1398

Colistin: How should It Be Dosed for theCritically Ill?Cornelia B. Landersdorfer, PhD1 Roger L. Nation, PhD1

1Drug Delivery, Disposition and Dynamics, Monash Institute ofPharmaceutical Sciences, Monash University, Melbourne, Australia

Semin Respir Crit Care Med 2015;36:126135.

Address for correspondence Roger L. Nation, PhD, Drug Delivery,Disposition and Dynamics, Monash Institute of PharmaceuticalSciences, Monash University (Parkville Campus), 381 Royal Parade,Parkville, Victoria 3052, Australia (e-mail: [email protected]).

Cornelia B. Landersdorfer, PhD (e-mail: [email protected]).

Colistin, together with polymyxin B, belongs to the group ofpolymyxin antibiotics which were discovered in the 1940sand introduced into patient care in 1959, but their clinicaluse was largely abandoned in the 1970s mainly due toconcerns about their potential to cause nephrotoxicity.1

Over the last two decades, the emergence of gram-negativesuperbugs that are resistant to essentially all contempo-rary antibiotics and the lack of newly developed antibacte-rials have led to a resurgence in the use of the polymyxins.24

Parenteral products of both polymyxins exist; of the twopolymyxins, colistin is more widely available around the

world. For successful clinical use of any antibiotic, dosageregimens need to be optimized to maximize bacterial killingand minimize emergence of resistance and potential toxici-ty. This is important for any patient group but particularly sofor the critically ill as they aremost at risk for highmorbidityandmortality.5 In addition, the above statement is especiallytrue for colistin because, as reviewed below, it is an antibi-otic with a narrow therapeutic window such that plasmaconcentrations that increase the risk for nephrotoxicity arenot far above those required for the desired antibacterialeffect.

Keywords

colistin critically ill polymyxins colistin

methanesulfonate pharmacokinetics pharmacodynamics toxicodynamics optimized dosing

Abstract Colistin, an old polymyxin antibiotic, is increasingly being used as last-line treatmentagainst infections caused by multidrug-resistant gram-negative bacteria. It is adminis-tered in patients, parenterally or by inhalation, as its inactive prodrug colistin meth-anesulfonate (CMS). Scientically based recommendations on how to optimally dosecolistin in critically ill patients have become available over the last decade and areextremely important as colistin has a narrow therapeutic window. A dosing algorithmhas been developed to achieve desired plasma colistin concentrations in critically illpatients. This includes the necessary dose adjustments for patients with impairedkidney function and those on renal replacement therapy. Due to the slow conversion ofCMS to colistin, a loading dose is needed to generate effective concentrations within areasonable 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 colistinminimum inhibitory concentration above 1 mg/L, as increasing the dose may not befeasible due to the risk for nephrotoxicity. Inhalation of CMS achieves considerablyhigher colistin concentrations in lung uids than is possible with intravenous adminis-tration, with negligible plasma exposure. Similarly, for central nervous system infec-tions, dosing CMS directly into the cerebrospinal uid generates signicantly highercolistin concentrations at the infection site compared with what can be achieved withsystemic administration. While questions remain to be addressed via ongoing research,this article reviews the signicant advances that have been made toward optimizing theclinical use of colistin.

Issue Theme Antimicrobial Resistance:Management of Superbugs; Guest Editor,David L. Paterson, MBBS, PhD, FRACP,FRCPA

Copyright 2015 by Thieme MedicalPublishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.

DOI http://dx.doi.org/10.1055/s-0034-1398390.ISSN 1069-3424.

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Colistin was never subjected to modern drug developmentand regulatory approval procedureswhichmeans thatmuchofthe information required to ensure its optimal use in patientshas been unavailable. The recent researcher-led redevelop-ment of colistin has resulted in an improved understanding ofits chemistry, parenteral formulations, pharmacokinetics (PK),pharmacodynamics (PD), and toxicodynamics (TD).3,6,7A goodunderstanding of all of these key characteristics is required tooptimize the clinical use of colistin and therefore these topicsare briey summarized below, followed by a review of thecurrent knowledge on how to optimally dose colistin incritically ill patients.

