Abstract
In this review, we provide an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last-line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS), when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin passes through physiological membranes poorly and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin are very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and a plasmid-mediated resistance mechanism (MCR-1) was recently described in animals and humans. In vitro, bacteria develop various resistance mechanisms rapidly when exposed to colistin. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Because colistin binds to laboratory materials, many experimental issues are raised. |
The dosing regimen of colistin methanesulfonate should be adapted to the renal function of patients, and the use of a loading dose is recommended. |
Therapeutic drug monitoring of colistin is warranted. |
Because the resistance of bacteria to colistin is increasing, its use in combination seems necessary. |
1 Introduction
Colistin, also called polymyxin E, belongs to the group of polymyxin antibiotics (antibacterials). It is an old antibiotic discovered in the 1940s but its clinical use was largely abandoned in the 1970s mainly due to its nephrotoxicity. However, the increase of multidrug resistance (MDR) in Gram-negative bacteria (GNB), particularly Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, led to the re-emergence of its use during the last few years [1]. Parenteral and nebulisation formulations for colistin contain the sodium salt of colistin methanesulfonate (CMS), also called colistimethate, which is an inactive prodrug. The aim of this review is to give an updated summary on colistin with respect to its complex pharmacokinetics and pharmacodynamics. A literature search was conducted using PubMed where colistin or colistin methanesulfonate were combined with key words such as “chemistry”, “bioanalysis”, “pharmacokinetics” or “pharmacodynamics” to identify relevant literature. Additional references were identified from the references lists of published articles.
2 Conventions Used to Describe Doses of Colistin
At the first International Conference of Polymyxins in Prato, Italy, in 2013, it was stated that colistin doses should be referred to using international units (IU) or mg of colistin base activity (CBA) in order to avoid medication errors [2]. In Europe, India and few other countries, doses of CMS are expressed in million international units (MIU), but also in mg of CMS. By contrast, in North and South America, Southeast Asia and Australia, doses are expressed in mg CBA. In order to convert these different units, it should be known that 1 MIU is equivalent to about 30 mg of CBA, which corresponds to about 80 mg of CMS [2].
3 Chemistry
Colistin (commercially available as the sulfate salt) is a decapeptide compound, corresponding to a complex mixture of about 30 different compounds with two main components, colistin A and colistin B, the proportion of which can vary from batch to batch [3]. Colistin A and B are large molecules with molecular weights of 1169 and 1155 g/mol, respectively. They are composed of a hydrophilic cycloheptapeptide ring, a tail tripeptide moiety and a hydrophobic acyl chain tail, being one carbon shorter for colistin B than for colistin A (Fig. 1) [4]. Colistin is a hydrophilic drug (logP = −2.4 [5]) but with an amphipathic property due to the presence of both lipophilic and hydrophilic groups [6]. Colistin exhibits basic properties (acid dissociation constant [pKa] of about 10) due to the unmasked γ-amino groups of the five l-α,γ-diaminobutyric acid (Dab) residues present in the cyclopeptide ring and tripeptide moiety (Fig. 1) [7]. Therefore, colistin is polycationic at pH 7.4 [8].
Structure of colistin methanesulfonate and colistin. Sulfomethyl groups of colistin methanesulfonate are highlighted with grey circles. Fatty acyl: 6-methyloctanyl for colistin A and 6-methylheptanyl for colistin B; α and γ indicate the respective –NH2 involved in the peptide linkage. Dab α ,γ-diaminobutyric acid, Leu leucine, Thr threonine
Colistin is administered parenterally as a prodrug, CMS. CMS differs from colistin by additional sulfomethyl groups on each of the five Dab residues (Fig. 1). In vivo, CMS undergoes hydrolysis to form a mixture of partially sulfomethylated derivatives that can eventually convert to colistin [9]. CMS A and B molecular weights are higher than for colistin (1635 and 1621 g/mol, respectively) due to the five additional sulfomethyl groups. CMS is more hydrophilic (logP = −12.1 [10]), and is supposed to be less basic than colistin, but to our knowledge its pKa has not been reported yet [11, 12]. At a physiological pH of 7.4, CMS is a polyanion [1].
CMS and colistin were shown to aggregate into micelles at high concentrations in aqueous solution: their critical micelle concentrations (CMCs) were 3.5 mmol/L (5.7 g/L) and 1.5 mmol/L (1.8 g/L), respectively [13]. The conversion of CMS into colistin was much faster when the concentration of CMS was below the CMC (60% over 48 h) than when it was above the CMC (1% over 48 h) [13]. The instability of CMS at low concentrations in pharmaceutical formulations is of concern, particularly because active colistin is much more toxic than CMS [14].
4 Bioanalysis
It is important that bioanalytical methods discriminate between colistin and CMS. Yet in old studies (overall before the start of the twenty-first century), colistin concentrations were measured by microbiological assays that could not discriminate between the two components because CMS was converted into colistin during the experimental time-course. By contrast, recent methods use high-performance liquid chromatography (HPLC) or liquid chromatography–tandem mass spectrometry (LC–MS/MS) that separate CMS and colistin. Colistin concentrations are generally calculated by summing the peak areas of the major components, i.e. colistin A and B. The internal standard is generally polymyxin B [15]. The measurement of CMS concentrations implies a two-step method with firstly the quantitation of colistin alone and secondly the hydrolysis of CMS into colistin by sulphuric acid, and the quantitation of the total colistin formed [15, 16]. CMS concentration is then obtained by subtracting the concentration of colistin measured before hydrolysis to that measured after hydrolysis. This method does not allow the discrimination of the different sulfomethyl derivatives and therefore the reported CMS concentrations should be interpreted as the summed concentrations of all these derivatives. Therefore, the reported pharmacokinetic parameters for CMS may best be considered as hybrid parameters for CMS and partially sulfomethylated derivatives [17].
For measuring plasma concentration, sample preparation can include a simple protein precipitation using trichloroacetic acid and methanol [18,19,20,21] and/or a solid-phase extraction [15, 18,19,20,21]. After separation by chromatography, detection is carried out either by LC–MS/MS [15, 21] or fluorimetry after derivatisation of colistin [18, 19]. The reported limits of quantification for colistin concentration in plasma are 0.03–0.04 mg/L with LC–MS/MS [15, 21] and 0.1–0.3 mg/L by HPLC-fluorimetry [18, 19]. It is of note that for measuring colistin concentrations in broth culture medium, urine, broncho-alveolar liquid and other biological fluids (cerebrospinal fluid [CSF], peritoneal, etc.) it has been recommended to spike the samples with blank plasma in order to avoid matrix effect and colistin binding to experimental materials [15, 21, 22].
5 Mechanism of Action
Most investigations on the mechanisms of action of polymyxins were carried out with polymyxin B, but the similarities between the chemical structures of polymyxin B and colistin suggest that their mechanisms of action are identical [23]. The lipopolysaccharide (LPS) present at the surface of the outer membrane of GNB prevents the penetration of hydrophobic and/or large antibiotics (antibacterials) [24]. Due to its positive charge, colistin interacts electrostatically with the negatively charged outer membrane of GNB and competitively displaces calcium (Ca2+) and magnesium (Mg2+) ions from the phosphate groups of LPS [7, 25]. Binding of colistin on the outer membrane is antagonised by divalent cations [26,27,28], resulting in a decreased antibacterial activity. It is of note that CMS, which differs from colistin by the addition of sulfomethyl groups masking the amines responsible for the positive charge, has a very weak antibacterial activity. Moreover, as the outer leaflet of mammalian cell membranes is charged neutral at physiological pH, colistin interacts less with mammalian cells [29]. Destabilisation of LPS leads to the disruption of the outer membrane, the loss of periplasmic and cytoplasmic contents and eventually bacterial death [24, 25, 30].
The endotoxin of GNB consists of the lipid A portion of the LPS, which can be shed by bacteria during antimicrobial therapy and can be responsible for endotoxic shock [31]. Colistin has an anti-endotoxin activity by binding to and neutralising the LPS [31,32,33,34,35].
Colistin also acts by several other mechanisms [36], such as an inhibition of vital respiratory enzymes (nicotinamide adenine dinucleotide [NADH]-quinone oxidoreductase) in the bacterial inner membrane [37].
6 Minimum Inhibitory Concentration Determination
For the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI), the reference method for minimum inhibitory concentration (MIC) determination of Enterobacteriaceae, P. aeruginosa and Acinetobacter spp. is the ISO (International Organization for Standardization)-standard broth microdilution [38, 39]. Cation-adjusted Mueller-Hinton broth (CAMHB) is used as the broth medium, with no additives included (in particular no polysorbate-80 or surfactants), the tray must be of plain polystyrene and not treated before use, and sulfate salt of colistin must be used [38, 39]. Addition of polysorbate-80 reduces the adsorption of colistin to polystyrene wells (see Sect. 12.1.1), but is currently not recommended by EUCAST and CLSI [40, 41]. The disc diffusion method should be avoided because colistin poorly diffuses in agar [42]. Moreover, the E-test method should be used with caution because about 50% of the results were reported to be false when compared with the results of the broth microdilution method [41, 43].
7 Antibacterial Activity
Susceptibility breakpoints for colistin published by EUCAST are 2 mg/L for P. aeruginosa, Acinetobacter spp. and Enterobacteriaceae [44]. For now, the susceptibility breakpoint published by CLSI is 2 mg/L for both P. aeruginosa and Acinetobacter spp. (resistance if MIC ≥8 and 4 mg/L, respectively) [38], but this breakpoint should be revised in 2017.
Colistin is active against several GNB including Acinetobacter spp., P. aeruginosa, Klebsiella spp., Enterobacter spp., Escherichia coli, Salmonella spp., Shigella spp., Yersinia spp. and Citrobacter spp. [40, 45]. By contrast, colistin is inactive on Gram-positive bacteria, anaerobes and some GNB (Proteus spp., Providencia spp., Morganella morganii, Serratia spp. and Burkholderia cepacia) [40, 45].
8 Resistance
Increasing use of colistin has led to the emergence of colistin resistance worldwide and although resistance to colistin is generally less than 10%, colistin resistance rates are continually increasing [24]. Resistance to colistin has been described in many GNB species such as A. baumannii, K. pneumoniae and P. aeruginosa [24, 46].
Colistin resistance in GNB is most commonly related to LPS modifications via diverse routes, of which several involve two-component regulatory systems (TCSs) [24]. PhoPQ and PmrAB are two TCSs whose functions and regulations overlap [47]. PhoPQ and PmrAB both include a sensor kinase (PhoQ and PmrB, respectively), which senses environmental signals such as low Mg2+, low pH or the presence of antimicrobial peptides. Moreover, exposure to colistin might also change the expression patterns of these TCSs [48, 49]. Activation of these sensor kinases lead to the phosphorylation of a response regulator (PhoP and PmrA, respectively), which, once phosphorylated, typically enhances their binding to promoters of regulated genes. Hence, phosphorylation of PhoP enhances the transcription of several genes, including pmrD, whose product binds to and stabilises PmrA in its phosphorylated state. Phosphorylation of PmrA upregulates the transcription of enzymes that are required for the addition of 4-aminoarabinose (l-ara4N) and/or ethanolamine to the lipid A component of LPS [6, 49,50,51]. These additions contribute to colistin resistance by reducing the negative charge of the bacterial membrane, and thereby decreasing the binding of positively charged colistin [50, 52, 53]. These adaptive mechanisms of resistance were generally of moderate level [52].
Recently, a plasmid-mediated colistin resistance mechanism MCR-1 was described for an E. coli strain in animals and human [54]. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression resulting in the addition of an ethanolamine moiety to the lipid A. Despite its relatively low level (MICs about 4–8 mg/L), this plasmid-mediated mechanism of resistance causes concern about a possible spread of colistin resistance into a range of enteric bacteria in humans and animals [55].
