Colistin Use in Patients With Reduced Kidney Function

Narrative Review Colistin Use in Patients With Reduced Kidney Function Enrico Fiaccadori, MD, PhD,1 Elio Antonucci, MD,2 Santo Morabito, MD,3 Antonio d’Avolio, BSc, MSc, SM,4 Umberto Maggiore, MD, PhD,5 and Giuseppe Regolisti, MD 1 Colistin (polymyxin E) is a mainly concentration-dependent bactericidal antimicrobial active against multidrug-resistant Gram-negative bacteria. After being abandoned over the past 30 years due to its neuroand nephrotoxicity, colistin has been reintroduced recently as a last-resort drug for the treatment of multidrugresistant Gram-negative bacteria infections in combination with other antimicrobials. Unfortunately, although renal toxicity is a well-known dose-related adverse effect of colistin, relatively few studies are currently available on its peculiar pharmacodynamic/pharmacokinetic properties in clinical settings at high risk for drug accumulation, such as acute or chronic kidney disease. In these specific contexts, the risk for underdosing is also substantial because colistin can be easily removed by dialysis/hemofiltration, especially when the most efficient modalities of renal replacement therapy (RRT) are used in critically ill patients. For this reason, recent recommendations in patients undergoing RRT have shifted toward higher dosing regimens, and therapeutic drug monitoring is advised. This review aims to summarize the main issues related to chemical structure, pharmacodynamics/pharmacokinetics, and renal toxicity of colistin. Moreover, recent data and current recommendations concerning colistin dosing in patients with reduced kidney function, with special regard to those receiving RRT such as dialysis or hemofiltration, are also discussed. Am J Kidney Dis. -(-):---. ª 2016 by the National Kidney Foundation, Inc. INDEX WORDS: Acute kidney injury (AKI); colistin; colistin methanesulfonate; polymyxin E; continuous renal replacement therapies (CRRTs); renal toxicity; nephrotoxicity; chronic kidney disease (CKD); critical illness; dialysis; hemofiltration; kidney function; colistin pharmacokinetics; colistimethate; therapeutic drug monitors.

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olistin is a mainly concentration-dependent bactericidal antibiotic active against multidrugresistant Gram-negative bacteria (Pseudomonas aeruginosa, Acinetobacter baumannii, carbapenemaseproducing Enterobacteriaceae, etc)1,2 originally introduced in 1958 and subsequently abandoned because of its toxicity.3 Colistin is now increasingly used as a last-resort drug for multidrug-resistant Gram-negative bacteria infections, that is, ventilatorassociated pneumonia, urinary tract infections, bacteremia, central catheter–associated sepsis, peritonitis, and meningitis.3,4 Colistin pharmacokinetics still remain ill defined, especially in clinical settings at high risk for both over- and underdosing, such as chronic kidney disease (CKD) and acute kidney injury (AKI), especially when renal replacement therapies (RRTs) are needed. This narrative review is aimed at describing pharmacodynamic/pharmacokinetic issues, dosing recommendations, and toxicity of colistin, as well as the changes in its pharmacokinetic properties associated with reduced kidney function (AKI and CKD), with or without RRT need.

SEARCH STRATEGY A review of the English language literature was performed to identify relevant articles describing pharmacodynamics/pharmacokinetics, renal toxicity, and dosing adjustments for colistin in AKI, CKD, and RRT. We searched PubMed, Embase, the Cumulative Am J Kidney Dis. 2016;-(-):---

Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane databases for relevant articles using the following search terms: “acute kidney injury OR acute renal failure,” “chronic kidney disease,” “continuous venovenous hemofiltration, CVVH,” “continuous venovenous hemodialysis, CVVHD,” “continuous renal replacement therapy, CRRT,” “colistin,” “colistin methanesulphonate,” “colistimethate,” “critical illness,” “dialysis OR hemofiltration,” “intravenous,” “nephrotoxicity,” “neurotoxicity,” “peritoneal dialysis,” “pharmacokinetics,” “pharmacodynamics,” “renal

From the 1Renal Failure Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma; 2Intermediate Care Unit, Emergency Department “Guglielmo da Saliceto” Hospital, Piacenza; 3Hemodialysis Unit, Department of Nephrology and Urology, University of Rome “Sapienza,” Rome; 4 Laboratory of Clinical Pharmacology and Pharmacogenetics, Infectious Disease Unit, Department of Medical Sciences, University of Turin, Turin; and 5Kidney-Pancreas Transplantation Unit, Parma University Hospital, Parma, Italy. Received December 30, 2015. Accepted in revised form March 21, 2016. Address correspondence to Enrico Fiaccadori, MD, PhD, Unità di Fisiopatologia dell’Insufficienza Renale Acuta e Cronica, Dipartimento di Medicina Cinica e Sperimentale, Università degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: enrico.fi[email protected]  2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.03.421 1

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replacement therapy,” “therapeutic drug monitoring,” and “toxicity.” Medical Subject Heading (MeSH) terms were used to enhance electronic searches. Additional studies of interest were identified by hand searches of reference lists. Studies including patients younger than 18 years, case reports, or conference proceedings were excluded. The search was last updated on March 13, 2016.

