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The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus '' Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics called cephems. Cephalosporins were discovered in 1945, and first sold in 1964.


Discovery

The aerobic mold which yielded cephalosporin C was found in the sea near a
sewage outfall Sewage (or domestic sewage, domestic wastewater, municipal wastewater) is a type of wastewater that is produced by a community of people. It is typically transported through a sewer system. Sewage consists of wastewater discharged from residen ...
in Su Siccu, by
Cagliari Cagliari (, also , , ; sc, Casteddu ; lat, Caralis) is an Italian municipality and the capital of the island of Sardinia, an autonomous region of Italy. Cagliari's Sardinian name ''Casteddu'' means ''castle''. It has about 155,000 inhabitant ...
harbour A harbor (American English), harbour (British English; see spelling differences), or haven is a sheltered body of water where ships, boats, and barges can be docked. The term ''harbor'' is often used interchangeably with ''port'', which is a ...
in Sardinia, by the Italian pharmacologist Giuseppe Brotzu in July 1945.


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.


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 ''Staphylococcus'' is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical (cocci), and form in grape-like clusters. ''Staphylococcus'' species are facultative ...
'' and '' Streptococcus''. They are therefore used mostly for skin and soft tissue infections and the prevention of hospital-acquired surgical 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.


Side effects

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 Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases. In a medical context, the label ''colitis'' (without qualification) ...
, superinfection,
eosinophilia Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/ L (i.e. 1,500/μL). The hypereosinophilic syndro ...
, nephrotoxicity,
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
, thrombocytopenia, and fever. The commonly quoted figure of 10% of patients with allergic hypersensitivity to
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...
s and/or carbapenems also having cross-reactivity with cephalosporins originated from a 1975 study looking at the original cephalosporins, and subsequent "safety first" policy meant this was widely quoted and assumed to apply to all members of the group. 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.Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. 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. 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 Cefixime, sold under the brand name Suprax among others, is an antibiotic medication used to treat a number of bacterial infections. These infections include otitis media, strep throat, pneumonia, urinary tract infections, gonorrhea, and Lyme ...
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. 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). Several cephalosporins are associated with hypoprothrombinemia and a
disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of ...
-like reaction with ethanol. These include
latamoxef Latamoxef (or moxalactam) is an oxacephem antibiotic usually grouped with the cephalosporins. In oxacephems such as latamoxef, the sulfur atom of the cephalosporin core is replaced with an oxygen atom. Latamoxef has been associated with prolo ...
(
moxalactam Latamoxef (or moxalactam) is an oxacephem antibiotic usually grouped with the cephalosporins. In oxacephems such as latamoxef, the sulfur atom of the cephalosporin core is replaced with an oxygen atom. Latamoxef has been associated with prolonged ...
), cefmenoxime,
cefoperazone Cefoperazone is a third-generation cephalosporin antibiotic, marketed by Pfizer under the name Cefobid. It is one of few cephalosporin antibiotics effective in treating ''Pseudomonas'' bacterial infections which are otherwise resistant to these ...
,
cefamandole Cefamandole (INN, also known as cephamandole) is a second-generation broad-spectrum cephalosporin antibiotic. The clinically used form of cefamandole is the formate ester cefamandole nafate, a prodrug which is administered parenterally. Cef ...
,
cefmetazole Cefmetazole is a cephamycin antibiotic, usually grouped with the second-generation cephalosporins. __TOC__ Adverse effects The chemical structure of cefmetazole, like that of several other cephalosporins, contains an ''N''-methylthiotetrazole ( ...
, and
cefotetan Cefotetan is an injectable antibiotic of the cephamycin type for prophylaxis and treatment of bacterial infections. It is often grouped together with second-generation cephalosporins and has a similar antibacterial spectrum, but with additional ...
. This is thought to be due to the N-methylthiotetrazole side-chain of these cephalosporins, which blocks the enzyme
vitamin K epoxide reductase Vitamin K epoxide reductase (VKOR) is an enzyme () that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are pre ...
(likely causing hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance). Thus, consumption of alcohol after taking Cephalosporin orally or intravenously is contraindicated, and in severe cases can lead to death.