Chemistry, Units of Dosage, andFormulations

Colistin is a cyclic polypeptide which is a cation atphysiological pH. Being a fermentation product it consistsof several components, the major ones being colistin A andcolistin B.8 It is administered parenterally (most often intra-venously) and by inhalation as its inactive prodrug colistinmethanesulfonate (CMS, also known as colistimethate) whichhas a lower potential for acute toxicity than colistin.9,10

Conversion of CMS to colistin occurs in aqueous solutionsboth in vitro (e.g., water, bacterial growth media) and in vivo(e.g., plasma, urine).9,11,12 Indeed, the conversion is a prereq-uisite for antibacterial activity to be unmasked.

CMS products for parenteral and inhalational use arestandardized to the in vitro microbiological activity of colis-tin, but unfortunately labeling differs between geographicregions.2,13Most notably in Europe, the United Kingdom, andIndia, CMS content and doses are expressed as the number ofinternational units (IU). In North and South America, South-east Asia, and Australia the amount in milligrams of colistinbase activity (CBA) is used. A dose of one million IU corre-sponds to approximately 30 mg of CBA (and approximately80 mg of the chemical CMS). These different conventions(especially expression of milligram amounts of two distinctentities) used for labeling and dosing have a great potential tocause confusion in clinical practice resulting in medicationerrors and serious consequences for patients.13,14 Awarenessof the different terminology is required in clinical practice,especially when following recommendations in journal re-ports from different geographic regions. Articles for publica-tion should use the recently recommended standardizedterminology in expressing CMS doses.13

Colistin Antibacterial Activity andPharmacodynamics

CMS is an inactive prodrug and therefore it is essential thatcolistin is used in in vitro studies, including measurement ofminimum inhibitory concentration (MIC), that investigateactivity against bacterial strains.9 Colistin is active against arange of gram-negative bacteria with most strains ofPseudomonas aeruginosa, Klebsiella pneumonia, andAcinetobacter baumannii being susceptible, even strainsthat are multiresistant to other antibiotics.1518 The current

susceptibility breakpoints for colistin are 2 mg/L forA. baumannii and Enterobacteriaceae, and 2 mg/L or 4 mg/L for P. aeruginosa.19,20

Although the ultimate mechanism of bacterial killing isstill not known, the initial bacterial target of colistin is thelipopolysaccharide (LPS) in the outer leaet of the outermembrane of gram-negative bacteria.21 A key element inthe interaction is electrostatic attraction of the positivelycharged amine groups of colistin with negatively chargedphosphate and carboxylate groups on the lipid A and core-oligosaccharide of LPS. This electrostatic interaction enablesinteraction of the fatty acyl tail and other hydrophobicregions of the colistin molecule with hydrophobic domainsof LPS. These electrostatic and hydrophobic interactions arebelieved to weaken the packing of adjacent lipid A fatty acylchains causing substantial disruption and permeabilization ofthe outer membrane, including to colistin, a process termedself-promoted uptake.22 Subsequent steps in the killingaction are not well dened and are subject to ongoinginvestigation. Clearly, the initial interaction between colistinand LPS is analogous to a lock and key arrangement andexplains why colistin has very limited activity against gram-positive bacteria. Not unexpectedly, most of the knownmechanisms whereby gram-negative bacteria develop resis-tance to colistin involve either chemical modication of thephosphate groups of lipid A or elaboration of an outermembrane that lacks LPS, both being changes that attenuatethe initial electrostatic interaction between colistin and theouter membrane.21,23