CHEMICAL STRUCTURE OF COLISTIN Colistin (polymyxin E) is produced by strains of Bacillus polymyxa subspecies colistinus.3,4 Colistin is a multicomponent lipopeptide that contains colistin A and colistin B, which only vary in the fatty acid chain attached to the cyclic decapeptide moiety of the drug. Its molecular weight is 1,163 Da, and it is an amphiphilic molecule: its hydrophilic properties arise from the polycationic cyclic peptide and the hydrophobic portion is the fatty acyl tail (Fig 1).4 Colistin is primarily distributed in the extracellular fluid with limited penetration in the intracellular compartment and reaches adequate concentrations in many tissues (liver, kidney, skeletal muscle, heart, and lungs), but does not cross the blood-brain barrier when intact.4 The drug is commercially available as its prodrug colistimethate sodium (colistin methanesulfonate sodium; molecular weight, 1,743 Da), also administered by the intramuscular route and nebulization. As a sulfate salt, colistin can only be administered orally, for intestinal decontamination, or as a topical drug, for cutaneous infections. Colistimethate is a variable mixture of the methanesulfonic sodium salts of colistin A and colistin B that after administration spontaneously converts by hydrolysis to colistin (20%-30% of colistin methanesulfonate sodium dose).4 Bactericidal activity of colistin is considered mainly concentration dependent, with a mild postantibiotic effect at higher concentrations; however, colistin is classified as both a concentration- and time-dependent antibiotic.5 Given the toxicity of the parental antibiotic, colistin is administered as its prodrug colistin methanesulfonate sodium, by

Figure 1. Chemical structure of colistin (polymyxin E). 2

intravenous delivery or nebulization. Thus, the available brands for parenteral colistin therapy contain colistin methanesulfonate sodium. International units or milligrams of colistin methanesulfonate sodium are used for dosing in Europe, the United Kingdom, and India, whereas in the remaining regions, including North and South America, Southeast Asia, and Australia, milligrams of colistin base activity are used. One million international units of colistin methanesulfonate sodium corresponds to 80 mg and equals 30 mg of colistin base activity.

PHARMACODYNAMICS OF COLISTIN Colistin in water-containing solutions acquires cationic and surfactant properties, thus increasing the permeability of the Gram-negative bacteria cellular envelope by inducing a loss of integrity of the cytoplasmic membrane.3,4 The polycationic region of colistin interacts with the anionic region of lipopolysaccharide, the major component of the outer Gramnegative bacterial membrane, displacing divalent calcium and magnesium cations that normally stabilize the external lipopolysaccharide leaflet, with secondary membrane instability and cell lysis. The antibacterial action of colistin is rapid (1-2 hours) on both quiescent and actively replicating bacteria, and this partially explains the delay between colistin administration and the development of bacterial resistance. Also, direct binding to the lipid portion of the lipopolysaccharide molecule, with ensuing endotoxin neutralization, may contribute to the antibacterial effect of colistin by direct antiendotoxin activity.

SPECTRUM OF BACTERIAL SUSCEPTIBILITY AND BACTERIAL RESISTANCE TO COLISTIN Colistin has a limited spectrum of antimicrobial activity (Table 1).3,4 The reference method recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) to evaluate colistin sensitivity remains the broth microdilution method: according to EUCAST criteria, sensitivity and resistance break points are #2 mg/L and .2 mg/L for Enterobacteriaceae and #4 mg/L and .4 mg/L for P aeruginosa, respectively.6 Resistance against colistin has been rarely detected7 because of its mechanism of action and its uncommon use in clinical practice in the past. Resistance to polymyxins is usually attributed to chromosomal mutations leading to modification of lipid A and lipopolysaccharide composition with consequent reduction of affinity for colistin. However, recently, horizontal gene transfer (ie, plasmid-mediated resistance) between Enterobacteriaceae has been reported in China in both farm animals and humans.8 The usual recommendation is to administer colistin not in single-drug antibiotic Am J Kidney Dis. 2016;-(-):---

Colistin Use in Reduced Kidney Function Table 1. The Spectrum of Bacterial Susceptibility/Resistance to Colistin Susceptible Species

Enterobacteriaceae

Citrobacter Escherichia coli Enterobacter Klebsiella Salmonella Shigella

Pseudomonas

P aeruginosa P fluorescens P malthophilia P putida Acinetobacter Bordetella Haemophilus influentiae Legionella pneumophila Moraxella Pasteurella Bacteroides melaninogenicus Bacteroides oralis

Other Gram-negative bacteria

Anaerobic bacteria

Resistant Species

Brucella Campyobacter Morganella Nocardia Proteus Providencia Serratia P Psuedomalle P cepacia P picketti Vibrio cholera

