Determination by LC–MS/MS of Colistins A and B in Plasma and Ultrafiltrate From Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Leporati, Marta; Bua, Rosaria Ornella; Mariano, Filippo; Carignano, Paola; Stella, Maurizio; Biancone, Luigi; Vincenti, Marco

doi:10.1097/ftd.0b013e3182a8997c

Cited by 34 publications

(20 citation statements)

References 27 publications

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“…Taken together, these findings suggest that CMS clearance may be filter limited, while colistin CRRT clearance depends on blood flow. Two other studies both using 9-MU daily maintenance doses and a blood flow of 120 ml/min (comparable to the present study) in seven and four patients undergoing CRRT (11,24) showed colistin CRRT clearances of about 0.7 liter/h, which compared to our findings. For daily clinical practice, we therefore suggest starting CMS in patients that are undergoing CVVHD using low blood flows with a loading dose of 9 MU and a maintenance dose of 3 MU every 8 h (independent of body weight), so that therapeutic colistin concentrations have a high likelihood of being achieved.…”

Section: Discussionsupporting

confidence: 89%

“…Critically ill patients may develop acute or acute-on-chronic renal failure requiring a period of continuous renal replacement therapy (CRRT). Although pharmacokinetic (PK) studies and dosing recommendations for CMS in critically ill patients with normal or impaired renal function exist, there are only a few systematic studies of the pharmacokinetics of CMS and colistin in patients undergoing CRRT (10)(11)(12)(13). Dose recommendations in these patients therefore differ widely, and there is evidence that certain recommendations might lead to underdosing (14).…”

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confidence: 99%

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Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

Leuppi-Taegtmeyer

Décosterd

Osthoff

et al. 2019

Antimicrob Agents Chemother

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Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

Leuppi-Taegtmeyer

Décosterd

Osthoff

et al. 2019

Antimicrob Agents Chemother

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“…Thus, based on these findings, also confirmed elsewhere (82,85), a CMS maintenance dose similar to or higher than that used in patients with preserved kidney function is needed to achieve adequate colistin C ss during CRRT (83,(86)(87)(88). A further study reported relatively high SA during CVVHDF (0.42 for colistin A and 0.48 for colistin B) with a high extent of colistin removal, suggesting the dose should not be reduced (89). In patients with septic shock and AKI undergoing coupled plasma filtration-adsorption/CVVHDF or hemoperfusion with polymyxin B fiber cartridges, colistin removal was high, especially in the case of coupled plasma filtration-adsorption/CVVHDF; however, the short duration of hemoperfusion probably resulted in very little impact on total-body colistin content (90).…”

Section: Polymyxinssupporting

confidence: 62%

A Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy

Pistolesi

Morabito

Mario

et al. 2019

Antimicrob Agents Chemother

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A careful management of antimicrobials is essential in the critically ill with acute kidney injury, especially if renal replacement therapy is required. Acute kidney injury may lead per se to clinically significant modifications of drugs' pharmacokinetic parameters, and the need for renal replacement therapy represents a further variable that should be considered to avoid inappropriate antimicrobial therapy. The most important pharmacokinetic parameters, useful to determine the significance of extracorporeal removal of a given drug, are molecular weight, protein binding, and distribution volume. In many cases, the extracorporeal removal of antimicrobials can be relevant, with a consistent risk of underdosing-related treatment failure and/or potential onset of bacterial resistance. It should also be taken into account that renal replacement therapies are often not standardized in critically ill patients, and their impact on plasma drug concentrations may substantially vary in relation to membrane characteristics, treatment modality, and delivered dialysis dose. Thus, in this clinical scenario, the knowledge of the pharmacokinetic and pharmacodynamic properties of different antimicrobial classes is crucial to tailor maintenance dose and/or time interval according to clinical needs. Finally, especially for antimicrobials known for a tight therapeutic range, therapeutic drug monitoring is strongly suggested to guide dosing adjustment in complex clinical settings, such as septic patients with acute kidney injury undergoing renal replacement therapy. The most important factors able to affect drug PK during RRT are volume of distribution (V), protein binding, and molecular weight (MW); the knowledge of these parameters, along with total body clearance (CL TB ), allows determination of the significance of extracorporeal removal of a given drug.The volume of distribution corresponds to the ratio of the amount of drug in the body at a given time and plasma concentration at that time (11). In other terms, it represents the theoretical volume necessary to contain the total amount of an administered drug at the same concentration measured in plasma (12), and it should be regarded as a proportionality factor between a plasma concentration and the corresponding amount of drug in the whole body (11). As snapshot plasma drug concentrations may vary according to the state of drug disposition (i.e., just after intravenous [i.v.] administration, during the distribution phase, during the terminal phase of drug disposition, or at equilibrium), the proportionality ratio between the amount of drug in the body and the plasma concentration will change; thus, several V will be obtained in different situations (11). In clinical practice, V at equilibrium (V ss ), obtained when plasma concentrations are measured under steady-state conditions (i.e., during continuous i.v. drug infusion or multiple-drug administration once steady-state plasma concentrations have been achieved), represents the most appropriate V to compute a "loading dose" (11)...

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“…These renal replacement modalities were shown to have a substantial impact on the plasma colistin concentration achieved from a given daily dose of CMS; this was in agreement with reports from case studies and case series. 54,[61][62][63][64][65][66] There are two reasons why renal replacement therapy has such a substantial impact on dosage requirements of CMS. First, the circulating plasma concentrations of CMS are considerably higher than those of formed colistin (►Figs.…”

Section: Intravenous Administration Of Cmsmentioning

confidence: 99%

Colistin: How should It Be Dosed for the Critically Ill?

Landersdorfer

Nation

2015

Semin Respir Crit Care Med

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Colistin, an "old" polymyxin antibiotic, is increasingly being used as last-line treatment against infections caused by multidrug-resistant gram-negative bacteria. It is administered in patients, parenterally or by inhalation, as its inactive prodrug colistin methanesulfonate (CMS). Scientifically based recommendations on how to optimally dose colistin in critically ill patients have become available over the last decade and are extremely important as colistin has a narrow therapeutic window. A dosing algorithm has been developed to achieve desired plasma colistin concentrations in critically ill patients. This includes the necessary dose adjustments for patients with impaired kidney function and those on renal replacement therapy. Due to the slow conversion of CMS to colistin, a loading dose is needed to generate effective concentrations within a reasonable time period. Therapeutic drug monitoring is warranted, where available; because of the observed high interpatient variability in plasma colistin concentrations. Combination therapy should be considered when the infecting pathogen has a colistin minimum inhibitory concentration above 1 mg/L, as increasing the dose may not be feasible due to the risk for nephrotoxicity. Inhalation of CMS achieves considerably higher colistin concentrations in lung fluids than is possible with intravenous administration, with negligible plasma exposure. Similarly, for central nervous system infections, dosing CMS directly into the cerebrospinal fluid generates significantly higher colistin concentrations at the infection site compared with what can be achieved with systemic administration. While questions remain to be addressed via ongoing research, this article reviews the significant advances that have been made toward optimizing the clinical use of colistin.

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Determination by LC–MS/MS of Colistins A and B in Plasma and Ultrafiltrate From Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Abstract: Two simple methods for the simultaneous determination of colistins A and B have been developed and validated. Their application in the clinical setting demonstrates that CVVHDF treatment lasting 48 hours produces a relatively constant and efficient removal of the drug.

Cited by 34 publications

References 27 publications

Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

A Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy

Colistin: How should It Be Dosed for the Critically Ill?

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