Table 1.
Identification of resistance/reduced sensitivity of P. falciparum isolates to artesunate (AS)-mefloquine (MQ) combination therapy was analysed based on clinico-parasitological response, and in vitro sensitivity and systemic drug exposure during the acute phase of infection and relationship with pfmdr1 copy number in 17 cases with treatment failure following a three-day combination regimen
|
Systemic drug exposure |
Case No. |
Parasite slope half-life (h)a |
In vitro sensitivity (IC50: nM)b |
Pfmdr1 copy number |
MQ/DHA Systemic exposure |
Conclusion on cause(s) of treatment failure |
||
|---|---|---|---|---|---|---|---|---|
| AS | MQ | AUC0-7d/ AUC0-24h/ | Day Re | |||||
| Adequate DHA exposure alone (n=5) |
1 |
3.12 |
Reduced (3.5±0.42) |
Resistant (58.8±5.1) |
>1 |
7.55c |
610 (day 21) |
-Possible AS resistant |
| -MQ resistant + Inadequate MQ exposure | ||||||||
| -Predicted by increased in pfmdr1 copy number | ||||||||
| 2 |
3.56 |
Reduced (4.8±1.07) |
Resistant (69.5±4.7) |
>1 |
8.02c |
100 (day 28) |
-Possible AS resistant |
|
| -MQ resistant + Inadequate MQ exposure | ||||||||
| -Predicted by increased in pfmdr1 copy number | ||||||||
| 3 |
4.23 |
Sensitive (1.2±0.27) |
Sensitive (10.6±1.9) |
1 |
6.98c |
300 (day 28) |
-Inadequate MQ exposure |
|
| 4 |
3.88 |
Sensitive (0.7±0.13) |
Sensitive (6.6±0.4) |
1 |
7.99c |
600 (day 33) |
-Inadequate MQ exposure |
|
| 5 |
3.42 |
Sensitive (0.9±0.10) |
Sensitive (19.4±0.7) |
>1 |
8.07c |
720 (day 14) |
-Inadequate MQ exposure |
|
| -Predicted by increased in pfmdr1 copy number | ||||||||
| Adequate MQ exposure alone (n=5) |
6 |
3.55 |
Reduced (3.0±0.06) |
Resistant (45.3±3.1) |
>1 |
320d |
324 (day 27) |
-Possible AS resistant + Inadequate DHA exposure |
| -MQ resistant | ||||||||
| -Predicted by increased in pfmdr1 copy number | ||||||||
| 7 |
3.39 |
Reduced (3.1±0.05) |
Resistant (70.3±6.3) |
>1 |
208d |
212 (day 28) |
-Possible AS resistant + Inadequate DHA exposure |
|
| -MQ resistant | ||||||||
| -Predicted by increased in pfmdr1 copy number | ||||||||
| 8 |
3.56 |
Reduced (4.2±0.07) |
Resistant (50.0±4.2) |
>1 |
309d |
489 (day 21) |
-Possible AS resistant + Inadequate DHA exposure |
|
| -Mefloquine resistant | ||||||||
| -Predicted by increased in pfmdr1 copy number | ||||||||
| |
9 |
3.64 |
Sensitive (1.8±0.30) |
Resistant (55.3±4.4) |
>1 |
378d |
510 (day 28) |
- Inadequate DHA concentration |
| -MQ resistant | ||||||||
| -Predicted by pfmdr1 copy number | ||||||||
| 10 |
3.22 |
Sensitive (1.4) |
Resistant (35.0±2.9) |
>1 |
489d |
402 (day 21) |
- Inadequate DHA exposure |
|
| -MQ resistant | ||||||||
| -Predicted by pfmdr1 copy number | ||||||||
| Adequate DHA and MQ exposure (n=7) |
11 |
3.97 |
Reduced (2.9±0.01) |
Resistant (118.4±6.1) |
>1 |
- |
1,250 (day 17) |
-Possible AS resistant |
| -MQ resistant, | ||||||||
| -Predicted by increased in Pfmdr1 copy number | ||||||||
| 12 |
3.45 |
Reduced (3.7±0.32) |
Resistant (95.8±5.4) |
>1 |
- |
578 (day 14) |
-Possible AS resistant |
|
| -MQ resistant | ||||||||
| -Predicted by increased in Pfmdr1 copy number | ||||||||
| 13 |
3.33 |
Sensitive (1.7±0.16) |
Resistant (28.8±5.5) |
>1 |
- |
102 (day 35) |
-MQ resistant |
|
| -Predicted by pfmdr1 copy number | ||||||||
| 14 |
3.56 |
Sensitive (1.9±0.10) |
Resistant (60.8±7.1) |
>1 |
- |
620 (day 14) |
-MQ resistant |
|
| -Predicted by pfmdr1 copy number | ||||||||
| 15 |
3.65 |
Reduced (3.7±0.21) |
Resistant (25.5±0.2) |
1 |
- |
610 (day 24) |
-Possible AS resistant |
|
| -MQ resistant | ||||||||
|
16 |
3.56 |
Reduced (5.2±0.85) |
Sensitive (16.6±0.8 |
1 |
- |
107 (day 35) |
-Possible AS resistant |
|
| 17 | 3.44 | Sensitive (0.9±0.08) | Sensitive (16.5±2.4) | 1 | - | 67 (day 42) | -Other host-related factors | |
aDelayed parasite slope half-life if >2.99 h.
bMean+SD of three experiments, triplicate each.
cMQ AUC0-7dwhich was lower than the lower limit of 95% CI (8.48 mg.day/ml).
dDHA AUC0-24hwhich was lower than the lower limit of 95% CI (8.48 ng.h/ml).
eDay of recrudescence.