to confer stability to some β- lactamases. Two structural features confer broadly based resistance to β- lactamases among the cephalosporins: An alkoximino function in the aminoacyle group. A methoxyl substituent at position 7 of the cephem nucleus having α stereochemistry. (R-O-CH3)

Classification Cephalosporins are divided into first, second, third and fourth generation agents, based roughly on their time of discovery and their antimicrobial properties. The first cephalosporins were designated first-generation cephalosporins, whereas, later, more extended- spectrum cephalosporins were classified as second-generation cephalosporins.

Each newer generation has significantly greater Gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against Gram-positive organisms. Fourth-generation cephalosporins, however, have true broad-spectrum activity. The classification of cephalosporins into "generations" is commonly practised, although the exact categorization is often imprecise.

For example, the fourth generation of cephalosporins is not recognized as such in Japan. In Japan, cefaclor is classed as a first-generation cephalosporin, though in the United States it is a second-generation one. Most first-generation cephalosporins were originally spelled "ceph-" in English-speaking countries. This continues to be the preferred spelling in the United States, Australia, and New Zealand, while European countries spell as "cef-".

Newer first-generation cephalosporins and all cephalosporins of later generations are spelled "cef-", even in the United States. Some state that cephalosporins can be divided into five or even six generations, although the usefulness of this organization system is of limited clinical relevance.

Cephalexin Cephalexin is first generation cephalosporin and it is orally effective.

Cefadroxil Is first generation cephalosporin and it is orally effective.

Cephalothin Is first generation cephalosporin and it is parentally effective.

Cefprozil Is second generation cephalosporin and it is orally effective.

Cefuroxime Is second generation cephalosporin and it is parentrally and orally effective.

Cefixime Is third generation cephalosporin and it orally effective.

Cefotaxime Is third generation cephalosporin and it parenterally effective.

Cefepime Is fourth generation cephalosporin and it parenterally effective.

Thank you . . .