Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, second-generation cephalosporins, ATC code: J01DC02

Mechanism of action
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) extended- spectrum beta- lactamases (ESBLs), and Amp-C enzymes, that may be induced or stably derepressed in certain aerobic Gram-negative bacterial 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 sodium breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows: Microorganism                                                Breakpoints (mg/L) Susceptible                       Resistant

Enterobacteriaceae1                                                          ≤82                              >8 Staphylococcus spp.                                                         Note3                            Note3 Streptococcus A, B, C and G                                                 Note4                            Note4 Streptococcus pneumoniae                                                    ≤0.5                              >1 Streptococcus (other)                                                          ≤0.5                          >0.5 Haemophilus influenzae                                                          ≤1                               >2 Moraxella catarrhalis                                                           ≤4                               >8 Non-species related breakpoints  1                                             ≤4 5                             >85 1 The cephalosporin breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms 
(including ESBL and plasmid mediated AmpC). Some strains that produce beta- lactamases are susceptible or intermediate to 3rd or 4th generation cephalosporins with these breakpoints and should be reported as found, i.e. the presence or absence of an ESBL does not in itself influence the categorization of susceptibility. In many areas, ESBL detection and characterization is recommended or mandatory for infection control purposes.
2 Breakpoint relates to a dosage of 1.5 g × 3 and to E. coli, P. mirabilis and Klebsiella spp. only
3 Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility except for ceftazidme and  cefixime and ceftibuten, which do not have breakpoints and should not be used for staphylococcal infections.
4 The susceptibility of streptococcus groups A, B, C and G to cephalosporins is inferred from the benzylpenicillin
 susceptibility.
5 Breakpoints apply to daily intravenous dose of 750 mg × 3 and a high dose of at least 1.5 g × 3.


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-suscpetible) $
Streptococcus pyogenes
Streptococcus agalactiae
Gram-negative aerobes:
Haemophilus parainfluenzae
Moraxella catarrhalis
Microorganisms for which acquired resistance may be a problem
Gram-positive aerobes:
Streptococcus pneumoniae
Streptococcus mitis (viridans group)
Gram-negative aerobes:
Citrobacter spp. not including C. freundii
Enterobacter spp. not including E. aerogenes and E. cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Proteus mirabilis
Proteus spp. not including P. penneri and P. Vulgaris
Providencia spp.
Salmonella spp.
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.
Burkholderia cepacia
Campylobacter spp.
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Morganella morganii
Proteus penneri
Proteus vulgaris
Pseudomonas aeruginosa
Serratia marcescens
Stenotrophomonas maltophilia
Gram-positive anaerobes:
Clostridium difficile
Gram-negative anaerobes:
Bacteroides fragilis
Others:
Chlamydia spp.
Mycoplasma spp.
Legionella spp.
$ All methicillin-resistant S. aureus are resistant to cefuroxime.
In vitro the activities of cefuroxime sodium and aminoglycoside antibiotics in combination have been shown to be at least additive with occasional evidence of synergy.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
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.
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 metabolized.

Elimination
Cefuroxime is excreted by glomerular filtration and tubular secretion. 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
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
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 (see section 4.2).

Paediatrics
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
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 (see section 4.2).
Cefuroxime is effectively removed by haemodialysis and peritoneal dialysis.

Hepatic impairment
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).