Cephalosporin

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Not to be confused with
cyclosporin
.

Cephalosporin
Penicillin binding proteins
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Structure of the classical cephalosporins

The cephalosporins (sg.

β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.[3]

Together with cephamycins, they constitute a subgroup of β-lactam antibiotics called cephems. Cephalosporins were discovered in 1945, and first sold in 1964.[4]

Discovery

The

pharmacologist Giuseppe Brotzu in July 1945.[5]

Structure

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

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]

Side effects

Common

pseudomembranous colitis, superinfection, eosinophilia, nephrotoxicity, neutropenia, thrombocytopenia, and fever.[citation needed
]

Allergic hypersensitivity

The commonly quoted figure of 10% of patients with allergic hypersensitivity to

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

See also: Disulfiram-like drug
MTT and MTDT sidechains
Methyl­thio­tetrazole
Methyl­thio­dioxo­triazine

Several cephalosporins are associated with

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

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]

Resistance

β-lactamases. Currently, some Citrobacter freundii, Enterobacter cloacae, Neisseria gonorrhoeae, and Escherichia coli strains are resistant to cephalosporins. Some Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae strains have also developed resistance to cephalosporins to varying degrees.[21][22]

Classification

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.

First generation

Cefalotin, cefazolin, cefalexin, cefapirin, cefradine, and cefadroxil are drugs belonging to this group.

Second generation

Cefoxitin, cefuroxime, cefaclor, cefprozil, and cefmetazole are classed as second-generation cephems.

Third generation

Ceftazidime, ceftriaxone, and cefotaxime are classed as third-generation cephalosporins. Flomoxef and latamoxef are in a new, related class called oxacephems.[24]

Fourth generation

Drugs included in this group are cefepime and cefpirome.

Further generations

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]

Fifth-generation cephalosporins (e.g. ceftaroline) are effective against MRSA, Listeria spp., and Enterococcus faecalis.[27][26]

Overview table

Generation
 Name
Approval status
Coverage
 Description
Common Alternate name or spelling Brand
(#) = noncephalosporins similar to generation # H,
anaerobe
1 Cefalexin cephalexin Keflex H V 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.[citation needed]

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.[citation needed]

Cefadroxil cefadroxyl Duricef H
Cefazolin cephazolin Ancef, Kefzol H
Cefapirin cephapirin Cefadryl V
Cefacetrile cephacetrile
Cefaloglycin cephaloglycin
Cefalonium cephalonium
Cefaloridine
 cephaloradine
Cefalotin cephalothin Keflin
Cefatrizine
Cefazaflur
Cefazedone
Cefradine cephradine Velosef
Cefroxadine
Ceftezole
2 Cefuroxime Altacef, Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym,[28] Xorimax H Gram-positive: Less than first-generation.[citation needed]

Gram-negative: Greater than first-generation: HEN

Enterobacter aerogenes and some Neisseria + the PEcK described above.[citation needed
]

Cefprozil cefproxil Cefzil H
Cefaclor Ceclor, Distaclor, Keflor, Raniclor H
Cefonicid Monocid
Cefuzonam
Cefamandole W
(2) Cefoxitin Mefoxin H An Cephamycins sometimes grouped with second-generation cephalosporins
Cefotetan Cefotan H An
Cefmetazole Zefazone An
Cefminox
Cefbuperazone
Cefotiam Pansporin
Loracarbef Lorabid The carbacephem analog of cefaclor
3 Cefdinir Sefdin, Zinir, Omnicef, Kefnir H Gram-positive: Some members of this group (in particular, those available in an oral formulation, and those with antipseudomonal activity) have decreased activity against gram-positive organisms.