In vitro static and dynamic (the latter conducted in PK/PDmodels to mimic clinically relevant uctuating concentra-tions in patients) concentration time-kill studies have dem-onstrated very rapid, concentration-dependent killing bycolistin of multidrug-resistant P. aeruginosa,2428 K. pneumo-nia,29,30 and A. baumannii.3134 A common feature of suchtime-kill proles is the regrowth of bacteria with enhancedresistance to colistin. This regrowth is often related to thephenomenon of colistin heteroresistance, which is the pres-ence of a subpopulation of colistin-resistant bacteria in anisolate that would be considered susceptible on the basis ofMIC.31 Following eradication of the predominant susceptiblepopulation, the colistin-resistant subpopulation undergoesunopposed amplication. The rate and extent of killing of P.aeruginosa in in vitro studies are considerably decreased at ahigh initial inoculum of 108 or 109 colony-forming units(CFU)/mL compared with a low initial inoculum of 106 CFU/mL.35 At inocula of 108 and 109 CFU/mL, killing of susceptiblebacterial populations was approximately 6-fold and 23-foldslower, respectively, compared with an inoculum of 106 CFU/mL. Clearly, the impact of the inoculum on the bactericidalactivity of colistin requires further examination. However, theresults of the study above35 imply that high-inoculum in-fections in patients may require more aggressive dosing.Colistin combination therapy should be considered for suchinfections because the risk of colistin-associated nephrotoxi-city increases with plasma colistin concentrations above2.53 mg/L as revealed by recent PK/TD analyses.36,37However, as discussed in the next section, it is important to

Seminars in Respiratory and Critical Care Medicine Vol. 36 No. 1/2015

Dosing of Colistin for the Critically Ill Landersdorfer, Nation 127

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be aware of uncertainties that surround the role of colistincombination therapy.

Recent studies in an in vitro PK/PD infectionmodel againstP. aeruginosa26 and in the gold standard mouse thighinfection model against P. aeruginosa38 and A. baumannii39

have demonstrated that the PK/PD index that best correlateswith the antibacterial activity of colistin is the ratio of the areaunder the concentration versus time curve to the MIC. Thesestudies26,38,39 suggest that it is important to achieve anaverage steady-state plasma colistin concentration of approx-imately 2 mg/L for isolates with MICs 1 mg/L. This ndingtogether with the relationship between plasma colistin con-centration and risk of nephrotoxicity,36,37 as discussed above,indicates that colistin is an antibiotic with a narrow thera-peutic window.

Activity of Colistin in Combination withOther Antibiotics

Studies conducted in in vitro static and dynamic infectionmodels using clinically relevant concentrations of colistin andvarious second antibiotics have provided evidence for in-creased bacterial killing and decreased emergence of resis-tance with the use of certain colistin combinations against P.aeruginosa, A. baumannii, and K. pneumoniae.27,28,30,34,40Notunexpectedly, the relative value of a combination may varyfrom bacterial strain to strain.41 Arguably, themost common-ly tested second antibiotic has been a member of the carba-penem class. A recent systematic review andmeta-analysis ofin vitro studies explored the relative activity of colistin versuscolistin plus carbapenem combinations.42 In general, acrossseveral carbapenems and bacterial species, bactericidal effectwas enhanced and resistance emergence suppressed by thecombination relative to the use of colistin alone. Across allbacterial species, of the carbapenems examined doripenemmost consistently achieved synergy with colistin.42

Notwithstanding the growing evidence from in vitro stud-ies for a benecial effect of colistin combinations, the situa-tion remains unclear in regard to the role of colistincombinations in patients. Very recently, an analysis wasconducted of all clinical studies (12 retrospective cohortstudies or case series, 2 prospective observational studies,and 2 randomized controlled trials [RCTs]) which comparedcolistin monotherapy versus colistin-based combinationtherapy for the treatment of infections caused by carbape-nemase-producing or carbapenem-resistant gram-negativebacteria.43 A requirement for inclusion in the analysis wasthat the original studies reported quantitatively on the asso-ciation between the treatment regimen and all-cause mor-tality. The analysis revealed that there was no difference inmortality between colistin alone and colistin/carbapenemcombination therapy in any of the individual studies or whenthey were pooled. Pooling the only two RCTs showed similarmortality for colistin monotherapy versus colistin/rifampicincombination therapy. However, the authors of the analysisindicated that numerous sources of bias in the original studiesexisted, including the following: the retrospective nature ofmost of the studies; differences between the monotherapy

