Cephalosporin compounds were first time taken from the Cephalosprium acremonium culture by an Italian scientist named Giuseppe Brotzu. Cephalosporin C is the naturally occurring agent from which other cephalosporins are derived by making some modifications in their structures. Cephalosporins and penicillins are linked with each other in sense of their structures and functions because both have a common beta-lactam ring. This ring plays an important role to stop the cell-wall synthesis of bacteria, in this way they perform their bactericidal activity. Parental cephalosporins are used frequently in hospital therapy because of their broad-spectrum activity against various pathogens.
Cephalosporins are classified into 5 generations based on their discovery and anti-microbial activities.
1ST generation cephalosporins:-They have activity against gram +ve bacteria (for example:-streptococcus and staphylococcus) and have a little bit of activity against gram –ve bacteria.
2nd generation cephalosporins:-They have remarkable activity against gram –bacteria as compared to 1st generation cephalosporin drugs. And they are less active against gram +ve bacteria when making a comparison with 1st generation bacteria.
3rd generation cephalsporins:-They is also known as broad-spectrum antibiotics, they have excellent activity against gram +ve and gram –ve bacteria, but they ideally work against gram –ve bacteria.
4th generation cephalosporins:-They are extended-spectrum antibiotics but have resistance against beta-lactamase enzymes.
5th generation cephalosporins:-These cephalosporins have wonderful activity against MRSA (methicillin-resistant staphylococcus aureus).
All cephalosporins interfere with the bacterial cell wall synthesis step which makes the membrane less stable against osmotic pressure due to which bacteria become die therefore they are known as bactericidal, so for this purpose, cephalosporins bind with the transpeptidase enzyme which is also known as penicillin-binding proteins which are essential for the synthesis of the cell wall of bacteria and bacterial cell wall helps to survive the bacteria in unfavourable conditions. Cephalosporins are only active against the growing organism that manufactures a peptidoglycan cell wall. Therefore they are inactive against those organisms which do not contain peptidoglycan in their cell walls structure like viruses, fungi and protozoa. In addition, the differences in PBPs can change the activity of cephalosporins which opposes Enterobacteriaceae and pseudomonas aeruginosa. Cephalosporins make more post-antibiotic effect (the reduction of bacterial growth after a short sensitivity towards microbes) in gram +ve bacteria but they produce a negligible effect in gram –ve bacteria.
Bacteria are also able to develop different mechanisms to prevent the lethal activity of cephalosporins against them. Like alteration of PBPs, production of beta-lactamase enzyme and change in cell wall permeability of gram –ve bacteria. Every strain of bacteria has different kinds of PBPs and gram –bacteria have more types of PBPs than the gram -ve bacteria. Initially, first-generation cephalosporins are resistant to staphylococcal penicillinases. Cefazolin is not that responsible to be hydrolyzed by the varieties of penicillinase as compared to other cephalosporins. 2nd and 3rd-generation cephalosporins are well developed/strong to prevent the hydrolysis by the common lactamase enzymes of gram–bacteria. The limiting use of these antibiotics can prevent resistance and inactivation of these drugs towards bacteria.
Pharmacokinetic properties and anti-bacterial spectrum of cephalosporins are affected by the two side chains at positions 3 and 7.
• Oral cephalosporins:-
Commonly, oral cephalosporins absorb rapidly like cefaclor cefadroxil, cephradine and cephalexin are rapidly and fully absorbed, but some cephalosporins like cefixime and cefuroxime are absorbed into the minimum extent. These all above compounds get their therapeutic effect mainly in bones, synovial fluids and pleural fluids. All oral cephalosporins are excreted via urine except cefixime which is excreted by the non-renal route.
• Parental cephalosporins:-
These parents can be given via intravenous or intramuscular route. They are largely propagated to the tissues and fluid, including bones, cerebrospinal fluids, pleural fluids and cerebrospinal fluid. 1st or 2nd generation cephalosporins and ceftriaxone, ceftazidime, ceftizoxime, cefotaxime, and cefuroxime can get their therapeutic activity in the CSF even the meningitis is there. Cephalosporins can pass through the placenta and excrete out in small amounts by breast milk. Ceftizoxime, cefuroxime, ceftazidime and cefazolin are metabolized slowly. Cefotaxime, cephapirin and cephalothin are converted to a diacetyl metabolite by metabolism. Parental cephalosporins are water-soluble and polar therefore they are mostly excreted out in the urine in unchanged form. Approximately 40% of ceftriaxone is excreted out via bile whereas cefoperazone up to 70% excrete out via bile.