The phenomenon of colistin heteroresistance due to mutations in the chromosomal genes, involved in mechanisms such as lipid A biosynthesis (lpxA, lpxC, lpxD) or addition of l-ara4N, have also been described in A. baumannii and P. aeruginosa [53, 56,57,58]. This mechanism of resistance was shown to be of high level (MIC >128 mg/L) and was associated with a fitness cost for the bacteria [53, 56, 58]. Mutant strains were stable but in some patients the original susceptible isolate was able to re-emerge [53]. The reasons of this re-emergence were unclear, and could be due to the presence of a dormant persister population [59] or to the bacterial presence in locations inaccessible to colistin. Moreover, resistance was lost in one patient via the acquisition of a secondary mutation, which compensated for the fitness cost of drug resistance [53].
9 Clinical Pharmacokinetics
9.1 Plasma Concentrations in Healthy Volunteers
After a 1 h intravenous (IV) infusion of 1 MIU of CMS to healthy volunteers the CMS plasma concentrations reached a mean maximal value of 4.8 mg/L at the end of administration [60]. Thereafter, CMS concentrations declined biexponentially with a distribution half-life (t ½α) of 0.5 h and a terminal half-life (t ½β) of 2.0 h (Fig. 2).
Colistin methanesulfonate (open circles) and colistin (filled circles) mean (±standard deviation) plasma concentrations observed in 12 healthy volunteers after a single 1 h infusion of colistin methanesulfonate 1 MIU (million international units) (data from Couet et al. [60]). Conc. concentrations
The time to maximal plasma concentrations (C max) of the active compound colistin was 2 h after the start of the infusion (1 h after the infusion stop), and the mean colistin C max was 0.83 mg/L. Colistin plasma concentrations declined monoexponentially with a t ½β of 3.0 h. It is of note that as the t ½β of colistin was longer than that of CMS, meaning that colistin elimination is not rate-limited by its formation.
9.2 Clearance and Metabolism
CMS was two-thirds cleared by renal excretion in healthy volunteers [60]. The renal clearance of CMS in healthy volunteers was about 100 mL/min, which was close to the glomerular filtration rate (GFR; around 120 mL/min) [60]. However, as the unbound fraction (f u) of CMS in plasma is unknown, tubular reabsorption and secretion of CMS were not able to be estimated.
The non-renal clearance of CMS in healthy volunteers was about 50 mL/min [60]. One of the non-renal pathways for CMS clearance is its conversion into colistin by hydrolysis and removal of the five sulfomethyl groups from Dab residues. This hydrolysis leads to the formation of a series of different sulfomethylated derivatives (25 = 32 possible different derivatives) and to colistin. Other non-renal pathways, such as hydrolysis of peptide bonds, are possible for CMS but have not yet been assessed (Fig. 3).
Overview of the elimination pathways for colistin methanesulfonate and colistin. The thickness of the arrows indicates the relative magnitude of the respective clearance pathways when kidney function is normal. Colistin methanesulfonate includes fully and partially sulfomethylated derivatives of colistin (adapted from Nation et al. [23]). CMS colistin methanesulfonate
The colistin average concentration at steady state (C ss,avg) depends on both the fraction of CMS that is converted into colistin and the colistin clearance (adapted from Couet et al. [61]) (Eq. 1):
where CLconv is the conversion clearance of CMS into colistin, CLR is the renal clearance of CMS, CLNR is the non-renal clearance of CMS (=CLconv + clearance due to other non-renal pathways), τ is the dosing interval and CLcoli is the total clearance of colistin. As the fraction of CMS eventually converted into colistin is unknown, clearance and volume of distribution parameters for colistin are apparent parameters.
Colistin renal clearance was very low in healthy volunteers (1.9 mL/min) due to extensive tubular reabsorption [60]. The renal reabsorption of colistin may involve organic cation transporters (OCTN1), peptide transporters (PEPT2) and megalin, which is a low-density lipoprotein receptor. The renal reabsorption process is sensitive to the pH of urine [62,63,64]. Although renal excretion of colistin is very low, urine concentrations of colistin after administration of CMS can be high because of post-excretion hydrolysis of CMS into colistin within the urinary tract.
Elimination pathways of colistin are for the most part unknown. Considering its peptidic structure, colistin should be eliminated through hydrolysis but the enzymes involved and their localisation are still unknown. Blood, liver and kidneys are likely important sites for colistin elimination because they contain large amounts of proteases and peptidases; however, due to the ubiquitous availability of these enzymes throughout the body, proteolytic degradation of colistin should not be limited to classic elimination organs [65]. It is of note that the cyclic structure of colistin helps to protect colistin from proteolytic endopeptidases and the hydrophobic acyl chain helps to protect against exopeptidases, thus explaining that the colistin half-life (t ½) is longer than that of many peptides [65].
9.3 Distribution After Systemic Administration
Due to their large molecular weights and electric charge (polyanionic for CMS and polycationic for colistin) at physiologic pH, CMS and colistin cross cellular membranes and physiological barriers poorly. Indeed, volumes of distribution of CMS and colistin in healthy volunteers (14.0 and 12.4 L, respectively, apparent volume for colistin) have been shown to be consistent with a distribution restricted to the extracellular space [60].
9.3.1 Protein Binding
Colistin has been reported to bind to α-1-acid glycoprotein (AGP), whereas the binding to other plasma components such as albumin, lipoproteins or globulins remains to be elucidated [66]. Colistin is a large molecule that cannot enter the cavity of AGP to form a tight complex and instead a two-step process of binding has been proposed [66]. An initial electrostatic attraction occurs between the positive Dab residues of colistin and the negative sialyloligosaccharides proximal to the binding cavity of AGP. The second step consists of a stabilisation of the liaison by insertion of the lipophilic tail of colistin into the hydrophobic ligand binding cavity of AGP and/or binding to lipidic substances, such as phospholipid, bound to AGP. Therefore, both the positive charge and the amphipathic properties of colistin seem necessary for its binding to AGP in plasma. The importance of the charge is exemplified by the fact that CMS, for which Dab moieties are masked, does not bind to AGP [66]. It has been shown that colistin binds to AGP with less affinity than for bacterial LPS, thus suggesting that in vivo the affinity for LPS is strong enough to dissociate and sequester the colistin from AGP [66].
Protein binding can be determined either by ultrafiltration or equilibrium dialysis [67]. However, the extensive non-specific binding (>99%) of colistin to commonly used membranes [68] requires these experiments to be implemented with specific dialysis cells and membranes [67]. The assessment of colistin protein binding using a microdialysis method raises the same problem of colistin adhesion to experimental equipment [69].
In animals, plasma protein binding of 55% (f u = 45%) has been reported for colistin in rats, dogs and calves [68, 70]. In mice, the average percentage bound was around 91% (f u = 9%) in the total concentration range of 2–50 mg/L [67].
In critically ill patients, colistin binding to plasma components was about 59–74% [71]. Across the 0.01–15 mg/L range of total concentrations, at 37 °C, the bound fraction of colistin B was constant (average 57%), whereas the bound fraction of colistin A was dependent on the concentration. At 0.1 mg/L the average binding of colistin A was 84% against 69% at 10 mg/L, meaning that the f u of colistin A varied greatly as a function of the concentration (average 16% at 0.1 mg/L and 31% at 10 mg/L). This greater binding of colistin A, also demonstrated in rats [68], is most probably due to its longer fatty acid chain, since it is the only difference with colistin B. Whereas there is a difference in protein binding between colistin A and colistin B, to our knowledge, no difference in potency has been reported.
The level of plasma AGP can increase, depending on the disease condition, particularly bacterial infection [72]. Therefore, protein binding of colistin is expected to be higher in critically ill patients than in healthy volunteers. This has not been reported yet; however, protein binding of colistin was greater in infected mice than in healthy mice [66]. Moreover, protein binding of polymyxin B, which is chemically close to colistin, is greater in critically ill patients than in healthy volunteers [73].
In airways, colistin binds to mucin, which may reduce its antibacterial efficacy as illustrated by the >100-fold increase of MICs when mucin is added to growth medium [74].
9.3.2 Distribution Within Lung
Concentrations of CMS and colistin in epithelial lining fluid (ELF) are generally determined from concentrations measured in bronchoalveolar lavage (BAL) fluid after correction for dilution. The dilution factor is estimated based on the assumption that urea concentration is identical in plasma and ELF, by measurement of urea concentrations in plasma and BAL [22]. The determination of colistin concentration in BAL fluid should take into account the non-specific binding to the BAL material, which can be particularly high at low concentrations (80% for colistin concentrations <1 mg/L; unpublished data).
Intravenous (IV) Administration After repeated IV administrations of 2 MIU CMS every 8 h to critically ill patients, Imberti et al. [75] could not measure colistin in BAL (limit of quantification = 0.1 mg/L). By contrast, Boisson et al. [76] reported colistin concentrations in the ELF at steady state ranging between 0.1 and 29 mg/L. For their part, Yapa et al. [77] reported colistin concentrations in sputum lower than 1 mg/L after a single IV administration of CMS 5 MIU. No active transport has been reported yet for the passage of the pulmonary barrier by colistin. However, OCTN1 and PEPT2, which are involved in the renal reabsorption of colistin, are also present in the lung [78]. Moreover, the involvement of these proteins in the pulmonary transport of active substances has already been suggested: the uptake of anti-cholinergic drugs for OCTN [79] and transport of bacterial peptides for PEPT2 [80]. In addition to their capability to pass through pulmonary barrier, CMS and colistin distribution into lung also depends on their binding to lung components. This issue is not yet elucidated but it has been shown that colistin binds to mucin [74].
Inhalation Aerosolised colistin, administered as CMS, is used to treat nosocomial pneumonia caused by MDR GNB [76, 80,81,82,84]. After pulmonary administration of CMS, the presence of colistin in plasma can either result from the absorption of CMS followed by systemic conversion into colistin or from the pre-systemic conversion of CMS into colistin followed by its absorption [22]. When nebulised directly as colistin, the absolute bioavailability was shown to be high (69%) in rats [85]. However, after nebulisation of CMS to critically ill or cystic fibrosis (CF) patients, colistin plasma concentrations were either below the limit of quantification [77] or low (<0.73 mg/L) [76, 86], except for one study for which concentrations up to 2 mg/L were reported [87]. In critically ill patients, when nebulised as CMS, only 9% of the dose reached the systemic circulation: 1.4% as colistin converted presystemically and 7.6% as CMS [76].
After aerosol delivery of CMS to critically ill patients ELF colistin concentrations were much higher than those in plasma (5- to 1000-fold) but varied considerably, from 1 to 1100 mg/L, depending on dose (1 or 2 MIU single dose or every 8 h), time (1–8 h post-dose) and the study [76, 87].
In CF patients, CMS and colistin concentrations are generally determined in sputum. In these patients, after nebulisation of single 2 or 4 MIU doses of CMS, systemic exposure to colistin was very low, whereas colistin concentrations measured in sputum ranged from 1 to 45 mg/L [77, 86]. However, a conversion of CMS to colistin during the preparation of sputum samples before bioanalytical assay cannot be ruled out in one of these studies, due to a relatively high concentration of trifluoroacetic acid used for sample preparation [86].
Overall, these studies show that colistin systemic exposure is low after CMS nebulisation, whereas colistin concentrations in lung are high.
9.3.3 Distribution Within the Central Nervous System
IV Administration The passage across the blood–brain barrier (BBB) by CMS and colistin is limited. Colistin penetration into the CSF after repeated IV administrations of CMS was demonstrated to be low (5%) in critically ill patients [88]. The presence of meningeal inflammation enhanced penetration in CSF (11%) [89]. In paediatric patients the CSF/serum ratios were reported to be 34–67% in the presence of meningitis (measurement before and after IV CMS administration), whereas it was minimal in the absence of meningeal inflammation [90]. Moreover, it has been shown in mice that LPS can induce BBB disruption by decreasing the tight junction function; this effect depends on the bacterial species and can increase colistin uptake into the brain [91]. For now, the effect of transporters on the passage of BBB by CMS or colistin has not been reported.
