TABLE 4.

Estimated breakpoints for various scenarios of distribution of amoxicillin-clavulanic acid and bacteria^f

Scenario	Presence of drug or drug/bacteria inf:							PK-PD breakpoint for cortical bonea
	Vascular space	Interstitial fluid	Total bone fluidc	Bone cells	Organic matrix	Hydroxyapatite	Sequestered area
Ae	Yes	Yes/yes	Yes/yes	Yes/yes	Yes/yes	Yes/yes	No/no	Breakpoint, 1.5 μg/g (as reported in Table 2); binding of β-lactams to hydroxyapatite disagrees with binding studies in literature (1, 55)
B	Yes	Yes/yes	No/no	No/no	No/no	No/no	No/no	Breakpoint, 28 μg/g,d as concentrations in bone homogenate are lower than those in interstitial fluid and the vascular space
C	Yes	Yes/yes	Yes/yes	No/no	No/no	No/no	No/no	Breakpoint, 7.5 μg/g, as concentrations in total body fluid are higher than those in bone homogenated
D	Yes	Yes/yes	Yes/yes	No/yes	No/no	No/no	No/no	Breakpoint, 7.5 μg/gd for acute infection but risk of relapse,b unless treatment is combined with an antibiotic with high intracellular penetration
E	Yes	Yes/yes	Yes/yes	No/no	Yes/yes	No/no	No/no	Breakpoint, 4.3 μg/gd
F	Yes	Yes/yes	Yes/yes	No/no	No/no	No/no	No/yes	Antibiotic therapy alone not effective, surgery needed
G	Yes	Yes/yes	Yes/yes	Yes/yes	Yes/yes	No/no	No/no	Breakpoint, 4.3 μg/gd

^aThe target is an fT_>MIC of ≥50% (on the basis of a level of protein binding in bone of 18% and treatment with 2,000 mg amoxicillin-200 mg clavulanic acid q6h). Further binding studies, e.g., for binding of β-lactams to collagen, are needed.

^bRisk for relapse due to the survival of bacteria, e.g., S. aureus as small-colony variants (2, 31, 35, 38) in osteoblasts.

^cWhereas the total fluid space in bone has been reported to be 0.245 ml/ml (45) and 0.287 ml/ml (33), some is bound in pores of the hydroxyapatite crystals (45).

^dThe breakpoint is higher than that reported in Table 2, since the total concentrations in bone homogenate are lower than the antibiotic concentrations in the part of the bone into which the antibiotic is distributed in this scenario.

^eThis scenario was used for the simulations reported in Table 2.

^fThe volumes of the vascular space, interstitial fluid, total bone fluid, bone cells, organic matrix, and hydroxyapatite crystals are assumed to be 1.3% (17, 45), 4.0% (17, 41, 45), 20% (33, 44, 45), 1.5% (14), 35% (14, 25, 48), and 65% (14, 25, 32, 48, 54) of the total bone volume. The density of bone is assumed to be 1.0 g/ml. Reported values are between 1.3 and 1.9 g/ml (10, 11, 18, 42, 43). For a bone density of 1.5 g/ml, breakpoints would be 42, 11.3, and 2.5 for scenarios B, C, and A and 6.5 μg/ml for scenarios E and G. The binding of amoxicillin-clavulanic acid to hydroxyapatite crystals is unlikely on the basis of studies described in the literature (1, 55); therefore, this scenario was included only in scenario A.