Commonly, cephalosporins produce minor adverse reactions. Skin rash along with arthritis and fever (serum sickness-like syndrome), are reported during the cefaclor therapy but they are uncommon. Renal diseases are observed during the use of cephalosporins along with the increase in blood nitrogen urea and serum creatinine levels. Cephalosporins were first time found as a substance of nephrotoxicity in 1965. Cefazolin and cefamandole produce necrosis of proximal tubule in subjects and it shows that they are less nephrotoxic with rabbits. Cephalosporins are also responsible to increase nephrotoxicity which is caused by the aminoglycosides. It was seen during the cephalothin therapy, so different tests are held in which it has been confirmed that penicillins give protection against aminoglycosides induced nephrotoxicity while cephalosporins assist to increase aminoglycosides induced nephrotoxicity. GIT complications like nausea, vomiting and diarrhoea are also found in oral therapy. Tally & associated gave the conclusion that cefixime produces diarrhoea in 13.4% of patients during therapy while changing the bowel habits in 12.8% of people. During the ceftriaxone therapy, cholecystitis occurs due to the billary deposits which are frequently observed but maybe it occurs due to the formation of calcium salt precipitates of ceftriaxone in the gall bladder.
Cephradine, cephalexin, cefadroxil and cefaclor are used for the treatment of acute and chronic upper and lower respiratory tract infections, which are caused by the streptococcus pyrogens, streptococcus pneumonia, staphylococcus aureus, H. influenza and klebsiella. Erythromycin/sulfamethoxazole and amoxicillin / clavulanic acid both are effective and cheap as compared to oral cephalosporins when they are used for the treatment of ampicillin-resistant strain of B. catarhalis & Haemophilus influenza. For UTI therapy, cefuroxime is also used and also shows its activity against various organisms which cause otitis media. Cefuroxime and probenecid combination is useful as a single daily dose for the treatment of rectal, urethral and endocervical gonorrhoea. Cefixime therapy causes the GIT problems but when it is compared with amoxicillin it is more potent against Haemophilus influenza, B. catarhalis and middle ear infections but it has potency like amoxicillin in case of urinary tract infection treatment in adults.
• 1st generation parental cephalosporins:-
These cephalosporins are provided in pre and post-operative situations to maintain the hygienic conditions in contaminated procedures like C- section, cholecystectomy and vaginal hysterectomy etc. They are also broadly used in people subjected to clean surgeries, for example:-cardiovascular procedures and arthroplasty etc.
• 2nd generation parental cephalosporins:-
Cefoxitin has more potency against B. fragile species and various gram +ve and –ve bacteria. It is used to treat intra-abdominal and pelvic infections. Cefoxitin is repeatedly used as a preventive agent for those patients who have done colorectal or pelvic surgery. Cefoxitin is also very useful and helpful in the form of combination with clindamycin and aminoglycosides. Cefotetan is responsible for the treatment of gynaecological infection, lower respiratory tract, obstetric, serious UTI, intra– abdominal and skin and soft tissue infections which are caused by the bacteria.
• 3rd generation parental cephalosporins:-
Commonly cefotaxime is prescribed to treat meningitis which is caused by the gram–bacilli. It has more potency against S. pneumonia, Neisseria meningitis and H. influenza. Sometimes it is given to treat meningitis in young children and infants. Cefotaxime and ceftizoxime both are responsible to treat complicated gram–bacillary infections such as serious UTI, gynecologic, bone, intra-abdominal and lower RTI infections. Ceftriaxone has supreme activity against the Neisseria gonorrhoea in which tetracycline N. gonorrhoea is also included. It is also frequently used in experimental monotherapy against many infections. 3rd generation agents are properly used to treat salmonellosis which is induced by ampicillin and chloramphenicol-resistant bacteria. Ceftazidime has activity against hospital-acquired gram–bacteria.
• 4th generation parental cephalosporin:-
According to some experiments it has been revealed about the good activity of cefepime and cefpirome against complicated and uncomplicated UTIs, gynaecological and upper and lower respiratory tract infections. Patients with ventilator-associated pneumonia can be treated with the 4th generation cephalosporins. Cefepime 2g BID dose has great efficiency to treat hospital-acquired pneumonia.
• 5th generation parental cephalosporins:-
It is an advanced generation of cephalosporins, which is used to treat the methicillin-resistant staphylococcus aureus strain (MRSA) and also streptococcus species otherwise they have similar activity like 3rd generation cephalosporins but it has not that much activity against pseudomonas aeruginosa.
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