Intrathecal–Intraventricular Administrations Colistin concentrations in CSF are higher when patients are treated by intraventricular or intrathecal CMS administration than when they are treated intravenously. Imberti et al. [92] reported CSF concentrations continuously above 2 mg/L if the intraventricular CMS dose was greater than 0.06 MIU every 24 h. Ziaka et al. [89] reported CSF concentrations ranging between 0.6 and 1.5 mg/L when patients were treated with combined IV CMS 3 MIU every 8 h and intraventricular CMS 0.125 MIU every 24 h.
9.3.4 Distribution in Peritoneal Fluid
In one case report, after multiple administrations of CMS 2 MIU every 8 h, colistin distributed slowly into the peritoneal fluid of a patient with severe peritonitis, but colistin concentrations in peritoneal fluid were close to that in plasma at steady state [93].
9.4 Oral Route of Administration
Colistin absorption from the gastrointestinal tract is slight or absent [94]. In simulated gastric fluid it has been shown that colistin was rapidly degraded by rupture of peptide bonds in the tail tripeptide moiety under the action of pepsin [4], the formed metabolites keeping an antimicrobial activity. Colistin sulfate is sometimes used for perioperative decontamination of the digestive tract, particularly for the suppression of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E). In this indication, colistin sulfate is generally administered orally following a dosing regimen of 100 mg every 6 h, in combination with other anti-infective agents (e.g., amphotericin B, tobramycin) [94,95,96,97,99]. However, this practice has been shown to select colistin-resistant bacteria and its use is controversial [99,100,101,103].
9.5 Pharmacokinetics in Special Populations
9.5.1 Pharmacokinetics in Critically Ill Patients
Maintenance Dose After IV administration of CMS to critically ill patients, the pharmacokinetics of CMS was very variable (Fig. 4). The C max values were observed at the end of infusion; thereafter, CMS concentrations decreased in a mono- or bi-exponential manner, with a mean t ½β ranging from 1.9 to 4.5 h depending on the study [103,104,106]. The mean plasma profile was comparable to that observed in healthy volunteers, except when the renal function of the patient was altered. Indeed, concentrations of colistin are related to the renal clearance of CMS (Eq. 1), which correlates with creatinine clearance [104, 105]. For illustration, for patients with creatinine clearance values of 120, 50 and 25 mL/min, the typical renal clearances of CMS were about 100, 50 and 25 mL/min, respectively. The main impact of this decrease of CMS renal clearance when the renal function was impaired was that the fraction of CMS converted into colistin increased, e.g. 33, 50 and 67% for the three different values of creatinine clearance of 120, 50 and 25 mL/min, thus resulting in greater colistin concentrations for patients with altered renal function. Moreover, the volume of distribution of CMS was shown to be proportional to the body weight, which after a single dose impacts on the C max of CMS and colistin (to a lesser extent) and after repeated administrations impacts on the fluctuation of concentrations, i.e. the larger the volume of distribution is, the lower the concentrations fluctuate [104, 105]. However, even when considering individual renal function and body weight, the pharmacokinetics of CMS were very variable between patients after IV administration of CMS [104, 105].
Colistin methanesulfonate and colistin plasma concentrations observed (×) in 73 critically ill patients after first colistin methanesulfonate dose and at steady state. Reproduced from Grégoire et al. [105] with permission of the American Society of Microbiology. CMS colistin methanesulfonate, Conc. concentrations
Concerning the pharmacokinetics of colistin after administration of CMS to critically ill patients, some discrepancies were observed between studies. Indeed, after a first dose of 2 MIU of CMS, Grégoire et al. [105] observed typical colistin C max values of about 2 mg/L, whereas after a first dose of 3 MIU of CMS Plachouras et al. [106] observed a colistin C max of 0.6 mg/L [106] (Fig. 5). Moreover, the C max values were reached sooner for Grégoire et al. [105] (about 3 h) than for Plachouras et al. [106] (maximum not reached at next administration, i.e. 8 h). These different time to C max values were related to greater apparent volumes of distribution, resulting in longer typical t ½ values for colistin (9–14 vs. 3 h) [103,104,106]. One major consequence of a longer t ½is that from Plachouras et al. [106] at least 48 h is necessary to reach steady state, whereas from Grégoire et al. [105] steady state should be reached after as soon as 12 h. At steady state there were fewer discrepancies between studies: for a patient with a clearance of creatinine of 82 mL/min, treated with CMS 3 MIU every 8 h, the typical colistin C ss,avg was predicted to be between 1.5 and 3.5 mg/L depending on the study (Fig. 5) [103,104,106]. Plachouras et al. [106] were the first to point out the difficulties in attaining a C ss,avg of 2 mg/L for patients with a creatinine clearance ≥80 mL/min [106]. Recently, Nation et al. [107] suggested the use of an algorithm to calculate the CMS dose to administer according to the creatinine clearance, and demonstrated that less than 40% of the patients with creatinine clearance above 80 mL/min attained a C ss,avg >2 mg/L, even with a maximal 12 MIU daily dose.
Colistin concentrations following a 3 MIU (million international units) dose of colistin methanesulfonate infused over 60 min every 8 h in a critically ill patient with a creatinine clearance of 82 mL/min and a body weight of 80 kg, predicted from Grégoire et al. [105] (solid black line), Plachouras et al. [106] (dashed grey line) and Garonzik et al. [104] (dashed black line). Reproduced from Grégoire et al. [105] with permission of the American Society of Microbiology. Conc. concentrations
Loading Dose Plachouras et al. [106] suggested that administration of a loading dose is necessary to achieve effective colistin concentrations as soon as the first CMS administration; two subsequent studies have assessed this suggestion [71, 108]. In the first study, after administration of 6 MIU of CMS to ten critically ill patients, colistin C max values were on average 1.3 mg/L (range 0.3–2.6 mg/L) at 8 h following dosing and the mean colistin t ½ was 18.5 h [71]. In the second study, following administration of a 9 MIU loading dose to 19 critically ill patients the C max values of colistin were also very variable (mean 2.65 mg/L, range 0.9–5.1 mg/L) and the mean colistin t ½ was 11.2 h [108]. Colistin concentrations observed in this latter study were therefore higher than expected from previous studies performed by the same team [71, 106] but lower than those predicted by Grégoire et al. [105]. Overall, these discrepancies of colistin pharmacokinetics between studies were attributed either to (1) a higher proportion of the A and B forms in the more recent CMS formulations [108]; (2) the use of different CMS brands; (3) the inclusion of patients with different renal function; (4) CMS solutions for infusions at concentrations below or above the CMCs of 5.7 g/L (71,250 IU/mL); (5) in vitro conversion of CMS to colistin after blood collection [109]; or (6) potential discrepancies in the analytical methods (e.g. in the quantification of partly sulfomethylated compounds and potential hydrolysis during work-up) [108].
Dosing Suggestions Considering the pharmacokinetics of both CMS and colistin, the CMS dose has to be adapted to each patient’s renal function. In case of normal renal function, all of the previous cited studies recommend a maintenance dose of 9 MIU of CMS per day in two or three injections [105, 106], which corresponds to the calculated maintenance dose suggested by the algorithm of Garonzik et al. [104]. It is of note that the most recent publications all agree that CMS should be administered twice daily [105,106,108]. The maintenance dose should be adapted to the renal function of the patient. The European Medicines Agency (EMA) suggests that for patients with a creatinine clearance above 50 mL/min the daily dose should be 9 MIU (up to 12 MIU in some cases, for patients with good renal function), for patients with a creatinine clearance between 30 and 50 mL/min the daily dose should be between 5.5 and 7.5 MIU, and for patients with a creatinine clearance between 10 and 30 mL/min the daily dose should be 5 MIU [110, 111].
Concerning the loading dose, Garonzik et al. [104] suggest it should be adapted to the patient’s body weight without exceeding 10 MIU, whatever their renal function, and to begin maintenance doses 24 h later. Karaiskos et al. [108] demonstrated that a loading dose of 9 MIU followed by the beginning of a maintenance dose 24 h later was safe for their 19 critically ill patients with normal renal function. The Committee for Medicinal Products for Human Use (CHMP) of the EMA proposed a loading dose of 9 MIU for patients above 60 kg and 6 MIU for patients below 60 kg; doses up to 12 MIU may be required for patients but the clinical experience with such doses is limited [110]. The loading dose should apply to all patients regardless of renal function. Recently, it was suggested that the first maintenance dose be administered 12 h after the loading dose [107].
9.5.2 Pharmacokinetics in Patients with Haemodialysis
In patients with highly impaired renal function, CMS is poorly excreted in urine and therefore the fraction of dose available for conversion to colistin is higher. As a consequence, on days without a haemodialysis session, colistin exposure was threefold greater in critically ill patients requiring haemodialysis than in patients with preserved renal function and treated with the same dosage [112].
Considering their molecular weights, CMS and colistin fractions unbound in plasma can freely pass through dialysis membranes. Moreover, colistin might also adsorb on dialysis membranes, notably those used for continuous renal replacement therapy, which could contribute to the removal mechanism [113]. Indeed, during intermittent haemodialysis sessions, CMS and colistin are efficiently cleared [104, 113,114,116]. Mean clearance of CMS during haemodialysis session was reported to be between 71 and 95 mL/min [104, 114, 116], and associated estimation of inter-individual variability was sometimes low (26% coefficient of variation) [114] but sometimes high (96%) [104]. Mean clearance of colistin during haemodialysis session was reported to be between 57 and 134 mL/min [104, 114, 116]; inter-individual variability was estimated to be moderate (15 and 44%) [104, 114].
Dosing Suggestions for Intermittent Renal Replacement Therapy Previous data suggested that during a non-haemodialysis day, the CMS daily dose should not exceed 3 MIU [104, 112], but recently Nation et al. [107] suggested administration of 3.95 MIU per day to achieve the average steady-state colistin concentration of 2 mg/L. During a haemodialysis day, it is suggested that a supplemental dose be administered at the end of the haemodialysis session (30–50% of the daily dose) [104]. In each study, CMS was administered twice daily [104, 107, 112].
During continuous venovenous haemofiltration (CVVH) Garonzik et al. [104] reported mean CMS and colistin removal clearances slightly lower than those measured during intermittent haemodialysis (64 vs. 95 mL/min and 34 vs. 57 mL/min for CMS and colistin, respectively). During continuous venovenous haemodiafiltration (CVVHDF) Markou et al. [117] reported that extracorporeal clearance contributed to about 50% of total colistin clearance; however, the total colistin clearance was lower than that in patients with normal renal function, suggesting that a dose reduction may be needed in critically ill patients with CVVHDF. By contrast, Karvanen et al. [118] reported that colistin concentrations obtained under CVVHDF and receiving 2 MIU CMS every 8 h were lower than those for corresponding patients without CVVHDF, and consequently that CMS dosage should not be reduced for patients undergoing CVVHDF. More strongly, Karaiskos et al. [119] recommended an increased dose for patients under CVVH with a loading dose of 12 MIU of CMS followed by 13–15 MIU daily maintenance doses.
Dosing Suggestions for Patients Under Continuous Venovenous Haemofiltration The last recommendations published by Nation et al. [107] correspond with those published by Karaiskos et al. [119] and suggest a maintenance dose of 13 MIU daily divided into two doses. Concerning the loading dose, even if a loading dose of 12 MIU has been found more appropriate, clinical data of safety are limited and it is recommended not to exceed 9 MIU [107, 119]. Considering the large inter-individual variability, therapeutic drug monitoring (TDM) is advised for patients undergoing CVVHDF [120].