and combination groups in regard to the nature and severityof infection; small sample sizes; appropriateness of the initialempirical antibiotic treatment; and the inclusion in somestudies of multiple noncolistin antibiotics in the combinationgroup.43 Additional limitations include the following: the useof dosage regimens of colistin and/or the second antibioticthat were not optimized based upon PK/PD principles; lack ofmeasurement of plasma concentrations of colistin in bothgroups to gauge the equivalence of exposure to colistin;failure to stratify outcomes based on the site and/or severityof illness; and, the administration of antibiotics other thanthe index second antibiotic to patients in both the so-calledcolistin monotherapy group and the combination group.Clearly, given ethical and practical considerations, it is muchmore difcult to study colistin combinations in patients in theabsence of potentially confounding effects than it is in apreclinical model where much tighter control over the ex-perimental conditions is possible. Well designed and ade-quately powered RCTs are needed to dene the role of colistincombination therapy. Two such RCTs (see NCT01732250 andNCT01597973 at ClinicalTrials.gov) are currently underwayto compare colistin/carbapenem combination therapy versuscolistin monotherapy for invasive infections caused by car-bapenem-resistant gram-negative bacteria.

Pharmacokinetics of CMS and FormedColistin: General Considerations

To optimize dosing of CMS/colistin, a good understanding ofthe PK of CMS and colistin is essential. Considerable progresshas been made in this eld since the beginning of theredevelopment of colistin and many reports of preclinicaland clinical studies are available.4450 It is important to beaware that old PK data (certainly the information generatedbefore the start of the 21st century) based on CMS/colistinconcentrations determined by microbiological assays areinvalid due to the ongoing conversion of CMS to colistinduring the incubation period of the assay.6 Despite this, PKdata based on these outdated and erroneous ndings are stillincluded in product information and package inserts.2,51 Thisreview will only consider PK data determined by high-per-formance liquid chromatography or liquid chromatography-tandem mass spectrometry methods that are capable ofseparately quantifying CMS and formed colistin in biologicaluids.

The inactive prodrug (CMS) and formed colistin (the activeantibacterial) have very different PK (Fig. 1).2,52 CMS iseliminated mainly via the kidneys, by glomerular ltrationand there may also be a component of tubular secretion.45

Because in a renally healthy individual the renal clearance ofCMS is much greater than its conversion clearance to colistin,only approximately 20% (or less) of a CMS dose is converted invivo to the active entity colistin.2,52 Not only is the extent ofconversion very low, but also the rate of conversion isslow.48,50 Thus, CMS is a highly inefcient prodrug, and theclinical consequences of these characteristics for therapeuticuse in critically ill patients will be discussed in the followingsection. In contrast, renal excretion plays a minor role in the


Dosing of Colistin for the Critically Ill Landersdorfer, Nation128

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overall elimination of formed colistin because followingglomerular ltration colistin is subject to very extensivetubular reabsorption (Fig. 1).2,3,7,44 The reabsorptive traf-cking of colistin through renal tubular cells is almost cer-tainly linked to its propensity to cause nephrotoxicity.

Pharmacokinetics of CMS and FormedColistin in Critically Ill Patients: Implicationsfor Dosing

Initially, PK following intravenous administration of CMSwillbe considered. Subsequently, consideration will be given toadministration of CMS directly to sites such as the lungs andthe central nervous system. There has been only one briefreport relating to three pediatric patients who ranged in agefrom 1.5 months to 14 years,53 and therefore the studiesreviewed below relate to critically ill adult patients.

Intravenous Administration of CMSThe rst report on the PK of intravenous CMS and the colistinformed from it in a critically ill patient, with plasma concen-trations measured using specic chromatographic methods,was by Li et al.54 The patient was receiving continuousvenovenous hemodialtration as part of management ofmultiorgan failure. Because the product information forCMS provided no information to guide dosage selection forsuch a patient, the patient was administered intravenously2.5 mg CBA per kg every 48 hour. This was a regimen that hadbeen proposed in a review on antibiotic dosing in patientsreceiving continuous renal replacement therapy, althoughthere was no supporting data for the suggested dosageregimen.55 The report of Li et al54 demonstrated that both

CMS and colistin were cleared by the renal replacementmodality. As a consequence of the extracorporeal clearanceand the inappropriately low daily dose of CMS, plasmaconcentrations of colistin were substantially lower than 1mg/L, the MIC of the infecting organism, for almost 90% of the48-hour dosage interval. Unfortunately, the patient did notsurvive. This case report sent a strong signal of the need for PKinformation to assist clinicians when selecting dosage regi-mens of CMS for various categories of critically ill patients.

