Colistin Methanesulfonate Research Articles

Risk factors for acute kidney injury in patients treated with polymyxin B or colistin methanesulfonate sodium

Polymyxin B (PMB) and colistin, administered as the prodrug colistin methanesulfonate sodium (CMS), are increasingly used to treat carbapenem-resistant Gram-negative bacteria. Nephrotoxicity is the major dose-limiting adverse effect of both polymyxins. A retrospective cohort study of 132 patients was conducted to evaluate risk factors for acute kidney injury (AKI), classified according to Acute Kidney Injury Network criteria, in patients treated with ≥48h of intravenous PMB or CMS, with particular focus on potential differences between each polymyxin. The overall incidence of AKI was 25.8% (34/132) [20.8% (20/96) and 38.9% (14/36) in patients treated with PMB and CMS, respectively; P=0.06]. In the Cox regression model, doses ≥2million International Units (MIU) of PMB or >9MIU of CMS were the only variable independently associated with AKI [adjusted hazard ratio (aHR)=2.11, 95% confidence interval (CI) 1.01–4.41; P=0.04]. Vancomycin co-administration was strongly associated with AKI, although this was not statistically significant (aHR=2.22, 95% CI 0.98–5.04; P=0.058). There was no statistically significant difference in the incidence of AKI between patients treated with PMB or CMS in the multivariate model (aHR=1.74, 95% CI 0.82–3.69; P=0.15). High dose was the main risk factor for AKI regardless of the polymyxin administered. Vancomycin co-administration likely increases the risk of AKI. Although there was a higher overall incidence of AKI in patients treated with CMS compared with PMB, CMS was not significantly associated with this outcome after adjusting for the above variables.

Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in End-Stage Renal Disease Patients Receiving Continuous Ambulatory Peritoneal Dialysis

Colistin, administered intravenously as its inactive prodrug colistin methanesulfonate (CMS), is increasingly used as last-line therapy to combat multidrug-resistant Gram-negative bacteria. CMS dosing needs to be adjusted for renal function. The impact of continuous ambulatory peritoneal dialysis (CAPD) on the pharmacokinetics of both CMS and colistin has not been studied. No CMS dosing recommendations are available for patients receiving CAPD. Eight CAPD patients received a single intravenous CMS dose (150 mg colistin base activity [CBA]) over 30 min. Serial blood and dialysate samples, and cumulative urine where applicable, were collected over 25 h. CMS and colistin concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations were conducted. The total body clearance of CMS (excluding CAPD clearance) was 1.77 liters/h (44%) [population mean (between-subject variability)], while CAPD clearance was 0.088 liter/h (64%). The population mean terminal half-life of CMS was 8.4 h. For colistin, the total clearance/fraction of CMS metabolized to colistin (fm) (excluding CAPD clearance) was 2.74 liters/h (50%), the CAPD clearance was 0.101 liter/h (34%), and the mean terminal half-life was 13.2 h. Monte Carlo simulations suggested a loading dose of 300 mg CBA on day 1 and a maintenance dose of either 150 mg or 200 mg CBA daily to achieve a target average steady-state plasma colistin concentration of 2.5 mg/liter. Clearance by CAPD was low for both CMS and formed colistin. Therefore, CMS doses should not be increased during CAPD. Modeling and simulation enabled us to propose the first evidence-based CMS dosage regimen for CAPD patients.

Intravenous colistin in a patient with serious burns and borderline syndrome: The benefits of therapeutic drug monitoring

Colistin is a decades-old drug that fell out of favour due to its nephrotoxicity. Today, colistin is experiencing a renaissance as a treatment against multiresistant Gram-negative bacteria such as Pseudomonas and Acinetobacter in critically ill patients. The optimal dosing of colistin for most infections is unknown. Here we present the intravenous dosing, optimised by therapeutic drug monitoring (TDM), of a borderline patient with severe burns and a consecutive transfemoral amputation. A 32-year-old woman with severe burns (35% total body surface area) and sepsis exhibited normal serum creatinine (SCr) concentrations at the beginning of her intensive care unit (ICU) stay, but over the course of her ICU stay her SCr increased to 100μmol/L. With the colistin standard dose of 3×3 million units (MU) colistin/day after a loading dose of 9 MU, she failed to achieve effective plasma concentrations. The estimated glomerular filtration rate (eGFR) via CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) revealed GFRs between 180mL/min and 63mL/min after correcting for body surface. The patient required a high daily dosage of colistin (3×6 MU) that exceeded the approved maximum dose. Most clinicians rely heavily on SCr concentrations as the primary biochemical marker of GFR. At most, the CKD-EPI formula is helpful in determining creatinine clearance. The pharmacokinetics of colistin are currently poorly understood. TDM of colistin methanesulfonate and colistin may represent an invaluable approach to optimise colistin drug exposure in ICU patients with fluctuating renal clearance.

Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study

BackgroundData regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels.MethodsA prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.ResultsOne hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with ≥ 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT.ConclusionsWhen using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI.

Population Pharmacokinetics of Colistin Methanesulfonate in Rats: Achieving Sustained Lung Concentrations of Colistin for Targeting Respiratory Infections

Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections.

Synergy of imipenem/colistin methanesulfonate combinations against imipenem-nonsusceptible multidrug-resistant Acinetobacter baumannii

The optimal combination ratio of imipenem to colistin methanesulfonate (CMS) against imipenem-nonsusceptible multidrug-resistant Acinetobacter baumannii (INS-MDRAB) has not been determined in previous studies. To provide an alternative therapeutic option for clinical INS-MDRAB isolates, we investigated whether clinically achievable serum concentrations of CMS in combination with imipenem enhance the in vitro activity of imipenem against the INS-MDRAB isolates. Fifty-nine INS-MDRAB isolates with imipenem minimal inhibitory concentration (MIC) values of ≥8 mg/L were selected randomly from the Clinical Microbiology Laboratory at a university-affiliated medical center between July 1998 and May 2005. The in vitro activity of imipenem among these 59 clinical isolates was explored via serial two-fold dilutions containing a range of imipenem concentration from 0.125 mg/L to 256 mg/L, in combination with two fixed CMS concentrations at 0.5 mg/L and 1 mg/L. Genotype classification was performed using the pulsed-field gel electrophoresis method and infrequent-restriction-site polymerase chain reaction. A significant reversal of imipenem resistance (i.e., MICs ≤ 4 mg/L) was observed in 34 (57.6%) isolates and 44 (74.6%) isolates with the tests of CMS concentrations at 0.5 mg/L and 1 mg/L, respectively (p = 0.041). Genotype 1 was predominant (43 isolates, 72.9%) with imipenem resistance reversal rates of 51.2% and 79.1% (p = 0.004) in the tests of CMS at 0.5 mg/L and 1 mg/L, respectively. The synergy of imipenem/CMS against INS-MDRAB was significantly better for the CMS concentration at 1 mg/L than that at 0.5 mg/L, especially in our predominant clone. Our results provided insightful information for treating INS-MDRAB infections in clinical practice.

Polymyxins as Novel and Safe Mucosal Adjuvants to Induce Humoral Immune Responses in Mice

There is currently an urgent need to develop safe and effective adjuvants for enhancing vaccine-induced antigen-specific immune responses. We demonstrate here that intranasal immunization with clinically used polypeptide antibiotics, polymyxin B (PMB) and colistin (CL), along with ovalbumin (OVA), increases OVA-specific humoral immune responses in a dose-dependently manner at both mucosal and systemic compartments. Enhanced immunity by boosting was found to persist during 8 months of observation. Moreover, mice intranasally immunized with OVA plus various doses of PMB or CL showed neither inflammatory responses in the nasal cavity and olfactory bulbs nor renal damages, compared to those given OVA alone. These data suggest that polymyxins may serve as novel and safe mucosal adjuvants to induce humoral immune responses. The polymyxin adjuvanticity was found to be independent of endotoxins liberated by its bactericidal activity, as indicated by similar enhancing effects of PMB in lipopolysaccharide (LPS)-hyporesponsive and LPS-susceptible mice. However, despite the presence of preexisting anti-PMB antibodies, we observed no reduction in the adjuvant function of polymyxins when they were given intranasally. Furthermore, the titers of OVA-specific Abs in mice intranasally immunized with OVA plus PMB or CL were significantly higher than those in mice administered with polymyxin analogues, such as polymyxin B nonapeptide and colistin methanesulfonate. The levels of released β-hexosaminidase and histamine in mast cell culture supernatants stimulated by PMB or CL were also significantly higher than those stimulated by their analogues. These results suggest that both the hydrophobic carbon chain and hydrophilic cationic cyclic peptide contribute to the mucosal adjuvanticity of PMB and CL.