Bacteroides fragilis

regimens, but in combination with other antibiotics.9 Different studies have shown a synergistic activity of colistin with rifampin against A baumannii,10 with ceftazidime against P aeruginosa,11 and with carbapenems against Klebsiella pneumoniæ.12

PHARMACOKINETICS OF COLISTIN Conflicting data have been reported about the pharmacokinetics of intravenous colistin because of the methodological limitations of the available studies.4 Furthermore, colistin measurement in biological fluids may overestimate true levels due to both lack of discrimination between colistin methanesulfonate sodium and colistin by old analytical techniques and the ex vivo conversion phenomenon from colistin methanesulfonate sodium to colistin in blood/ plasma that may continue even after blood withdrawal. Colistin is not absorbed in the gastrointestinal tract (except in neonates or in the case of severely damaged intestinal mucosa) and is weakly bound to plasma proteins (in critically ill patients, a median of 34% [range, 26%-41%] is present in bound form).13 More colistin can be protein bound if high levels of acute-phase proteins are present.14 In healthy volunteers, colistin methanesulfonate sodium and colistin show a low apparent volume of distribution (14.0 and 12.4 L, respectively), approximating extracellular fluid volume.15 Conversely, critically ill patients may have higher volumes of distribution (up to 0.3-0.4 L/kg for colistin).16 After parenteral administration, 60% of colistin methanesulfonate sodium is excreted unaltered in urine by glomerular filtration and active Am J Kidney Dis. 2016;-(-):---

tubular secretion, with ,30% being hydrolyzed to colistin; renal clearance is 103 mL/min and biliary excretion is nearly absent.15-18 Less than 1% of colistin formed from colistin methanesulfonate sodium (15%-30% of colistin methanesulfonate sodium) is excreted in urine because colistin undergoes tubular reabsorption. Serum half-lives of colistin methanesulfonate sodium and colistin are 2.3 and 14.4 hours, respectively.19 In patients with CKD or AKI, urinary excretion of colistin methanesulfonate sodium is reduced, with a greater fraction of the prodrug being converted to colistin. Colistimethate is usually administered by the intravenous route, with peak plasma concentration of colistin at about 7 hours,19 usually reaching steady state after 48 to 72 hours of therapy when no initial antibiotic load is given.16 Thus, in patients with normal kidney function, it has been suggested that 6 to 9 million IU of colistin methanesulfonate sodium be administered as a loading dose, followed by 4.5 million IU every 8 to 12 hours as a maintenance dose, in order to reach more rapidly the target concentrations and maintain adequate levels of the drug.4 Nebulized colistin methanesulfonate sodium (1-3 million IU every 8-12 hours) has also recently been used as an adjunct to parenteral colistin methanesulfonate sodium in the management of multidrug-resistant Gram-negative bacteria–induced ventilator-associated pneumonia,20 while not significantly affecting renal toxicity.20-25 Studies investigating which pharmacokinetic/pharmacodynamic index best predicts colistin bactericidal activity2,23 indicate total colistin area under the concentration curve over 24 hours in the steady state divided by the minimum inhibitory concentration (the AUC24/MIC index) as the most reliable predictor of antibacterial activity.26 The strong correlation between antibacterial activity of colistin in vivo and AUC24/MIC ratio is in line with the potent concentration-dependent killing seen in vitro versus the same bacteria.27 The same relationship also stresses the importance to achieve adequate timeaveraged exposure to colistin over 24 hours.2,5

TOXICITY OF COLISTIN Colistin neurotoxicity and nephrotoxicity both represent well-known dose-dependent phenomena.3,28,29 Other adverse effects are rare (incidence , 2%) and include itching, urticaria, and eczema; pseudomembranous colitis; and liver failure. Neurotoxicity Colistin neurotoxicity (paresthesias, seizures, visual disturbances, ataxia, vertigo, delirium, myasthenia and neuromuscular deficits, and apnea) is dose dependent and usually reversible.4,30,31 Risk factors 3

