Cephalosporin

Cephalosporin
Drug class
Core structure of the cephalosporins
Use	Bacterial infection
Biological target	Penicillin binding proteins
ATC code	J01D
External links
MeSH	D002511
AHFS/Drugs.com	Drug Classes

Structure of the classical cephalosporins

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

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

Medical use

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, nephrotoxicity, neutropenia, thrombocytopenia, 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,^[2] and subsequent "safety first" policy meant this was widely quoted and assumed to apply to all members of the group.^[3] 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.^[4] 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 in the studies examined.^[3][5] 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, ceftazidine, and ceftriaxone can be used with caution, but the use of cefaclor, cefadrocil, cefalexin, and cefradine should be avoided.^[6]

Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol.^[7][8] 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).^[9]

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 irreversibly inhibiting PBP crosslinking of peptidoglycan.

Resistance

Resistance to cephalosporin antibiotics can involve either reduced affinity of existing penicillin-binding-protein components or the acquisition of a supplementary β-lactam-insensitive penicillin-binding-protein. Currently, some Citrobacter freundii, Enterobacter cloacae and Escherichia coli strains are resistant to cephalosporin. Some Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa and Serratia marcescens strains have also developed resistance to cephalosporin to varying degrees.^[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 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.^{[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.

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.

Some state, 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]

The mnemonic "LAME" is used to note organisms against which cephalosporins do not have activity: Listeria, Atypicals (including Mycoplasma and Chlamydia), MRSA, and enterococci.

Fifth-generation cephalosporins are effective against MRSA, however.

Other

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.^{[citation needed]}Nitrocefin,a chromogenic cephalosporin substrate is used for detection of beta-lactamase enzymes.

History

Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu.^[20] He noticed 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.

References