Antibiotic treatment of otitis media with effusion.

There are various forms of medical treatment for otitis media with effusion (OME) in children. One of these is a four week course of an antibiotic. A trial was carried out comparing cotrimoxazole with amoxicillin-potassium clavulanate in 102 cases with 181 affected ears. In addition this trial used various procedures to increase and monitor compliance, and the results showed that the compliant cases did much better than the noncompliant cases and cotrimoxazole was more effective than amoxicillin-potassium clavulanate. When the ethnic groupings were analysed the compliance was lower for the Maori (24%) and Pacific Islander (29%) than the European (49%). The success rate for the compliant cases whose middle ear effusion resolved in one or both ears had a similar result with Maori (40%), Pacific Islander (60%) and European (71%) probably indicating an increased nonmeasured compliance in the latter.

A sensitive assay for clavulanic acid and sulbactam in biological fluids by high-performance liquid chromatography and precolumn derivatization.

Precolumn derivatization procedures using 1,2,4-triazole for the detection and quantitation of sulbactam and clavulanic acid spiked into urine and blood serum at trace levels have been developed. Sulbactam and clavulanic acid produced derivatives which absorbed maximally at 325 and 315 nm, respectively. The methods allow the detection of clavulanic acid and sulbactam down to 0.05 micrograms ml-1 in serum and 0.5 micrograms ml-1 in urine. The relative standard deviation for five replicate analyses of sulbactam and clavulanic acid at a concentration of 20 micrograms ml-1 in serum and urine ranged from 2-6%. In further HPLC experiments with sulbactam in phosphate buffer solution, ampicillin was found as a contaminant (0.5% by mass) in the sulbactam sample provided. The significance of this finding is discussed.

[Direct determination of clavulanic acid in biological fluids using HPLC]. / Détermination directe de l'acide clavulanique dans les liquides biologiques par HPLC.

The so far described HPLC methods for clavulanic acid (CA) monitoring needed post-column derivatization with imidazole, resulting in poorly practicable methods. We propose here a direct determination of CA in human biological fluids with a ion-pairing technology using the bathochromic shift of tetrabutylammonium bromide (TBAB). The separation is performed on a reversed phase analytical column (250 X 4.6 mm) with the following mobile phase: 10% acetonitrile in 1 mM TAB and 20 mM ammonium acetate (pH = 5). The U.V. detection is at 214 nm. Serum and bile are prepared with acetonitrile and methylene chloride, and urines are diluted 1/10 prior the analysis. Retention time of CA is 8.4 min. Detection limit for bile and serum is 0.1 mg/l and 5 mg/l for urines. Within and between-day reproducibility is respectively 5.4% and 7.2% for serum and bile, and 4.7% and 6.8% for urine. This method may be suitable for clinical routine analysis and pharmacokinetic studies.

Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function.

The disposition of coadministered ticarcillin (3 g/1.73 m2) and clavulanic acid (100 mg/1.73 m2) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CLCR). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CLCR. The half-lives increased with reduced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CLCR. Calculations of expected steady-state maximum and minimum concentrations in plasma using constant doses and an extended dosing interval related to CLCR further rationalized use of the 30:1 drug combination ratio for all patients.

The disposition of clavulanic acid in man.

Following oral administration of potassium 14C-clavulanate to four human subjects, at least 73% of the radioactive dose was absorbed. The mean absolute bioavailability was 64%. Absorption was rapid with peak plasma concentrations of radioactivity and clavulanic acid (2-6 micrograms/ml) occurring between 45 min and three hours after dosing. Values for the volume of distribution at steady-state and terminal half-life of clavulanic acid in the plasma were 12.01 and 0.8 h respectively. Following intravenous administration of clavulanic acid to the same subjects, the clearance, and volume of distribution at steady-state were 0.21 l/min, and 12.01, respectively. Clavulanic acid was the major radioactive component present in 0-24 h urine following oral dosing (23% of the dose). The two major metabolites were 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid (15% of the dose) and 1-amino-4-hydroxybutan-2-one (8.8% of the dose). Clavulanic acid and 1-amino-4-hydroxybutan-2-one were the major components in plasma following oral administration (52 and 21% of plasma radioactivity respectively at two hours after dosing). The major route of excretion of radioactivity following oral administration was via the urine (73% of the dose). Most of this radioactivity was excreted in the first 24 h after dosing (68% of the dose). The renal clearance of clavulanic acid was 0.1 l/min. Elimination of radioactivity also occurred via the expired air (17% of the dose) and the faeces (8% of the dose).

[A simple enzyme assay for the simultaneous determination of penicillin derivatives and clavulanic acid in biological fluids]. / Ein einfaches enzymatisches Verfahren zur simultanen Bestimmung von Penicillinderivaten und Clavulansäure in biologischen Flüssigkeiten.

A simple enzymatic assay for simultaneous determinations of amino-/ureidopenicillins and clavulanic acid concentrations in various body fluids is described; no pretreatment of the samples is required. The assay is based on the competitive inhibition of the chromogenic compound Padac by clavulanic acid in the presence of Proteus vulgaris beta-lactamase. Detection limit for clavulanic acid amounts 0.02 mg/l. Interferences with other antibiotics such as aminoglycosides, macrolides, quinolones etc. can be ruled out.