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include high dose; hypoxia; female sex; use of muscle relaxants, steroids, or sedatives; myasthenia gravis; AKI; and CKD.27,28 A direct toxic effect on neurons seems to be the main pathogenetic factor, with a first phase of competitive antagonism between colistin and acetylcholine and a second phase characterized by persistent depolarization and calcium depletion.30 Mechanical ventilation may be required in case of respiratory failure, whereas RRT has been proposed when AKI coexists.31 The evidence supporting the efficacy of cholinesterase inhibitor administration is limited. Nephrotoxicity Incidence Estimating the true incidence of colistin-induced nephrotoxicity is difficult due to the heterogeneity of patient populations, different sites of infection, variable antibiotic doses, different definitions of AKI, and lack of complete clinical records. Studies in critically ill patients show an incidence ranging from 14% to 19% up to 48% to 49% in the most recent reports.24,32-37 Mechanisms of Renal Toxicity of Colistin Nephrotoxicity usually occurs in the first 5 to 7 days of treatment.38 Risk factors include high doses, duration of therapy and cumulative dose, septic shock, hypoalbuminemia, hyperbilirubinemia, concurrent administration of calcineurin inhibitors, obesity, and coexistence of factors associated with AKI (administration of iodine-containing contrast medium, kidney hypoperfusion, and high doses of aminoglycosides or glycopeptides).39-43 Nephrotoxicity seems to be related partially to the D-amino acid and fatty acyl chain of the drug, which may increase cell membrane permeability through interaction with surface lipids and subsequent leakage of anions/cations.4 Colistin accumulates in the cortical region of the kidney,44 especially in cells of the proximal convoluted tubule,45 where tubular carriers reabsorb most of the drug.46 Oxidative stress, apoptosis, and altered inducible nitric oxide synthase levels could also play a role in colistin-induced nephrotoxicity,47,48 suggesting a potential benefit of the prophylactic administration of antiapoptotic and antioxidative agents.24,47,49-53 Clinical Manifestations Clinical manifestations include hematuria, cylindruria, proteinuria, and oligoanuria. Renal adverse effects are usually reversible, but persistent kidney injury can be observed; in this case, histologic examination of kidney biopsy specimens may show tubulointerstitial damage, whereas glomeruli are usually spared.29 4

Prevention and Treatment Colistin treatment should be withdrawn if signs of nephrotoxicity appear, and other potentially nephrotoxic drugs must be avoided. Data from experimental and clinical studies of the protective effects of antioxidant agents are controversial.24,52,53 Ascorbic acid was found to have a protective role against AKI following the administration of high colistin doses in one observational study,24 but not in another.53 The efficacy of RRT in colistin overdosing is uncertain. Plasmapheresis may weakly remove colistin, as reported in a single case report.54

RECOMMENDED DOSES AND SCHEDULES OF ADMINISTRATION IN PATIENTS WITH CKD AND AKI Based on recent studies with administration of higher colistin methanesulfonate sodium doses, earlier recommendations are likely to be inadequate, especially in the case of patients receiving RRT.55,56 Although the loading dose should not change, irrespective of baseline kidney function, maintenance doses should be adjusted according to reduced renal clearance and/or the efficiency of drug removal by RRT (Table 2).56-59 Patients With CKD and AKI Not Receiving RRT The available recommendations suggest dose modulation based on estimated glomerular filtration rate or creatinine clearance (Tables 2 and 3).56-58 The use of dosing formulas,16 now also incorporated in mobile apps (for iOS 8.0 and Android 4.0 and above),59 taking into account kidney function and target colistin blood level, may provide an alternative approach. Critically Ill Patients Receiving RRT Sparse data are available for colistin pharmacokinetics during RRT because of the different operational characteristics of the modalities adopted in the intensive care unit (ICU), as well as the variable antibiotic doses and limited numbers of enrolled patients. Again, the loading dose should be fixed, with subsequent adjustments based on the specific RRT technique (Table 2). Continuous RRT Clearance of colistin by continuous RRT (CRRT) may become a relevant component of the total-body clearance. In a patient with AKI receiving colistin methanesulfonate sodium at 150 mg every 48 hours, significant lowering of colistin levels during continuous venovenous hemodiafiltration (CVVHDF; effluent volume, 3 L/h; dialysis fluid, 1 L; replacement fluid, 2 L; and blood flow, 200 mL/min) was observed.60 From hours 0 to 8 after dosing, 20.3% of Am J Kidney Dis. 2016;-(-):---

Colistin Use in Reduced Kidney Function Table 2. Intravenous Colistin Dosing in Critically Ill Patients With Kidney Failure Loading Dose

9-12 million IU

5 mg/kg

Maintenance Dose

Comments

Critically Ill Patients Not Receiving RRT eGFR . 60 mL/min/1.73 m2: 4.5 million IU Loading dose independent of kidney Kift et al56 function, calculated according to ideal every 12 h body weight (12 million IU CMS for 70 kg eGFR 30-60 mL/min/1.73 m2: 3.0 million IU and 9 million IU for 55 kg); maintenance every 12 h dose adjusted on basis of eGFRa eGFR 10-,30 mL/min/1.73 m2: 2.0 million IU every 12 h eGFR , 10 mL/min/1.73 m2: 1.0 million IU every 12 h Loading dose independent of kidney John et al57 GFR $ 50 mL/min: 5.0 mg/kg in 3 divided function; maintenance dose adjusted on doses, start 8 h after load basis of creatinine clearance GFR 30-49 mL/min: 3.5 mg/kg in 2 divided doses, start 12 h after load GFR 10-29 mL/min: 2.5 mg/kg in 2 divided doses, start 12 h after load GFR , 10 mL/min: 1.5 mg/kg in 1 dose, start 24 h after load