Combined Intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection

Colistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls, n = 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv, n = 3) or combined intravenous/intraventricular administration (EVDVcomb, n = 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%, P ≤ 0.05) and in EVDVcomb compared to all other patients (P < 0.0001). CSF colistin concentrations above the MIC of 0.5 μg/ml were achieved only in EVDVcomb patients.

Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study

IntroductionUse of colistin methanesulfonate (CMS) was abandoned in the 1970s because of excessive nephrotoxicity, but it has been reintroduced as a last-resort treatment for extensively drug-resistant infections caused by gram-negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia). We conducted a retrospective cohort study to evaluate risk factors for new-onset acute kidney injury (AKI) in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics.MethodsThe cohort consisted of 279 adults admitted to two general ICUs in teaching hospitals between 1 April 2009 and 30 June 2011 with 1) no evidence on admission of acute or chronic kidney disease; and 2) treatment for more than seven days with CMS and/or other nephrotoxic antimicrobials (NAs, that is, aminoglycosides, glycopeptides). Logistic regression analysis was used to identify risk factors associated with this outcome.ResultsThe 279 cases that met the inclusion criteria included 147 patients treated with CMS, alone (n = 90) or with NAs (n = 57), and 132 treated with NAs alone. The 111 (40%) who developed AKI were significantly older and had significantly higher Simplified Acute Physiology Score II (SAPS II) scores than those who did not develop AKI, but rates of hypertension, diabetes mellitus and congestive heart failure were similar in the two groups. The final logistic regression model showed that in the 147 patients who received CMS alone or with NAs, onset of AKI during the ICU stay was associated with septic shock and with SAPS II scores ≥43. Similar results were obtained in the 222 patients treated with CMS alone or NAs alone.ConclusionsIn severely ill ICU patients without pre-existing renal disease who receive CMS high-dose for more than seven days, CMS therapy does not appear to be a risk factor for this outcome. Instead, the development of AKI was strongly correlated with the presence of septic shock and with the severity of the patients as reflected by the SAPS II score.

The importance of protecting the mechanical ventilator during colistin methanesulfonate nebulization

The importance of protecting the mechanical ventilator during colistin methanesulfonate nebulization

Colistin Methanesulfonate and Colistin Pharmacokinetics in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration

This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C(max)) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (f(m)) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.

Pharmacokinetics and pharmacodynamics of ‘old’ polymyxins: what is new?

‘Old’ colistin and polymyxin B are increasingly used as last-line therapy against multidrug-resistant Gram-negative bacteria Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. For intravenous administration, colistin is dosed as its inactive prodrug colistin methanesulfonate (sodium), while polymyxin B is used as its sulfate (active antibacterial). Over the last decade, significant progress has been made in understanding their chemistry, pharmacokinetics (PK), and pharmacodynamics (PD). The first scientifically based dosing suggestions are now available for colistin methanesulfonate to generate a desired target steady-state plasma concentration of formed colistin in various categories of critically ill patients. As simply increasing polymyxin dosage regimens is not an option for optimizing their PK/PD due to nephrotoxicity, combination therapy with other antibiotics has great potential to maximize the efficacy of polymyxins while minimizing emergence of resistance. We must pursue rational approaches to the use of polymyxins and other existing antibiotics through the application of PK/PD principles.

Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study

Repeated isolation of multidrug-resistant Acinetobacter baumannii (MDRAB) from respiratory secretions poses a great challenge for infection control. We conducted a retrospective case-control study to evaluate the efficacy and adverse effect of inhaled colistin methanesulfonate (CMS) in the eradication of MDRAB from the respiratory tract. Patients who were admitted to Taipei Veterans General Hospital between February 2009 and June 2010, had at least two sets of monomicrobial culture of MDRAB from respiratory secretions, and remained in hospital for at least 14 days after the first isolation of MDRAB (index day) were included. Patients who received intravenous CMS were excluded. Patients who received CMS inhalation for ≥3 days were selected as cases whereas the controls were matched for age and Acute Physiology and Chronic Health Evaluation II score. Thirty-nine cases and controls were identified. The duration of CMS inhalation was 10.9 ± 3.6 days. The use of inhaled CMS was the only independent factor associated with the eradication of MDRAB within 14 days after the index day (OR 266.33; 95% CI 11.26–6302.18, p <0.001), and shortened the duration of MDRAB recovery from the respiratory tract by 13.3 ± 1.45 days. The adverse effects were similar for both groups. The increase of colistin minimal inhibitory concentrations in the last isolate compared with the index isolate from the same patient did not differ between the two groups. In conclusion, our study demonstrated that inhaled CMS enhanced the eradication of MDRAB from the respiratory tract without significant clinical adverse effect or impact on colistin resistance.

