Cephalosporins and Related Antibiotics

The effectiveness of penicillin in tlie treatinent of infections prompted research directed toward finding new antibiotics witli a wider range of antibacterial activity. The cephalosporins are a valuable group of dni tliat are effective in the treatment of almost all of tlie strains of bacteria affected by tlie iDenicillins, as well as some strains of bacteria tliat have become resistant to penicillin. The cephalosporins are structurally and chemically related to penicillin. 

Cephalosporins affect tlie bacterial cell wall, making it defective and unstabla Tins action is similar to the action of penicillin. The cephalosporins are usually bactericidal (capable of destroying bacteria). 

The cephalosporins are used in tlie treatment of infections caused by susceptible microorganisms. EIxamples of microorganisms that may be susceptible to tlie cephalosporins include streptococci, staphylococci. 

DISPLAY 8-1 Examples of First-, Second-, and Third-Generation Cephalosporins 

Rrst generation-cephalexin (Kefiex), cefazolin (Ancef), cephapirin (Cefadyi) Second generation-cefaclor (Cedor), cefoxitin (Mefoxin), cefuroxime (Zinacef) 

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Among the four-membered heterocycles, 2-azetidinones have received considerable attention due to the presence of a -lactam ring as an important structural feature for the biological activity of penicillins, cephalosporins and related antibiotics.Recent reviews of B-lactam syntheses have been given by Sammes, Isaacs, Mukerjee, Hegedus, Labia and Barrett. The most complete and exhaustive ac-... 

Major classes of antibiotics include more than 200 peptides such as the gramicidins, bacitracin, tyrocidines and valinomycin (Fig. 8-22)k more than 150 penicillins, cephalosporins, and related compounds tetracyclines (Fig. 21-10) the macrolides, large ring lactones such as the erythromycins (Fig. 21-11) and the polyene antibiotics (Fig. 21-10). 

Papich MG, Riviere JE, -lactam antibiotics Penicillms, cephalosporins and related drugs, in Riviere JE, Papich MG, eds.. Veterinary Pharmacology and Therapeutics, 9th ed., Wiley-Blackwell, Iowa State Univ. Press, lA, 2009 865-894. 

LACTAM ANTIBIOTICS - deals with the chemical and biochemical aspects of the -lactam antibiotics. Topics selected include the synthesis, biosynthesis, chemical reactivity, anti-microbial activity, pharmacodynamics, metabolism, toxicology, detection and analysis, and pharmaceutical applications of the penicillins, cephalosporins, and related compounds. 

Antibiotics based on a related ring system, termed the cephems (figure 23.2), are highly useful. Here the five-membered ring has been expanded to six and the double bond of the penems retained. These are the cephalosporins and include such important antibiotics as cephalothin (Keflin), cefazolin (Ancef), cephalexin (Keflex), cefamandole (Cefam), cefuroxime (Zinacef), cefeclor (Ceclor) and cefoxitin (Mefoxin). 

As was already stated, and which is visible from the scheme of synthesis, moxalactam contains a dihydrooxazine ring instead of the dihydrothiazine ring common to all cephalosporins, and thus this compound cannot be formally numbered with cephalosporins, cephamicins, or penicillins however, in terms of pharmacological action, it is related to all three of the antibiotics listed above, and it is classified as a third-generation cephalosporin. 

The reaction of cysteine and related compounds with penicillins and cephalosporins. Journal of Antibiotics,... 

The cephalosporins are p-lactam antibiotics that are closely related both structurally (Figure 30.7) and functionally to the penicillins. Most cephalosporins are produced semi-synthetically by the chemical attachment of side chains to 7-aminocephalosporanic add. Cephalosporins and cephamydns have the same mode of action as the penidllins and are affected by the same resistance mechanisms, but they tend to be more resistant than the penidllins to p-lactamases. 

Imipenem, which is related to meropenem, has also been reported to cause toxic epidermal necrolysis (34). The authors stated that to the best of their knowledge, this was the first report of a possible cross-reaction between two classes of antibiotics in causing toxic epidermal necrolysis. The time between first administration and the occurrence of epidermal necrolysis is considerably shorter in recurrence or provocation testing (35,36). They also claimed that it is likely that the beta-lactam ring is responsible for this hypersensitivity reaction, citing the evidence that the patient had been given amoxicillin 15 days before the cephalosporin, and that could have served as the sensitizing event. They did not discuss whether aztreonam, a monobactam, also could have caused a cross-reaction however, it has been involved in two cases of fatal toxic epidermal necrolysis (37). 

Finally, there are a mixed bag of oxidases, catalysing ethylene formation in plants and many other diverse reactions, illustrated in Figure 13.20, by isopenicillin N-synthase, IPNS, which catalyses the cyclisation of the heterocyclic P-lactam ring. The importance of penicillin- and cephalosporin-related antibiotics in clinical medicine cannot be underestimated and has stimulated the study of their biosynthetic pathways. A key step in the biosynthesis of these antibiotics involves oxidative ring closure reactions of S-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to form isopenicillin N, the precursor of penicillins and cephalosporins, catalysed by IPNS (Figure 13.20). The overall reaction utilizes the full oxidative potential of O2, reducing it to two molecules of H2O. As discussed earlier, these enzymes are technically oxidases and the four electrons required for dioxygen reduction come from the substrate. 

B. anthracis typically is susceptible to penicillin, amoxicillin, erythromycin, doxycycline, ciprofloxacin, and chloramphenicol. The bioterrorism-related strain was susceptible to the fluoroquinolones, rifampin, tetracycline, vancomycin, imipenem, meropenem, chloramphenicol, clindamycin, and the aminoglycosides. However, the strain was resistant to third-generation cephalosporins and trimethoprim-sulfamethoxazole. Ciprofloxacin or doxycycline plus one or two of the aforementioned antibiotics is the currently recommended regimen for the treatment of inhalational anthrax, but doxycycline is not recommended for the treatment of anthrax meningitis owing to poor CNS penetration and recent in vitro resistance. ... 

The production of 7-ACA and related precursors from Cephalosporin C is outlined in Figure 6-10. The antibiotic itself is now produced from mutant strains of C. acremonium. 

The (2 + 2)-cycloaddition reactions of ketenes with heterocycles via an endocyclic imino group have contributed substantially to the synthesis of penicillin (92a) and cephalosporin C (93a) antibiotics and structurally related heterobicyclic /Mactams.7 11 Reactions with relatively stable ketenes, e.g., diphenylketene, have been reported as well as reactions of heterocycles with mixtures of acid chlorides and tertiary amines. 

The molecular targets for the antibacterial activity of the penicillin and related j8-lactam antibiotics such as the cephalosporins are a group of bacterial enzymes known as penicillin-binding proteins (PBPs). The PBPs are essential to the final stages of bacterial cell wall biosynthesis. Penicillin and other j8-lactam antibiotics inhibit PBPs, thereby inhibiting bacterial cell wall biosynthesis, which eventually results in bacterial cell lysis. (Vancomycin and cycloserine are nonpenicillin antibiotics that also inhibit bacterial cell wall biosynthesis through other mechanisms.)... 

The outstanding success of penicillin, in both local and systemic bacterial infections, followed from its high selectivity, the reason for which is discussed in Section 13.1. The mammalian toxicity is so low that it has come to be regarded as the most innocuous of all antibacterial drugs (however, a small proportion of patients become sensitized to it). In 1948, Brotzu found (in a sewage outfall on the Sardinian coast) another mould, Cephalosporium, which gave rise to the related cephalosporin series of antibiotics (see Section 13.2). 

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