TABLE 3.
In vitro interaction between miconazole and terbinafine against S. prolificans
| Method and strain | Result according to theory
|
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|---|---|---|---|---|---|---|---|
| LA
|
BIa
|
||||||
| Nonparametric [median (range)]
|
Parametricb (α ± 95% CI) | Nonparametric
|
Semiparametricc
|
||||
| FICi-2 | FICi-1 | ΣSYN (n) | ΣANT (n) | ΣSYN (n) | ΣANT (n) | ||
| SP48 | |||||||
| 7898 | 0.13 (0.02-0.28) | 0.04 (0.01-0.05) | 302.1 ± 32.6 | 173 (15) | 0 (0) | 242 (17) | 0 (0) |
| 7901 | 0.11 (0.02-0.14) | 0.05 (0.02-0.06) | 3,072.0 ± 441.7 | 243 (15) | 0 (0) | 396 (22) | 0 (0) |
| 7902 | 0.17 (0.14-0.28) | 0.08 (0.01-0.28) | 111.1 ± 17.5 | 163 (20) | 0 (0) | 206 (22) | −4 (1) |
| 7906 | 0.17 (0.09-0.28) | 0.04 (0.01-0.13) | 565.0 ± 110.7 | 160 (11) | 0 (0) | 284 (18) | 0 (0) |
| 7918 | 0.06 (0.03-0.15) | 0.03 (0.02-0.08) | 9,462.1 ± 1,194.5 | 460 (33) | 0 (0) | 615 (40) | 0 (0) |
| Median | 0.13 | 0.04 | 565.0 | 178 | 0 | 284 | 0 |
| SP72 | |||||||
| 7898 | 0.06 (0.02-0.09) | 0.05 (0.03-0.08) | 552.1 ± 77.6 | 57 (5) | 0 (0) | 135 (13) | 0 (0) |
| 7901 | 0.05 (0.02-0.08) | 0.05 (0.03-0.06) | 5,516.6 ± 966.9 | 146 (10) | 0 (0) | 365 (21) | 0 (0) |
| 7902 | 0.06 (0.03-0.28) | 0.06 (0.03-0.14) | 1,374.9 ± 242.9 | 10 (2) | 0 (0) | 78 (8) | −6 (1) |
| 7906 | 0.09 (0.03-0.13) | 0.05 (0.02-0.07) | 434.5 ± 124.9 | 67 (4) | 0 (0) | 138 (11) | 0 (0) |
| 7918 | 0.06 (0.03-0.16) | 0.05 (0.03-0.27) | 5,464.7 ± 1,082.9 | 392 (27) | 0 (0) | 505 (33) | 0 (0) |
| Median | 0.06 | 0.05 | 1,374.9 | 67 | 0 | 138 | 0 |
| COL72 | |||||||
| 7898 | 0.06 (0.03-0.09) | 0.04 (0.02-0.06) | 817.5 ± 297.5 | 7 (1) | 0 (0) | 14 (1) | 0 (0) |
| 7901 | 0.19 (0.06-0.28) | 0.03 (0.02-0.04) | 180.1 ± 50.3 | 17 (3) | 0 (0) | 92 (11) | −25 (2) |
| 7902 | 0.05 (0.02-0.08) | 0.05 (0.02-0.08) | 128.2 ± 28.4 | 8 (1) | 0 (0) | 0 (0) | 0 (0) |
| 7906 | 0.03 | 0.05 (0.03-0.16) | 55.5 ± 23.8 | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| 7918 | 0.08 (0.03-0.19) | 0.04 (0.02-0.09) | 633.2 ± 162.2 | 57 (3) | 0 (0) | 0 (0) | 0 (0) |
| Median | 0.06 | 0.04 | 180.1 | 8 | 0 | 0 | 0 |
| MCOL48 | |||||||
| 7898 | 0.27 (0.27-0.28) | 0.05 (0.04-0.13) | 9.8 ± 2.2 | 556 (49) | 0 (0) | 567 (43) | −6 (1) |
| 7901 | 0.16 (0.09-0.31) | 0.05 (0.04-0.05) | 44.3 ± 11.4 | 955 (55) | 0 (0) | 941 (49) | 0 (0) |
| 7902 | 0.27 (0.27-0.50) | 0.04 (0.03-0.05) | 34.1 ± 8.2 | 354 (41) | 0 (0) | 392 (35) | 0 (0) |
| 7906 | 0.38 (0.31-0.51) | 0.04 (0.04-0.05) | 18.5 ± 5.0 | 539 (35) | 0 (0) | 526 (37) | 0 (0) |
| 7918 | 0.27 (0.13-0.28) | 0.31 (0.05-0.31) | 3,807.5 ± 1,479.4 | 259 (32) | 0 (0) | 372 (33) | 0 (0) |
| Median | 0.27 | 0.05 | 34.1 | 539 | 0 | 526 | 0 |
| MCOL72 | |||||||
| 7898 | 0.03 (0.03-0.04) | 0.06 (0.06-0.13) | 9,505.2 ± 2,824.2 | 487 (30) | 0 (0) | 518 (28) | −9 (1) |
| 7901 | 0.03 (0.02-0.04) | 0.09 (0.06-0.09) | 6,768.1 ± 2,078.9 | 1,051 (37) | 0 (0) | 1,006 (36) | 0 (1) |
| 7902 | 0.03 (0.02-0.03) | 0.06 (0.06-0.13) | 7,740.3 ± 1,887.3 | 1,751 (61) | 0 (0) | 1,295 (46) | 0 (0) |
| 7906 | 0.03 (0.02-0.04) | 0.13 (0.06-0.13) | 7,872.5 ± 3,421.3 | 606 (39) | 0 (0) | 517 (38) | 0 (0) |
| 7918 | 0.06 (0.03-0.09) | 0.08 (0.06-0.08) | 534.6 ± 141.8 | 595 (45) | 0 (0) | 538 (34) | 0 (0) |
| Median | 0.03 | 0.08 | 7,740.3 | 606 | 0 | 538 | 0 |
The median absolute coefficient of variation of the differences between observed and predicted percent growth at each drug combination among the replicates of all strains ranged from 60 to 124% (median, 95%) for the SP method, 142 to 227% (median, 173%) for the COL method, and 24 to 49% (median, 40%) for the mCOL method with the semiparametric approach and from 69 to 191% (median, 123%) for the SP method, 118 to 343% (median, 236%) for the COL method, and 23 to 56% (median, 36%) for the mCOL method with the nonparametric approach.
The R2 from the nonlinear regression analysis for the fully parametric Greco model ranged from 0.76 to 0.93 (median, 0.88). The IC50s ranged from 0.23 × 103 to −7.2 × 103 mg/liter (geometric mean, 22.1 mg/liter) of terbinafine and from 0.53 to 32.9 mg/liter (geometric mean, 4.2 mg/liter) of miconazole. Relatively high IC50s of terbinafine were obtained after 72 h of incubation. The slope (m) ranged from −0.1 to −0.53 (median, −0.16) for terbinafine and from −0.27 to −4.4 (median, −0.44) for miconazole.
The R2 from the nonlinear regression analysis for the Emax model of the semiparametric approach ranged from 0.73 to 0.99 (median, 0.88). The IC50s ranged from 0.57 to 1,028 mg/liter (geometric mean, 11.4 mg/liter) of terbinafine and from 0.19 to 43.74 mg/liter (geometric mean, 4.43 mg/liter) of miconazole. The slope (m) ranged from −0.10 to −0.86 (median, −0.35) for terbinafine and from −0.24 to −1.63 (median, −0.45) for miconazole.