9.5.3 Pharmacokinetics in Cystic Fibrosis (CF) Patients
The pharmacokinetics of colistin in CF patients have been described after IV administration [77, 121] and after nebulisation of CMS. Following IV infusion of CMS, plasmatic pharmacokinetics for CMS were consistent between studies [77, 121] and with healthy volunteers [60], i.e. the reported values for clearance were about 100 mL/min, volume of distribution about 18 L and t ½ about 2.5 h. Colistin pharmacokinetics in plasma after infusion of CMS were also characterised by a t ½ close to that in healthy volunteers (4–7 h) [77, 121]. However, it should be noted that after a single IV infusion with the same CMS brand (Colimycin®), colistin (the active compound) exposure was 39% lower in CF patients than in healthy volunteers, suggesting that colistin clearance could be higher in CF patients [122].
After single nebulisation of CMS 2 or 4 MIU to CF patients, Yapa et al. [77] reported CMS and colistin concentrations in sputum that were higher (C max for colistin in sputum ranging from 2.09 to 21.2 mg/L) than those resulting from IV administration (C max < 1.0 mg/L) [77]. Moreover, the systemic availability of CMS was low (about 6%) and systemic exposures to CMS and colistin were minimal. Ratjen et al. [86] reported colistin concentrations that were significantly higher (mean C max about 40 mg/L) than those reported by Yapa et al. [77] in sputum following nebulisation of a single dose of 2 MIU of CMS, but their bioanalytical method for quantitating colistin might have promoted the conversion of CMS into colistin and thus overestimate colistin concentrations in sputum.
Dosing Suggestion for CF Patients Local administration of CMS by nebulization with or without IV administration is suggested for this population. CF centres worldwide have adopted different inhaled CMS dosing regimens (dose and dosing interval), with current therapies ranging from 1 MIU of CMS twice daily to 2 MIU of CMS three times daily [122,123,125].
9.5.4 Pharmacokinetics in Burn Patients
In burn patients, after IV administration of CMS 5 MIU every 12 h, the typical t ½ of colistin was reported to be 6.6 h [126] and the clearance of colistin was comparable to that of critically ill patients [103,104,106] and healthy volunteers [60, 127], suggesting that it was not affected by the hypermetabolism in burn patients. The volume of distribution of colistin was slightly greater than that reported in healthy volunteers and either greater [105] or lower [104, 106] than those reported in critically ill patients.
10 Adverse Events
Two main types of toxicity, nephrotoxicity and neurotoxicity, are reported with the use of colistin. However, recent studies have reported that the incidence of nephrotoxicity is less common and severe than that reported in studies and case reports published until 1983 [128]. The observed nephrotoxicity was as high as 50% in old studies versus 15–25% in recent studies, although the definition of nephrotoxicity was not standardised between the studies [128]. However, in a recent study in patients with severe sepsis or septic shock, there was an incidence rate of acute kidney injury (AKI) of 44% following colistin administration [129]. Risk factors for nephrotoxicity include baseline renal impairment, age, severity of illness, nephrotoxic agents, duration of therapy and daily dose by ideal body weight [129, 130]. A residual concentration of colistin >2.42 mg/L was also reported as a predictor for AKI [131]. In contrast, CF might be protective against the development of nephrotoxicity [130].
Colistin-associated nephrotoxicity usually occurs within the first 5 days of treatment and is reversible upon cessation of treatment [132, 133]. Renal insufficiency generally manifests as a decrease in creatinine clearance but haematuria, proteinuria, cylindruria or oliguria can also occur [128]. The nephrotoxicity of colistin is certainly related to its extensive renal tubular reabsorption due to the numerous transporters located in the proximal tubules, particularly the megalin (see Sect. 9.2) [64, 134]. Colistin toxicity could be due to its accumulation in the endoplasmic reticulum and mitochondria of renal tubular cells, resulting in a modification of the cell fate under oxidative stress [135]. Coadministration of ascorbic acid at a daily dose of 2–4 g in patients with severe sepsis was shown to reduce the AKI risk to four times lower than that in patients who did not receive ascorbic acid [129]. This effect could be explained by a double kidney-protective effect toward both colistin-induced and septic renal damage [129]. However, in another study with moderately ill patients the ascorbic acid did not offer a nephroprotective effect [134].
The incidence of neurotoxicity related to the use of colistin is lower than that of nephrotoxicity [128]. The most frequent neurological adverse effect is paraesthesia, which in old studies was reported to occur in 27 and 7.3% of patients receiving IV and intramuscular CMS, respectively. Other neurological adverse events include mental confusion, vertigo, ataxia and seizure, but the most dreaded complication is neuromuscular blockade presenting as respiratory muscle paralysis and apnoea [128, 136]. Like renal toxicity, neurological toxicity is considered to be dose dependent and is usually reversible after early discontinuation of the treatment [128].
Colistin aerosol therapy is generally well-tolerated, with few reported adverse events such as throat irritation, cough and bronchospasm [137, 138].
Intrathecal/intraventricular administration is also well-tolerated. One of the adverse effects reported is chemical meningitis (5/153 cases reported between 1972 and 2016) with complete resolution after the discontinuation of the intrathecal administrations, and there is no mention of nephrotoxicity [139].
11 Therapeutic Drug Monitoring
Because the pharmacokinetics of colistin is very variable between patients (Fig. 4), and because its therapeutic window is narrow, TDM of colistin is warranted after IV administration [140]. TDM of colistin requires a validated bioanalytical method (see Sect. 4). Because CMS can hydrolyse into colistin after sampling, it is recommended that blood specimens be drawn just before the next dose (trough), i.e. when the CMS concentrations are the lowest, and to handle the samples quickly.
It has been reported that colistin C ss,avg values should be higher than 2 mg/L to be effective [107]. These plasma concentrations of colistin should allow the pharmacokinetic/pharmacodynamic indices to reach target values determined in the mouse thigh infection model (ratio of the area under the unbound concentration–time curve to the MIC [fAUC/MIC] of about 12) for bacteria with an MIC lower than 2–4 mg/L [111], which correspond to the EUCAST breakpoint for susceptibility [44]. However, minimum plasma concentrations (C min) of colistin higher than 2.5 mg/L have been associated with an increased risk of nephrotoxicity [131, 141]. Therefore, to be effective and avoid adverse events, C ss,avg should ideally be between 2 and 2.5 mg/L. In practice, the clinically desirable range of C ss,avg is rather from 2 to 4 mg/L [107], but renal function has to be monitored. Because it is preferable to draw the samples just before the next dose and because the fluctuations of plasma concentrations are relatively weak, this therapeutic window can also apply to residual concentrations. CMS dosing regimen has to be individualised according to concomitant medications and to the risk/benefit ratio for each patient.
12 Pharmacodynamics
12.1 In Vitro Pharmacodynamics
12.1.1 Experimental Issues
As the presence of Ca2+ and Mg2+ ions modifies the susceptibility of bacteria to colistin, their concentration into broth should be controlled and CAMHB is generally used for in vitro pharmacodynamic experiments with colistin [41]. From an experimental point of view, the fraction of colistin bound to CAMHB with initial colistin concentrations of 10 and 30 mg/L was 5% [142]. Therefore, the growth medium seems to not affect unbound concentrations of colistin used for in vitro experiments.
The in vitro determination of bacterial susceptibility to colistin poses numerous experimental problems. Several studies reported potential non-specific binding of colistin to experimental material [142,143,145]. Karvanen [146] characterised the extent of the colistin loss in different types of laboratory materials during simulated time-kill experiments without bacteria. The type of material and the concentration of colistin were the two main factors contributing to non-specific binding of colistin: out of four tested materials (glass, polypropylene, polystyrene and low protein-binding polypropylene), none performed well enough to enable to ignore binding to material at concentrations between 0.125 and 8 mg/L. The best performing material was low protein-binding polypropylene with colistin loss between 45 and 10%. The relative loss due to binding increased when the concentration decreased; for instance in CAMHB, when using large polypropylene tubes, at 24 h the measured colistin concentration represented 13 and 62% of the 0 h concentrations of 0.125 and 4 mg/L, respectively. In polystyrene microplates the colistin losses were even larger, e.g. the measured concentration represented 4% of the expected 8 mg/L concentrations [146]. The impact of this non-specific binding on in vitro pharmacodynamic results is unclear. However, it is recommended, when possible, that low protein-binding polypropylene be used and colistin concentrations are measured during the time course of the experiments.
12.1.2 Pharmacokinetics/Pharmacodynamics of Colistin Alone
For colistin, in vitro pharmacokinetic/pharmacodynamic studies mainly focused on three Gram-negative pathogens: P. aeruginosa, A. baumannii and K. pneumoniae.
Determination of the pharmacokinetic/pharmacodynamic index that best predicted colistin efficacy on P. aeruginosa was performed using a dynamic in vitro pharmacokinetic model. fAUC/MIC was shown to be the pharmacokinetic/pharmacodynamic index that most closely correlated with the killing of P. aeruginosa, with target values for 2 log10 kill at 24 h of between 27.2 and 41.7 for reference strains (ATCC27853 and PAO1) [147].
In time-kill experiments, with a constant concentration of colistin over time, colistin was shown to be bactericidal on 21 P. aeruginosa strains at concentrations higher than 0.5 × MIC, with complete killing happening very quickly and bacteria becoming undetectable 4 h after treatment initiation. At concentrations equal to 0.5 × MIC, a small initial decrease in the concentration of colony forming units (cfu) was observed, followed by regrowth at 24 h [148] (Fig. 6). Time-kill experiments were also performed on the A. baumannii ATCC19606 reference strain and on 16 clinical isolates. Similar to what was observed with P. aeruginosa, low concentrations of colistin produced an initial decrease in cfu/mL followed by regrowth at 24 h [149]. In time-kill experiments on reference and clinical strains of K. pneumoniae, a regrowth was also observed after an initial rapid killing, even at a high colistin concentration (i.e. 64 × MIC) [150].
Typical observed profile from one experiment for static time-kill curves for Pseudomonas aeruginosa exposed to colistin. Time-kill curve experiments for wild-type (ATCC27853) P. aeruginosa with concentrations ranging between 0.042 and 12 mg/L (minimum inhibitory concentration [MIC] = 1 mg/L). Reproduced from Mohamed et al. [155] with permission of the American Society of Microbiology. cfu colony-forming units
Dynamic in vitro models allow mimicking of human clinical regimens and evaluation of antimicrobial efficacy at concentrations varying over time. In this way, the efficacy of four different clinical dosing regimens of colistin against A. baumannii were compared, but none were able to eradicate the bacterial strain [151].
Population analysis profiles (PAPs) can be performed during time-kill or dynamic experiments in order to explore the heteroresistance phenomenon, characterised by the presence of several subpopulations of bacteria with different susceptibilities to colistin. A dynamic in vitro pharmacokinetic model was used to compare the efficacy of colistin regimens with 8, 12 or 24 h dosing intervals against P. aeruginosa [152]. No difference in bacterial kill was observed between regimens, but PAPs suggested that the 8 h dosing interval minimised the emergence of resistance [152]. PAPs on A. baumannii strains showed that 15 of 16 clinical isolates contained a resistant subpopulation, representing a small fraction of bacteria, at the start of the experiment. This so-called ‘heteroresistance’ was observed even though all strains were classified as colistin sensitive according to their MIC values [149]. Heteroresistance was also observed with reference and clinical K. pneumoniae strains, even in strains categorised as colistin sensitive based on their MIC [150].
