Clavulanate - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium for oral suspension is an antibacterial drug [see Microbiology ].

12.3 Pharmacokinetics The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric patients, 8 months to 11 years, given amoxicillin and clavulanate potassium for oral suspension at an amoxicillin dose of 45 mg/kg q12h with a snack or meal.

The mean plasma amoxicillin and clavulanate pharmacokinetic parameter values are listed in Table 3.

Mean (±SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter Values Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for Oral Suspension Every 12 Hours to Pediatric Patients * Arithmetic mean ± standard deviation, except T max values which are medians (ranges).

Parameter Amoxicillin Clavulanate C max (mcg/mL) 15.7 ± 7.7 1.7 ± 0.9 T max (hr) 2 (1 to 4) 1.1 (1 to 4) AUC 0-T (mcg*hr/mL) 59.8 ± 20 4 ± 1.9 T½ (hr) 1.4 ± 0.3 1.1 ± 0.3 CL/F (L/hr/kg) 0.9 ± 0.4 1.1 ± 1.1 The effect of food on the oral absorption of amoxicillin and clavulanate potassium for oral suspension has not been studied.

Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of 10 mL of 250 mg/5 mL suspension of amoxicillin and clavulanate potassium.

Neither component in amoxicillin and clavulanate potassium for oral suspension is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Oral administration of a single dose of amoxicillin and clavulanate potassium for oral suspension at 45 mg/kg (based on the amoxicillin component) to pediatric patients, 9 months to 8 years, yielded the following pharmacokinetic data for amoxicillin in plasma and middle ear fluid (MEF): Table 4.

Amoxicillin Concentrations in Plasma and Middle Ear Fluid Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for Oral Suspension to Pediatric Patients* *Dose administered immediately prior to eating.

Timepoint Amoxicillin concentration in plasma (mcg/mL) Amoxicillin concentration in MEF (mcg/mL) 1 hour mean median range 7.7 9.3 1.5 to 14 (n = 5) 3.2 3.5 0.2 to 5.5 (n = 4) 2 hour mean median range 15.7 13 11 to 25 (n = 7) 3.3 2.4 1.9 to 6 (n = 5) 3 hour mean median range 13 12 5.5 to 21 (n = 5) 5.8 6.5 3.9 to 7.4 (n = 5) Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain and spinal fluid.

The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Drug Interaction Studies Clinical Studies Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

12.4 Microbiology Mechanism of Action Amoxicillin is a semisynthetic antibacterial with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms.

Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, its spectrum of activity does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam, structurally related to penicillin, which possesses the ability to inactivate a wide range of beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins.

In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently found responsible for transferred drug resistance.

The clavulanic acid component of amoxicillin and clavulanate potassium for oral suspension protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other beta-lactam antibacterials.

Thus, amoxicillin and clavulanate potassium for oral suspension possesses the distinctive properties of a broad spectrum antibacterial and a beta-lactamase inhibitor.

Antimicrobial Activity Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage ].

Gram-positive bacteria: Streptococcus pneumoniae (including isolates with penicillin MICs less than or equal to 2 mcg/mL) Gram-negative bacteria: Haemophilus influenzae (including beta-lactamase-producing isolates) Moraxella catarrhalis (including beta-lactamase-producing isolates) The following in vitro data are available, but their clinical significance is unknown.