Two subsequent small studies reported the steady-stateplasma concentrations of formed colistin, but not CMS, follow-ing intravenous administration of CMS to critically ill patients,all of whom had creatinine clearance greater than about 50mL/min.56,57 Patients were administered either 3 million IU(approximately 90 mg CBA) every 8 hours56 or 2 million IU(approximately 60 mg CBA) every 8 hours.57 Concern wasexpressed by the authors of both reports about the relativelylow plasma colistin concentrations achieved in the patients. Inthese two studies, it was not possible to identify any patientfactors that inuenced the steady-state plasma colistin con-centrations achieved. This was most likely due to the smallnumber of patients (n 14 and 13) included in the respectivestudies and the fact that all patients had creatinine clearancevalues greater than 46 and 96 mL/min.56,57

The PK of both CMS and formed colistin were investigatedin two clinical studies involving a total of 28 critically illpatients who received intravenously 1 to 3 million IU (ap-proximately 3090 mg CBA) every 8 hours andmost of whomhad moderate-to-good renal function (creatinine clearancerange 24214 mL/min).48,58 These and other studies48,50,58

identied a signicant problem that may arise if CMS regi-mens are not initiated with a loading dose. Because of theslow conversion of CMS to colistin mentioned above and thelong half-life of formed colistin, in the absence of a loadingdose of CMS plasma concentrations of colistin (the activeantibacterial) rise slowly over the rst 2 to 3 days of therapy.In the study of Plachouras et al,48 a loading dose was notadministered and plasma colistin concentrations were gen-erally below 1 mg/L after the rst dose (Fig. 2, panel B). Thelong delay in achieving plasma colistin concentrations thatare likely to be effective is of concern given the link betweentimely initiation of appropriate antibiotic therapy and clinicaloutcome in critically ill patients.59,60 Thus, a loading dose ofCMS at the initiation of therapy is advised.

In the two studies mentioned above,48,58 plasma concen-trations of CMS and colistin were also measured across adosage interval at steady state. While accumulation hadoccurred relative to concentrations after the rst dose, theplasma colistin concentrations across the dosage interval atsteady state in several patients were less than 2mg/L (Fig. 2,panel D). The authors expressed concern that the steady-stateplasma concentrations of colistin were low in relation tocurrent MIC breakpoints.48 The steady-state data alongwith those collected after the initial dose of CMSwere pooledacross the two studies and subjected to population PKanalysis.58 The clearance of the prodrug CMS was 13.1 L/h,its renal clearancewas similar to creatinine clearance and theterminal half-life was 2.2 hours. The half-life of formed

Fig. 1 Schematic diagram of the pharmacokinetic pathways forcolistin methanesulfonate (CMS) and colistin. The thickness of thearrows indicates the relative magnitude of the respective clearancepathways when kidney function is normal. After administration ofCMS, extensive renal excretion of the prodrug occurs with some of theexcreted CMS converting to colistin within the urinary tract. Adaptedwith permission from Nation et al.52



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colistin was considerably longer at 18.5 hours. A comprehen-sive search for patient covariates (e.g., body weight, renalfunction) that may inuence the disposition of CMS and/orcolistin was conducted by the authors. However, no cova-riateswere identied,most likely because of the small samplesize (total of 28 patients across the two studies) and only 3 ofthese patients had a creatinine clearance less than 50mL/min.

Garonzik et al50 reported the results of the largest studythus far on the PK of CMS and colistin in critically ill patients.The study population was 105 patients, including 89 not onrenal replacement who had a large range of renal function(creatinine clearance 3169 mL/[min1.73 m2]), 12 on inter-mittent hemodialysis and 4 on continuous renal replacement

therapy. The daily dose of intravenous CMS was at thediscretion of the treating medical team. Across all patientsthe daily dose ranged from 75 to 410 mg CBA (approximately2.513.7 million IU) with a median of 200 mg CBA (approxi-mately 6.67 million IU), and achieved an average plasmacolistin concentration at steady state (Css,avg) of 0.48 to9.38 mg/L (median 2.36 mg/L)(Fig. 3, panel B). That is, theapproximately 5.5-fold range in the daily dose of CMSresulted in approximately 20-fold range in the Css,avg ofcolistin in plasma. Initial graphical analysis of the datasuggested the likelihood that renal function, along with dailydose of CMS, was an important contributor to the wide rangeof plasma colistin concentrations observed (Fig. 4). Also,