Semi-Mechanistic Modelling Traditional analysis of pharmacokinetic/pharmacodynamic experiments are mostly qualitative, based on the variations of bacteria counts at a given time. Analysis data with semi-mechanistic mathematical models are useful to quantify the phenomenon observed during time-kill or dynamic experiments, such as bacterial resistance, antimicrobial efficacy or inoculum effect. Moreover, once a model has been developed it can be used to simulate different dosing regimens.
These pharmacokinetic/pharmacodynamic models have to describe the bacterial resistance to colistin. Resistance of P. aeruginosa and A. baumannii has been modelled either by splitting the bacterial population into several growing subpopulations with different susceptibility to colistin [153, 154], or with one sensitive subpopulation that adapts itself in the presence of colistin and gradually becomes resistant to it, but that can also switch to a non-growing ‘persistent’ form [155].
Mechanistic models can take into account some other aspects of the colistin mechanism of action, such as the inoculum effect and the competitive binding between cations (i.e. Ca2+ and Mg2+) and colistin on the bacterial LPS [153, 154].
These models enable characterisation of the susceptibility of a specific strain to colistin (e.g. concentration of drug producing 50% of maximum effect [EC50] = 1.16 mg/L for P. aeruginosa ATCC27853 [155]), the bacterial growth rate (e.g. mean turnover time of 75 min for A. baumannii ATCC19606 [154]) or the adaptation development rate (first-order adaptation rate constant of 7.2 h−1 for A. baumannii ATCC19606 [154]).
Based on a pharmacokinetic/pharmacodynamic model, recommendation of a flat fixed loading dose followed by 8- or 12-hourly maintenance doses with an infusion duration of up to 2 h was made for patients infected with P. aeruginosa [155]. In A. baumannii infection, these simulations suggested that with current regimens used in the clinical setting, polymyxin B administration was better than colistin administered as CMS because of more rapid target concentration attainment [154].
12.1.3 Pharmacokinetics/Pharmacodynamics of Colistin in Combination
In order to counteract the growing number of colistin-resistant strains, recent studies have shifted from studying colistin monotherapy to studying colistin activity in combination. Multiple methods have been used to evaluate the efficacy of combinations. Chequerboards and E-tests have been used for initial screening but, given the problems encountered with colistin E-tests (see Sect. 12.1.1), results obtained with this method are not covered in this review. Interesting combinations have been more thoroughly studied using time-kill experiments, with data resulting from these experiments being analysed with traditional methods or mathematical modelling.
Chequerboards Chequerboard results reported in the literature are summarised in Table 1. Chequerboard studies were interpreted by calculating the Fractional Inhibitory Concentration Index (FICI). Thresholds for FICI were usually as follows: FICI ≤0.5 indicated synergy, FICI between 0.5 and <4 indicated indifference/additivity and FICI ≥4 indicated antagonism [23, 155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,171].
The most studied species was A. baumannii (n = 670) and the most tested antibiotic family were β-lactams (n = 370). From this review of the literature, the global rate of synergy between colistin and various antibiotics was 29% (280/965). When synergy was not elicited, the different combinations were at least additive or indifferent, except for some very rare cases of antagonism. Therefore, these chequerboard results support the use of colistin in combination, even if no particular antibiotic class seems to be synergistic with colistin.
Time-Kill Experiments In time-kill experiments, combinations were considered synergistic when they led at least to a 2 log10 cfu/mL decrease compared to the most active monotherapy at 24 h.
Colistin was shown to be synergistic with imipenem, doripenem, vancomycin, rifampicin (rifampin), trimethoprim and trimethoprim/sulfamethoxazole against A. baumannii strains [167, 171,172,174]. The addition of sulbactam improved the efficacy of the doripenem–colistin combination [173].
Against K. pneumoniae strains, colistin was shown to be synergistic with aztreonam, fosfomycin, meropenem, rifampicin, trimethoprim, trimethoprim/sulfamethoxazole and vancomycin [168, 174]. The same was true for aztreonam, fosfomycin and rifampicin in triple-antibiotic combinations with meropenem and colistin [168].
Colistin was shown to be synergistic with trimethoprim, trimethoprim/sulfamethoxazole and vancomycin against one colistin-resistant strain of P. aeruginosa [174].
Traditional time-kill criteria for evaluating synergy (e.g. ∆log10 cfu/mL at 24 h) have the same limitations as FICI to show a synergy when one of the tested drugs is already effective against the studied strain, because it is hard to improve an already important effect. This could explain why synergy was more often observed against strains that were resistant to one antibiotic of the combination than against sensitive strains. Moreover, time-kill studies found synergistic combinations more often than chequerboards. This could be either because the time-kill experiments are a more powerful tool to demonstrate synergy or because time-kill experiments focused on more resistant strains. Indeed, the number of strains tested by chequerboards was generally greater than that tested by time-kill experiments because chequerboards are quicker and cheaper.
Semi-Mechanistic Modelling Built on a previously developed pharmacokinetic/pharmacodynamic model for colistin against P. aeruginosa [153], a model for the colistin–doripenem combination effect on P. aeruginosa was developed from time-kill and PAPs data [163]. In this study, multiple dosing regimens and inocula were tested. Results suggested that colistin monotherapy, even at a high dose, should be avoided due to rapid amplification of resistant subpopulations. In contrast, the results suggest that the colistin–doripenem combination would be efficient. The impact of the combination on the different subpopulations characterised by the PAPs was also assessed.
Based on another previously developed pharmacokinetic/pharmacodynamic model of colistin on P. aeruginosa [155], a model of the colistin–meropenem combination effect on P. aeruginosa was developed from time-kill data [175]. This pharmacokinetic/pharmacodynamic model suggested that the combination at clinically achievable concentrations would be efficient to treat infections with meropenem-resistant P. aeruginosa.
12.2 In Vivo Pharmacodynamics
Only a few in vivo pharmacodynamic studies have been performed with colistin alone or in combination. Studies of colistin monotherapy focused on the determination of the best pharmacokinetic/pharmacodynamic index and its target value. Studies of colistin combination therapy used ∆log10 cfu/mL at different timepoints to assess synergism.
12.2.1 Colistin Alone
The pharmacokinetic/pharmacodynamic index that best predicted in vivo colistin efficacy was determined in mice thigh and lung infection models with three P. aeruginosa strains and three A. baumannii strains. Initially, two studies reported in vivo pharmacokinetic/pharmacodynamic index target values [176, 177], but errors in the determination of the in vivo f u of colistin led the experiments to be repeated [67]. In this next study, fAUC/MIC was the pharmacokinetic/pharmacodynamic index that most closely correlated with the killing of bacteria. In the thigh infection model, target values for 2 log10 kill were between 7.4 and 13.7 for P. aeruginosa strains and between 7.4 and 17.6 for A. baumannii strains. In the lung infection model the target values for efficacy were much higher. It was possible to achieve 2 log10 kill in lung for only two-thirds of P. aeruginosa and one-third of A. baumannii strains (target values of fAUC/MIC between 36.8 and 105) [178].
12.2.2 Colistin in Combination
A murine thigh infection model was used to evaluate combinations of colistin and several antibiotics against extensively drug-resistant (XDR) A. baumannii [179] and against K. pneumoniae and E. coli [180]. Efficacy was evaluated with bacterial counts in thigh at 24 h. Rifampicin, fusidic acid and meropenem combined with colistin were synergistic against XDR A. baumannii [179]. By contrast, colistin and tigecycline in association were antagonist against several strains of K. pneumoniae and E. coli [180].
Colistin monotherapy and its combination with tigecycline were compared in a mice sepsis model infected by carbapenem-resistant K. pneumoniae [181]. Colistin and tigecycline monotherapies significantly reduced bacterial counts in liver and lung tissues, but the combination therapy was not superior to these monotherapies.
Readers especially interested in clinical combinations of polymyxins are referred to Lenhard et al. [182] for a more detailed review.
13 Conclusion
Pharmacokinetic and pharmacodynamic studies on colistin are difficult to carry out because it binds to many types of laboratory materials. Colistin renal clearance is very low due to intensive tubular reabsorption. However, the dosing regimen of colistin should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Moreover, because the pharmacokinetics of colistin are very variable, and because its therapeutic window is narrow, TDM of colistin is warranted. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses. In vitro, when exposed to colistin, bacteria develop resistance mechanisms rapidly. In these cases, pharmacokinetic/pharmacodynamic models can be used to quantify the loss of colistin efficacy and determine optimal dosing regimens. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary. Some pharmacokinetic/pharmacodynamic studies of colistin in combination have already been conducted, but further investigations are necessary.
References
Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006;6(9):589–601.
Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis. 2015;15(2):225–34.
He H, Li JC, Nation RL, Jacob J, Chen G, Lee HJ, et al. Pharmacokinetics of four different brands of colistimethate and formed colistin in rats. J Antimicrob Chemother. 2013;68(10):2311–7.
Rhouma M, Beaudry F, Theriault W, Bergeron N, Laurent-Lewandowski S, Fairbrother JM, et al. Gastric stability and oral bioavailability of colistin sulfate in pigs challenged or not with Escherichia coli O149: F4 (K88). Res Vet Sci. 2015;102:173–81.
Shah SR, Henslee AM, Spicer PP, Yokota S, Petrichenko S, Allahabadi S, et al. Effects of antibiotic physicochemical properties on their release kinetics from biodegradable polymer microparticles. Pharm Res. 2014;31(12):3379–89.
Velkov T, Roberts KD, Nation RL, Thompson PE, Li J. Pharmacology of polymyxins: new insights into an ‘old’ class of antibiotics. Future Microbiol. 2013;8(6):711–24.
Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents. 2005;25(1):11–25.
Bergen PJ, Landersdorfer CB, Zhang J, Zhao M, Lee HJ, Nation RL, et al. Pharmacokinetics and pharmacodynamics of ‘old’ polymyxins: what is new? Diagn Microbiol Infect Dis. 2012;74(3):213–23.
Bergen PJ, Landersdorfer CB, Lee HJ, Li J, Nation RL. ‘Old’ antibiotics for emerging multidrug-resistant bacteria. Curr Opin Infect Dis. 2012;25(6):626–33.
Yapa SWS, Li J, Porter CJ, Nation RL, Patel K, McIntosh MP. Population pharmacokinetics of colistin methanesulfonate in rats: achieving sustained lung concentrations of colistin for targeting respiratory infections. Antimicrob Agents Chemother. 2013;57(10):5087–95.
DrugBank. Colistimethate. https://www.drugbank.ca/drugs/DB01111. Accessed 30 Oct 2016.
DrugBank. Colistin. https://www.drugbank.ca/drugs/DB00803. Accessed 30 Oct 2016.
Wallace SJ, Li J, Nation RL, Prankerd RJ, Velkov T, Boyd BJ. Self-assembly behavior of colistin and its prodrug colistin methanesulfonate: implications for solution stability and solubilization. J Phys Chem B. 2010;114(14):4836–40.
Wallace SJ, Li J, Rayner CR, Coulthard K, Nation RL. Stability of colistin methanesulfonate in pharmaceutical products and solutions for administration to patients. Antimicrob Agents Chemother. 2008;52(9):3047–51.
Gobin P, Lemaitre F, Marchand S, Couet W, Olivier JC. Assay of colistin and colistin methanesulfonate in plasma and urine by liquid chromatography tandem mass spectrometry (LC–MS/MS). Antimicrob Agents Chemother. 2010;22(54):1941–8.
Li J, Milne RW, Nation RL, Turnidge JD, Coulthard K, Valentine J. Simple method for assaying colistin methanesulfonate in plasma and urine using high-performance liquid chromatography. Antimicrob Agents Chemother. 2002;46(10):3304–7.
Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate. J Antimicrob Chemother. 2004;53(5):837–40.
