Cephalosporin

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Cephalosporin nucleus
Cephalosporin nucleus

The cephalosporins (pronounced /ˌsɛfələˈspɔrən/, /ˌkɛfə-/) are a class of β-lactam antibiotics. Together with cephamycins they belong to a sub-group called cephems.

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Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu [1]. He noticed that these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever. Researchers at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C, which had resistance to β-lactamases but was not sufficiently potent for clinical use. The cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA), was derived from cephalosporin C and proved to be analogous to the penicillin nucleus 6-aminopenicillanic acid. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent cephalothin (cefalotin) was launched by Eli Lilly in 1964.

Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. beta-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan.

Cephalosporins are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are predominantly active against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).

Common adverse drug reactions (ADRs) (≥1% of patients) associated with the cephalosporin therapy include: diarrhea, nausea, rash, electrolyte disturbances, and/or pain and inflammation at injection site. Infrequent ADRs (0.1–1% of patients) include: vomiting, headache, dizziness, oral and vaginal candidiasis, pseudomembranous colitis, superinfection, eosinophilia, and/or fever.

The commonly quoted figure of 10% of patients with allergic hypersensitivity to penicillins and/or carbapenems also having cross-reactivity with cephalosporins originated from a 1975 study looking at the original cephalosporins,[2] and subsequent "safety first" policy meant this was widely quoted and assumed to apply to all members of the group.[3] Hence it was commonly stated that they are contraindicated in patients with a history of severe, immediate allergic reactions (urticaria, anaphylaxis, interstitial nephritis, etc) to penicillins, carbapenems or cephalosporins.[4] This however should be viewed in the light of recent epidemiological work suggesting that for many 2nd generation (or later) cephalosporins that the cross-reactivity rate with penicillin is much lower, having no significantly increased risk of reactivity in the studies examined.[5][3]

Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction.[6][7] These include latamoxef, cefmenoxime, moxalactam, cefoperazone, cefamandole, cefmetazole, and cefotetan. This is thought to be due to the N-methylthiotetrazole (NMTT) side chain of these cephalosporins, which blocks the enzyme vitamin K epoxide reductase.

The cephalosporin nucleus can be modified to gain different properties. Cephalosporins are sometimes grouped into "generations" by their antimicrobial properties. The first cephalosporins were designated first generation, whereas later, more extended spectrum cephalosporins were classified as second-generation cephalosporins. Each newer generation of cephalosporins 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 categorisation of cephalosporins is often imprecise. For example, the fourth generation of cephalosporins is not yet recognized in Japan. In Japan, cefaclor is classed as a first-generation cephalosporin, even though in the United States it is a 2nd generation; and cefbuperazone, cefminox, and cefotetan are classed as second-generation cephalosporins. Cefmetazole and cefoxitin are classed as third-generation cephems. Flomoxef, latamoxef are in a new class called oxacephems.

Most first-generation cephalosporins were originally spelled "ceph-" in English-speaking countries. This continues to be the preferred spelling in the US and Australia, while European countries have adopted International Nonproprietary Names, which are usually spelt "cef-". Newer first-generation cephalosporins and all cephalosporins of later generations are spelled "cef-".

Structure of the classical cephalosporins
Structure of the classical cephalosporins

Although first-generation cephalosporins are moderate spectrum agents, with a spectrum of activity or treatable range of bacteria that includes penicillinase-producing, methicillin-susceptible staphylococci and streptococci, they are not the drugs of choice for such infections. They also have activity against some Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, but have no activity against Bacteroides fragilis, enterococci, methicillin-resistant staphylococci, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia.

The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase.

Second generation cephalosporins with antianaerobe activity

The following cephems are also sometimes grouped with second-generation cephalosporins:

Third-generation cephalosporins have a broad spectrum of activity and further increased activity against Gram-negative organisms. Some members of this group (in particular, those available in an oral formulation, and those with anti-pseudomonal activity) have decreased activity against Gram-positive organisms. They may be particularly useful in treating hospital-acquired infections, although increasing levels of extended-spectrum beta-lactamases are reducing the clinical utility of this class of antibiotics. They are also able to penetrate the CNS, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae.

Third-generation cephalosporins with antipseudomonal activity

The following cephems are also sometimes grouped with third-generation cephalosporins:

Fourth-generation cephalosporins are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. They also have a greater resistance to beta-lactamases than the third-generation cephalosporins. Many can cross blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa.

The following cephems are also sometimes grouped with third-generation cephalosporins:

These cephems have progressed far enough to be named, but have not been assigned to a particular generation. Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance.

  1. ^ Podolsky, M. Lawrence (1998) Cures Out of Chaos: How Unexpected Discoveries Led to Breakthroughs in Medicine and Health, Harwood Academic Publishers
  2. ^ Dash CH (1975). "Penicillin allergy and the cephalosporins". J. Antimicrob. Chemother. 1 (3 Suppl): 107–18. PMID 1201975. 
  3. ^ a b Pegler S, Healy B (10 November 2007). "In patients allergic to penicillin, consider second and third generation cephalosporins for life threatening infections". BMJ 335 (7627): 991. doi:10.1136/bmj.39372.829676.47. PMID 17991982. 
  4. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  5. ^ Pichichero ME (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients" (PDF). The Journal of family practice 55 (2): 106–12. PMID 16451776. 
  6. ^ Kitson TM (1987). "The effect of cephalosporin antibiotics on alcohol metabolism: a review". Alcohol 4 (3): 143–8. doi:10.1016/0741-8329(87)90035-8. PMID 3593530. 
  7. ^ Shearer MJ, Bechtold H, Andrassy K, et al (1988). "Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status". Journal of clinical pharmacology 28 (1): 88–95. PMID 3350995. 
  8. ^ Jędrzejczyk, Tadeusz. "Internetowa Encyklopedia Leków". leki.med.pl. Retrieved on 2007-03-03.

v • d • e
Antibacterials for systemic use: cell wall disruption - beta-lactam antibiotics - cephalosporins and related (J01D)
Cephalosporins
First generation
Second generation
Third generation
Fourth generation
Fifth generation
Monobactams
Carbapenems
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