Fig. 3 Plasma concentration versus time proles of the prodrug colistin methanesulfonate (CMS) (panel A) and formed colistin (panel B) across adosage interval at steady state in 105 critically ill patients (89 not on renal replacement, 12 on intermittent hemodialysis, and 4 on continuousrenal replacement therapy). Physician-selected CMS dosage intervals ranged from 8 to 24 hour and hence the interdosing blood sampling intervalspanned the same range. Reproduced with permission from Garonzik et al.50

Fig. 2 Plasma concentrations of colistin methanesulfonate (CMS) (panels A and C) and formed colistin (panels B and D) in individual critically illpatients after the administration of the rst dose of CMS (left panels) and the fourth dose of CMS (right panels). The dose of CMS was 3 million IU(90 mg colistin base activity [CBA]) every 8 hours in all except one patient who received 2 million IU (60 mg CBA) every 8 hours. Adapted withpermission from Plachouras et al.48



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evident from these graphs was that administration of a dailydose of CMS at the upper limit of the currently approveddosage range (300 mg CBA/d) was unable to reliably achieve aCss,avg of colistin in plasma of 2 mg/L. As noted above, thisconcentrationmay be considered as a reasonable target basedupon translation of current evidence from PK/PD studies inanimal infection models38,39 and given that PK/TD analysesindicate that the risk of nephrotoxicity in critically ill patientsincreases substantially as plasma colistin concentrationsexceed approximately 2.5 to 3 mg/L.36,37 Thus, in patientswith relatively good renal function (>80 mL/min), combi-nation therapy should be considered, particularly if the MICfor the infecting organism is toward the upper end of thecurrent breakpoint range.50

As the study of Garonzik et al50 comprised a large numberof patients, including those with very low renal function,population PK analysis was able to identify creatinine clear-ance as a patient covariate that inuenced the PK of both CMSand formed colistin. Because the prodrug (CMS) is predomi-nantly cleared by renal excretion (Fig. 1) it is easy tounderstand that its total body clearance declines with de-creasing kidney function. It may be more difcult to under-stand the impact of declining renal function on thedisposition of formed colistin given that renal excretion is avery small contributor to its overall elimination from thebody. The explanation lies in the relatively complex interplayof the dispositions of CMS and colistin. In a patient with goodkidney function, only a small fraction of each dose of CMS isconverted to colistin (Fig. 1). However, with declining renalfunction, a progressively larger fraction of each CMS dose isconverted to the active antibacterial. Thus, the apparentclearance of colistin decreases in parallel with creatinineclearance. Not unexpectedly, creatinine clearance was thepatient factor included in the algorithm developed by theauthors to calculate the CMS daily maintenance dose neededto generate a desired target steady-state plasma concentra-tion of formed colistin in a patient not receiving renalreplacement therapy.50

Reected by the data in Fig. 4, at a given creatinineclearance there was a very large degree of interpatient

variability (up to 10-fold) in the apparent clearance ofcolistin and consequently in the CMS daily dose to achievea desired steady-state plasma colistin concentration. Theinterpatient variability in the plasma colistin concentrationachieved at a certain creatinine clearance and daily dose ofCMS serves to complicate the clinical use of CMS, particularlysince colistin has a narrow therapeutic window. Because ofthis wide interpatient variability in PK, clinicians are encour-aged to use therapeutic drug monitoring (TDM) when avail-able to assist in titration of the dailymaintenance dose of CMSto achieve the desired steady-state plasma concentration ofcolistin.52

