[Sinusal penetration of amoxicillin-clavulanic acid. Formulation 1 g./125 mg., twice daily versus formulation 500 mg./125 mg., three times daily].

INTRODUCTION

In order to meet the evolution of pneumococcus resistance to beta-lactam antibiotics, a new formulation of amoxicillin (AMX) and clavulanic acid (CA), with twice as much AMX (1 g/125 mg vs. 500 mg/125 mg) was developed for the treatment of acute pneumonia in patients at risk. This formulation can also be used in the treatment of acute maxillary sinusitis using a 1 g/125 mg regimen twice-daily.

OBJECTIVES

Compare the sinusal penetration of AMX and CA (1 g/125 mg twice-daily vs. 500 mg/125 mg three times a day) when administered at both regimens to demonstrate equivalent pharmacokinetic and pharmacodynamic behaviour of the former when compared to the latter.

METHODS

Concentrations of AMX and CA were measured in the anterior ethmoid, maxillary, posterior ethmoid sinus and in the middle nasa concha in 62 patients undergoing surgery for nasosinusal polyps. Patients randomised in two groups corresponding to 2 oral regimens, received either 1 g/125 mg twice a day or 500 mg/125 mg three times a day for 4 days. The last dose in both groups was administered 1 h 30, 3, 5 or 8 hrs prior to surgery. Serum samples were taken simultaneously to tissue samples. AMX and CA were measured by high performance liquid chromatography. Exogenous and above all endogenous blood contamination were taken into account with the hematocrit as well as blood and tissue haemoglobin concentrations. Comparisons of tissue concentrations were made for each sampling time, according to values obtained for a specific tissue with both doses on one hand, and on the other to values obtained with a specific dose in different tissues. The calculated pharmacodynamic parameters, which are considered to be predictive for bacteriological and clinical efficacy, result directly from tissue concentrations of AMX. tissue inhibitory quotients (IQtissue = Tissue concentration/MIC). time above MICs for serum and tissue concentrations (T > MIC).

RESULTS

As regards AMX, whatever the dose, at 1 h 30 and at 3 hrs, tissue concentrations did not differ significantly whatever the tissue studied (from 1.1 to 2.5 micrograms/g). Conversely, at 5 and 8 hrs, they were greater than after the 1 g/125 mg regimen given twice-daily (0.06-0.7 vs. 0.7-1.8 micrograms/g). If we consider a given dose, the comparison between the various tissues showed identical concentrations in the four tissues studied at each sampling time, except in two cases with the dose of 500 mg/125 mg 3 times a day. T > MIC for serum and tissue showed higher values than those required for AMX/pneumococcus association (40-50%) with, nevertheless, greater tissue values for the 1 g/125 mg dose given twice-daily when MIC was of 1 microgram/ml (40-52% vs. 50-66%). The maximum tissue inhibitory quotients were also greater with the twice-daily 1 g/125 mg dose, when calculated with MIC 50 or 90 of S. Pneumoniae, H. influenzae, M. catarrhalis or S. pyogenes. As for CA, concentrations were equivalent for both doses at each sampling time and greater than those required in vitro during respectively 4 and 5 hours for beta-lactamases H. influenzae and M. catarrhalis.

DISCUSSION-CONCLUSION: A least an equivalence between both dose regimens was observed, with occasionally a superiority of the twice-daily 1 g/125 mg dose, in terms of pharmacokinetics, tissue penetration and pharmacodynamics for both AMX and CA. This new regimen therefore appears more appropriate for the treatment of acute maxillary sinusitis in adults.