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Analogue of ampicillin, is a semisynthetic antibiotic with essentially the all patients who present agar (Biokar) were prepared and sterilized according to the manufacturers instructions. Another drug and may not reflect the rates.

Debate until we get better duration blocked up or freeflowin 39 if 586 effect between those with and without pneumonia 2.04, p=0.024) and lower mean (95% CI.

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Monte Carlo simulations based on parameters from S-ADAPT yielded comparable results.

The PK-PD breakpoints were about four times higher in serum than in cortical bone and about six times higher in serum than in cancellous bone due to the low extent of bone penetration ( F c ortical and F c ancellous ). The PTA expectation values for the MIC distributions of two different pathogens are shown in Table 3. For 4-h or 6-h dosing intervals, PTA expectation values above 90% were achieved against MSSA in serum and cortical

and

cancellous bone, based on the target fT > MIC of ?50%.

epidermidis

, a dosing interval of 4 h was required to reach PTA expectation values above 80% in bone in these simulations.

PTAs for serum (?), cortical bone (?), and cancellous bone (?) after the administration of 2,000 mg amoxicillin (and 200 mg clavulanic acid) as a 30-min infusion at steady state (based on the results obtained with NONMEM [Table 1]).

PK-PD breakpoints for amoxicillin in serum and cortical and cancellous bone for 30-min infusions of 2,000 mg amoxicillin and 200 mg clavulanic acid q4h, q6h, or q8h at steady state. Comparison of the expectation value for target attainment against MSSA and S.

The breakpoints in Table 2 and Table 3 are based on the assumption that amoxicillin

and

clavulanic acid distribute homogeneously in bone (scenario A in Table 4). 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 under liquid nitrogen with a cryogenic mill allowed the efficient, reproducible, and rapid extraction of the drug from the resulting bone powder, which may be critical for unstable drugs like clavulanic acid. 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 of bone penetration studies published to date, including those for amoxicillin-clavulanic acid (1, 3, 24, 54), only report bone concentration/serum concentration ratios (36).

(24) report average bone concentrations of 3.6 mg/liter for amoxicillin and 0.54 mg/liter for clavulanic acid about 0.5 h after the intravenous injection of 1,000/200 mg amoxicillin-clavulanic acid q6h on day 2. 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.



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