Cephalosporin

See also: Discovery and development of cephalosporins

Core structure of the cephalosporins

Structure of the classical cephalosporins

The cephalosporins (sg.  /ˌsɛfəlɵˈspɔrɨn/) are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".^[1]

Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.

History

Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu.^[2] He noticed that these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever, which had beta-lactamase. Guy Newton and Edward Abraham at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C. 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 (6-APA), but it was not sufficiently potent for clinical use. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent cefalotin (cephalothin) was launched by Eli Lilly and Company in 1964.

Mechanism of action

Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins) but are less susceptible to penicillinases. 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 the D-Ala-D-Ala site, thereby competitively inhibiting PBP crosslinking of peptidoglycan.

Clinical use

Indications

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

Adverse effects

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,^[3] and subsequent "safety first" policy meant this was widely quoted and assumed to apply to all members of the group.^[4] 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.^[5] This, however, should be viewed in the light of recent epidemiological work suggesting that, for many second-generation (or later) cephalosporins, the cross-reactivity rate with penicillin is much lower, having no significantly increased risk of reactivity in the studies examined.^[4][6] The British National Formulary previously issued blanket warnings of 10% cross reactivity, but, since the September 2008 edition, suggests in the absence of suitable alternatives that oral cefixime or cefuroxime and injectable cefotaxime, ceftazidine, and ceftriaxone can be used with caution, but to avoid cefaclor, cefadrocil, cefalexin, and cefradine.^[7]

Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol.^[8][9] 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 (likely causing hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance).^[10]

Classification

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 cephalosporins, 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 categorization of cephalosporins is often imprecise. For example, the fourth generation of cephalosporins is not recognized as such, in Japan.^{[citation needed]} In Japan, cefaclor is classed as a first-generation cephalosporin, even though in the United States it is a second-generation one; 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 United States and Australia, while European countries (including the United Kingdom) have adopted the International Nonproprietary Names, which are always spelled "cef-". Newer first-generation cephalosporins and all cephalosporins of later generations are spelled "cef-", even in the United States.

Some state that, although cephalosporins can be divided into five or even six generations, the usefulness of this organization system is of limited clinical relevance.^[11]

Fourth-generation Cephalosporins as of March, 2007 were considered to be "a class of highly potent antibiotics that are among medicine's last defenses against several serious human infections" according to the Washington Post.^[12]

#	Members	Description
1	Cefacetrile (cephacetrile), Cefadroxil (cefadroxyl; Duricef), Cephalexin (cephalexin; Keflex), Cefaloglycin (cephaloglycin), Cefalonium (cephalonium), Cefaloridine (cephaloradine), Cefalotin (cephalothin; Keflin), Cefapirin (cephapirin; Cefadryl), Cefatrizine, Cefazaflur, Cefazedone, Cefazolin (cephazolin; Ancef, Kefzol), Cefradine (cephradine; Velosef), Cefroxadine, Ceftezole.	Gram-positive: Activity against penicillinase-producing, methicillin-susceptible staphylococci and streptococci (though they are not the drugs of choice for such infections). No activity against methicillin-resistant staphylococci or enterococci. Gram-negative: Activity against Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae ("PEcK"), but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia.
2	Cefaclor (Ceclor, Distaclor, Keflor, Raniclor), Cefonicid (Monocid), Cefprozil (cefproxil; Cefzil), Cefuroxime (Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym,[13] Xorimax), Cefuzonam. Second generation cephalosporins with antianaerobe activity: Cefmetazole, Cefotetan, Cefoxitin. The following cephems are also sometimes grouped with second-generation cephalosporins: Carbacephems: loracarbef (Lorabid); Cephamycins: cefbuperazone, cefmetazole (Zefazone), cefminox, cefotetan (Cefotan), cefoxitin (Mefoxin).	Gram-positive: Less than first-generation. Gram-negative: Greater than first-generation: HEN (Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + the PEcK described above.
3	Cefcapene, Cefdaloxime, Cefdinir (Zinir, Omnicef, Kefnir), Cefditoren, Cefetamet, Cefixime (Zifi, Suprax), Cefmenoxime, Cefodizime, Cefotaxime (Claforan), Cefovecin (Convenia), Cefpimizole, Cefpodoxime (Vantin, PECEF), Cefteram, Ceftibuten (Cedax), Ceftiofur, Ceftiolene, Ceftizoxime (Cefizox), Ceftriaxone (Rocephin). Third-generation cephalosporins with antipseudomonal activity: Cefoperazone (Cefobid), Ceftazidime (Fortum, Fortaz). The following cephems are also sometimes grouped with third-generation cephalosporins: Oxacephems: latamoxef (moxalactam).	Gram-positive: 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. Gram-negative: Third-generation cephalosporins have a broad spectrum of activity and further increased activity against Gram-negative 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. Since 2007, third-generation cephalosporins (ceftriaxone or cefixime) have been the only recommended treatment for gonorrhea in the United States.[14]
4	Cefclidine, Cefepime (Maxipime), Cefluprenam, Cefoselis, Cefozopran, Cefpirome (Cefrom), Cefquinome. The following cephems are also sometimes grouped with fourth-generation cephalosporins: Oxacephems: flomoxef	Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. Gram-negative: Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative bacteria.[15] They also have a greater resistance to beta-lactamases than the third-generation cephalosporins. Many can cross the blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa.
5	Ceftobiprole, Ceftaroline	Ceftobiprole has been described as "fifth-generation" cephalosporin,[16][17] though acceptance for this terminology is not universal. 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. Ceftaroline has also been described as "fifth-generation" cephalosporin.[18]

