Cephalosporin
The cephalosporins 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 in Su Siccu, by Cagliari harbour in Sardinia, by the Italian pharmacologist Giuseppe Brotzu in July 1945.Medical uses
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. 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 associated with the cephalosporin therapy include: diarrhea, nausea, rash, electrolyte disturbances, and pain and inflammation at injection site. Infrequent ADRs 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, 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 to penicillins, carbapenems, or cephalosporins. This, however, should be viewed in the light of recent epidemiological work suggesting, for many second-generation 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 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, and this is the reason the β-lactams are associated with different frequencies of serious reactions.
Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol. These include latamoxef, 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 and aldehyde dehydrogenase. 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 and have the same mode of action as other β-lactam antibiotics, 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 bind to the D-Ala-D-Ala at the end of muropeptides 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. 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.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. 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 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 that cephalosporins can be divided into five or even six generations, although the usefulness of this organization system is of limited clinical relevance.
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.
The mnemonic "LAME" is used to note organisms against which cephalosporins do not have activity:
- Listeria
- Atypicals
- MRSA
- Enterococci
| Generation | Members | Description |
| 1 | Gram-positive: Activity against penicillinase-producing, methicillin-susceptible staphylococci and streptococci. No activity against methicillin-resistant staphylococci or enterococci.Gram-negative: Activity against Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae, but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia. | |
| 2 | Antianaerobe activity: The following cephems are also sometimes grouped with second-generation cephalosporins:
| Gram-positive: Less than first-generation.Gram-negative: Greater than first-generation: HEN Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + the PEcK described above. |
| 3 |
These cephems are also sometimes grouped with third-generation cephalosporins:
| Gram-positive: Some members of this group 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. 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. Cefixime is no longer recommended as a first-line treatment due to evidence of decreasing susceptibility. |
| 4 | These cephems are also sometimes grouped with fourth-generation cephalosporins:
| Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. Gram-negative: Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative bacteria. 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. Cefiderocol has been called a fourth-generation cephalosporin by only one source as of November 2019. |
| 5 | Ceftobiprole has been described as "fifth-generation" cephalosporin, 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 activity against Pseudomonas aeruginosa or vancomycin-resistant enterococci that ceftobiprole has. 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. | |
| Other: | 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. |