Conventional Intermittent HD 1.0 million IU every 12 h 1 1 million IU after Loading dose independent of kidney each dialysis session function 5 mg/kg 1.5 mg/kg in 1 dose, start 24 h after load Loading dose independent of kidney function CBA (mg) 5 Css,avg 3 Daily dose of CBA on a non-HD day to reach Loading dose independent of kidney function; first maintenance dose should 2.0 3 body weight (kg) each 1.0 mg/L colistin 5 Css,avg 3 30 mg be given 24 h after loading dose; (creatinine clearance is zero) membrane: SF190E (surface area, 1.5Supplemental dose of CBA on an HD day: 1.9 m2); blood flow: 200-350 mL/min; add 50% to daily maintenance dose if supplemental dose is given during last h of dialysate flow: 500-600 mL/min; HD HD session, or add 30% to daily session length: 195-255 (median, 240) maintenance dose if supplemental dose is min; HD daily or every other day given after HD session; twice-daily dosing is suggested 1.5 million IU 1.5 million IU twice daily on non-HD day; HD should be done at end of dosing supplemental dose of 1.5 million IU should interval; HD every other day; blood flow be given after HD, together with standard rate: 300 mL/min; dialysate flow rate: dose (ie, total dose of 4.5 million IU for HD 500-600 mL/min; 3 PMMA filter: 1.6 m2 day) 9-12 million IU

6 million IU

Reference

Sustained Low-Efficiency Dialysis 3.0 million IU every 8 h Single patient study; mean length of dialytic session: 9 h; mean blood flow: 190 mL/min; mean dialysis fluid flow: 121 mL/min

Kift et al56 John et al57 Garonzik et al16

Jacobs et al67

Strunk et al68

Continuous RRT Loading dose independent of kidney Kift et al56 function CBA (mg) 5 Css,avg 3 Daily dose of CBA to reach each 1.0-mg/L Loading dose independent of kidney Garonzik et al16 2.0 3 body weight (kg) colistin Css,avg target 5 192 mg; doses function; first maintenance dose should be given 24 h after loading dose; may be given every 8-12 h; mean dose: 200 (range, 75-410) mg CVVHD (3 patients; membrane: AN69HF 0.9 m2; blood flow: 150 mL/ min; dialysate flow: 42 mL/min); CVVH (1 patient; parameters not specified) 9-12 million IU

4.5 million IU every 12 h

Note: Colistin doses given as IUs of CMS or milligrams of CBA. Abbreviations and definitions: CBA, colistin base activity; Css,avg, colistin steady-state target (mg/L) based on minimum inhibitory concentration, site, and severity of infection; CMS, colistimethate sodium; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodiafiltration; eGFR, estimated glomerular filtration rate; HD, hemodialysis; PMMA, polymethylmethacrylate; RRT, renal replacement therapy. a Formulas for eGFR may not adequately reflect kidney function in critically ill patients when GFR is not stable.

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Fiaccadori et al Table 3. Intravenous Colistin Dosing in Patients With CKD Loading Dose

5 mg/kg

Maintenance Dose

Comments

Reference

CKD Not Receiving RRT Loading dose independent of kidney John et al57 GFR $ 50 mL/min: 5.0 mg/kg in 3 function; maintenance dose adjusted on divided doses, start 8 h after load basis of creatinine clearance GFR 30-49 mL/min: 3.5 mg/kg in 2 divided doses, start 12 h after load GFR 10-29 mL/min: 2.5 mg/kg in 2 divided doses, start 12 h after load GFR , 10 mL/min: 1.5 mg/kg in 1 dose, start 24 h after load

ESRD Receiving Intermittent HD CBA (mg) 5 Css,avg 3 Daily dose of CBA on a non-HD day to Loading dose independent of kidney Garonzik et al16 function; first maintenance dose should 2.0 3 body weight (kg) reach each 1.0-mg/L colistin 5 be given 24 h after loading dose; Css,avg 3 30 mg (creatinine clearance membrane: SF190E, Rex 18, or SF150 is 0) (surface area, 1.5-1.9 m2); blood flow: Supplemental dose of CBA on an HD day: add 50% to daily maintenance 200-350 mL/min; dialysate flow: 500dose if supplemental dose is given 600 mL/min; HD session length: 195during last h of HD session, or add 255 (median, 240) min 30% to daily maintenance dose if supplemental dose is given after HD session; twice-daily dosing is suggested 300 mg

150-200 mg CBA/d

ESRD Receiving PD First maintenance dose should be given 24 h after loading dose; CAPD (8 patients): 2 L exchanges, 43/d, dwell time of 6 h

Koomanachai et al58

Note: Colistin doses are given as milligrams of CBA. Abbreviations and definitions: CAPD, continuous ambulatory peritoneal dialysis; CBA, colistin base activity; CKD, chronic kidney disease; Css,avg, colistin steady-state target (mg/L) based on minimum inhibitory concentration, site, and severity of infection; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy.

