Cefisal-200 Mechanism of Action

Pharmacotherapeutic group: Antibacterial (Third-generation cephalosporin). ATC code: J01DD08.
Pharmacology: Pharmacodynamics: Mode of Action: Cefixime is an antibacterial agent of the cephalosporin class. Like other cephalosporins, cefixime exerts antibacterial activity by binding to and inhibiting the action of penicillin-binding proteins involved in the synthesis of bacterial cell walls. This leads to bacterial cell lysis and cell death.
PK/PD relationship: The time that the plasma concentration of cefixime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in PK/PD studies.
Mechanisms of resistance: Bacterial resistance to cefixime may be due to one or more of the following mechanisms: Hydrolysis by extended-spectrum beta-lactamases and/or by chromosomally-encoded (AmpC) enzymes that may be induced or de-repressed in certain aerobic gram-negative bacterial species; Reduced affinity of penicillin-binding proteins; Reduced permeability of the outer membrane of certain gram-negative organisms restricting access to penicillin-binding proteins; Drug efflux pumps.
More than one of these mechanisms of resistance may co-exist in a single bacterial cell. Depending on the mechanism(s) present, bacteria may express cross-resistance to several or all other beta-lactams and/or antibacterial drugs of other classes.
Breakpoints: Clinical minimum inhibitory concentration (MIC) breakpoints established by EUCAST (May 2009) for Cefixime are: H. influenzae: sensitive ≤0.12 mg/L, resistant >0.12 mg/L; M. catarrhalis: sensitive ≤0.5 mg/L, resistant >1.0 mg/L; Neisseria gonorrhoeae: sensitive ≤0.12 mg/L, resistant >0.12 mg/L; Enterobacteriaceae: sensitive ≤1.0 mg/L, resistant >1.0 mg/L (for uncomplicated urinary tract infections only). The breakpoints for Enterobacteriaceae will detect reduced susceptibility mediated by most clinically important beta-lactamases in Enterobacteriaceae. Occasional ESBL-producing strains will be reported susceptible. For purposes of infection control, epidemiology and surveillance, laboratories may wish to use specific tests to screen for and confirm ESBL-production. Non-species related breakpoints: insufficient data.
Susceptibility: The prevalence of resistance may vary geographically and over 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 such that the utility of the agent in at least some types of infections are questionable. (See Table 1.)

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Pharmacokinetics: Absorption: The absolute oral bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly modified by the presence of food. Cefixime may therefore be given without regard to meals.
Distribution: Serum protein binding is well characterized for human and animal sera; cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of cefixime is only concentration dependent in human serum at very high concentrations which are not seen following clinical dosing. From in vitro studies, serum or urine concentrations of 1 mg/L or greater were considered to be adequate for most common pathogens against which cefixime is active. Typically, the peak serum levels following the recommended adult or pediatric doses are between 1.5 and 3 mg/L. Little or no accumulation of cefixime occurs following multiple dosing.
Metabolism and elimination: Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.
Transfer of 14C-labelled cefixime from lactating rats to their nursing offspring through breast milk was quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data are available on secretion of cefixime in human breast milk. Placental transfer of cefixime was small in pregnant rats dosed with labeled cefixime.
Special age groups: The pharmacokinetics of cefixime in healthy elderly (age >64 years) and young volunteers (11-35) compared the administration of 400 mg doses once daily for 5 days. Mean C_max and AUC values were slightly greater in the elderly. Elderly patients may be given the same dose as the general population.
Toxicology: Preclinical safety data: There are no findings from chronic toxicity investigations suggesting that any side effects unknown to date could occur in humans. Furthermore, in vivo and in vitro studies did not yield any indication of a potential to cause mutagenicity. Long-term studies on carcinogenicity have not been conducted.
Reproduction studies have been performed in mice and rats at doses up to 400 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefixime. In the rabbit, at doses up to 4 times the human dose, there was no evidence of a teratogenic effect; there was a high incidence of abortion and maternal death, which is an expected consequence of the known sensitivity of rabbits to antibiotic-induced changes in the population of the microflora of the intestine.