Dosing of CMS

PK and PK/PD studies (Plachouras et al) have been validated in the critical care setting.  A higher dosing than originally thought and advised in the product information for the old drug colistin produces better clinical outcomes. A prospective observational study showed that colistin adminstered at a higher than previously recommended dose of 9 Mill IU CMS (300 mg CBA= colistin base activity) loading dose, followed by 4.5 Mill IU (150 mg CBA) intravenously every 12 hours (with adjustments for renal dysfunction) achieved a higher cure rate (82%) than any previous studies (L. Dalfino et al 2012).

1 Mill IU is equivalent to ~30 mg of CBA

Similarly, higher colistin dose independently predicted microbiological success, which may partially explain the similar association with 7-day mortality. However, higher colistin doses may also precipitate worsening renal function (G. Vicari et al 2012)

A correlation of dose and mortality shown by a stepwise decrease in mortality associated with increasing daily colistin dose highlights the importance of adequate dosages. The mortality associated with 3 Mill IU (100 mg CBA) was 38.6%, with 6 Mill IU (200 mg CBA) 27.8%, and  with 9 Mill IU (300 mg CBA) 21.7% (ME Falagas et al 2010). A small prospective open-label pharmacokinetic study noted a significant association between dose and survival, and a trend with patients weighing ≤ 60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality (ND Karnik et al, 2013).

Based on extensive PK/PD modeling and preliminary clinical results a 9 Mill IU twice-daily fractioned dosing regimen of colistin, along with a 9 Mill IU loading dose, can be used with satisfactory efficacy and relatively low nephrotoxicity in life-threatening infections, provided that an ongoing adaption of dosing regimen to renal function is ensured. A multicenter study in Europe (European FP7 funded project AIDA RESERVING OLD ANTIBIOTICS FOR THE FUTURE) and in the US  (funded by NIH) aim at confirming these preliminary data and defining the relationships between individual colistin blood levels, renal toxicity, and development of resistance.

A recent global survey revealed that colistin dosing schedules vary considerably worldwide (H Wertheim et al 2013). Approximately one-quarter of the respondents were dosing their patients in the lower range (2.5 mg/kg/day or <6 MIU). Such doses are connected to a low probability of reaching active concentrations and a high probability of emergence of resistance. Of the respondents, only 21.2% reported a loading dose and most of these were in Europe and North America. No Asian respondent reported that they used a loading dose. In Europe, the most common loading dose was 9 MIU and in South America it was 4.5 MIU (H Wertheim et al 2013).

 In vitro PK/PD simulations

PK/PD models can predict the impact of various dosing schedules on bacterial loads and facilitate the dose finding process.

Model predictions of colistin concentration (upper panels) with bacterial counts for a wild-type P.aeruginosa strain (lower panels) for three individuals with typical population values (A, D, E and F), lowest measured colistin concentration (B) and highest measured colistin concentration (C) (AF S Mohamed, 2012):
Colistin dose modeling
According to in vitro models (AF Mohamed et al 2014) a weight-based loading dose may result in lower bacterial killing in low-weight patients as the central volume of CMS has very limited impact on the time course of the active drug, colistin.
A patient’s kidney function, however, already influences the degree of bacterial killing during the loading dose.
The predictions showed that an infusion duration of 15 minautes up to 2 h can be effectively used. It was not clear so far when the maintenance dosage regimen should be initiated after the loading dose. According to the in vitro model there appeared to be some benefit in increasing the bacterial killing by introducing the maintenance dose before 24 h after the loading dose (AF Mohamed et al 2014).

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