the dose was recovered in the effluent fluid as colistin methanesulfonate sodium, and 6.9%, as colistin; clearances of colistin methanesulfonate sodium (11.2 mL/min) and colistin (11.9 mL/min) were similar. Among 105 critically ill patients receiving colistin methanesulfonate sodium doses selected by the attending physicians, 4 patients underwent CRRT (3 with continuous venovenous hemodialysis at 150 mL/min blood flow with 42 mL/min dialysate flow, and 1 with continuous venovenous hemofiltration [CVVH]).16 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 that used in patients with preserved kidney function (mean daily colistin methanesulfonate sodium dose expressed as colistin base activity, 200 [range, 75-410] mg).16 Three further small case series reported colistin pharmacokinetic data during CRRT. In the first study, 3 critically ill patients underwent CVVHDF in postdilution (effluent rate, 1.9-2.3 L/h) while on colistin therapy.61 Colistimethate dose was chosen at the attending physician’s discretion and in every case was lower than that recommended for 6

people with intact kidney function: 150 mg every 18 hours in one case and 75 mg per 8 hours in the other 2 cases. Extracorporeal clearance of colistin was 43% to 59% of total clearance and was related to both hemodiafiltration (removal by convection and diffusion) and adsorption by the filter membrane. Colistimethate doses were inadequately low when actual colistin concentrations (1.4-1.7 mg/L) were compared with the theoretical steady-state concentrations (at least 2.5 mg/L) needed to maintain AUC24/ MIC . 60. The second study62 investigated colistin pharmacokinetics in 5 critically ill patients undergoing CVVHDF (filter, AN69HF; membrane surface, 0.9 m2; blood flow, 120-150 mL/min; dialysate flow, 1.5-2.5 L/h; and reinfusion rate, 0.6-0.9 L/h); colistimethate dose was 160 mg (2 million IU) every 8 hours. After the fourth dose (ie, at steady state), colistin peak serum concentration was 6.92 mg/L, with total clearance of 8.23 L/h; average colistin concentration was 0.92 mg/L with a metabolized fraction of 18.9 L/h. Thus, colistin concentrations were less than MIC breakpoints, suggesting dosing inadequacy. Furthermore, colistin concentration was w50% of that obtained in nondialyzed patients Am J Kidney Dis. 2016;-(-):---

Colistin Use in Reduced Kidney Function

receiving 240 mg every 8 hours. It was concluded that critically ill patients undergoing CVVHDF should receive the same colistin doses as in the case of preserved kidney function because of the elevated total clearance of the drug. A third study (2 patients) investigated colistin dosing in burned patients during CVVH.63 Pharmacokinetic/pharmacodynamic data analysis suggested that a dose increase from 2.9 to 4.4 mg/kg/d as colistin base activity was insufficient to reach AUC24/MIC . 60 during CVVH when MIC was .1 mg/mL. Moreover, significant variability in colistin levels was observed during CVVH, suggesting a possible toxicity risk. A recent study reported relatively high mean sieving coefficients during CVVHDF (0.42 for colistin A; 0.48, colistin B).64 Finally, membrane adsorption has also been suggested as a possible removal mechanism of colistin during CRRT.31 In patients with septic shock and AKI undergoing coupled plasma filtrationadsorption/CVVHDF or hemoperfusion with polymyxin B fiber cartridges, colistin removal was high; colistin levels were decreased by about 4-fold by the treatment in the case of coupled plasma filtrationadsorption/CVVHDF, while in the initial part of the 2-hour hemoperfusion session, after-cartridge colistin levels were w30% lower than before-cartridge levels. However, the short application duration probably resulted in very little impact of hemoperfusion on total-body colistin content.65 Conventional Intermittent RRT Colistin pharmacokinetics was evaluated in 12 critically ill patients undergoing intermittent RRT (blood flow, 200-350 mL/min; dialysate flow, 500-600 mL/ min; filter, SF190E; membrane surface, 1.5-1.9 m2; and median hemodialysis session length, 4 hours daily or every 48 hours).16 They required a colistin methanesulfonate sodium maintenance dose 6 times higher than in patients on CRRT to achieve adequate plasma concentration, with an addition of 50% of the maintenance dose if the antibiotic was given during the last hour of the treatment, or 30% if the antibiotic was given at the end of the dialysis session.16 An additional dose of 1.5 mg/kg of colistin methanesulfonate sodium after dialysis was suggested. A case report analyzed the variations in colistin plasma levels in 2 patients with pneumonia sustained by multidrug-resistant Gramnegative bacteria and AKI on intermittent RRT (dialysis session length, 4 hours; blood flow, 300 mL/ min; effluent fluid rate, 500 mL/min; and polymethylmethacrylate membrane surface area, 1.6 m2).66 The first patient received colistin methanesulfonate sodium, 1 million IU, every 48 hours (alternate-day intermittent RRT sessions); the second patient received colistin methanesulfonate sodium, 2 million IU, every 12 hours (daily sessions of intermittent RRT). The first Am J Kidney Dis. 2016;-(-):---

