the common side groups at c-3 for first class cephalosporins are small uncharged groups like methyl. the methyl group at position c-3 gives low affinity for common pbp which can in part explain the relatively low activity of these first drugs. cefaclor however has a cl group at position c-3 which gives it better binding to pbp and thus better antimicrobial activity. there is not an agreement on classifying cefaclor as a first generation cephalosporin because of the cl group at the c-3 position and therefore its improved activity, but it is often classified as such because of its c-7 side chain which is more related to the first generation than the second. all of the first generation cephalosporins have an α-amino group at position c-7. this structure makes them vulnerable to hydrolysis by β-lactamases. examples of 1st generation cephalosporins : a) cephadrine b) cefadroxil c) cefalexin 2nd generation cephalosporins the basic structure of 2nd generation cephalosporinsearly second generation cephalosporins are very similar in basic structure to the first generation. loracarbef however does not have the normal dihydrothiazin ring but is a carbacephem that has a carbon atom in the ring instead of a sulfur atom making it a tetrahydropyridine ring. this chemical property gives loracarbef better stability in plasma while retaining oral absorption characteristics and affinity for binding to pbp. the 7-phenyl-glycine makes it orally available and the chlorine at position c-3 makes it as active as cefaclor. an important structural change in the development of second generation cephalosporins was the introduction of an α-iminomethoxy group to the c-7 side chain. this gave an increased resistance to β-lactamases due to stereochemical blocking of the beta-lactam ring. cefuroxime was the first cephalosporin to incorporate this side chain. another very important group in the second generation is the aminothiazole ring to the c-3 side chain. this development drastically increased binding affinity to pbp and increased antimicrobial activity. the aminothiazole ring can be seen in the structure of cefotiam. examples of 2nd generation cephalosporins : a) loracarbef b) cefuroxime c) cefotiam 3rd generation cephalosporins the basic structure of 3rd generation cephalosporinsthe majority of third generation cephalosporins have the aminothiazole group at position c-7. different groups are found at the 7-α-position like 7-α-iminohydroxy and 7-α-iminomethoxy. ceftibuten however possesses a 7-α-ethylidene group. this group gives ceftibuten higher resistance to enhanced spectrum β-lactamases. many of the oral third generation cephalosporins are esters of parenteral forms and are hydrolysed by esterases in the digestive tract (cefteram-pivoxil). some of the third generation drugs can be absorbed orally without the need of esterification. this is for example done with cefixime and cefdinir by putting a vinyl group in the c-3 position. examples of 3rd generation cephalosporins : a) cefdinir b) cefixime c) ceftibuten 4th generation cephalosporins the fourth generation cephalosporins have greater activity against gram-negative bacteria than the second and third generation. this difference is attributed to them being dipolar ionic zwitterion compounds. the c-7 side chain is similar to third generation cephalosporins usually containing iminomethoxy-aminothiazole group or in the case of cefclidine an aminothiadiazole. because of the positively charged quaternary nitrogen in the c-3 side chain fourth generation cephalosporins can diffuse through the gram-negative bacterial membrane more readily than earlier cephalosporins. it is thought that the positive charge orients the drug molecule to the entrance of the porin channel. examples of 4th generation cephalosporins : a) cefzopran b) cefclidine c) cefepime 5th generation cephalosporins currently there are only two drugs in this category, ceftobiprole and ceftaroline. these new drugs are also the only β-lactam antibiotics that are effective against methicillin-resistant-staphylococcus-aureus (mrsa). ceftobiprole is a pyrrolidinone-3-ylidenemethyl cephem. the c-3 side chain was specifically designed to have a strong binding affinity to pbp2a and pbp2x. pbp2a is known to give staphylococci resistance to other β-lactam drugs and pbpx does the same for pneumococci. ceftobiprole also has an aminothiazoylhydroxyimino side chain at the c-7 position which is known to give good resistance to β-lactamase from s. aureus. together these active groups make ceftobiprole bactericidal to mrsa. ceftobiprole has poor water solubility and is therefore administered intravenously as an ester prodrug called ceftobiprole medocaril. it is rapidly broken down into active ceftobiprole by plasma esterases. ceftaroline was developed from the fourth generation cephalosporin cefozopran. it retains the alkoxyimino group at position c-7 from earlier generations so it is fairly stable in the presence of many β-lactamases. since mrsa and penicillin resistant streptococcus pneumoniae have resistance dedicated to new types of pbp, pbp2a and pbp2x respectively, both ceftaroline and ceftobiprole have c-3 side chains specially engineered to bind these new pbp. in the case of ceftaroline this side chain contains a 2-thioazolythio spacer linkage optimised for its anti-mrsa activity. ceftaroline has low water solubility but this problem was overcome by attaching a n-phosphonoamino group to the molecule making the intravenous prodrug ceftaroline fosamil. the prodrug is dephosphorylated in plasma to form active ceftaroline. 5th generation cephalosporins : a) ceftaroline fosamil (prodrug) and b) ceftobiprole medocaril (prodrug) current status antimicrobial resistance is the driving force for the development of new antimicrobial agents. the complexity and diversity of resistance mechanisms has defined the need for new and improved β-lactam antibiotics. with their broad spectrum the cephalosporins have come to dominate β-lactam chemotherapy although they often lack oral bioavailability. on 29 october 2010, a new cephalosporin agent - ceftarolin - was approved by the food and drug administration (fda). teflaro (ceftaroline fosamil) is an injectable antibiotic prodrug to treat adults with acute bacterial skin and skin structure infections (abssi) and community acquired bacterial pneumonia (cabp). ceftobiprole has been approved for the treatment of adult patients with hospital acquired pneumonia (excluding vap) and community acquired pneumonia in 12 european countries, canada and switzerland.