Mechanism of action

Cephalosporins are
bactericidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their ...
and, like other β-lactam antibiotics, disrupt the synthesis of the peptidoglycan layer forming the bacterial
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...
. 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 protein Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discov ...
s (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

Resistance to cephalosporin antibiotics can involve either reduced affinity of existing PBP components or the acquisition of a supplementary β-lactam-insensitive PBP. Compared to other β-lactam antibiotics (such as penicillins), they are less susceptible to β-lactamases. Currently, some '' Citrobacter freundii, Enterobacter cloacae'', ''
Neisseria gonorrhoeae ''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular), or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Ludwig Sigesmund Neisser, Albert Neisser in 1879. It causes the sexually transmit ...
'', and '' Escherichia coli'' strains are resistant to cephalosporins. Some ''
Morganella morganii ''Morganella morganii'' is a species of Gram-negative bacteria.eMedicineMorganella infections/ref> It has a commensal relationship within the intestinal tracts of humans, mammals, and reptiles as normal flora. Although ''M. morganii'' has a wide ...
'', ''
Proteus vulgaris ''Proteus vulgaris'' is a rod-shaped, nitrate-reducing, indole-positive and catalase-positive, hydrogen sulfide-producing, Gram-negative bacterium that inhabits the intestinal tracts of humans and animals. It can be found in soil, water, and feca ...
,
Providencia rettgeri ''Providencia rettgeri'' (commonly ''P. rettgeri''), is a Gram negative bacterium that is commonly found in both water and land environments. ''P. rettgeri'' is in the genus Providencia, along with '' Providencia stuartii'', '' Providencia alca ...
, Pseudomonas aeruginosa'', '' Serratia marcescens'' and '' Klebsiella pneumoniae'' strains have also developed resistance to cephalosporins to varying degrees.


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 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 is often imprecise. For example, the fourth generation of cephalosporins is not recognized as such in Japan. 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.


Third generation

Cefmetazole and cefoxitin are classed as third-generation cephems. Flomoxef and latamoxef are in a new class called
oxacephem An oxacephem is a β-lactam molecule similar to a cephem, but with an oxygen substituted for the sulfur. They are synthetic compounds not seen in nature, generally used as β-lactam antibiotic β-lactam antibiotics (beta-lactam antibiotics) a ...
s.


Fourth generation

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''.


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.


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.


Activity

The mnemonic "LAME" is used to note organisms against which cephalosporins do not have activity: *'' Listeria'' * Atypicals (including ''
Mycoplasma ''Mycoplasma'' is a genus of bacteria that, like the other members of the class ''Mollicutes'', lack a cell wall around their cell membranes. Peptidoglycan (murein) is absent. This characteristic makes them naturally resistant to antibiotics ...
'' and '' Chlamydia'') * MRSA *
Enterococci ''Enterococcus'' is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococci) or short chains, and are difficult to distinguish from streptococci on physical charac ...
Fifth-generation cephalosporins, however, are effective against MRSA.


Overview table


History

Cephalosporin compounds were first isolated from cultures of ''
Acremonium strictum ''Acremonium strictum'' is an environmentally widespread saprotroph species found in soil, plant debris, and rotting mushrooms. Isolates have been collected in North and Central America, Asia, Europe and Egypt. ''A. strictum'' is an agent of hyal ...
'' from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu. He noticed these cultures produced substances that were effective against '' Salmonella typhi'', the cause of typhoid fever, which had β-lactamase.
Guy Newton Guy Geoffrey Frederick Newton (1919 – 1969) was a British rower and biochemist. He was the co-discoverer of cephalosporin C. Newton was born in St. Ives, Cambridgeshire, the son of Bernard Newton a gentleman farmer of Fairfield Bury, St I ...
and
Edward Abraham Sir Edward Penley Abraham, (10 June 1913 – 8 May 1999) was an English biochemist instrumental in the development of the first antibiotics penicillin and cephalosporin. Early life and education Abraham was born on 10 June 1913 at 47 South V ...
at the
Sir William Dunn School of Pathology The Sir William Dunn School of Pathology is a department within the University of Oxford. Its research programme includes the cellular and molecular biology of pathogens, the immune response, cancer and cardiovascular disease. It teaches undergra ...
at the University of Oxford isolated cephalosporin C. The cephalosporin nucleus,
7-aminocephalosporanic acid 7-ACA (7-aminocephalosporanic acid) is the core chemical structure (a synthon) for the synthesis of cephalosporin antibiotics and intermediates. It can be obtained by chemoenzymatic hydrolysis of cephalosporin C. See also * 6-APA 6-APA ((+)- ...
(7-ACA), was derived from cephalosporin C and proved to be analogous to the penicillin nucleus
6-aminopenicillanic acid 6-APA ((+)-6-aminopenicillanic acid) is a chemical compound used as an intermediate in the synthesis of β-lactam antibiotics. The major commercial source of 6-APA is still natural penicillin G: the semi-synthetic penicillins derived from 6-APA a ...
(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 Cefalotin (INN) or cephalothin (USAN) is a first-generation cephalosporin antibiotic. It was the first cephalosporin marketed (1964) and continues to be widely used. It is an intravenously administered agent with a similar antimicrobial spec ...
(cephalothin), was launched by
Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
in 1964.


References


External links


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