Chepyala D, Tsai IL, Sun HY, Lin SW, Kuo CH. Development and validation of a high-performance liquid chromatography-fluorescence detection method for the accurate quantification of colistin in human plasma. J Chromatogr B Anal Technol Biomed Life Sci. 2015;1(980):48–54.
Li J, Milne RW, Nation RL, Turnidge JD, Coulthard K, Johnson DW. A simple method for the assay of colistin in human plasma, using pre-column derivatization with 9-fluorenylmethyl chloroformate in solid-phase extraction cartridges and reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 2001;761(2):167–75.
Van den Meersche T, Pamel EV, Poucke CV, Herman L, Heyndrickx M, Rasschaert G, et al. Development, validation and application of an ultra high performance liquid chromatographic-tandem mass spectrometric method for the simultaneous detection and quantification of five different classes of veterinary antibiotics in swine manure. J Chromatogr A. 2016;15(1429):248–57.
Jansson B, Karvanen M, Cars O, Plachouras D, Friberg LE. Quantitative analysis of colistin A and colistin B in plasma and culture medium using a simple precipitation step followed by LC/MS/MS. J Pharm Biomed Anal. 2009;49(3):760–7.
Marchand S, Gobin P, Brillault J, Baptista S, Adier C, Olivier JC, et al. Aerosol therapy with colistin methanesulfonate: a biopharmaceutical issue illustrated in rats. Antimicrob Agents Chemother. 2010;54(9):3702–7.
Nation RL, Velkov T, Li J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis. 2014;59(1):88–94.
Bialvaei AZ, Samadi Kafil H. Colistin, mechanisms and prevalence of resistance. Curr Med Res Opin. 2015;31(4):707–21.
Dixon RA, Chopra I. Leakage of periplasmic proteins from Escherichia coli mediated by polymyxin B nonapeptide. Antimicrob Agents Chemother. 1986;29(5):781–8.
Chen CC, Feingold DS. Locus of divalent cation inhibition of the bactericidal action of polymyxin B. Antimicrob Agents Chemother. 1972;2(5):331–5.
Schindler M, Osborn MJ. Interaction of divalent cations and polymyxin B with lipopolysaccharide. Biochemistry. 1979;18(20):4425–30.
Davis SD, Iannetta A, Wedgwood RJ. Activity of colistin against Pseudomonas aeruginosa: inhibition by calcium. J Infect Dis. 1971;124(6):610–2.
Clausell A, Garcia-Subirats M, Pujol M, Busquets MA, Rabanal F, Cajal Y. Gram-negative outer and inner membrane models: insertion of cyclic cationic lipopeptides. J Phys Chem B. 2007;111(3):551–63.
Peterson AA, Hancock RE, McGroarty EJ. Binding of polycationic antibiotics and polyamines to lipopolysaccharides of Pseudomonas aeruginosa. J Bacteriol. 1985;164(3):1256–61.
Gough M, Hancock RE, Kelly NM. Antiendotoxin activity of cationic peptide antimicrobial agents. Infect Immun. 1996;64(12):4922–7.
Martis N, Leroy S, Blanc V. Colistin in multi-drug resistant Pseudomonas aeruginosa blood-stream infections: a narrative review for the clinician. J Infect. 2014;69(1):1–12.
Gardiner KR, Erwin PJ, Anderson NH, McCaigue MD, Halliday MI, Rowlands BJ. Lactulose as an antiendotoxin in experimental colitis. Br J Surg. 1995;82(4):469–72.
Escartin P, Rodriguez-Montes JA, Cuervas-Mons V, Rossi I, Alvarez-Cienfuegos J, Maganto P, et al. Effect of colistin on reduction of biliary flow induced by endotoxin in E. coli. Dig Dis Sci. 1982;27(10):875–9.
Lopes J, Inniss WE. Electron microscopy of effect of polymyxin on Escherichia coli lipopolysaccharide. J Bacteriol. 1969;100(2):1128–9.
Storm DR, Rosenthal KS, Swanson PE. Polymyxin and related peptide antibiotics. Annu Rev Biochem. 1977;46:723–63.
Deris ZZ, Akter J, Sivanesan S, Roberts KD, Thompson PE, Nation RL, et al. A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity. J Antibiot (Tokyo). 2014;67(2):147–51.
Clinical and Laboratory Standards Institute (CLSI). M100-S25. Performance standards for antimicrobial susceptibility testing; twenty-fifth informational supplement. Wayne: Clinical and Laboratory Standards Institute; 2015.
EUCAST. Recommendations for MIC determination of colistin (polymyxin E). As recommended by the joint CLSI-EUCAST Polymyxin Breakpoints Working Group. European Committee on Antimicrobial Susceptibility Testing; 2016. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/General_documents/Recommendations_for_MIC_determination_of_colistin_March_2016.pdf. Accessed 24 May 2017.
Cai Y, Lee W, Kwa AL. Polymyxin B versus colistin: an update. Expert Rev Anti Infect Ther. 2015;13(12):1481–97.
Hindler JA, Humphries RM. Colistin MIC variability by method for contemporary clinical isolates of multidrug-resistant Gram-negative bacilli. J Clin Microbiol. 2013;51(6):1678–84.
Lo-Ten-Foe JR, de Smet AM, Diederen BM, Kluytmans JA, van Keulen PH. Comparative evaluation of the VITEK 2, disk diffusion, etest, broth microdilution, and agar dilution susceptibility testing methods for colistin in clinical isolates, including heteroresistant Enterobacter cloacae and Acinetobacter baumannii strains. Antimicrob Agents Chemother. 2007;51(10):3726–30.
Dafopoulou K, Zarkotou O, Dimitroulia E, Hadjichristodoulou C, Gennimata V, Pournaras S, et al. Comparative evaluation of colistin susceptibility testing methods among carbapenem-nonsusceptible Klebsiella pneumoniae and Acinetobacter baumannii clinical isolates. Antimicrob Agents Chemother. 2015;59(8):4625–30.
European Committee on Antimicrobial Susceptibility Testing. Version 7.1, 2017. Breakpoint tables for interpretation of MICs and zone diameters. Available from: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_7.1_Breakpoint_Tables.pdf. Accessed 24 May 2017.
Kwa AL, Tam VH, Falagas ME. Polymyxins: a review of the current status including recent developments. Ann Acad Med Singap. 2008;37(10):870–83.
Park YK, Choi JY, Shin D, Ko KS. Correlation between overexpression and amino acid substitution of the PmrAB locus and colistin resistance in Acinetobacter baumannii. Int J Antimicrob Agents. 2011;37(6):525–30.
Gunn JS. The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Trends Microbiol. 2008;16(6):284–90.
Kim SY, Choi HJ, Ko KS. Differential expression of two-component systems, pmrAB and phoPQ, with different growth phases of Klebsiella pneumoniae in the presence or absence of colistin. Curr Microbiol. 2014;69(1):37–41.
Raetz CR, Guan Z, Ingram BO, Six DA, Song F, Wang X, et al. Discovery of new biosynthetic pathways: the lipid A story. J Lipid Res. 2009;50(Suppl):S103–8.
Fernandez L, Jenssen H, Bains M, Wiegand I, Gooderham WJ, Hancock RE. The two-component system CprRS senses cationic peptides and triggers adaptive resistance in Pseudomonas aeruginosa independently of ParRS. Antimicrob Agents Chemother. 2012;56(12):6212–22.
McPhee JB, Bains M, Winsor G, Lewenza S, Kwasnicka A, Brazas MD, et al. Contribution of the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems to Mg2+-induced gene regulation in Pseudomonas aeruginosa. J Bacteriol. 2006;188(11):3995–4006.
Beceiro A, Llobet E, Aranda J, Bengoechea JA, Doumith M, Hornsey M, et al. Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother. 2011;55(7):3370–9.
Snitkin ES, Zelazny AM, Gupta J, Palmore TN, Murray PR, Segre JA. Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment. Genome Res. 2013;23(7):1155–62.
Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16(2):161–8.
Schwarz S, Johnson AP. Transferable resistance to colistin: a new but old threat. J Antimicrob Chemother. 2016;71(8):2066–70.
Moffatt JH, Harper M, Harrison P, Hale JD, Vinogradov E, Seemann T, et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother. 2010;54(12):4971–7.
Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006;50(9):2946–50.
Lee JY, Park YK, Chung ES, Na IY, Ko KS. Evolved resistance to colistin and its loss due to genetic reversion in Pseudomonas aeruginosa. Sci Rep. 2016;06(6):25543.
Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5(1):48–56.
Couet W, Gregoire N, Gobin P, Saulnier PJ, Frasca D, Marchand S, et al. Pharmacokinetics of colistin and colistimethate sodium after a single 80-mg intravenous dose of CMS in young healthy volunteers. Clin Pharmacol Ther. 2011;89(6):875–9.
Couet W, Gregoire N, Marchand S, Mimoz O. Colistin pharmacokinetics: the fog is lifting. Clin Microbiol Infect. 2012;18(1):30–9.
Ma Z, Wang J, Nation RL, Li J, Turnidge JD, Coulthard K, et al. Renal disposition of colistin in the isolated perfused rat kidney. Antimicrob Agents Chemother. 2009;53(7):2857–64.
Lu X, Chan T, Xu C, Zhu L, Zhou QT, Roberts KD, et al. Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins. J Antimicrob Chemother. 2016;71(2):403–12.
Suzuki T, Yamaguchi H, Ogura J, Kobayashi M, Yamada T, Iseki K. Megalin contributes to kidney accumulation and nephrotoxicity of colistin. Antimicrob Agents Chemother. 2013;57(12):6319–24.
Diao L, Meibohm B. Pharmacokinetics and pharmacokinetic–pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet. 2013;52(10):855–68.
Azad MA, Huang JX, Cooper MA, Roberts KD, Thompson PE, Nation RL, et al. Structure-activity relationships for the binding of polymyxins with human alpha-1-acid glycoprotein. Biochem Pharmacol. 2012;84(3):278–91.
Cheah SE, Wang J, Nguyen VT, Turnidge JD, Li J, Nation RL. New pharmacokinetic/pharmacodynamic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: smaller response in lung infection. J Antimicrob Chemother. 2015;70(12):3291–7.
Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration. Antimicrob Agents Chemother. 2003;47(5):1766–70.
Matzneller P, Gobin P, Lackner E, Zeitlinger M. Feasibility of microdialysis for determination of protein binding and target site pharmacokinetics of colistin in vivo. J Clin Pharmacol. 2015;55(4):431–7.
al-Khayyat AA, Aronson AL. Pharmacologic and toxicologic studies with the polymyxins. 3. Consideration regarding clinical use in dogs. Chemotherapy. 1973;19(2):98–108.
Mohamed AF, Karaiskos I, Plachouras D, Karvanen M, Pontikis K, Jansson B, et al. Application of a loading dose of colistin methanesulphonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012;56(8):4241–9.
Kremer JM, Wilting J, Janssen LH. Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev. 1988;40(1):1–47.
Zavascki AP, Goldani LZ, Cao G, Superti SV, Lutz L, Barth AL, et al. Pharmacokinetics of intravenous polymyxin B in critically ill patients. Clin Infect Dis. 2008;47(10):1298–304.
Huang JX, Blaskovich MA, Pelingon R, Ramu S, Kavanagh A, Elliott AG, et al. Mucin binding reduces colistin antimicrobial activity. Antimicrob Agents Chemother. 2015;59(10):5925–31.
Imberti R, Cusato M, Villani P, Carnevale L, Iotti GA, Langer M, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically Ill patients after IV colistin methanesulfonate administration. Chest. 2010;138(6):1333–9.
Boisson M, Jacobs M, Gregoire N, Gobin P, Marchand S, Couet W, et al. Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of cms in critically ill patients. Antimicrob Agents Chemother. 2014;58(12):7331–9.
Yapa SWS, Li J, Patel K, Wilson JW, Dooley MJ, George J, et al. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration. Antimicrob Agents Chemother. 2014;58(5):2570–9.
