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If amoxicillin and clavulanic acid distribute only into certain parts of the bone (Table 4), the total concentration in bone homogenate will be higher than the total concentration at these sites in the bone. Therefore, breakpoints for the other scenarios in Table 4 are higher than those for scenario A, assuming that the binding of antibiotics in bone is similar to the binding of antibiotics in serum and that bacteria distribute to the same sites as amoxicillin-clavulanic acid. If bacteria distribute intracellularly or reside in sequestered areas into which antibiotics do not penetrate or penetrate only poorly, the risk for relapse after the termination of antibiotic therapy (scenario D) or the failure of therapy (scenario F) seems high. Estimated breakpoints for various scenarios of distribution of amoxicillin-clavulanic acid and bacteria f.

The amoxicillin and clavulanic acid concentrations in bone that have been published previously vary widely (1, 3, 24, 50, 54).

Average bone concentration/serum concentration ratios differ up to 3-fold for amoxicillin and 25-fold for clavulanic acid between various studies.

Possible reasons might be that the determination of concentrations in bone is methodologically more complex than the determination of concentrations in serum and the use of microbiological assays in studies performed in the 1980s. The assay developed and validated in the present study relies on a highly standardized LC-MS/MS method. The pulverization of bone

tissue

The degree of extraction was tested over time to ensure that it was reproducible.

Amoxicillin-clavulanic acid was stable during the extraction. Calibration standards for bone concentrations were prepared in blank bone tissue and not in buffer or serum, as is often reported by other authors. We recently reviewed the limitations of bone sample preparation and analysis (36). The vast

majority

The concentrations in bone were at least 10-fold lower than those in serum (24).

(54) administered 2,000/200 mg amoxicillin-clavulanic acid as an intravenous infusion. They related the concentrations determined to the organic bone mass, which accounts for about 30 to 40% of the total bone mass.

The slightly higher concentrations in cortical bone than in cancellous bone that they found are in agreement with the findings of our study.

When calculated in relation to total bone, the average amoxicillin concentrations were about 8 mg/kg of bone and the average clavulanic acid concentrations were 0.7 to 0.8 mg/kg at up to 2 h after administration of the dose, and the average amoxicillin concentrations were about 2.5 mg/kg of bone and the average clavulanic acid concentrations were about 0.3 mg/kg 2 to 4 h after administration of the dose. This corresponds to average ratios for total bone concentration/serum concentration of approximately 8 to 14% and 4 to 8% for amoxicillin and clavulanic acid during the first 2 h and 15 to 18% and 6 to 7% for amoxicillin and clavulanic acid at 2 to 4 h (54).

(3) studied amoxicillin bone penetration in 26 patients on average 2 h (range, 1 to 2.5 h) after the administration of a single oral dose of 500 mg.

The average bone concentration-to-serum concentration ratios were 16% (range, 3.7% to 28%) for mandibular bone and 26% (range, 5.6% to 55%) for maxillary bone, which were similar to the findings of our study. (50) reported an average bone concentration/serum concentration ratio of 8.2% in the jaw bones of nine patients who were receiving 500 mg amoxicillin every 8 h for 2 days and to whom the last dose was given at about 2 h before surgery.

(1) found 9.8 mg/kg clavulanic-acid in

cancellous