High-performance liquid chromatographic assay of clavulanate in human plasma and urine by fluorimetric detection.

A high-performance liquid chromatographic method with fluorimetric detection has been developed for the determination of clavulanate in human urine and plasma. Clavulanate in plasma samples was ultrafiltered using YMT membrane and reacted with benzaldehyde in phosphate buffer solution (pH 3.8) at 100 degrees C for 20 min. Clavulanate in urine samples was filtered with a polyacrylate membrane after ten-fold dilution, and reacted under the same conditions as those for plasma samples. The fluorescent product thus formed from clavulanate was separated from ordinary components of plasma and urine on a reversed-phase C18 column followed by fluorimetric detection (lambda ex = 386 nm, lambda em = 460 nm). The within- and between-run precisions were of the order of 4.02% (n = 10) and 6.23% (n = 5) for plasma samples at a level of 0.67 microgram/ml. The detection limit was as low as 10 ng/ml in plasma samples with a 50-microliter injection. Coexisting ticarcillin, amoxicillin or 1-amino-4-hydroxybutan-2-one (which is a metabolite of clavulanate in rat and dog) did not interfere in the clavulanate assay.

Pharmacokinetics of a syrup formulation of amoxycillin-potassium clavulanate in children.

The pharmacokinetics of a syrup formulation consisting of four parts of amoxycillin and one part of potassium clavulanate (Augmentin) were studied in 11 paediatric patients, 3 to 14 years of age. Single oral doses of 25 mg of Augmentin per kg body weight (20 mg of amoxycillin per kg plus 5 mg of potassium clavulanate per kg, i.e. 1 mg of the syrup per kg) were administered on an empty stomach, and were well accepted and tolerated. Mean peak plasma concentrations 60-90 min after dosing were 7.2 mg/l for amoxycillin and 2.0 mg/l for clavulanic acid. Mean terminal phase plasma half-lives were 1.4 and 1.0 h, respectively. It is concluded that 25-mg/kg doses of this syrup formulation of Augmentin administered three times daily should be adequate therapy for various childhood bacterial infections.

Clavulanate-potentiated ticarcillin: high-performance liquid chromatographic assays for clavulanic acid and ticarcillin isomers in serum and urine.

High-performance liquid chromatographic assays for the determination of clavulanic acid and ticarcillin in biological fluids are described. The clavulanic acid assay uses serum ultrafiltrate and direct injection of diluted urine with reversed-phase ion-pair/counter-ion chromatography. The ticarcillin assay allows, for the first time, the separation and quantitation of two isomers of ticarcillin. The performance of these assays has been evaluated and found to be satisfactory for routine clinical use and thus the assays have been applied to the study of the pharmacokinetics of these analytes in a subject with renal failure.

Pharmacokinetics and urinary excretion of clavulanic acid after oral administration of amoxicillin and potassium clavulanate.

Clavulanic acid is a beta-lactamase inhibitor which prevents microbial lactamase inactivation of beta-lactam antibiotics. The pharmacokinetics and urinary excretion of clavulanic acid were studied in eight healthy adult volunteers after oral administration of 500 mg amoxicillin and 125 mg potassium clavulanate. Serum and urine clavulanic acid concentrations were assayed using high-performance liquid chromatography. Pharmacokinetic parameters were: t 1/2 beta = 1.019 +/- 0.090 hour, t 1/2 alpha = 0.276 +/- 0.031 hour, lag time = 0.321 +/- 0.018 hour, tmax = 1.042 +/- 0.80 hour, Cmax = 2.098 +/- 0.441 micrograms/ml, and AUC = 4.897 +/- 0.979 micrograms X hr/ml. Cumulative urinary excretion of clavulanic acid (as percentage of dose administered) was: 14.05 +/- 2.87 within 2 hours, 25.77 +/- 3.98 within 4 hours, and 27.85 +/- 4.27 within 6 hours after administration.

Parenteral augmentin: pharmacokinetics.

The pharmacokinetics of intravenous Augmentin have been investigated and the data found to fit a two compartment model. In the first study, to a crossover design, a bolus injection of 1.2 g Augmentin was given to 8 healthy volunteers with and without probenecid. It was found that the serum concentrations of amoxycillin were increased in the presence of probenecid, but those of clavulanic acid were unaffected. In a second study a further 8 volunteers received an infusion over 30 min of 2.2 g Augmentin. At the end of the infusion, peak concentrations in excess of 100 micrograms/ml were recorded for amoxycillin and 14 micrograms/ml for clavulanic acid. In both studies the serum and urinary concentrations of amoxycillin and clavulanic acid obtained were well above those considered necessary to achieve a therapeutic effect.

Absorption, metabolism and excretion studies on clavulanic acid in the rat and dog.

At least one third of an oral dose of sodium [G-14C]clavulanate was absorbed by rat and dog. Excretion of radioactivity was rapid in both species. In addition to urinary and faecal excretion of radioactivity, appreciable elimination of 14CO2 occurred, particularly in the rat. This was produced in part by the action of the gut microflora. In the rat, only a small proportion of the radioactive dose was secreted in the bile. The major metabolite in urine was identified as 1-amino-4-hydroxybutan-2-one. Clavulanic acid was also a major component in urine.