Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis

Abstract

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients. Over the last several years, colistin (polymyxin E) has been increasingly used as a last option for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae (1, 2), for which the mortality rate has increased (3).Colistin is administered as a prodrug, colistin methanesulfonate (CMS), which is mostly excreted unchanged in urine (70%) and is partly converted to colistin (30% at most), whereas renal excretion of colistin is negligible (4). As a result, in patients with renal failure, a greater fraction of the CMS dose may be converted into colistin (5); therefore, all other things being equal, colistin plasma concentrations at steady state should increase. The elimination of colistin is nonrenal-it undergoes extensive renal tubular reabsorption-and nonbiliary by unknown mechanism (1).It has recently been shown that in intensive care unit (ICU) patients, colistin plasma concentrations at steady state are mostly governed by renal function and that creatinine clearance can be used for dosing regimen adaptation ...

Polymyxin B Pharmacokinetics in Adult Cystic Fibrosis Patients

“…In this vein, polymyxin‐type antibiotics are increasingly used to treat CF. However, most PK studies of intravenous polymyxin B are in critically ill patients or animal models, and we are not aware of any studies that have described polymyxin B PK in patients with CF . In adult patients without CF, renal clearance is a minor elimination pathway for polymyxin B, but less is known about the pharmacokinetics of polymyxin B in patients with CF .…”

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)

“…Colistin methanesulfonate and formed colistin are efficiently cleared by intermittent and continuous renal support modalities; less information is available for SLED than for shorter forms of IHD and CRRT . Supplementary doses of CMS are needed for patients receiving IHD or SLED.…”

“…Apparent clearance of colistin and hence the dose requirements of CMS are greater in patients on CRRT than for patients with normal renal function . Detailed dose suggestions for patients receiving renal support have been proposed …”

“…Colistin methanesulfonate and formed colistin are efficiently cleared by intermittent and continuous renal support modalities; less information is available for SLED than for shorter forms of IHD and CRRT. 6,33,[70][71][72][73][74][75][76][77] Supplementary doses of CMS are needed for patients receiving IHD or SLED. IHD, SLED, and CRRT, each removes~10% of colistin an hour necessitating replacement of 10% of the daily dose per hour on these modalities.…”

Intravenous polymyxins: Revival with puzzle

“…And it's also indicated that to achieve colistin plasma concentrations at the steady state considered adequate (2.5 mg/L), the colistin methanesulfonate sodium maintenance dose during CRRT had to be similar to or even higher than that used in patients with preserved kidney function (73,77). For patients receiving intermittent RRT, it's suggested to give an additional dose of colistin methanesulfonate sodium after dialysis (77,88), but no standardized dose recommendations are currently available for these long-lasting modalities of intermittent RRT. For end-stage renal disease (ESRD) patients receiving intermittent hemodialysis (HD), evidence from 10 patients indicated that HD should be conducted at the end of a dosing interval and a supplemental dose should be administered (89).…”