Axcel Cefuroxime Mechanism of Action

Pharmacology: Mechanism of Action: Capsule and Oral suspension: Cefuroxime axetil is an oral prodrug of the bactericidal cephalosporin antibiotic cefuroxime, which is resistant to most β-lactamases and is active against a wide range of Gram-positive and Gram-negative organisms. It is indicated for the treatment of infections caused by susceptible bacteria. Cefuroxime is a well-characterized and effective antibacterial agent which has bactericidal activity against a wide range of common pathogens, including β-lactamase-producing strains. Cefuroxime has good stability to bacterial β-lactamase and consequently is active against many ampicillin-resistant or amoxycillin-resistant strains. The bactericidal action of cefuroxime results from inhibition of cell wall synthesis by binding to essential target proteins. Cefuroxime is usually active against the following organisms in vitro: Aerobes, Gram-negative: Haemophilus influenzae (including ampicillin-resistant strains); Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Escherichia coli; Klebsiella spp.; Proteus mirabilis; Proteus inconstans; Providencia rettgeri and Neisseria gonorrhoeae (including penicillinase and non-penicillinase-producing strains).
Aerobes, Gram-positive: Staphylococcus aureus (including penicillinase-producing strains but excluding methicillin-resistant strains), Staphylococcus epidermidis (including penicillinase-producing strains but excluding methicillin-resistant strains), Streptococcus pyogenes (and other β-haemolytic streptococci), Streptococcus pneumoniae, Streptococcus Group B (Streptococcus agalactiae).
Anaerobes, Gram-positive and Gram-negative cocci (including Peptococcus and Peptostreptococcus spp); Gram-positive bacilli (including Clostridium spp.) and Gram-negative bacilli (including Bacteroides and Fusobacterium spp); Propionibacterium spp.
Some strains of the following genera are not susceptible to Cefuroxime: Enterococcus (Streptococcus) faecalis, Morganella morganii, Proteus vulgaris, Enterobacter spp., Citrobacter spp., Serratia spp. and Bacteroides fragilis.
Oral suspension: Other organisms: Borrelia burgdorferi.
The following organisms are not susceptible to Cefuroxime: Clostridium difficile, Pseudomonas spp., Campylobacter spp., Acinetobacter calcoaceticus, Listeria monocytogenes, Methicillin-resistant strains of Staphylococcus aureus and Staphylococcus epidermidis and Legionella spp.
Tablet: Cefuroxime axetil undergoes hydrolysis by esterase enzymes to the active antibiotic, cefuroxime. Cefuroxime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.
Mechanism of Resistance: Bacterial resistance to cefuroxime may be due to one or more of the following mechanisms: Hydrolysis by beta-lactamases; including (but not limited to) by extended-spectrum beta-lactamases (ESBLs), and AmpC enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacteria species; Reduced affinity of penicillin-binding proteins for cefuroxime; Outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in Gram-negative bacteria; Bacterial efflux pumps.
Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime. The prevalence of acquired resistance is geographically and time dependent and for select species may be very high. Local information on resistance is desirable, particularly when treating severe infections. Cefuroxime is usually active against the following organisms in vitro. In vitro susceptibility of microorganisms to Cefuroxime where clinical efficacy of cefuroxime axetil has been demonstrated in clinical trials this is indicated with an asterisk (*): Commonly susceptible species: Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible)*, Coagulase negative staphylococcus (methicillin-susceptible), Streptococcus pyogenes, Beta-hemolytic streptococci.
Gram-negative aerobes: Haemophilus influenzae* including ampicillin-resistant strains, Haemophilus parainfluenzae*, Moraxella catarrhalis*, Neisseria gonorrhoea* including penicillinase and non-penicillinase producing strains.
Gram-Positive Anaerobes: Peptostreptococcus spp., Propionibacterium spp.
Spirochaetes: Borrelia burgdorferi*.
Microorganisms for which acquired resistance may be a problem: Gram-positive aerobes: Streptococcus pneumoniae*.
Gram-negative aerobes: Citrobacter spp. not including C. freundii, Enterobacter spp. not including E. aerogenes and E. cloacae, Escherichia coli*, Klebsiella spp. including Klebsiella pneumoniae*, Proteus mirabilis, Proteus spp. not including P. penneri and P. vulgaris, Providencia spp.
Gram-positive anaerobes: Clostridium spp. not including C. difficile.
Gram-negative anaerobes: Bacteroides spp. not including B. fragilis, Fusobacterium spp.
Inherently resistant microorganisms: Gram-Positive Aerobes: Enterococcus spp. including E.faecalis and E. faecium, Listeria monocytogenes.
Gram-negative aerobes: Acinetobacter spp., Burkholderia cepacia, Campylobacter spp., Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Proteus penneri, Proteus vulgaris, Pseudomonas spp. including Pseudomonas aeruginosa, Serratia spp., Stenotrophomonas maltophilia.
Gram-Positive anaerobes: Clostridium difficile.
Gram-negative anaerobes: Bacteroides fragilis.
Others: Chlamydia species, Mycoplasma species, Legionella species.
Pharmacokinetics: Cefuroxime axetil is slowly absorbed from the gastrointestinal tract after oral administration and rapidly hydrolysed in the intestinal mucosa and blood to release cefuroxime into the circulation. Serum levels of cefuroxime are reduced by dialysis.
Capsule and Oral suspension: In presence of food, the absorption of Cefuroxime axetil is enhanced.
Tablet and Oral suspension: The absorption of cefuroxime from the suspension is more prolonged compared with tablets, leading to later, lower peak serum levels and slightly reduced systemic bioavailability (4-17% less). Post peak levels, the serum half-life is between 1 and 1.5 hours. Protein binding has been variously stated as 33-50% depending on the methodology used. Cefuroxime is not metabolised and is excreted by glomerular filtration and tubular secretion. Concurrent administration of probenecid increases the area under the mean serum concentrations time curve by 50%.
Capsule: Peak plasma concentrations are reported about 2 to 3 hours after an oral dose. Up to 50% of Cefuroxime in the circulation is bound to plasma proteins and the plasma half-life is about 70 minutes and is prolonged in patients with renal impairment and in neonates. Cefuroxime is distributed widely in the body including pleural fluid, sputum, bones, synovial fluid and aqueous humour. It crosses the placenta and has been detected in breast milk. Cefuroxime is excreted unchanged by glomerular filtration and renal tubular secretion, and high concentrations are achieved in the urine. Probenecid competes for renal tubular secretion with Cefuroxime resulting in higher and more prolonged plasma concentrations of Cefuroxime. Small amounts of Cefuroxime are excreted in bile.
Tablet: Optimum absorption occurs when it is administered shortly after a meal. Peak serum level (2.1 mg/l for a 125 mg dose, 4.1 mg/l for a 250 mg dose, 7.0 mg/l for a 500 mg dose and 13.6 mg/l for a 1 g dose) occur approximately two to three hours after dosing when taken after food, unlike iv dosing which peaks immediately.
Renal impairment: Cefuroxime pharmacokinetics have been investigated in patients with various degrees of renal impairment. Cefuroxime elimination half-life increases with decrease in renal function which serves as the basis for dosage adjustment recommendations in this group of patients (see Dosage & Administration). In patients undergoing haemodialysis, at least 60% of the total amount of cefuroxime present in the body at the start of dialysis will be removed during a 4-hour dialysis period. Therefore, an additional single dose of cefuroxime should be administered following the completion of haemodialysis.