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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.

Daily, with clarithromycin, 500 mg orally twice daily for 7–14 days aminopenicillin Therapeutic classification bone penetration studies published to date, including those for.

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30.04.2016

Amoxicillin and bronchitis

Amoxicillin and bronchitis, amoxicillin 50, azithromycin and amoxicillin

Simulated ratios for the AUC between bone and serum for amoxicillin (A) and clavulanic acid (B) during one dosing

interval

at steady state (based on the results obtained with NONMEM [Table 1]).

The visual predictive checks showed a highly sufficient predictive performance of the final NONMEM model for both drugs (Fig. This qualified our model for use in the Monte Carlo simulation.

Visual predictive check after treatment with 2,000 mg amoxicillin and 200 mg clavulanic acid.

The plots show the observed data, the 90% prediction (P) intervals (5th to 95th percentiles), and the interquartile ranges (25th to 75th percentiles).

Ideally, 50% of the raw data points should fall inside the interquartile range at each time point and 90% of the raw data should fall inside the 90% prediction interval.

Visual predictive checks are based on the results obtained with NONMEM. The PTA-versus-MIC plots based on the estimates from NONMEM are shown in Fig.

5; and the respective PK-PD breakpoints for serum, cortical bone, and cancellous bone are listed in Table 2.

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.

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.



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04.05.2016 - Pantera
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