Cephalosporins general

The cephalosporins generally cause few side effects (80,132,219—221). Thrombophlebitis occurs as a result of intravenous administration of all cephalosporins. Hypersensitivity reactions related to the cephalosporins are the most common side effects observed, but these are less common than found with the penicillins. Clinically only about 5—10% of patients with allergic reactions to the penicillins manifest the same reactions to the cephalosporins, and data would contradict any tme cross-reactivity to cephalosporins in patients who have previously reacted to penicillin (80,132,219). 

Closely related to the penicillins are the cephalosporins, a group of /3-lactam antibiotics that contain an unsaturated six-membered, sulfur-containing ring. Cephalexin, marketed under the trade name Keflex, is an example. Cephalosporins generally have much greater antibacterial activity than penicillins, particularly against resistant strains of bacteria. 

In cephalosporins suseeptible to / -lactamases, opening of the y8-lactam ring occurs with concomitant loss of the substituent at (except in cephalexin, where represents H see Fig. 5.4). This is followed by fragmentation of the molecule. Provided that they are not inaetivated by "-laetamases, the cephalosporins generally have a broad spectrum of activity, although there may be a wide variation. Haemophilus influenzae, for example, is partieularly suseeptible to eefuroxime see also Table 5.2. 

The cephalosporins generally cause few side effects. Thrombophlebitis occurs as a result of intravenous administration of all cephalosporins. Hypersensitivity reactions related to the cephalosporins are the most common side effects observed, hut these are less common than found with the penicillins. 

Third-generation cephalosporins generally require parenteral administration and are reserved for use in secondary care for serious infections. 

Second-generation cephalosporins generally have been displaced by third-generation agents. The oral second-generation cephalosporins can be used to treat respiratory tract infections, although they are inferior to amoxiciUin for treatment of peniciUin-resistant S. pneumoniae pneumonia and otitis media. Cefoxitin and cefotetan both are effective in situations where facultative gramnegative bacteria and anaerobes are involved e.g., intra-abdominal infections, pelvic inflammatory disease, and diabetic foot infection). 

Fig. 3. Structures of major cephalosporins. General structure (top) A, j9-lactam ring B, di-hydrothiazine ring R, side chain...

As the P-lactam ring of cephalosporins generally has a reactivity comparable with that of ethyl acetate, it is not surprising that hydrolysis of an acetoxy ester side chain at C(3) is competitive with hydrolysis of the P-lactam. The second-order rate constant for the base-catalysed conversion of the ester to the 3-hydroxylmethylcephalosporin is usually similar to that for P-lactam hydrolysis (Yamana and Tsuji, 1976 Berge et al., 1983 Bundgaard, 1975). 

Antibiotics. Solvent extraction is an important step in the recovery of many antibiotics (qv) such as penicillin [1406-05-9] streptomycin [57-92-17, novobiocin [303-81-1J, bacitracin [1405-87-4] erythromycin, and the cephalosporins. A good example is in the manufacture of penicillin (242) by a batchwise fermentation. Amyl acetate [628-63-7] or -butyl acetate [123-86-4] is used as the extraction solvent for the filtered fermentation broth. The penicillin is first extracted into the solvent from the broth at pH 2.0 to 2.5 and the extract treated with a buffet solution (pH 6) to obtain a penicillin-rich solution. Then the pH is again lowered and the penicillin is re-extracted into the solvent to yield a pure concentrated solution. Because penicillin degrades rapidly at low pH, it is necessary to perform the initial extraction as rapidly as possible for this reason centrifugal extractors are generally used. 

Superior penicillin producing cultures ate capable of producing in excess of 30 mg/mL of penicillin G (154). Cephalosporin producing strains, however, generally grow poorly and cephalosporin C production is not as efficient as is that of penicillin. Factors such as strain maintenance, strain improvement, fermentation development, inoculum preparation, and fermentation equipment requkements ate discussed in the hterature (3,154). 

The antibacterial spectmm of moxalactam (Table 9) is similar in breadth and potency to that of cefotaxime (36). Hence, moxalactam (48) is classified with the third-generation cephalosporins. In general 1-oxacephalosporins are considerably more susceptible to P-lactamases than their sulfur counterparts... 

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

Compared to penicillins, cephalosporins are generally effective against a broader range of organisms and are more resistant to /3-lactamases. /3-Lactamases are bacterial enzymes that efficiently hydrolyze /3-lactam antibiotics to inactive species in which the /3-lactam bond has been cleaved. Cephalothin was the first cephalosporin to be marketed and continues... 

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