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Cephalosporin

Drug class

Core structure of the cephalosporins

Class identifiers

Use Bacterial infection

ATC code J01D

Biological target Penicillin binding proteins

Clinical data

Drugs.com Drug Classes

External links

MeSH D002511

In Wikidata
 Structure of the classical cephalosporins

The cephalosporins (sg. /ˌsɛfələˈspɔːrɪn, ˌkɛ-, -loʊ-/[1][2]) are a class of 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]

Contents

 1Discovery
 2Medical uses
 3Side effects
 4Mechanism of action
 5Resistance
 6Classification
 7History
 8References
 9External links

Discovery[edit]
The aerobic mold which yielded cephalosporin C was found in the sea near a sewage outfall in Su
Siccu, by Cagliari harbour in Sardinia, by the Italian pharmacologist Giuseppe Brotzu in July 1945.[5]

Medical uses[edit]
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, such as Staphylococcus and Streptococcus.[6] They
are therefore used mostly for skin and soft tissue infections. Successive generations of
cephalosporins have increased activity against Gram-negative bacteria, albeit often with reduced
activity against Gram-positive organisms.
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.[6]

Side effects[edit]
Common adverse drug reactions (ADRs) (≥ 1% of patients) associated with the cephalosporin
therapy include: diarrhea, nausea, rash, electrolyte disturbances, and 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, nephrotoxicity, neutropenia, thrombocytopenia, and 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,[7] and subsequent "safety first" policy meant this
was widely quoted and assumed to apply to all members of the group.[8] 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.[9] This, 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.[8][10] 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, cefadrocil, cefalexin, and cefradine
should be avoided.[11]
Overall, the research shows that all beta lactams have the intrinsic hazard of very serious hazardous
reactions in susceptible patients. Only the frequency of these reactions vary, based on the structure.
Recent papers have shown that a major feature in determining frequency of immunological reactions
is the similarity of the side chains (e.g., first generation cephalosporins are similar to penicillins), and
this is the reason the β-lactams are associated with different frequencies of serious reactions (e.g.,
anaphylaxis).[citation needed]
See also: Disulfiram-like drug
Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with
ethanol.[12][13] These
include latamoxef (moxalactam), cefmenoxime, cefoperazone, cefamandole, cefmetazole,
and cefotetan. This is thought to be due to the N-methylthiotetrazole side-chain of these
cephalosporins, which blocks the enzyme vitamin K epoxide reductase (likely causing
hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance).[14] Thus,
consumption of alcohol after taking Cephalosporin orally or intravenously is contraindicated, and in
severe cases can lead to death.[citation needed]

Mechanism of action[edit]
Cephalosporins are bactericidal and have the same mode of action as other β-lactam antibiotics
(such as penicillins), but are less susceptible to β-lactamases. Cephalosporins 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.

Resistance[edit]
Resistance to cephalosporin antibiotics can involve either reduced affinity of existing PBP
components or the acquisition of a supplementary β-lactam-insensitive PBP. 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, and Serratia marcescens strains have also developed resistance
to cephalosporins to varying degrees.[15]

Classification[edit]
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 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.[16]
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. Cefmetazole and
cefoxitin are classed as third-generation cephems. Flomoxef and latamoxef are in a new class
called oxacephems.[17]
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]
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.[18]
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.[19]
The mnemonic "LAME" is used to note organisms against which cephalosporins do not have
activity:[citation needed]

 Listeria
 Atypicals (including Mycoplasma and Chlamydia)
 MRSA
 Enterococci
Fifth-generation cephalosporins, however, are effective against MRSA.[citation needed]

Generation Members Description

 Cefacetrile (cephacetrile)
 Cefadroxil (cefadroxyl; Duricef)
 Cefalexin (cephalexin; Keflex) Gram-positive: Activity against penicillinase-
 Cefaloglycin (cephaloglycin) producing, methicillin-
 Cefalonium (cephalonium) susceptible staphylococci and streptococci (though
 Cefaloridine (cephaloradine) they are not the drugs of choice for such infections).
 Cefalotin (cephalothin; Keflin) No activity against methicillin-resistant staphylococci
or enterococci.[citation needed]
 Cefapirin (cephapirin; Cefadryl)
1
 Cefatrizine Gram-negative: Activity against Proteus mirabilis,
 Cefazaflur some Escherichia coli, and Klebsiella
 Cefazedone pneumoniae ("PEcK"), but have no activity
against Bacteroides
 Cefazolin (cephazolin; Ancef,
fragilis, Pseudomonas, Acinetobacter, Enterobacter,
Kefzol)
indole-positive Proteus, or Serratia.[citation needed]
 Cefradine (cephradine; Velosef)
 Cefroxadine
 Ceftezole
 Cefaclor (Ceclor, Distaclor,
Keflor, Raniclor)
 Cefonicid (Monocid)
 Cefprozil (cefproxil; Cefzil)
 Cefuroxime (Altacef, Zefu,
Zinnat, Zinacef, Ceftin, Gram-positive: Less than first-generation.[citation needed]
Biofuroksym,[20] Xorimax) Gram-negative: Greater than first-generation:
2  Cefuzonam HEN Haemophilus influenzae, Enterobacter
aerogenes and some Neisseria + the PEcK described
Antianaerobe activity:
above.[citation needed]
 Cefmetazole
 Cefotetan
 Cefoxitin
The following cephems are also
 sometimes grouped with second-
generation cephalosporins:

