Amoxicillin for boils

WinNonlin Professional (version 4.0.1; Pharsight Corp., Mountain View, CA) was used for statistical analysis. (vi) Estimation by three-stage hierarchical population approach. To independently confirm the results obtained with NONMEM, PK parameters were estimated by the three-stage hierarchical population approach in S-ADAPT (version 1.55) (7).

Priors for population means and BSV of the disposition parameters were obtained from previously published studies (4, 5, 29, 30, 49, 51). Informative priors were used for the population mean and variability of CL, V c entral , V peripheral , and CLic.

Physiologically plausible but uninformative priors were used for the population mean and variability of F cortical and F cancellous and the population mean of CLic bone on the basis of data reported in the literature (36). The residual unidentified variability was described by a proportional error model. As only one serum sample and one bone sample were available from each patient, informative priors were used for the residual unidentified variability on the basis of the bioanalytical assay data.

A systematic sensitivity analysis was performed to evaluate the effect of the choice of priors on the extent and the rate of bone penetration. The extent of drug exposure in bone was determined for amoxicillin and clavulanic acid by simulating the AUCs in serum and cortical and cancellous bone. On the basis of the final estimates from NONMEM, we simulated 10,000 virtual subjects at steady state and calculated the individual ratios of AUC for bone/AUC for serum as well as their BSV.

A time that the non-protein-bound drug concentration remained above the MIC ( fT > MIC ) of ?50% of the dosing interval was shown to be the PK-PD target for near-maximal bactericidal activity, and an fT > MIC of ?30% was shown to be the PK-PD target for the bacteriostasis of penicillins on the basis of the concentrations in plasma (16, 19).

We used fT > MIC for at least 30% or 50% of the dosing interval as the PK-PD target for serum concentrations.

As the PK-PD target for the successful treatment or prophylaxis of bone infections is unknown, we considered a wide range of PK-PD target values for amoxicillin in bone and reported the PK-PD breakpoints for fT > MIC targets of at least 30%, 50%, 70%, or 100% for bone concentrations. We studied a range of MICs from 0.25 to 64 mg/liter and used a protein binding of 18% for amoxicillin in serum (27). In the absence of data on the protein binding in bone, we assumed a protein binding of 18% for amoxicillin in bone.

Additionally, we provided the expected PK-PD breakpoints for various potential scenarios of the distribution of drug and bacteria in bone. A 30-min infusion of 2,000 mg amoxicillin every 4 h (q4h), q6h, or q8h was studied at steady state.

We simulated 10,000 virtual subjects in the absence of residual error.

The probabilities of target attainment (PTAs) were derived by calculating the fraction of subjects who attained zoloft and amoxicillin the PK-PD target at each MIC. The PK-PD breakpoint was defined as the highest MIC for which the PTA was at least 90%.

To determine the clinical relevance of the differences in the PTAs between the dosage regimens, the PTA expectation value was calculated on the basis of several

published

The PTA expectation value (also called the cumulative fraction of response [46]) was calculated by multiplying the PTA at each MIC with the frequency of how often this MIC occurs in the selected MIC distribution.

The individual products at each MIC were summed, and the sum yielded the PTA expectation value for the selected MIC distribution. The PTA expectation value is the PTA in a specific patient population for the treatment of infections caused by bacteria from a specific MIC distribution (ideally, the MIC distribution of each local hospital). Figure 1 shows the concentrations of amoxicillin and clavulanic acid observed in serum and cortical and cancellous bone. For both drugs, the concentrations were lower in cortical and cancellous bone than in serum. The concentrations in the femoral neck samples were similar to those in the femoral head samples. Figure 2 shows the high correlation of the ratio of the concentration in bone to the concentration in serum within the individual patients.

Concentrations in serum and bone of subjects undergoing hip replacement surgery after administration of a single intravenous dose of 2000 mg amoxicillin and 200 mg clavulanic acid as a short-term infusion.

Bone concentration-to-serum concentration ratios of amoxicillin versus clavulanic acid in cortical bone (A) and cancellous bone (B). The population PK parameter estimates from NONMEM and the three-stage hierarchical approach in S-ADAPT were comparable (Table 1).

The average estimated drug AUCs for bone relative to that for serum ( F c ortical and F c ancellous ) ranged from 19 to 21% for amoxicillin and from 12 to 19% for clavulanic acid.

The half-life of equilibration between bone and serum was rapid for both drugs (Table 1).

Averages and between-subject coefficients of variation (percent) calculated from individual PK parameter estimates a.

Figure 3 shows the simulated extent of amoxicillin and clavulanic acid penetration into cortical and cancellous bone and the BSV of penetration, calculated from the ratios of AUC cortical /AUC serum and AUC cancellous /AUC serum at steady state for 10,000 virtual subjects on the basis of the results obtained with amoxicillin clavulanate tablets NONMEM.

The median AUC ratios for amoxicillin were 20% (10th to 90th percentile, 16% to 25%) for cortical bone and 18% (10th to 90th percentile, 11% to 29%) for cancellous bone. The median AUC ratios for clavulanic acid were 15% (10th to 90th percentile, 11% to 21%) for cortical bone and 10% (10th to 90th percentile, 5.1% to 21%) for cancellous bone. Therefore, for both drugs the AUC ratio for cancellous bone was more variable (see also the variability for F c ortical and F c ancellous in Table 1) and (slightly) lower than that for cortical bone.

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

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.