PK/PD of colistin

In vitro

With ƒCmax values equal to or above the MIC, rapid killing was observed following the first dose; substantial regrowth occurred by 24 h with most regimens. The overall killing effect was best correlated with ƒAUC/MIC (PJ Bergen et al 2010):

Colistin PKPD in vitro

The magnitudes of the ƒAUC/MIC index required for 1- and 2-log10 reduction of 3 strains of P. aeruginosa (PJ Bergen et al 2010):

1-log kill 4-30
2-log kill 5-42

In vivo

The fAUC/MIC is the PK/PD index that correlats best with efficacy in both Acinetobacter and Pseudomonas and thigh and lung infection models. This result is consistent with the potent concentration-dependent killing observed in vitro. Amplification of colistin-resistant subpopulations was revealed for all strains in both models after 24 h colistin treatment (RV Dudhani et al 2010 and 2010).

Required fAUC/MIC targets that correlate with bacterial killing (RV Dudhani et al 2010 and 2010):
thigh infection model lung infection model
stasis 14-17 (PA), 2-8 (AB) 4-6 (PA), 2-7 (AB)
1-log 15-23 (PA), 7-14 (AB) 12-17 (PA), 8-42 (AB)
2-log kill 28-36 (PA), 16-43 (AB) 37-46 (PA), 23- >95 (AB)
3-log kill 53-77 (PA), – 05-141 (PA), –

PA: P. aeruginsa, AB: A. baumanii

Though animal experiments are usually welll comparable to results in humans colistin presents a special problem as knowledge on the unbound plasma concentrations of colistin in humans is sparse. In mouse plasma, the free fraction of colistin is highly concentration dependent. Additionally, colistin binds to the acute-phase plasma protein AAG.  (Dudhani et al ICAAC,A1-576, 2009).

Plasma binding in mice (RV Dudhani et al 2010):

Colistin proteinbinding

Therefore, it is important to carefully consider protein binding when comparing the required fAUC/MIC values observed in the murine models with the fAUC/MIC values for colistin achieved with currently used CMS dosage regimens in patients.

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