Pharmacology: Cefixime is a semisynthetic, 3rd-generation cephalosporin antibiotic, effective against a wide spectrum of sensitive gram-positive, gram-negative and anaerobic bacterial pathogens including β-lactamase-producing strains. It has high affinity for penicillin-binding proteins with varying site of activity. It acts by inhibition of bacterial cell wall synthesis. The elimination half-life is about 3 hrs with little variation over the usual therapeutic dosage range.
Clavulanic acid is a naturally derived β-lactamase inhibitor produced by Streptomyces clavuligerus. Clavulanic acid is an irreversible inhibitor of intracellular and extracellular β-lactamases, demonstrating concentration-dependent and competitive inhibition.
Cefixime is found to be ineffective against bacteria which produces extended-spectrum β-lactamases (ESBL) enzyme and resistance is seen in such types of bacteria. The combination of cefixime and clavulanic acid (β-lactamase inhibitor) provides a solution for treatment of bacterial infections caused by β-lactam resistant pathogens.
Pharmacokinetics: Combining clavulanic acid with β-lactam antibiotic causes no appreciable alteration of the pharmacokinetics of either drug compared with their separate administration. About 40-50% of cefixime is absorbed slowly following oral administration from gastrointestinal. Absorption is not significantly modified by the presence of food. After a 200-mg oral dose, peak plasma level on an average of 2.7 mg/L are achieved, between 3-4 hrs post-dose in fasting volunteers. Cephalosporins are widely distributed in most tissues and fluids. The mean volume of distribution of cefixime is 0.11 L/kg. Penetration into tissue fluid is slow (mean tmax 6.7 hrs) but peak concentrations similar to those of plasma have been achieved.
From in vitro studies, serum or urine concentrations of 1 mcg/mL 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 mcg/mL.
Cefixime is mainly excreted unchanged in bile and urine. The mean elimination half-life (t½) is 3 hrs. Urinary excretion accounts for about 40% of an orally administered dose, the rest of the excretion takes place through the biliary tract. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.
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.
Clavulanic acid is well absorbed from the gastrointestinal tract after oral administration. On administration of clavulanate potassium 57 mg, the maximum plasma concentration obtained is 1.03 mcg/mL and the area under the plasma concentration-time curve (AUC) for 24 hr is 2.17 mcg·hr/mL.
Microbiology: As with other cephalosporins, the bactericidal action of cefixime results from the inhibition of cell wall synthesis. Being a 3rd-generation cephalosporin, cefixime is highly stable in the presence of β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins, due to the presence of β-lactamase, may be susceptible to cefixime. Cefixime has been shown to be active against most strains of both in vitro and in clinical infections.
Gram-Positive: Streptococcus pneumoniae, Streptococcus pyogenes.
Gram-Negative: Haemophilus influenzae (β-lactamase-positive and -negative strains), Moraxella (Branhamella) catarrhalis (most of which are β-lactamase positive), Escherichia coli, Proteus mirabilis, Neisseria gonorrhoeae (including penicillinase- and nonpenicillinase-producing strains).
Note: Pseudomonas spp, strains of group D streptococci (including enterococci), Listeria monocytogenes, most strains of staphylococci (including methicillin-resistant strains) and most strains of Enterobacter are resistant to cefixime. In addition, most strains of Bacteroides fragilis and Clostridia are resistant to cefixime.