Pharmacotherapeutic group: Antibacterials for systemic use, second-generation cephalosporins. ATC Code: J01DC02.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Pharmacokinetics: Absorption: After oral administration cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolysed in the intestinal mucosa and blood to release cefuroxime into the circulation. Optimum absorption occurs when it is administered shortly after a meal.
Following administration of cefuroxime axetil tablets peak serum levels (2.9 µg/mL for a 125 mg dose, 4.4 µg/mL for a 250 mg dose, 7.7 µg/mL for a 500 mg dose and 13.6 µg/mL for a 1000 mg dose) occur approximately 2.4 hours after dosing when taken with food. The rate of absorption of cefuroxime from the suspension is reduced compared with the tablets, leading to later, lower peak serum levels and reduced systemic bioavailability (4 to 17% less). Cefuroxime axetil oral suspension was not bioequivalent to cefuroxime axetil tablets when tested in healthy adults and therefore is not substitutable on a milligramper-milligram basis. The pharmacokinetics of cefuroxime is linear over the oral dosage range of 125 to 1000 mg. No accumulation of cefuroxime occurred following repeat oral doses of 250 to 500 mg.
After intramuscular (IM) injection of cefuroxime to normal volunteers, the mean peak serum concentrations ranged from 27 to 35 µg/mL for a 750 mg dose and from 33 to 40 µg/mL for a 1000 mg dose, and were achieved within 30 to 60 minutes after administration. Following intravenous (IV) doses of 750 and 1500 mg, serum concentrations were approximately 50 and 100 µg/mL, respectively, at 15 minutes.
AUC and Cmax appear to increase linearly with increase in dose over the single dose range of 250 to 1000 mg following IM and IV administration. There was no evidence of accumulation of cefuroxime in the serum from normal volunteers following repeat intravenous administration of 1500 mg doses every 8 hours.
Distribution: Protein binding has been stated as 33 to 50%, depending on the methodology used.
Following a single dose of Cefuroxime axetil 500 mg tablet to 12 healthy volunteers, the apparent volume of distribution was 50 L (CV% = 28%). The average volume of distribution ranges from 9.3 to 15.8 L/1.73 m2 following IM or IV administration over the dosage range of 250 to 1000 mg. Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum and aqueous humour. Cefuroxime passes the blood-brain barrier when the meninges are inflamed.
Biotransformation: Cefuroxime is not metabolised.
Elimination: Cefuroxime is excreted by glomerular filtration and tubular secretion.
Tablet: The serum half-life is between 1 and 1.5 hours. The renal clearance is in the region of 125 to 148 mL/min/1.73 m2.
Injection: The serum half-life after either intramuscular or intravenous injection is approximately 70 minutes. There is an almost complete recovery (85 to 90%) of unchanged cefuroxime in urine within 24 hours of administration. The majority of the cefuroxime is excreted within the first 6 hours. The average renal clearance ranges from 114 to 170 mL/min/1.73 m2 following IM or IV administration over the dosage range of 250 to 1000 mg.
Special patient populations: Gender: Tablet: No differences in the pharmacokinetics of cefuroxime were observed between males and females.
Injection: No differences in the pharmacokinetics of cefuroxime were observed between males and females following a single IV bolus injection of 1000 mg of cefuroxime as the sodium salt.
Elderly: Tablet: No special precaution is necessary in the elderly patients with normal renal function at dosages up to the normal maximum of 1g per day. Elderly patients are more likely to have decreased renal function; therefore, the dose should be adjusted in accordance with the renal function in the elderly.
Injection: Following IM or IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function.
Paediatrics: Tablet: In older infants (aged >3 months) and in children, the pharmacokinetics of cefuroxime ae similar to that observed in adults.
There is no clinical trial data available on the use of cefuroxime axetil in children under the age of 3 months.
Injection: The serum half-life of cefuroxime has been shown to be substantially prolonged in neonates according to gestational age. However, in older infants (aged >3 weeks) and in children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.
Renal impairment: Tablet: The safety and efficacy of cefuroxime axetil in patients with renal failure have not been established.
Cefuroxime is primarily excreted by the kidneys. Therefore, as with all such antibiotics, in patients with markedly impaired renal function (i.e. Clcr <30 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by dialysis.
Injection: Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. Clcr <20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by haemodialysis and peritoneal dialysis.
Hepatic impairment: Tablet: There are no data available for patients with hepatic impairment. Since cefuroxime is primarily eliminated by the kidney, the presence of hepatic dysfunction is expected to have no effect on the pharmacokinetics of cefuroxime.
Injection: Since cefuroxime is primarily eliminated by the kidney, hepatic dysfunction is not expected to have an effect on the pharmacokinetics of cefuroxime.
PK/PD relationship: For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T>MIC).
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. No carcinogenicity studies have been performed; however, there is no evidence to suggest carcinogenic potential.
Gamma glutamyl transpeptidase activity in rat urine is inhibited by various cephalosporins; however, the level of inhibition is less with cefuroxime. This may have significance in the interference in clinical laboratory tests in humans.
Microbiology: 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.
Cefuroxime axetil breakpoints: Tablet: Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows: See Table 1.
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Microbiological susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is known and the utility of the agent in at least some types of infections is questionable.
Cefuroxime is usually active against the following microorganisms in vitro.
Commonly susceptible species: Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible)*, Streptococcus pyogenes, Streptococcus agalactiae.
Injection: Streptococcus mitis (viridans group).
Gram-negative aerobes: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis.
Spirochaetes: Tablet: Borrelia burgdorferi.
Microorganisms for which acquired resistance may be a problem: Gram-positive aerobes: Streptococcus pneumoniae.
Gram-negative aerobes: Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus spp. (other than P. vulgaris), Providencia spp, Salmonella spp. (for Injection only).
Gram-positive anaerobes: Peptostreptococcus spp., Propionibacterium spp.
Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp.
Inherently resistant microorganisms: Gram-positive aerobes: Enterococcus faecalis, Enterococcus faecium.
Gram-negative aerobes: Acinetobacter spp., Campylobacter spp. (for Tablet only), Morganella morganii, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens.
Gram-positive anaerobes: Injection: Clostridium difficile.
Gram-negative anaerobes: Bacteroides fragilis.
Others: Chlamydia spp., Mycoplasma spp., Legionella spp.
* All methicillin-resistant S. aureus are resistant to cefuroxime.
Injection: In vitro, the activities of cefuroxime sodium and aminoglycoside antibiotics in combination have been shown to beat least additive with occasional evidence of synergy.