TABLE 4.
Pharmacological descriptors, goodness of fit, and statistical analysis of the dose-response studies of cephalosporins against MSSA and MRSAa
| Cell line and antibioticb | MSSA ATCC 25923
|
MRSA ATCC 33591
|
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| E0c (95% CId) | Emaxe (95% CI) | EC50f (95% CI) | Csg | R2 | E0 (95% CI) | Emax (95% CI) | EC50 (95% CI) | Cs | R2 | |
| THP-1 macrophages | ||||||||||
| FOX | 1.90 (1.47-2.33) ad,A | −0.59 (−1.13-−0.06) ac,A | 5.30 (1.47-19.1) | 16.4 | 0.971 | 2.50 (1.98-3.01) abc,B | −0.001 (−0.49-0.49) a,B | 3.64 (1.10 to 12.0) | >200 | 0.951 |
| CRO | 1.91 (1.30-2.53) a,A | −1.17 (−1.67-−0.67) b,A | 2.13 (0.70-6.46) | 0.26 | 0.956 | 1.82 (1.35-2.30) c,A | −0.28 (−0.79-0.23) ab,B | 5.45 (1.44 to 20.7) | 35.5 | 0.934 |
| CFX | 1.50 (1.17-1.84) ad,A | −1.00 (−1.39-−0.61) ab,A | 3.49 (1.25-9.71) | 5.50 | 0.984 | 1.99 (1.75-2.23) ac,B | (1)h B | (1) | ∼ 170 | 0.955 |
| CXM | 1.97 (1.02-2.92) ad,A | −0.80 (−1.14-−0.47) abce,A | 0.11 (0.03-0.43) | 0.26 | 0.959 | 2.14 (1.90-2.38) ac,A | (1) B | (1) | >100 | 0.968 |
| BPR | 3.49 (2.84-4.14) c,A | −1.15 (−1.34-−0.95) b,A | 0.07 (0.04-0.12) | 0.21 | 0.991 | 2.47 (1.26-3.68) b,A | −0.78 (−1.37-−0.20) c,B | 0.27 (0.05 to 1.43) | 0.89 | 0.939 |
| Keratinocytes | ||||||||||
| FOX | 3.06 (2.530-3.588) bc,A | −0.91 (−1.24-−0.59) ae,A | 0.55 (0.27-1.13) | 1.84 | 0.989 | 2.36 (2.12-2.61) abc,B | (1) B | (1) | >200 | 0.946 |
| CRO | 2.44 (1.75-3.13) bc,A | −0.30 (−1.03-0.43) ce,A | 1.83 (0.39-8.52) | 14.8 | 0.967 | 2.09 (1.86-2.33) ac,A | (2)i B | (2) | >200 | 0.947 |
| CFX | 3.09 (1.82-4.36) bc,A | 0.035 (−0.57-0.64) d,A | 0.27 (0.03-2.19) | ∼ 200 | 0.928 | 2.42 (2.33-2.50) b,A | (1) B | (1) | ∼ 200 | 0.993 |
| CXM | 3.23 (1.52-4.93) bc,A | −0.42 (−1.37-0.52) e,A | 0.27 (0.02-2.96) | 0.26 | 0.943 | 2.75 (2.51-2.99) b,A | (1) B | (1) | ∼ 200 | 0.773 |
| BPR | 2.48 (1.82-3.14) be,A | −0.94 (−1.25-−0.63) ab,A | 0.35 (0.13-0.95) | 0.91 | 0.975 | 2.04 (1.44-2.65) ac,A | −1.14 (−1.60-−0.69) c,A | 1.08 (0.42 to 2.77) | 1.95 | 0.964 |
Data are from Fig. 4 for 24 h of incubation. See footnote b of Table 2 for the equation used for modeling. Statistical analysis was as follows: for analysis of the data in each column (one-way analysis of variance with the Tukey test for multiple comparisons), data with different lowercase letters are significantly different from each other (P < 0.01); for analysis of the data in each row (unpaired, two-tailed t test between corresponding parameters for MSSA and MRSA), data with different uppercase letters are significantly different from each other (P < 0.01). No statistical analysis was performed for the parameters EC50 and Cs, as these are related to weight concentrations that cannot be directly compared between antibiotics (see Discussion for the correlation with clinically achievable concentrations in serum).
FOX, cefoxitine; CRO, ceftriaxone; CFX, cephalexin; CXM, cefuroxime; BPR, ceftobiprole. See Table 3 for the MICs.
CFU increase (in log10 units) at 24 h from the corresponding original inoculum, as extrapolated for an infinitely low concentration of cephalosporin.
CI, confidence interval.
CFU decrease (in log10 units) at 24 h from the corresponding original inoculum, as extrapolated for the antibiotic concentration at an infinitely high concentration.
Concentration (mg/liter; total drug) causing a reduction of the inoculum halfway between E0 and Emax, as obtained from the Hill equation (by using a slope factor of 1).
Concentration (mg/liter; total drug) resulting in no apparent bacterial growth (the number of CFU was identical to that of the original inoculum), as determined by graphical interpolation.
(1), no meaningful calculation was possible since data points were obtained for the upper part of the sigmoidal function only.
(2), since there was only a minimal decrease in CFU within the limits of the experiment, the Emax, EC50, and Cs descriptors, as calculated from the Hill equation, become meaningless in the context of antimicrobial activity.