Of the 105 critically ill patients in the report of Garonzik etal,50 16 were receiving renal replacement therapy at the timeof initiating the CMS regimen (12 intermittent hemodialysisand 4 continuous renal replacement). These renal replace-ment modalities were shown to have a substantial impact onthe plasma colistin concentration achieved from a given dailydose of CMS; this was in agreement with reports from casestudies and case series.54,6166 There are two reasons whyrenal replacement therapy has such a substantial impact ondosage requirements of CMS. First, the circulating plasmaconcentrations of CMS are considerably higher than those offormed colistin (Figs. 2 and 3) and therefore a signicantproportion of thematerial dialyzed out of the patient is in theform of CMS, before there has been an opportunity forconversion to colistin in the body. Second, as noted above,colistin is subject to very extensive carrier-mediated tubularreabsorption in the kidney44 but a renal replacement car-tridge has no corresponding mechanism to return to thecirculation compounds, such as CMS and colistin, whichhave passively diffused into dialysate. As a result of theefcient extracorporeal clearance of CMS/colistin, dosageregimens of CMS for such patients must be carefully chosen.Garonzik et al50 by way of population PK modeling were ableto propose a daily maintenance dose of CMS to achieve adesired steady-state plasma concentration of formed colistinin patients receiving intermittent hemodialysis. Thealgorithm that was developed for designing dosage regimensfor patients on intermittent hemodialysis included

Fig. 4 Relationship of physician-selected daily dose of CMS (expressed as colistin base activity [CBA]) (panel A) and the resultant steady-stateplasma colistin concentration (panel B) with creatinine clearance in 105 critically ill patients. Reproduced with permission from Garonzik et al.50



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administration of a supplemental dose of CMS after thedialysis session to replace CMS and colistin that had beencleared by dialysis. These authors also developed a CMSdosage algorithm to achieve a desired plasma concentrationof formed colistin in patients receiving continuous renalreplacement therapy.50

The study of Garonzik et al50 also developed an algorithmfor calculating a loading dose of CMS to be administered topatients whether they are, or are not, receiving renal replace-ment therapy at the initiation of therapy. The loading dosealgorithm was based upon body weight being a covariate onthe volume of distribution of CMS. Alternatively, a nonweight-based loading dose may be used.67 The loading and mainte-nance doses proposed by Garonzik et al are the rst scienti-cally based regimens for CMS/colistin.50 The study went on torecruit a total of 230 critically ill patients and therefore theinterim dosing suggestions50 are not reproduced here as theywill be updated based upon the nal population PK/PDanalysis of the data.

There is very little information on the extent to whichcolistin distributes into important extravascular infectionsites (e.g., cerebrospinal uid [CSF], lungs) following intrave-nous administration of CMS. Concentrations of formed colis-tin in CSF are very low comparedwith those in plasma.53,68,69

In a similar way, following intravenously administered CMSthe concentrations of formed colistin in sputum of patientswith cystic brosis70 and in bronchoalveolar lavage (BAL)uid from critically ill patients57 are very low relative toconcomitant plasma concentrations. In relation to the latterstudy, it should be noted that BAL is an approximate 100-folddilution of epithelial lining uid (ELF) and given the limit ofquantication of the assay for colistin in BAL the result of thatstudy requires cautious interpretation. However, the currentdata overall suggest limited penetration of formed colistininto CSF and lung uids following intravenous administrationof CMS.

Administration of CMS Directly to the Central NervousSystem and LungsIt is axiomatic that bacterial killing by an antibiotic at anextravascular infection site requires achievement of adequateconcentrations of the antibiotic at that site. CMS is commonlyadministered to critically ill patients for the treatment ofventilator-associated pneumonia and less commonly for thetreatment of infections within the central nervous system.However, as reviewed briey in the last paragraph of thesection above, the emerging data suggest that followingintravenous administration of CMS the concentrations offormed colistin achieved in CSF and lung uids are very low.

