Together with cephamycins, they constitute a subgroup of β-lactam antibiotics called cephems. Cephalosporins were discovered in 1945, and first sold in 1964.[4]
Cephalosporin contains a 6-membered dihydrothiazine ring. Substitutions at position 3 generally affect pharmacology; substitutions at position 7 affect antibacterial activity, but these cases are not always true.[6]
Medical uses
Cephalosporins can be 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, such as Staphylococcus and Streptococcus.[7] They are therefore used mostly for skin and soft tissue infections and the prevention of hospital-acquired surgical infections.[8] Successive generations of cephalosporins have increased activity against Gram-negative bacteria, albeit often with reduced activity against Gram-positive organisms.[citation needed]
The antibiotic may be used for patients who are allergic to penicillin due to the different β-lactam antibiotic structure. The drug is able to be excreted in the urine.[7]
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,[9] and subsequent "safety first" policy meant this was widely quoted and assumed to apply to all members of the group.[10] 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 or carbapenems.[11]
The contraindication, however, should be viewed in the light of recent epidemiological work suggesting, for many second-generation (or later) cephalosporins, the cross-reactivity rate with penicillin is much lower, having no significantly increased risk of reactivity over the first generation based on the studies examined.[10][12] 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, oral cefixime or cefuroxime and injectable cefotaxime, ceftazidime, and ceftriaxone can be used with caution, but the use of cefaclor, cefadroxil, cefalexin, and cefradine should be avoided.[13] A 2012 literature review similarly finds that the risk is negligible with third- and fourth-generation cephalosporins. The risk with first-generation cephalosporins having similar R1 sidechains was also found to be overestimated, with the real value closer to 1%.[14]
MTT side chain
MTT and MTDT sidechains
Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol.[15][16] These include latamoxef (moxalactam), cefmenoxime, cefoperazone, cefamandole, cefmetazole, and cefotetan. This is thought to be due to the methylthiotetrazole side-chain of these cephalosporins, which blocks the enzyme vitamin K epoxide reductase (likely causing hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance).[17] Thus, consumption of alcohol after taking these cephalosporin orally or intravenously is contraindicated, and in severe cases can lead to death.[18] The methylthiodioxotriazine sidechain found in ceftriaxone has a similar effect. Cephalosporins without these structural elements are believed to be safe with alcohol.[19]
Mechanism of action
Cephalosporins are bactericidal and, like other β-lactam antibiotics, disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by 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 irreversibly inhibiting PBP crosslinking of peptidoglycan.[20]
The cephalosporin nucleus can be modified to gain different properties. Cephalosporins are sometimes grouped into "generations" by their antimicrobial properties.[citation needed]
The first cephalosporins were designated first-generation cephalosporins, whereas, later, more extended-spectrum cephalosporins were classified as second-generation cephalosporins. Each newer generation 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.[23]
The classification of cephalosporins into "generations" is commonly practised, although the exact categorization 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, though in the United States it is a second-generation one; and cefbuperazone, cefminox, and cefotetan are classed as second-generation cephalosporins.
Some state that cephalosporins can be divided into five or even six generations, although the usefulness of this organization system is of limited clinical relevance.[25]
Naming
Most first-generation cephalosporins were originally spelled "ceph-" in English-speaking countries. This continues to be the preferred spelling in the United States, Australia, and New Zealand, 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.[citation needed]
Activity
There exist bacteria which cannot be treated with cephalosporins of generations first through fourth:[26]
^"cephalosporin – definition of cephalosporin in English from the Oxford dictionary". OxfordDictionaries.com. Archived from the original on 7 July 2012. Retrieved 20 January 2016.
^Dash, C. H. (1 September 1975). "Penicillin allergy and the cephalosporins". Journal of Antimicrobial Chemotherapy. 1 (suppl 3): 107–118. doi:10.1093/jac/1.suppl_3.107. PMID 1201975.
^ a bPegler, Scott; Healy, Brendan (10 November 2007). "In patients allergic to penicillin, consider second and third generation cephalosporins for life threatening infections". The BMJ. 335 (7627): 991. doi:10.1136/bmj.39372.829676.47. PMC 2072043. PMID 17991982.
^Pichichero, Michael E (2006). "Cephalosporins can be prescribed safely for penicillin-allergic patients". The Journal of Family Practice. 55 (2): 106–12. PMID 16451776.
^Campagna, JD; Bond, MC; Schabelman, E; Hayes, BD (May 2012). "The use of cephalosporins in penicillin-allergic patients: a literature review". The Journal of Emergency Medicine. 42 (5): 612–20. doi:10.1016/j.jemermed.2011.05.035. PMID 21742459.
^Kitson, Trevor M. (May 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.
^Shearer, M. J.; Bechtold, H.; Andrassy, K.; Koderisch, J.; McCarthy, P. T.; Trenk, D.; Jähnchen, E.; Ritz, E. (January 1988). "Mechanism of Cephalosporin-induced Hypoprothrombinemia: Relation to Cephalosporin Side Chain, Vitamin K Metabolism, and Vitamin K Status". The Journal of Clinical Pharmacology. 28 (1): 88–95. doi:10.1002/j.1552-4604.1988.tb03106.x. PMID 3350995. S2CID 30591177.
^Stork CM (2006). "Antibiotics, antifungals, and antivirals". In Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA (eds.). Goldfrank's toxicologic emergencies. New York: McGraw-Hill. p. 847. ISBN 978-0-07-143763-9.
^Mergenhagen, Kari A.; Wattengel, Bethany A.; Skelly, Megan K.; Clark, Collin M.; Russo, Thomas A. (21 February 2020). "Fact versus Fiction: a Review of the Evidence behind Alcohol and Antibiotic Interactions". Antimicrobial Agents and Chemotherapy. 64 (3): e02167-19. doi:10.1128/aac.02167-19. PMC 7038249. PMID 31871085.
^Tipper, D J; Strominger, J L (October 1965). "Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine". Proceedings of the National Academy of Sciences of the United States of America. 54 (4): 1133–1141. Bibcode:1965PNAS...54.1133T. doi:10.1073/pnas.54.4.1133. ISSN 0027-8424. PMC 219812. PMID 5219821.
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^Sutaria, Dhruvitkumar S.; Moya, Bartolome; Green, Kari B.; Kim, Tae Hwan; Tao, Xun; Jiao, Yuanyuan; Louie, Arnold; Drusano, George L.; Bulitta, Jürgen B. (25 May 2018). "First Penicillin-Binding Protein Occupancy Patterns of β-Lactams and β-Lactamase Inhibitors in Klebsiella pneumoniae". Antimicrobial Agents and Chemotherapy. 62 (6): e00282-18. doi:10.1128/AAC.00282-18. PMC 5971569. PMID 29712652.
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^Narisada, Masayuki; Tsuji, Teruji (1990). "1-Oxacephem Antibiotics". Recent Progress in the Chemical Synthesis of Antibiotics. pp. 705–725. doi:10.1007/978-3-642-75617-7_19. ISBN 978-3-642-75619-1.
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