These cephems have progressed far enough to be named, but have not been assigned to a particular generation: Cefaloram, Cefaparole, Cefcanel, Cefedrolor, Cefempidone, Cefetrizole, Cefivitril, Cefmatilen, Cefmepidium, Cefoxazole, Cefrotil, Cefsumide, Ceftioxide, Cefuracetime

References

1. ^ "cephalosporin" at Dorland's Medical Dictionary
2. ^ Podolsky, M. Lawrence (1998) Cures Out of Chaos: How Unexpected Discoveries Led to Breakthroughs in Medicine and Health, Harwood Academic Publishers
3. ^ Dash CH (1975). "Penicillin allergy and the cephalosporins". J. Antimicrob. Chemother. 1 (3 Suppl): 107–18. PMID 1201975. 
4. ^ ^{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): 991–991. doi:10.1136/bmj.39372.829676.47. PMC 2072043. PMID 17991982. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2072043. 
5. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
6. ^ Pichichero ME (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients" (PDF). The Journal of family practice 55 (2): 106–12. PMID 16451776. http://www.jfponline.com/pdf%2F5502%2F5502JFP_AppliedEvidence1.pdf. 
7. ^ "5.1.2 Cephalosporins and other beta-lactams". British National Formulary (56 ed.). London: BMJ Publishing Group Ltd and Royal Pharmaceutical Society Publishing. September 2008. pp. 295. ISBN 0-85369-778-7. 
8. ^ Kitson TM (1987). "The effect of cephalosporin antibiotics on alcohol metabolism: a review". Alcohol 4 (3): 143–148. doi:10.1016/0741-8329(87)90035-8. PMID 3593530. 
9. ^ 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. 
10. ^ Stork CM (2006). "Antibiotics, antifungals, and antivirals". In Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA. Goldfrank's toxicologic emergencies. New York: McGraw-Hill. pp. 847. ISBN 0-07-143763-0. http://books.google.com/books?id=cvJuLqBxGUcC&pg=PA847. Retrieved 2009-07-03. 
11. ^ "Case Based Pediatrics Chapter". http://www.hawaii.edu/medicine/pediatrics/pedtext/s06c05.html. 
12. ^ Weiss, Rick (4 March 2007). "FDA Rules override Warnings about Drugs". March 4, 2007. http://www.washingtonpost.com/wp-dyn/content/article/2007/03/03/AR2007030301311.html. 
13. ^ Jędrzejczyk, Tadeusz. "Internetowa Encyklopedia Leków". leki.med.pl. http://www.leki.med.pl/lek.phtml?id=428&idnlek=2682&menu=4. Retrieved 2007-03-03. 
14. ^ Barclay, Laurie (April 16, 2007). "CDC issues new treatment recommendations for gonorrhea". Medscape. http://cme.medscape.com/viewarticle/555228. Retrieved 2009-07-01. 
15. ^ Richard L Sweet; Ronald S. Gibbs (1 March 2009). Infectious Diseases of the Female Genital Tract. Lippincott Williams & Wilkins. pp. 403–. ISBN 9780781778152. http://books.google.com/books?id=wuR_ngItU5oC&pg=PA403. Retrieved 8 September 2010. 
16. ^ Widmer AF (March 2008). "Ceftobiprole: a new option for treatment of skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus". Clin. Infect. Dis. 46 (5): 656–658. doi:10.1086/526528. PMID 18225983. 
17. ^ Kosinski MA, Joseph WS (July 2007). "Update on the treatment of diabetic foot infections". Clin Podiatr Med Surg 24 (3): 383–396. doi:10.1016/j.cpm.2007.03.009. PMID 17613382. http://journals.elsevierhealth.com/retrieve/pii/S0891-8422(07)00026-2. 
18. ^ Kollef MH (December 2009). "New antimicrobial agents for methicillin-resistant Staphylococcus aureus". Crit Care Resusc 11 (4): 282–6. PMID 20001879.