 Carbacephems:
o Loracarbef (Lorabid)
 Cephamycins:
o Cefbuperazone
o Cefmetazole (Zefazone)
o Cefminox
o Cefotetan (Cefotan)
o Cefoxitin (Mefoxin)
o Cefotiam (Pansporin)
 Cefcapene
 Cefdaloxime
 Cefdinir (Sefdin, Zinir, Omnicef,
Kefnir)
 Cefditoren Gram-positive: Some members of this group (in
 Cefetamet particular, those available in an oral formulation, and
those with antipseudomonal activity) have decreased
 Cefixime (Fixx, Zifi, Suprax)
activity against gram-positive organisms.
 Cefmenoxime
 Cefodizime Activity against staphylococci and streptococci is less
 Cefotaxime (Claforan) with the third-generation compounds than with the
first- and second-generation compounds.[21]
 Cefovecin (Convenia)
 Cefpimizole Gram-negative: Third-generation cephalosporins
 Cefpodoxime (Vantin, PECEF, have a broad spectrum of activity and further increased
Simplicef) activity against gram-negative organisms. They may
 Cefteram be particularly useful in treating hospital-acquired
infections, although increasing levels of extended-
3  Ceftibuten (Cedax)
spectrum beta-lactamases are reducing the clinical
 Ceftiofur (Naxcel, Excenel) utility of this class of antibiotics. They are also able to
 Ceftiolene penetrate the central nervous system, making them
 Ceftizoxime (Cefizox) useful against meningitis caused by pneumococci,
 Ceftriaxone (Rocephin) meningococci, H. influenzae, and susceptible E.
coli, Klebsiella, and penicillin-resistant N.
Antipseudomonal activity:
gonorrhoeae. Since August 2012, the third-generation
cephalosporin, ceftriaxone, is the only recommended
 Cefoperazone (Cefobid) treatment for gonorrhea in the United States (in
 Ceftazidime (Meezat, Fortum, addition to azithromycin or doxycycline for
Fortaz) concurrent Chlamydia treatment). Cefixime is no
These cephems are also sometimes longer recommended as a first-line treatment due to
grouped with third-generation evidence of decreasing susceptibility.[22]
cephalosporins:

 Oxacephems:
o Latamoxef (moxalactam)
 Cefclidine Gram-positive: They are extended-spectrum agents
4  Cefepime (Maxipime) with similar activity against Gram-positive organisms
 Cefiderocol (Fetroja) as first-generation cephalosporins.[citation needed]
  Cefluprenam
Gram-negative: Fourth-generation cephalosporins
 Cefoselis are zwitterions that can penetrate the outer
 Cefozopran membrane of Gram-negative bacteria.[23] They also
 Cefpirome (Cefrom) have a greater resistance to β-lactamases than the third-
 Cefquinome generation cephalosporins. Many can cross the blood–
brain barrier and are effective in meningitis. They are
These cephems are also sometimes
also used against Pseudomonas aeruginosa.[citation needed]
grouped with fourth-generation
cephalosporins: Cefiderocol has been called a fourth-generation
cephalosporin by only one source as of November
 Oxacephems: 2019.[24]
o Flomoxef
Note:Cefquinome is not approved for human
use. It is for veterinary medicine.

Ceftobiprole has been described as "fifth-generation"

cephalosporin,[25][26] though acceptance for this
terminology is not universal. Ceftobiprole has anti-
pseudomonal activity and appears to be less
susceptible to development of
resistance. Ceftaroline has also been described as
"fifth-generation" cephalosporin, but does not have the
 Ceftobiprole activity against Pseudomonas aeruginosa or
5  Ceftaroline vancomycin-resistant enterococci that ceftobiprole
 Ceftolozane has.[27] Ceftaroline has activity against
MRSA. Ceftolozane is an option for the treatment of
complicated intra-abdominal infections and
complicated urinary tract infections. It is combined
with the β-lactamase inhibitor tazobactam, as multi-
drug resistant bacterial infections will generally show
resistance to all β-lactam antibiotics unless this
enzyme is inhibited.[28][29][30][31][32]
These cephems have progressed far
enough to be named, but have not been
assigned to a particular generation:

 Cefaloram
 Cefaparole
 Cefcanel
 Cefedrolor
 Cefempidone Nitrocefin is a chromogenic cephalosporin substrate,
Other:  Cefetrizole and is used for detection of β-lactamases.[citation needed]
 Cefivitril
 Cefmatilen
 Cefmepidium
 Cefoxazole
 Cefrotil
 Cefsumide
 Ceftioxide
 Cefuracetime
  Nitrocefin

History[edit]
See also: Discovery and development of cephalosporins
Cephalosporin compounds were first isolated from cultures of Acremonium strictum from a sewer
in Sardinia in 1948 by Italian scientist Giuseppe Brotzu.[33] He noticed these cultures produced
substances that were effective against 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.

References[edit]
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External links