Two recent studies, the rst in patients with cystic bro-sis70 and the second in mechanically ventilated critically illpatients,71 have demonstrated the substantially higher colis-tin concentrations that can be achieved in sputum and ELF,respectively, following inhalational delivery of CMS, com-pared with intravenous administration. Following pulmo-nary administration of CMS the extent of absorption intothe systemic circulation was minimal and the plasma con-centrations of formed colistin were very low.70,71 It was

possible in the study in cystic brosis patients to calculatethe pulmonary targeting advantage of inhalational adminis-tration (i.e., the relative values for inhalational versus intra-venous administration of CMS of the ratio of colistinconcentration in sputum to that in plasma).70 There was amassive targeting advantage with inhalational administra-tion, indicating the potential to achieve more effective bacte-rial killing in the lungs while sparing the kidneys. The role ofinhalational administration of CMS, possibly combinedwith asuitable intravenous regimen, in critically ill patients war-rants further investigation.

Intrathecal or intraventricular administration of CMS ap-pears to be a generally effective and safe treatment forventriculitis/meningitis caused by gram-negative bacte-ria.7275 A much lower dose is administered by these routesthan is typically administered intravenously. Because of therelatively small volume into which the intrathecal or intra-ventricular dose is delivered and the relatively slow turnoverof CSF, it is possible to achieve CSF colistin concentrations verymuch higher than is possible with intravenous administra-tion of a far larger dose.53,68,69 One would expect plasmacolistin concentrations following intrathecal or intraventric-ular administration of CMS to be very low, although thereappear to be no data to substantiate this. It can be noted,however, that colistin-associated nephrotoxicity appears tooccur rarely following these routes of delivery to the CNS.72,74

There may be benet in concomitant administration ofintravenous CMS.

Take-Home Messages

The following are some key points for those using colistin incritically ill patients to keep in mind:

How is colistin administered? Colistin is administeredintravenously and by inhalation as its inactive prodrugCMS (also known as colistimethate). CMS must be con-verted to colistin in the body. Care is needed to avoidconfusion arising from the different conventions used tolabel vials and specify doses.

What plasma concentration is appropriate for intravenousadministration? Based upon current evidence, a plasmacolistin concentration of 2 mg/L is a reasonable targetvalue for isolates with MICs 1 mg/L, and minimizes therisk of nephrotoxicity.

Should I consider colistin combination therapy? It is prudentto consider combination therapy for infections where thecausative organism has an MIC > 1 mg/L or when there isa high-inoculum or deep-seated infection (e.g., in lungs),especially in patients with moderate-to-good renal func-tion, although the clinical benet of colistin combinationsremains unproven.

Do I need to administer an intravenous loading dose? Yes,because CMS is relatively slowlyconverted to colistin in thebody and it may take many hours to achieve steady-stateplasma concentrations without a loading dose.

Do I need to adjust the daily maintenance dose if the patienthas renal impairment? The plasma concentrations of



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colistin achieved from a given intravenous daily dose areinuenced by kidney function. The recently developeddosing algorithm provides a means to tailor the daily dose.

Does renal replacement therapy have implications for selec-tion of intravenous dosage regimens? Yes, CMS and colistinare efciently removed from the body by both intermittenthemodialysis and continuous renal replacement therapy.The recently developed dosage algorithms for such pa-tients allow calculation of dosage regimens and of the sizeof a supplemental dose to be administered after eachintermittent hemodialysis session.

Is there a potential benet of using TDM to assist optimizingtherapy? Yes, colistin has a narrow therapeutic windowand plasma concentrations are subject to marked inter-patient variability, even at a given creatinine clearance anddaily dose of intravenous CMS. TDM is recommended if itis available.

Should I consider administration directly to the lungs or CNSfor infections in those sites? Intrathecal or intraventricularadministration of CMS is able to generate concentrations ofcolistin in CSF that are very much higher than can beachieved with intravenous administration, and the treat-ment appears to be safe and effective. Similarly, inhala-tional delivery of CMS generates concentrations of colistinin lung uids that are substantially higher than is possibleafter intravenous administration, with negligible plasmaconcentrations. The potential benets (more effectivebacterial killing in lung and sparing of the kidneys) areattractive, but remain to be proven.

In summary, over the last decade or so, considerableprogress has been made in understanding how to optimizethe clinical use of colistin in critically ill patients. However, asidentied in this article, answers are still required for severalimportant questions.

AcknowledgmentThis work was supported by the Australian NationalHealth and Medical Research Council (NHMRC, CareerDevelopment fellowship number 1062509 to C. B. L.).

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