patient had colistin predialytic plasma concentrations lower than the MIC breakpoint suggested by EUCAST (0.45 vs 2 mg/L), while colistin plasma values reached the target concentration in the second patient. Notwithstanding different colistin plasma levels in the 2 patients, colistin dialytic clearance was similar to that obtained during CRRT, albeit with higher absolute levels than those observed in the CRRT studies. However, because a CRRT session is intrinsically longer compared to intermittent RRT (typically 24 vs 4 hours), daily colistin clearance with either modality is likely to be comparable. The authors suggested 2 million IU every 12 hours as an appropriate dose in patients treated by intermittent RRT.66 Colistin methanesulfonate sodium nonrenal clearance was found to be greater in a case series of 8 ICU patients with AKI receiving conventional intermittent hemodialysis (4 hours daily).67 In these patients, colistin exposure was 3-fold higher than in ICU patients with preserved kidney function, probably due to a greater fraction of colistin methanesulfonate sodium converted into colistin. The authors suggested that in order to maintain colistin levels high enough (.3 mg/L) to obtain free AUC/MIC . 10 and free AUC/MIC . 50 for systemic and lung infections, respectively, colistin methanesulfonate sodium dosage should be 1.5 million IU twice daily on a nonhemodialysis day. The hemodialysis session should be done at the conclusion of a dosing interval, and a supplemental dose of 1.5 million IU should be given following the hemodialysis session (ie, total of 4.5 million IU for the hemodialysis day).67 Prolonged Intermittent RRT No standardized dose recommendations are currently available for these long-lasting modalities of intermittent RRT. A single case-report68 has evaluated colistin pharmacokinetics in a critically ill patient undergoing sustained low-efficiency dialysis. After a 6-million IU loading dose, a maintenance dose of 3 million IU every 8 hours was given. Mean length of dialytic sessions was 9 hours; mean blood flow, 190 mL/min; and mean dialysis fluid flow, 121 mL/min. Colistin concentrations were appropriate, suggesting the need for higher colistin doses compared with those used during conventional intermittent RRT due to high drug removal during sustained low-efficiency dialysis. However, it has not been clearly defined whether an administration schedule of colistin methanesulfonate sodium every 12 hours or every 8 hours is preferable given the prolonged half-life of the drug in this clinical condition.

End-Stage Renal Disease Patients Receiving Hemodialysis or Peritoneal Dialysis A recent study provided a thorough description of the disposition of colistin methanesulfonate sodium and colistin during conventional hemodialysis in patients with end-stage renal disease69 (Table 3). A 7

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single intravenous dose of colistin methanesulfonate sodium (corresponding to 150 mg of colistin base activity) was administered over 30 minutes to 10 patients with end-stage renal disease on long-term hemodialysis therapy, and the dialysis session was initiated 1.5 to 5.5 hours after the colistin methanesulfonate sodium infusion was begun. Colistin methanesulfonate sodium recovered in the dialysate was on average 30.6% of the administered dose. Colistin methanesulfonate sodium clearance by dialysis was 4.26 L/h; the dialysis clearance ascertained from the before-and-after membrane plasma concentrations was 5.67 L/h (21%) for colistin methanesulfonate sodium and 3.99 L/h (44%) for colistin. Consequently, colistin methanesulfonate sodium clearance by dialysis from transdialyzer extraction was 30% greater than that derived from the amount in dialysate, which indicates adsorption by the membrane. Therefore, it was suggested that in patients with end-stage renal disease, hemodialysis should be done at the conclusion of a dosing interval to minimize colistin methanesulfonate sodium removal before its conversion to colistin.69 A 9-million IU loading dose followed by a maintenance 6-million IU daily dose seems to be sufficient in patients undergoing continuous ambulatory peritoneal dialysis (CAPD)54 (Table 3). Eight CAPD patients received a single intravenous colistin methanesulfonate sodium dose over 30 minutes, corresponding to 150 mg of colistin base activity. Total-body clearance of colistin methanesulfonate sodium (excluding CAPD clearance) was 1.77 L/h, while CAPD clearance was 0.088 L/h. The population mean terminal half-life of colistin methanesulfonate sodium was 8.4 hours. For colistin, total clearance/ fraction of colistin methanesulfonate sodium metabolized to colistin (excluding CAPD clearance) was 2.74 L/h, CAPD clearance was 0.101 L/h, and mean terminal half-life was 13.2 hours. Monte Carlo simulations proposed a 300-mg colistin base activity loading dose on day 1 (9-10 million IU) and a maintenance dose of either 150 or 200 mg of colistin base activity daily (5-6 million IU) to reach a target average steady-state plasma colistin concentration of 2.5 mg/L. Thus, clearance by CAPD was low for colistin methanesulfonate sodium and for colistin, which indicates that colistin methanesulfonate sodium doses should not be increased during CAPD.