Activity against staphylococci and streptococci is less with the third-generation compounds than with the first- and second-generation compounds.[29]

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 central nervous system, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae. Since August 2012, the third-generation cephalosporin, ceftriaxone, is the only recommended treatment for gonorrhea in the United States (in addition to azithromycin or doxycycline for concurrent Chlamydia treatment). Cefixime is no longer recommended as a first-line treatment due to evidence of decreasing susceptibility.[30]

Ceftriaxone Rocephin H
Ceftazidime Meezat, Fortum, Fortaz H P
Cefixime Fixx, Zifi, Suprax H
Cefpodoxime Vantin, PECEF, Simplicef H V
Ceftiofur Naxcel, Excenel H V
Cefotaxime Claforan H
Ceftizoxime Cefizox H
Cefditoren Zostom-O H
Ceftibuten Cedax H
Cefovecin Convenia V
Cefdaloxime
Cefcapene
Cefetamet
Cefmenoxime
Cefodizime
Cefpimizole
Cefteram
Ceftiolene
Cefoperazone Cefobid W[31] P
(3) Latamoxef moxalactam W[31] An oxacephem sometimes grouped with third-generation cephalosporins
4 Cefepime Maxipime H P Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins.[citation needed]

Gram-negative: Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative bacteria.[32] They also have a greater resistance to β-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.[citation needed]

Cefiderocol has been called a fourth-generation cephalosporin by only one source as of November 2019.[33]

Cefiderocol Fetroja H
Cefquinome V
Cefclidine
Cefluprenam
Cefoselis
Cefozopran
Cefpirome Cefrom
(4) Flomoxef An oxacephem sometimes grouped with fourth-generation cephalosporins
5
Ceftaroline
 H MR
β-lactam antibiotics unless this enzyme is inhibited.[37][38][39][40][41]
Ceftolozane
 Zerbaxa H
Ceftobiprole MR
? Cefaloram These cephems have progressed far enough to be named, but have not been assigned to a particular generation. Nitrocefin is a chromogenic cephalosporin substrate, and is used for detection of β-lactamases.[citation needed]
Cefaparole
Cefcanel
Cefedrolor
Cefempidone
Cefetrizole
Cefivitril
Cefmatilen
Cefmepidium
Cefoxazole
Cefrotil
Cefsumide
Ceftioxide
Cefuracetime
Nitrocefin

History

See also: Discovery and development of cephalosporins

Cephalosporin compounds were first isolated from cultures of

Salmonella typhi, the cause of typhoid fever, which had β-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.[citation needed
]

References

  1. ^ "cephalosporin". Merriam-Webster.com Dictionary.
  2. OxfordDictionaries.com. Archived from the original
    on 7 July 2012. Retrieved 20 January 2016.
  3. ^ "cephalosporin" at Dorland's Medical Dictionary
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  6. ^ Prince, A. "Cephalosporins and vancomycin" (PDF). Columbia University. Archived from the original (PDF) on 19 August 2019. Retrieved 15 October 2022.
  7. ^ a b "Cephalosporins – Infectious Diseases". Merck Manuals Professional Edition. Retrieved 15 May 2019.
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  21. ^ "Cephalosporin spectrum of resistance". Retrieved 1 July 2012.
  22. PMID 29712652
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  23. ^ "Cephalosporins – Infectious Diseases – Merck Manuals Professional Edition". Merck Manuals Professional Edition. Retrieved 14 June 2018.
  24. ISBN 978-3-642-75619-1
    .
  25. ^ "Case Based Pediatrics Chapter".
  26. ^
    PMID 31855361
    , retrieved 2 June 2023
  27. PMID 21785568
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  28. ^ Jędrzejczyk, Tadeusz. "Internetowa Encyklopedia Leków". leki.med.pl. Archived from the original on 7 October 2007. Retrieved 3 March 2007.
  29. ISBN 978-0-19-512528-3
    .
  30. PMID 22874837
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  31. ^
    PMID 31751071. {{cite journal}}: Cite journal requires |journal= (help
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  32. ISBN 978-0-7817-7815-2
    . Retrieved 8 September 2010.
  33. ^ "CHEBI:140376 – cefiderocol". ebi.ac.uk. EMBL-EBI. Retrieved 22 November 2019.
  34. PMID 18225983
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  35. PMID 17613382
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  36. PMID 20001879
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  37. PMID 17145788
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  38. PMID 18701284
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  39. PMID 21321149
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  40. PMID 23274659
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  41. S2CID 44694926.{{cite journal}}: CS1 maint: numeric names: authors list (link
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  42. ISBN 978-1-4822-2973-8.[page needed
    ]

External links
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