Colistin pharmacokinetics: the fog is lifting Couet, W.; Grégoire, N.; Marchand, S. ...
Clinical microbiology and infection,
January 2012, 2012-Jan, 2012-01-00, 20120101, 2012-01, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Colistin is a re-emerging old antibiotic that is used to treat multidrug-resistant infections in critically ill patients. It corresponds to a mixture of at least 30 different compounds administered ...as inactive derivatives. Therefore, colistin pharmacokinetics are quite difficult to investigate and complex to predict. However specific chromatographic methods have been made available in recent years, leading to a series of modern pharmacokinetic studies after intravenous administration of the prodrug to critical-care patients; these have been conducted by a few groups and have only been recently published. The objective of this article was to conduct a critical review of these very informative modern pharmacokinetic studies and to provide prospective thoughts.
Colistin pharmacokinetics (PK) was investigated in young healthy volunteers after a 1‐h infusion of 80 mg (1 million international units (MIU)) of the prodrug colistin methanesulfonate (CMS). ...Concentration levels of CMS and colistin were determined in plasma and urine using a new chromatographic assay and analyzed simultaneously with a population approach after correcting the urine‐related data for postexcretion hydrolysis of CMS into colistin. CMS and colistin have low volumes of distribution (14.0 and 12.4 liters, respectively), consistent with distribution being restricted to extracellular fluid. CMS is mainly excreted unchanged in urine (70% on average), with a typical renal clearance estimated at 103 ml/min—close to the glomerular filtration rate. Colistin elimination is essentially extrarenal, given that its renal clearance is 1.9 ml/min, consistent with extensive reabsorption. Colistin elimination is not limited by the formation rate because its half‐life (3 h) is longer than that of CMS. The values of these pharmacokinetic parameters will serve as reference points for future comparisons with patients' data.
Clinical Pharmacology & Therapeutics (2011) 89 6, 875–879. doi:10.1038/clpt.2011.48
To expand on previous reports of synergy between polymyxin B (PMB) and minocycline (MIN) against Acinetobacter baumannii; and to gain insight into the qualitative and quantitative determinants of ...their synergy.
A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed on the basis of data from in vitro time-kill experiments with determination of resistant bacterial count to describe the effects of PMB and MIN alone and in combination. The model was enriched by complementary experiments providing information on the characteristics of the resistant subpopulation.
The model successfully described the data and made possible quantification of the strength of interaction between the two drugs and formulation of hypotheses about the mechanisms of the observed interaction. The effect of the combination was driven by MIN, with PMB acting as an helper drug; simulations at clinically achievable concentrations showed that 1.5 mg/L MIN +0.2 mg/L PMB is expected to produce sustained killing over 30 hours, while 0.3 mg/L MIN +1 mg/L PMB is met by bacterial regrowth. Interaction equations showed that maximal synergy is reached for PMB concentrations ≥0.1 mg/L and MIN concentrations ≥1 mg/L.
Semi-mechanistic PK/PD modelling was used to investigate the quantitative determinants of synergy between PMB and MIN on a PMB-resistant A. baumannii strain. The developed model, improving on usual study techniques, showed asymmetry in the drug interaction, as PMB acted mostly as a helper to MIN, and provided simulations as a tool for future studies.
Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as ...colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.
Pulmonary delivery of fluoroquinolones (FQs) is an interesting approach to treat lung infections as it may lead to high local concentrations while minimizing systemic exposure. However, FQs have a ...rapid diffusion through the lung epithelium giving the pulmonary route no advantage compared to the oral route. Interactions between FQs and metal cations form complexes which limit the diffusion through the epithelial barrier and would reduce the absorption of FQs and maintain high concentrations in the lung. The effects of this complexation depend on the FQ and the metal cations and optimum partners should be selected through in vitro experiments prior to aerosol drug formulation. In this study, CIP was chosen as a representative FQ and 5 cations (Ca2+, Mg2+, Zn2+, Al3+, Cu2+) were selected to study the complexation and its effects on permeability, antimicrobial efficacy and cell toxicity. The results showed that the apparent association constants between CIP and cations ranked with the descending order: Cu2+>Al3+>Zn2+>Mg2+>Ca2+. When a target of 80% complexation was reached with the adequate concentrations of cations, the CIP permeability through the Calu-3 lung epithelial cells was decreased of 50%. Toxicity of the CIP on the Calu-3 cells, with an EC50 evaluated at 7μM, was not significantly affected by the presence of the cations. The minimum inhibitory concentration of CIP for Pseudomonas aeruginosa was not affected or slightly increased in the range of cation concentrations tested, except for Mg2+. In conclusion, permeability was the main parameter that was affected by the metal cation complexation while cell toxicity and antimicrobial activity were not or slightly modified. Cu2+, with the highest apparent constant of association and with no effect on cell toxicity and antimicrobial activity of the CIP, appeared as a promising cation for the development of a controlled-permeability formulation of CIP for lung treatment.
Display omitted
Experiments were conducted with polymyxin B and two
isogenic strains (the wild type, KP_WT, and its transconjugant carrying the mobile colistin resistance gene, KP_MCR-1) to demonstrate that ...conducting two consecutive time-kill experiments (sequential TK) represents a simple approach to discriminate between pharmacokinetics/pharmacodynamics models with two heterogeneous subpopulations or adaptive resistance.
Colistin often remains the last resort antibiotic active against carbapenemase-producing Enterobacteriaceae. However, while in vitro inoculum effect has been reported, therapeutic relevance of this ...phenomenon remains questioned.
Ten E. coli strains were used that included the wild-type CFT073 and its transconjugant CFT073-MCR-1 and eight susceptible clinical isolates. Mice with peritonitis were treated for 24 h with colistin sulfate. Bacterial loads were determined in peritoneal fluid (PF) and spleen and colistin-resistant mutants were detected.
MICs of colistin against the eight susceptible clinical strains and CFT073 ranged from 0.125 to 0.5 mg/L with an inoculum of 105 CFU/mL and from 2 to 4 mg/L with a 107 CFU/mL inoculum; 5/9 strains with an MIC of 4 mg/L were considered resistant according to EUCAST breakpoint (resistance, > 2 mg/L). When the bacterial load of wild-type CFT073 inoculated in mice increased from 107 to 108 CFU: i) mean log10 CFU reduction generated by colistin in PF and spleen decreased from 5.8/mL and 3.1/g, respectively, (p < 0.01) to 0.9/mL and 0.8/g, respectively (NS); ii) mice survival rate decreased from 15/15 (100%) to 6/15 (40%) (p = 0.017); and iii) proportion of mice with selection of colistin-resistant mutants increased from 4/15 to 15/15 (p < 0.01). These results were comparable to those obtained when peritonitis was produced with a 107 CFU bacterial load of E. coli CFT073 expressing mcr-1, for which the mean log10 CFU reductions were 3.5/mL and 0.6/g in PF and spleen, respectively (NS), and survival rate was 8/15 (53%) (p < 0.01 versus survival of mice infected with wild-type CFT073).
Phenotypic colistin resistance in wild-type E. coli due to an increase in inoculum size had a therapeutic impact in mice with peritonitis that was comparable to that observed when the mcr-1 gene was expressed.
PDF
