Cephalosporins activity spectrum

Cefsulodin (60) has a sulfonic acid nx)iety on the C-7 acyl side chain. This moiety conveys antipseudomonal activity to certain penicillins, and it is interesting to note that this artifice works with cefsulodin as well. It is also interesting that, in contrast to the other so-called third-generation cephalosporins, the spectrum of cefsulodin is rather narrow and its clinical success will place a premium upon accurate diagnosis. Its synthesis begins by acylation of... 

Cefpiramide (64) is a third generation cephalosporin with a l-methyl-[lH)-tetra2ol-5-ylthio-methyl moiety at C-3 and an acylated -hydroxyphenylglycine moiety at C-7. It includes in its activity spectrum reasonable potency in vitro against many strains of Pseudomonas. It can be synthesized in a variety of ways including condensation of cephalosporin antibiotic 63 with 6-methyl-4-(l-H)-pyridone-3-carboxylic acid in the form of its active N-hydroxysuccinimide ester (62) to produce cefpiramide (64) [20,21],... 

A consequence of the development of the large number of cephalosporins is that the molecular structures have become more and more complex. Alterations in the cephalosporin molecule have resulted in differences between cephalosporins in spectrum of activity, protein binding, peak serum level, serum half-life, route of excretion, cerebrospinal fluid levels and toxicity. Cephalosporins are semi-synthetic antibiotics derived from 7-aminocephalosporanic acid, which is also called the cephalosporin nucleus. The cephem ring ( nucleus") is composed of a (3-lactam ring fused with a dihydrothiazine ring (Figure 1). 

Since the introduction of the first cephalosporin antibiotic in 1962, every year several new /1-lactam antibiotics of the cephalosporin-type have reached the market. Continual improvement in the activity spectrum is necessary to overcome resistance phenomena caused by the widespread application of antibiotics. Referring to the hit1 -list of the commercially most successful therapeutics, three /1-lactam antibiotics range among the top twenty. These are cefaclor by E. Lilly, ceftriaxone by Roche, and clavulanic acid as a most efficient /1-lacta-mase inhibitor marketed by Smith Kline-Beecham in combination with the semi-synthetic penicillin derivative amoxicillin under the trade name of Aug-... 

Second-generation cephalosporin active against a wide spectrum of gramnegative bacteria, including anaerobes (B fragilis). Does not enter the CNS. Cefotetan is similar. 

Cefmetazole is a cephamycin with a nonaromatic side chain at C-7. In addition to a fairly characteristic second-generation cephalosporin antimicrobial spectrum, it possess fairly significant anti-antiaerobic activity. The ejection of its C-3 side chain leads to alcohol intolerance of the disulfuram type and prolonged clotting times. 

Widespread clinical acceptance continues to be accorded to the cephalosporins, and the field is extremely active as firms search for the ultimate contender. Among the characteristics desired is retention of the useful features of the older members (relatively broad spectrum, less antigenicity than the penicillins, relative insensitivity toward 3-lactamases, and convenience of administration) while adding better oral activity and broader antimicrobial activity (particularly potency against Pseudomonas, anaerobes, meningococci, cephalosporinase-carrying organisms, and the like). To a considerable extent these objectives have been met, but the price to the patient has been dramatically increased. 

The class A enzymes have Mx values around 30,000. Their substrate specificities are quite variable and a large number of enzymes have emerged in response to the selective pressure exerted by the sometimes abusive utilization of antibiotics. Some of these new enzymes are variants of previously known enzymes, with only a limited number of mutations (1 4) but a significantly broadened substrate spectrum while others exhibit significantly different sequences. The first category is exemplified by the numerous TEM variants whose activity can be extended to third and fourth generation cephalosporins and the second by the NMCA and SME enzymes which, in contrast to all other SXXK (3-lactamases, hydrolyse carbapenems with high efficiency. Despite these specificity differences, the tertiary structures of all class A (3-lactamases are nearly superimposable. 

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. 

These agents are generally effective for susceptible bacteria. The extended-spectrum penicillins are more active against P. aeruginosa and enterococci and are preferred over cephalosporins. They are very useful in renally impaired patients or when an aminoglycoside is to be avoided. 

The large number and diversity of available /3-lactams, mainly penicillins and cephalosporins, necessitate their classification. Penicillins can be classified primarily according to chemical structure. Table 5.2 shows that there is good correspondence between chemical structure and properties. The categorization of cephalosporins into chemically similar groups is not useful because their antimicrobial spectrum is not closely correlated with chemical structure, and classification into generations is based on their spectrum of microbial activity (Table 5.3). 

Cefalexin is a first-generation cephalosporin and therefore an alternative preparation would be Zinnat tablets, which contains cefuroxime, a second-generation cephalosporin. A penicillin such as Augmentin, which contains co-amoxiclav, can be an appropriate alternative since it provides a very similar spectrum of activity. Klaricid contains clarithromycin, which is a macrolide. Utinor contains norfloxacin, which is a quinolone that is effective in uncomplicated urinary-tract infections. Rocephin contains ceftriaxone, which is a third-generation cephalosporin that is available for parenteral administration only. 

Hebeisen P, Heinze-Krauss 1, Angehm P, Hohl P, Page MGP, Then RL. (2001) In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillinresistant Staphylococci. Antimicrob Agents Chemother 45 825-836. 

First-generation cephalosporins, introduced into human medicine in the 1960 s and 1970 s, are basically similar in antibacterial activity and differ mainly in their pharmacokinetic properties. These include all of the currently available orally active cephalosporins, and are relatively susceptible to beta-lactamase, active against most Gram-positive bacteria and have a limited spectrum of activity against the Gram-negative organisms. 

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