Amoxicillin 500mg for tooth infection

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

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

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

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

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

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 bone and 15 mg/kg in cortical bone at 0.5 to 1 h after the end of a 20-min infusion of 200 mg clavulanic acid. The bone amoxicillin-clavulanic acid concentrations from Grimer et al. (54) were approximately 2 to 3 times lower than those from our study, whereas Adam et al. (1) reported clavulanic acid concentrations about 10 times higher than those obtained in our study (Fig.

This pronounced difference (20- to 30-fold for averages) for clavulanic acid calls for standardized methods of sample preparation, drug analysis, and PK evaluation. The concentrations of amoxicillin and clavulanic acid showed a high correlation in cortical bone ( r = 0.90; observed data) and cancellous bone ( r = 0.95; Fig.

This suggests that both drugs were stable and that sample preparation and drug analysis were precise and reproducible. The concentrations in cortical and cancellous bone were correlated for both drugs ( r = 0.75).

(54) and indicates that the equilibration rates between cortical bone and serum and between cancellous bone and serum were probably similar. Consequently, the equilibration half-lives for both types of bone were assumed to be the same in the final model.

Short equilibration half-lives between bone and serum were estimated for both drugs (Table 1; Fig.

This suggests that concentrations above the PK-PD breakpoints were reached within less than 30 min after the end of a 30-min infusion. As serum and bone concentrations are decreasing after the end of a short-term infusion, these fast equilibration half-lives suggest from a PK point of view that the surgery should start within the first 30 min after the end of a 30-min infusion.

As the breakpoints reported here are based on PK-PD targets for the treatment of infections and as these targets were derived on the basis of the plasma or serum concentrations, PK-PD targets for surgical prophylaxis need to be established and our simulation results

should

The inorganic matrix is formed by hydroxyapatite crystals (calcium phosphate) deposited within the organic matrix (14).

Neither antibiotics nor bacteria are expected to distribute homogeneously in bone. No techniques for the separation of bone samples into

extracellular

In addition, only the unbound fraction of drug is considered to be microbiologically active, and the extent of binding in bone is not known.

Binding experiments suggest that beta-lactams do not bind (or bind only to a minor extent) to bone powder or hydroxyapatite crystals (1, 55). Beta-lactams likely distribute mainly within the vascular and extracellular fluid spaces in bone (17, 26, 34, 41).

They pass the capillary walls of blood vessels located in the Haversian and Volkmann canals in bone, diffuse into the interstitial fluid space, and likely distribute in the lacunocanalicular system (Table 4, scenarios B and C) (15, 34).

Furthermore, bacteria are not expected to distribute into the inorganic matrix or collagen fibrils but mainly distribute in the interstitial and extracellular fluid spaces (scenarios B and C). Therefore, scenarios B and C in Table 4 seem to be the most likely, and the breakpoints reported in Table 2 appear to be conservative (i.e., low) estimates, if the bacteria do not distribute intracellularly and do not reside in sequestered areas.

As it is not known how drug and bacteria distribute within bone, Table 4 lists potential breakpoints for a dose of 2,000/200 mg amoxicillin-clavulanic acid q6h for various distribution scenarios.

The most realistic potential scenario might be scenario B or a scenario in which amoxicillin distributes in interstitial fluid plus part of the total bone fluid outside the interstitial space (a mix of scenarios B and C). As total bone fluid likely includes fluid in small pores of the hydroxyapatite crystals from which interstitial fluid markers (e.g., sucrose) are excluded (45), distribution throughout total bone fluid (scenario C) seems less likely. aureus to enter and survive in osteoblasts (31, 35) was suggested to be a possible reason for relapses of osteomyelitis (Table 4, scenario D).

As beta-lactams are not expected to penetrate cells well, an intracellular

bone

In any case, when bacteria reside in a part of the bone which is inaccessible to amoxicillin, treatment failure or relapse seems likely.

The volumes described in Table 4 refer to those in healthy bone. In patients with acute osteomyelitis, it has been suggested that the blood supply to the bone is increased, capillary permeability is higher, and potentially greater antibiotic concentrations reach bone (34).

In osteomyelitic canine bone, the volume of distribution of cefazolin was increased to 0.572 ml per ml bone, whereas in uninfected bone, it was 0.0662 ml per ml bone (17).

The results of few PK studies with patients with osteomyelitis are available.