Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination

Abstract

The pharmacokinetics of amoxicillin and clavulanic acid, administered alone and in combination, were studied in six male and six female normal human volunteers. Each ingested 500 mg of amoxicillin or 125 mg of clavulanic acid or the above agents in combination in randomized sequences. The results indicate that most of the parameters tested for either substance are essentially independent of the presence of the other one.Microorganisms which are resistant to certain antibiotics are increasingly posing problems in the therapy of bacterial infections. The preponderant reason for this resistance against P-lactam antibiotics is the spread of ,-lactamase genes among pathogenic strains (9). One modem concept of coping with these problems is the inhibition of P-lactamase activities concomitant with the antibiotic attack on the bacterial cell. A very potent 3-lactamase inhibitor is clavulanic acid, a fermentation product of Streptomyces clavuligerus (14,15). Although its intrinsic antibacterial activity is comparatively weak, it irreversibly inhibits a wide range of ,B-lactamases of Richmond types II through V (12), protecting the P-lactam antibiotics administered simultaneously (e.g., amoxicillin from inactivation) and rendering the lactamase-producing organisms susceptible to the action of the antibiotic (8, 18). A new formulation of amoxicillin plus clavulanic acid (4:1 by weight) exploits this strongly synergistic effect by combining the two components for oral application (see [1,7,13]).The purpose of the study presented here was to investigate the mutual influence of either one of the components on the pharmacokinetic data of the other. For this purpose, urine excretion and serum drug levels were measured in volunteers after oral administration of amoxicillin, clavulanic acid, or a combination of both drugs.MATERIALS AND METHODS Substances. The substances administered were amoxicillin trihydrate (corresponding to 500 mg of amoxicillin), potassium clavulanate (corresponding to 125 mg offree acid), and a combination (corresponding to 500 mg of amoxicillin + 125 mg of clavulanic acid) called "the combination" throughout this paper. All substances were supplied by Beecham-Wulfing, Neuss, West Germany.Experimental design. The investigation was carried out in the randomized crossover mode, with 12 healthy volunteers (6 females and 6 males). Their average age was 26.1 years (standard deviation [SD] = 2.4 years), the average weights were 58.0 kg (SD = 7.3 kg) for the females and 69.0 kg (SD = 8.7 kg) for the males, the average heights were 166.5 cm (SD = 4.6 cm) for the females and 177.7 cm (SD = 7.9 cm) for the males. Tests carried out before the study revealed that all of the volunteers were healthy; their renal functions, serum enzyme levels, and blood analysis data were normal. Each subject was given 500 mg of amoxicillin orally in course a, 125 mg of clavulanic acid in course b, and 625 mg of the combination in course c. All six possible sequences of courses a, b, and c were realized with one female and one male test...

Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis?

“…Confirming results previously reported by Zhang et al (36) for strain H37Rv, we demonstrated that the ␤-lactamase activity of its avirulent counterpart, strain H37Ra, was inhibited by clavulanic acid and sulbactam, with IC 50 s for hydrolysis of nitrocephin of 0.2 and 1.3 g/ml, respectively. These concentrations are well within the therapeutic ranges of these inhibitors (1,11).…”

Response of Streptococcus pyogenes to therapy with amoxicillin or amoxicillin-clavulanic acid in a mouse model of mixed infection caused by Staphylococcus aureus and Streptococcus pyogenes

“…The dose levels of amoxicillin and clavulanic acid used were chosen because in the mouse they produced concentrations in blood and tissue which were similar to those obtainable in humans (1,26). At 4 h after infection, the peak blood level of amoxicillin given alone was 13.7 ± 2.8 l.g/ml at 30 min and of clavulanic acid alone was 12.8 ± 1.7 ,.g/ml, falling to 1.25 + 0.97 and 1.37 + 0.80 ,ug/ml, respectively, by 120 min (Fig.…”

Development and Validation of Limited-Sampling Strategies for Predicting Amoxicillin Pharmacokinetic and Pharmacodynamic Parameters

“…A large number of plasma samples (n ϭ 1,152) collected from 48 closely monitored, healthy volunteers in two bioequivalence studies allowed the development and subsequent validation of LSS models by using several different procedures. The results show that the AUC 0-ϱ of amoxicillin, following administration of single oral doses (500 ) for amoxicillin in 11 previously published studies (1,3,7,10,13,14,(17)(18)(19)(20)26), and the corresponding AUC 0-ϱ derived from the three-point LSS model developed for the reference capsule formulation in the present study (Table 3, (Table 2). The statistical principle of parsimony advises in favor of models with fewer parameters; thus, we settled for three-sample regressions for independent estimation of amoxicillin's AUC 0-ϱ .…”

“…The robustness of the three-point LSS regression equation derived from the capsule formulation data set as a predictor of the plasma amoxicillin AUC 0-ϱ was confirmed when tested on data from 11 published studies (1,3,7,10,13,14,(17)(18)(19)(20)26), encompassing a large range of amoxicillin single doses (250 to 1,000 mg) and AUC 0-ϱ 's (9 to 55 g ⅐ h ⅐ ml Ϫ1 ). This result not only validates our proposed three-point LSS model but also extends its applicability to a variety of experimental conditions, both clinical and analytical, which prevailed in the 11 studies examined.…”

“…As a third test of the validity of the LSS models developed for estimating amoxicillin's AUC 0-ϱ , the most informative three-point LSS equation derived for the training data set (reference capsule formulation) was used to estimate the AUC 0-ϱ of subjects enrolled in 11 previously published studies after administration of single oral doses (250 to 1,000 mg) of various amoxicillin formulations (1,3,7,10,13,14,(17)(18)(19)(20)26). Scanned plots of the published AUCs were used to obtain the data points employed for the LSS-derived AUC 0-ϱ 's and to obtain the best estimated AUC 0-ϱ 's by means of the trapezoidal method.…”