Nickel S, Clerkin CG, Selo MA, Ehrhardt C. Transport mechanisms at the pulmonary mucosa: implications for drug delivery. Expert Opin Drug Deliv. 2016;13(5):667–90.
Nakamura T, Nakanishi T, Haruta T, Shirasaka Y, Keogh JP, Tamai I. Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm. 2010;7(1):187–95.
Swaan PW, Bensman T, Bahadduri PM, Hall MW, Sarkar A, Bao S, et al. Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2. Am J Respir Cell Mol Biol. 2008;39(5):536–42.
Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case–control study. Clin Infect Dis. 2010;51(11):1238–44.
Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME. Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect. 2010;16(8):1230–6.
Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z, et al. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study. Respir Med. 2008;102(3):407–12.
Tumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, et al. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria. Chest. 2013;144(6):1768–75.
Gontijo AV, Gregoire N, Lamarche I, Gobin P, Couet W, Marchand S. Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 2. Colistin. Antimicrob Agents Chemother. 2014;58(7):3950–6.
Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, et al. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006;57(2):306–11.
Athanassa ZE, Markantonis SL, Fousteri MZ, Myrianthefs PM, Boutzouka EG, Tsakris A, et al. Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients. Intensive Care Med. 2012;38(11):1779–86.
Markantonis SL, Markou N, Fousteri M, Sakellaridis N, Karatzas S, Alamanos I, et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother. 2009;53(11):4907–10.
Ziaka M, Markantonis SL, Fousteri M, Zygoulis P, Panidis D, Karvouniaris M, et al. Combined intravenous and intraventricular administration of colistin methanesulfonate in critically ill patients with central nervous system infection. Antimicrob Agents Chemother. 2013;57(4):1938–40.
Antachopoulos C, Karvanen M, Iosifidis E, Jansson B, Plachouras D, Cars O, et al. Serum and cerebrospinal fluid levels of colistin in pediatric patients. Antimicrob Agents Chemother. 2010;54(9):3985–7.
Jin L, Nation RL, Li J, Nicolazzo JA. Species-dependent blood–brain barrier disruption of lipopolysaccharide: amelioration by colistin in vitro and in vivo. Antimicrob Agents Chemother. 2013;57(9):4336–42.
Imberti R, Cusato M, Accetta G, Marino V, Procaccio F, Del Gaudio A, et al. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother. 2012;56(8):4416–21.
Mimoz O, Petitpas F, Gregoire N, Gobin P, Marchand S, Couet W. Colistin distribution into the peritoneal fluid of a patient with severe peritonitis. Antimicrob Agents Chemother. 2012;56(7):4035–6.
Guyonnet J, Manco B, Baduel L, Kaltsatos V, Aliabadi MH, Lees P. Determination of a dosage regimen of colistin by pharmacokinetic/pharmacodynamic integration and modeling for treatment of G.I.T. disease in pigs. Res Vet Sci. 2010;88(2):307–14.
Abis GS, Oosterling SJ, Stockmann HB, van der Bij GJ, van Egmond M, Vandenbroucke-Grauls CM, et al. Perioperative selective decontamination of the digestive tract and standard antibiotic prophylaxis versus standard antibiotic prophylaxis alone in elective colorectal cancer patients. Dan Med J. 2014;61(4):A4695.
Huttner B, Haustein T, Uckay I, Renzi G, Stewardson A, Schaerrer D, et al. Decolonization of intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013;68(10):2375–82.
Melsen WG, de Smet AM, Kluytmans JA, Bonten MJ. Selective decontamination of the oral and digestive tract in surgical versus non-surgical patients in intensive care in a cluster-randomized trial. Br J Surg. 2012;99(2):232–7.
Oren I, Sprecher H, Finkelstein R, Hadad S, Neuberger A, Hussein K, et al. Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: a prospective controlled trial. Am J Infect Control. 2013;41(12):1167–72.
Saidel-Odes L, Polachek H, Peled N, Riesenberg K, Schlaeffer F, Trabelsi Y, et al. A randomized, double-blind, placebo-controlled trial of selective digestive decontamination using oral gentamicin and oral polymyxin E for eradication of carbapenem-resistant Klebsiella pneumoniae carriage. Infect Control Hosp Epidemiol. 2012;33(1):14–9.
Brink AJ, Coetzee J, Corcoran C, Clay CG, Hari-Makkan D, Jacobson RK, et al. Emergence of OXA-48 and OXA-181 carbapenemases among Enterobacteriaceae in South Africa and evidence of in vivo selection of colistin resistance as a consequence of selective decontamination of the gastrointestinal tract. J Clin Microbiol. 2013;51(1):369–72.
Halaby T, Al Naiemi N, Kluytmans J, van der Palen J, Vandenbroucke-Grauls CM. Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob Agents Chemother. 2013;57(7):3224–9.
Lubbert C, Faucheux S, Becker-Rux D, Laudi S, Durrbeck A, Busch T, et al. Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: a single-centre experience. Int J Antimicrob Agents. 2013;42(6):565–70.
Strenger V, Gschliesser T, Grisold A, Zarfel G, Feierl G, Masoud L, et al. Orally administered colistin leads to colistin-resistant intestinal flora and fails to prevent faecal colonisation with extended-spectrum beta-lactamase-producing enterobacteria in hospitalised newborns. Int J Antimicrob Agents. 2011;37(1):67–9.
Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55(7):3284–94.
Grégoire N, Mimoz O, Mégarbane B, Comets E, Chatelier D, Lasocki S, et al. New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale. Antimicrob Agents Chemother. 2014;58(12):7324–30.
Plachouras D, Karvanen M, Friberg LE, Papadomichelakis E, Antoniadou A, Tsangaris I, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by Gram-negative bacteria. Antimicrob Agents Chemother. 2009;53(8):3430–6.
Nation RL, Garonzik SM, Thamlikitkul V, Giamarellos-Bourboulis EJ, Forrest A, Paterson DL, et al. Dosing guidance for intravenous colistin in critically-ill patients. Clin Infect Dis. 2016. doi:10.1093/cid/ciw839.
Karaiskos I, Friberg LE, Pontikis K, Ioannidis K, Tsagkari V, Galani L, et al. Colistin population pharmacokinetics after application of a loading dose of 9 MU colistin methanesulfonate in critically ill patients. Antimicrob Agents Chemother. 2015;59(12):7240–8.
Vardakas KZ, Rellos K, Triarides NA, Falagas ME. Colistin loading dose: evaluation of the published pharmacokinetic and clinical data. Int J Antimicrob Agents. 2016;48(5):475–84.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Assessment report. Polymyxin-based products. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Polymyxin_31/WC500179664.pdf. Accessed 23 March 2017.
Nation RL, Garonzik SM, Li J, Thamlikitkul V, Giamarellos-Bourboulis EJ, Paterson DL, et al. Updated US and European dose recommendations for intravenous colistin: how do they perform? Clin Infect Dis. 2016;62(5):552–8.
Jacobs M, Gregoire N, Megarbane B, Gobin P, Balayn D, Marchand S, et al. Population pharmacokinetics of colistin methanesulphonate (CMS) and colistin in critically ill patients with acute renal failure requiring intermittent haemodialysis. Antimicrob Agents Chemother. 2016;60(3):1788–93.
Honore PM, Jacobs R, Lochy S, De Waele E, Van Gorp V, De Regt J, et al. Acute respiratory muscle weakness and apnea in a critically ill patient induced by colistin neurotoxicity: key potential role of hemoadsorption elimination during continuous venovenous hemofiltration. Int J Nephrol Renovasc Dis. 2013;6:107–11.
Jitmuang A, Nation RL, Koomanachai P, Chen G, Lee HJ, Wasuwattakul S, et al. Extracorporeal clearance of colistin methanesulphonate and formed colistin in end-stage renal disease patients receiving intermittent haemodialysis: implications for dosing. J Antimicrob Chemother. 2015;70(6):1804–11.
Luque S, Sorli L, Li J, Collado S, Barbosa F, Berenguer N, et al. Effective removal of colistin methanesulphonate and formed colistin during intermittent haemodialysis in a patient infected by polymyxin-only-susceptible Pseudomonas aeruginosa. J Chemother. 2014;26(2):122–4.
Marchand S, Frat JP, Petitpas F, Lemaitre F, Gobin P, Robert R, et al. Removal of colistin during intermittent haemodialysis in two critically ill patients. J Antimicrob Chemother. 2010;65(8):1836–7.
Markou N, Fousteri M, Markantonis SL, Zidianakis B, Hroni D, Boutzouka E, et al. Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study. J Antimicrob Chemother. 2012;67(10):2459–62.
Karvanen M, Plachouras D, Friberg LE, Paramythiotou E, Papadomichelakis E, Karaiskos I, et al. Colistin methanesulfonate and colistin pharmacokinetics in critically ill patients receiving continuous venovenous hemodiafiltration. Antimicrob Agents Chemother. 2013;57(1):668–71.
Karaiskos I, Friberg LE, Galani L, Ioannidis K, Katsouda E, Athanassa Z, et al. Challenge for higher colistin dosage in critically ill patients receiving continuous venovenous haemodiafiltration. Int J Antimicrob Agents. 2016;48(3):337–41.
Fiaccadori E, Antonucci E, Morabito S, d’Avolio A, Maggiore U, Regolisti G. Colistin use in patients with reduced kidney function. Am J Kidney Dis. 2016;68(2):296–306.
Li J, Coulthard K, Milne R, Nation RL, Conway S, Peckham D, et al. Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J Antimicrob Chemother. 2003;52(6):987–92.
Marchand S, Diot P, Gregoire N, Henriet A, Gobin P, Couet W. Plasma pharmacokinetics and sputum concentrations of colistin after nebulization or intravenous administration of colistin methansulphonate (CMS) to ambulatories cystic fibrosis patients. In: 52nd international conference on antimicrobial agents and chemotherapy (ICAAC), 9–12 Sep 2012, San Francisco (Poster A-036).
Banerjee D, Stableforth D. The treatment of respiratory pseudomonas infection in cystic fibrosis: what drug and which way? Drugs. 2000;60(5):1053–64.
Hansen CR, Pressler T, Hoiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J Cyst Fibros. 2008;7(6):523–30.
Schuster A, Haliburn C, Doring G, Goldman MH. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax. 2013;68(4):344–50.
Lee J, Han S, Jeon S, Hong T, Song W, Woo H, et al. Population pharmacokinetic analysis of colistin in burn patients. Antimicrob Agents Chemother. 2013;57(5):2141–6.
Mizuyachi K, Hara K, Wakamatsu A, Nohda S, Hirama T. Safety and pharmacokinetic evaluation of intravenous colistin methanesulfonate sodium in Japanese healthy male subjects. Curr Med Res Opin. 2011;27(12):2261–70.
Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10(1):R27.
Dalfino L, Puntillo F, Ondok MJ, Mosca A, Monno R, Coppolecchia S, et al. Colistin-associated acute kidney injury in severely ill patients: a step toward a better renal care? A prospective cohort study. Clin Infect Dis. 2015;61(12):1771–7.
Phe K, Johnson ML, Palmer HR, Tam VH. Validation of a model to predict the risk of nephrotoxicity in patients receiving colistin. Antimicrob Agents Chemother. 2014;58(11):6946–8.
Sorli L, Luque S, Grau S, Berenguer N, Segura C, Montero MM, et al. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infect Dis. 2013;13:380.
Deryke CA, Crawford AJ, Uddin N, Wallace MR. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother. 2010;54(10):4503–5.
Kelesidis T, Falagas ME. The safety of polymyxin antibiotics. Expert Opin Drug Saf. 2015;14(11):1687–701.