THERAPEUTIC DRUG MONITORING OF COLISTIN A more extensive use of therapeutic drug monitoring could represent the most important step forward to optimize colistin dosing and reduce toxicity. However, methods for colistin measurement in biological fluids are still not widely available in clinical practice. In this regard, microbiological methods 8

have been applied initially, and afterward, analytical methods based on immunologic assays, thin layer chromatography, capillary electrophoresis, and highpressure liquid chromatography were developed. To date, there is no reference method for separate quantitative determination of colistin A and colistin B, but a few laboratories developed and validated in-house procedures that focused on colistin measurement in human plasma.64,70 More recently, liquid chromatography–mass spectrometry methods have been developed for the determination of polymyxin levels both in plasma64,70-73 and dialysate/ultrafiltrate.61 Substantial antibiotic dose adaptations have been made on the basis of therapeutic drug monitoring results in specific patient populations (eg, patients with burns, in the ICU, and receiving CVVH).58,63,73,74 The use of therapeutic drug monitoring to avoid overdosing is seemingly best for patients with reduced kidney function and obese patients. Trough levels . 3 mg/L at steady state at treatment day 7 have been associated with greater risk for nephrotoxicity.33 The use of therapeutic drug monitoring may also prevent underdosing in patients with preserved kidney function and in the case of infections, in which standard dosing is likely insufficient. From a theoretical point of view, the free (unbound) colistin concentration should be measured because the unbound fraction varies from 26% to 41% in the concentration range of 0.01 to 2.5 mg/L.11 However, which form of colistin (total or free colistin plasma concentration) should be measured with therapeutic drug monitoring is still controversial. When therapeutic drug monitoring data are available, the AUC24/MIC parameter is preferentially used due to its relationship with bacterial killing.21 Otherwise, a trough concentration could be used for estimating the AUC when a pharmacokinetic model is on hand. In patients with decreased kidney function and/or increased volume of distribution, colistin concentration seems rather constant at steady state, and the use of minimum blood plasma concentration (Cmin) related to the MIC might be proposed.11,21 For example, in the case of P aeruginosa, a concentration 4 times the MIC resulted in successful bacterial killing at a MIC of 1 mg/mL; thus, in this case, an AUC24/MIC value of 96 (24 mg 3 h/L 3 4 mg/L) could be used as a target for total colistin. Taking into account 26% to 41% protein binding, an AUC between 25 and 40 could be the goal for unbound colistin. However, it is to be highlighted that therapeutic drug monitoring methods for colistin measurements are technically difficult, are cumbersome, and can only be done in a few laboratories. Thus, it is unlikely that, at least in the short term, they could be routinely applied and extensively introduced in daily clinical practice. Am J Kidney Dis. 2016;-(-):---

Colistin Use in Reduced Kidney Function

CONCLUSIONS Colistin is an effective antimicrobial agent in the treatment of severe infections sustained by multidrugresistant Gram-negative bacteria. It has high concentration-dependent antibacterial activity and a low rate of antimicrobial resistance. However, its use is hindered by neurotoxicity and nephrotoxicity. Few data about colistin pharmacokinetics are currently available, especially in patients at high risk for both overdosing/accumulation and underdosing, such as in the case of AKI and patients with end-stage renal disease receiving dialysis/hemofiltration. Future studies, possibly based on therapeutic drug monitoring results, should also establish the appropriate maintenance doses in patients with kidney failure undergoing RRT. In this clinical setting, it is likely that patients may receive substantially inadequate doses due to the highly efficient removal of the drug by RRT. A quite recent review75 presented a critical analysis of the divergent recommendations by the Food and Drug Administration and the European Medicines Agency on colistin dosing that are based on the same literature illustrated in the present paper.

ACKNOWLEDGEMENTS Support: This article was supported in part by a grant of the Italian Kidney Foundation (Fondazione Italiana per il Rene) and the Italian Society of Nephrology (Società Italiana di Nefrologia) “Colistin pharmacokinetics in sustained low-efficiency dialysis.” Financial Disclosure: Dr Fiaccadori: research grants and consultancy from Abbott, BBraun Melsungen, Baxter-Gambro, Fresenius, and Otsuka. Dr Morabito: reimbursements for travel/ accommodation expenses and consultancy from Baxter/Gambro. Mr d’Avolio: research grants, reimbursements for travel/accommodation expenses, and consultancy from Novartis. Dr Maggiore: research grants, reimbursements for travel/accommodation expenses, and consultancy from Behring, Chiesi, Novartis, and Teva. Dr Regolisti: reimbursements for travel/accommodation expenses and consultancy from Baxter-Gambro, Otsuka. Dr Antonucci declares that he has no other relevant financial interests. Peer Review: Evaluated by 2 external reviewers, a Co-Editor, the Education Editor, and the Editor-in-Chief.

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