Sirijatuphat R, Limmahakhun S, Sirivatanauksorn V, Nation RL, Li J, Thamlikitkul V. Preliminary clinical study of the effect of ascorbic acid on colistin-associated nephrotoxicity. Antimicrob Agents Chemother. 2015;59(6):3224–32.
Yun B, Azad MA, Nowell CJ, Nation RL, Thompson PE, Roberts KD, et al. Cellular uptake and localization of polymyxins in renal tubular cells using rationally designed fluorescent probes. Antimicrob Agents Chemother. 2015;59(12):7489–96.
Spapen HD, Honore PM, Gregoire N, Gobin P, de Regt J, Martens GA, et al. Convulsions and apnoea in a patient infected with New Delhi metallo-beta-lactamase-1 Escherichia coli treated with colistin. J Infect. 2011;63(6):468–70.
Antoniu SA, Cojocaru I. Inhaled colistin for lower respiratory tract infections. Expert Opin Drug Deliv. 2012;9(3):333–42.
Gurjar M. Colistin for lung infection: an update. J Intensive Care. 2015;3(1):3.
Bargiacchi O, De Rosa FG. Intrathecal or intraventricular colistin: a review. Infez Med. 2016;24(1):3–11.
Landersdorfer CB, Nation RL. Colistin: how should it be dosed for the critically ill? Semin Respir Crit Care Med. 2015;36(1):126–35.
Horcajada JP, Sorli L, Luque S, Benito N, Segura C, Campillo N, et al. Validation of a colistin plasma concentration breakpoint as a predictor of nephrotoxicity in patients treated with colistin methanesulfonate. Int J Antimicrob Agents. 2016;48(6):725–7.
Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrob Agents Chemother. 2010;54(9):3783–9.
Dudhani RV, Turnidge JD, Coulthard K, Milne RW, Rayner CR, Li J, et al. Elucidation of pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;54(3):1117–24.
Mohamed AF, Cars O, Friberg LE. A pharmacokinetic/pharmacodynamic model developed for the effect of colistin on Pseudomonas aeruginosa in vitro with evaluation of population pharmacokinetic variability on simulated bacterial killing. J Antimicrob Chemother. 2014;69(5):1350–61.
Wiegand I, Hilpert K, Hancock RE. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc. 2008;3(2):163–75.
Karvanen M. Optimisation of colistin dosage in the treatment of multiresistant gram-negative infections. Uppsala: Uppsala Universitet; 2013.
Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrob Agents Chemother. 2010;54:3783–9.
Li J, Turnidge J, Milne R, Nation RL, Coulthard K. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 2001;45:781–5.
Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006;50:2946–50.
Poudyal A, Howden BP, Bell JM, Gao W, Owen RJ, Turnidge JD, et al. In vitro pharmacodynamics of colistin against multidrug-resistant Klebsiella pneumoniae. J Antimicrob Chemother. 2008;62:1311–8.
Tan C-H, Li J, Nation RL. Activity of colistin against heteroresistant Acinetobacter baumannii and emergence of resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2007;51:3413–5.
Bergen PJ, Li J, Nation RL, Turnidge JD, Coulthard K, Milne RW. Comparison of once-, twice- and thrice-daily dosing of colistin on antibacterial effect and emergence of resistance: studies with Pseudomonas aeruginosa in an in vitro pharmacodynamic model. J Antimicrob Chemother. 2008;61:636–42.
Bulitta JB, Yang JC, Yohonn L, Ly NS, Brown SV, D’Hondt RE, et al. Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model. Antimicrob Agents Chemother. 2010;54:2051–62.
Cheah S-E, Li J, Tsuji BT, Forrest A, Bulitta JB, Nation RL. Colistin and polymyxin B dosage regimens against Acinetobacter baumannii: differences in activity and the emergence of resistance. Antimicrob Agents Chemother. 2016;60:3921–33.
Mohamed AF, Cars O, Friberg LE. A pharmacokinetic/pharmacodynamic model developed for the effect of colistin on Pseudomonas aeruginosa in vitro with evaluation of population pharmacokinetic variability on simulated bacterial killing. J Antimicrob Chemother. 2014;69:1350–61.
Cirioni O, Ghiselli R, Silvestri C, Kamysz W, Orlando F, Mocchegiani F, et al. Efficacy of tachyplesin III, colistin, and imipenem against a multiresistant Pseudomonas aeruginosa strain. Antimicrob Agents Chemother. 2007;51:2005–10.
Di X, Wang R, Liu B, Zhang X, Ni W, Wang J, et al. In vitro activity of fosfomycin in combination with colistin against clinical isolates of carbapenem-resistant Pseudomas aeruginosa. J Antibiot. 2015;68:551–5.
Gaibani P, Lombardo D, Lewis RE, Mercuri M, Bonora S, Landini MP, et al. In vitro activity and post-antibiotic effects of colistin in combination with other antimicrobials against colistin-resistant KPC-producing Klebsiella pneumoniae bloodstream isolates. J Antimicrob Chemother. 2014;69:1856–65.
Gordon NC, Png K, Wareham DW. Potent synergy and sustained bactericidal activity of a vancomycin-colistin combination versus multidrug-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother. 2010;54:5316–22.
Hornsey M, Wareham DW. In vivo efficacy of glycopeptide-colistin combination therapies in a Galleria mellonella model of Acinetobacter baumannii Infection. Antimicrob Agents Chemother. 2011;55:3534–7.
Le Minh V, Thi Khanh Nhu N, Vinh Phat V, Thompson C, Huong Lan NP, Thieu Nga TV, et al. In vitro activity of colistin in antimicrobial combination against carbapenem-resistant Acinetobacter baumannii isolated from patients with ventilator-associated pneumonia in Vietnam. J Med Microbiol. 2015;64:1162–9.
Liu B, Liu Y, Di X, Zhang X, Wang R, Bai Y, et al. Colistin and anti-Gram-positive bacterial agents against Acinetobacter baumannii. Rev Soc Bras Med Trop. 2014;47:451–6.
Ly NS, Bulitta JB, Rao GG, Landersdorfer CB, Holden PN, Forrest A, et al. Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance. J Antimicrob Chemother. 2015;70:1434–42.
Marie MAM, Krishnappa LG, Alzahrani AJ, Mubaraki MA, Alyousef AA. A prospective evaluation of synergistic effect of sulbactam and tazobactam combination with meropenem or colistin against multidrug resistant Acinetobacter baumannii. Bosn J Basic Med Sci. 2015;15:24–9.
Mitsugui CS, Tognim MCB, Cardoso CL, Carrara-Marroni FE, Garcia LB. In vitro activity of polymyxins in combination with β-lactams against clinical strains of Pseudomonas aeruginosa. Int J Antimicrob Agents. 2011;38:447–50.
Ni W, Cui J, Liang B, Cai Y, Bai N, Cai X, et al. In vitro effects of tigecycline in combination with colistin (polymyxin E) and sulbactam against multidrug-resistant Acinetobacter baumannii. J Antibiot. 2013;66:705–8.
Sheng W-H, Wang J-T, Li S-Y, Lin Y-C, Cheng A, Chen Y-C, et al. Comparative in vitro antimicrobial susceptibilities and synergistic activities of antimicrobial combinations against carbapenem-resistant Acinetobacter species: Acinetobacter baumannii versus Acinetobacter genospecies 3 and 13TU. Diagn Microbiol Infect Dis. 2011;70:380–6.
Tangden T, Hickman RA, Forsberg P, Lagerback P, Giske CG, Cars O. Evaluation of double- and triple-antibiotic combinations for VIM- and NDM-producing Klebsiella pneumoniae by in vitro time-kill experiments. Antimicrob Agents Chemother. 2014;58:1757–62.
Wareham DW, Gordon NC, Hornsey M. In vitro activity of teicoplanin combined with colistin versus multidrug-resistant strains of Acinetobacter baumannii. J Antimicrob Chemother. 2011;66:1047–51.
Yang H, Chen G, Hu L, Liu Y, Cheng J, Li H, et al. In vivo activity of daptomycin/colistin combination therapy in a Galleria mellonella model of Acinetobacter baumannii infection. Int J Antimicrob Agents. 2015;45:188–91.
Yang H, Lv N, Hu L, Liu Y, Cheng J, Ye Y, et al. In vivo activity of vancomycin combined with colistin against multidrug-resistant strains of Acinetobacter baumannii in a Galleria mellonella model. Infect Dis. 2016;48:189–94.
Leite GC, Oliveira MS, Perdigão-Neto LV, Rocha CKD, Guimarães T, Rizek C, et al. Antimicrobial combinations against pan-resistant Acinetobacter baumannii isolates with different resistance mechanisms. PloS One. 2016;11:e0151270.
Oleksiuk LM, Nguyen MH, Press EG, Updike CL, O’Hara JA, Doi Y, et al. In vitro responses of Acinetobacter baumannii to two- and three-drug combinations following exposure to colistin and doripenem. Antimicrob Agents Chemother. 2014;58:1195–9.
Vidaillac C, Benichou L, Duval RE. In vitro synergy of colistin combinations against colistin-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates. Antimicrob Agents Chemother. 2012;56:4856–61.
Mohamed AF, Kristoffersson AN, Karvanen M, Nielsen EI, Cars O, Friberg LE. Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model. J Antimicrob Chemother. 2016;71(5):1279–90.
Dudhani RV, Turnidge JD, Coulthard K, Milne RW, Rayner CR, Li J, et al. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;54:1117–24.
Dudhani RV, Turnidge JD, Nation RL, Li J. fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models. J Antimicrob Chemother. 2010;65:1984–90.
Cheah S-E, Wang J, Nguyen VTT, Turnidge JD, Li J, Nation RL. New pharmacokinetic/pharmacodynamic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: smaller response in lung infection. J Antimicrob Chemother. 2015;70:3291–7.
Fan B, Guan J, Wang X, Cong Y. Activity of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin or sulbactam against extensively drug-resistant Acinetobacter baumannii in a murine thigh-infection model. PLoS One. 2016;11:e0157757.
Michail G, Labrou M, Pitiriga V, Manousaka S, Sakellaridis N, Tsakris A, et al. Activity of tigecycline in combination with colistin, meropenem, rifampin, or gentamicin against KPC-producing Enterobacteriaceae in a murine thigh infection model. Antimicrob Agents Chemother. 2013;57:6028–33.
Demiraslan H, Dinc G, Ahmed SS, Elmali F, Metan G, Alp E, et al. Carbapenem-resistant Klebsiella pneumoniae sepsis in corticosteroid receipt mice: tigecycline or colistin monotherapy versus tigecycline/colistin combination. J Chemother. 2014;26:276–81.
Lenhard JR, Nation RL, Tsuji BT. Synergistic combinations of polymyxins. Int J Antimicrob Agents. 2016;48:607–13.
D’Souza BB, Padmaraj SR, Rekha PD, Tellis RC, Prabhu S, Pothen P. In vitro synergistic activity of colistin and ceftazidime or ciprofloxacin against multidrug-resistant clinical strains of Pseudomonas aeruginosa. Microb Drug Resist. 2014;20:550–4.
Dong X, Chen F, Zhang Y, Liu H, Liu Y, Ma L. In vitro activities of rifampin, colistin, sulbactam and tigecycline tested alone and in combination against extensively drug-resistant Acinetobacter baumannii. J Antibiot. 2014;67:677–80.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No support was received for the preparation of this manuscript.
Conflicts of interest
Nicolas Grégoire, Vincent Aranzana-Climent, Sophie Magréault, Sandrine Marchand and William Couet declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Grégoire, N., Aranzana-Climent, V., Magréault, S. et al. Clinical Pharmacokinetics and Pharmacodynamics of Colistin. Clin Pharmacokinet 56, 1441–1460 (2017). https://doi.org/10.1007/s40262-017-0561-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-017-0561-1