Interaction of Colistin and Colistin Methanesulfonate with Liposomes: Colloidal Aspects and Implications for Formulation

Interaction of colistin and colistin methanesulfonate (CMS) with liposomes has been studied with the view to understanding the limitations to the use of liposomes as a more effective delivery system for pulmonary inhalation of this important class of antibiotic. Thus, in this study, liposomes containing colistin or CMS were prepared and characterized with respect to colloidal behavior and drug encapsulation and release. Association of anionic CMS with liposomes induced negative charge on the particles. However, degradation of the CMS to form cationic colistin over time was directly correlated with charge reversal and particle aggregation. The rate of degradation of CMS was significantly more rapid when associated with the liposome bilayer than when compared with the same concentration in aqueous solution. Colistin liposomes carried positive charge and were stable. Encapsulation efficiency for colistin was approximately 50%, decreasing with increasing concentration of colistin. Colistin was rapidly released from liposomes on dilution. Although the studies indicate limited utility of colistin or CMS liposomes for long duration controlled-release applications, colistin liposomes were highly stable and may present a potential opportunity for coformulation of colistin with a second antibiotic to colocalize the two drugs after pulmonary delivery.

Evaluation in vitro of the efficacy of colistin methanesulfonate against biofilm-forming multidrug-resistant Pseudomonas aeruginosa (MDRP)

The aim of this study was to evaluate in vitro the efficacy of clinically using colistin methanesulfonate against biofilm-forming multidrug-resistant Pseudomonas aeruginosa (MDRP), with minimum inhibitory concentrations (MICs) of ciprofloxacin, imipenem, and amikacin showing ≥4, 16, and 32μg/ml, respectively, by disk diffusion susceptibility testing (CLSI document M100-S21). The minimum eradication biofilm concentration (MBEC) of colistin methanesulfonate for strain MDRP-YMD isolated from a patient's urine, which formed a biofilm on plastic pegs attached to a microplate lid, was compared with that of P. aeruginosa ATCC27853 for quality control testing with MICs of ciprofloxacin, imipenem, and amikacin showing ≤1, 4, and 16μg/ml, respectively. In an uneven biofilm approximately 10μm thick, as determined with confocal laser scanning microscopy (CLSM), ratios of MBEC to MIC of colistin methanesulfonate against strains MDRP-YMD and ATCC27853 were 10.5 and 8.0, whereas those of minimum bactericidal concentration (MBC) to MIC in planktonic cells were 1.0 and 2.0μg/ml, respectively. Morphological examination using scanning electron microscopy and CLSM verified that embedded cells in biofilm matrices of the two strains were disrupted and died under the MBEC. Therefore, bactericidal effects of colistin methanesulfonate on biofilm-forming cells of strain MDRP-YMD as well as strain ATCC27853 were significantly decreased compared with those on the planktonic cells.

Mitogen-activated protein kinases-dependent induction of hepatocyte growth factor production in human dermal fibroblasts by the antibiotic polymyxin B

Hepatocyte growth factor (HGF) stimulates migration and proliferation of keratinocytes and has been suggested to be involved in wound healing. The cationic antibiotic polymyxin B (PMB) is commonly used as a topical antibiotic for wound care. If PMB possesses an HGF-inducing activity, the antibiotic is potentially beneficial for wound healing in addition to minimizing chances of infection. In this study, we found that PMB markedly induced HGF production from various types of cells including human dermal fibroblasts. Its effect was stronger than the effects of epidermal growth factor and cholera toxin and was comparable to the effect of 8-bromo-cAMP. Among the polymyxin family and polymyxin derivatives, colistin was also effective, whereas colistin methanesulfonate had only a marginal effect and PMB nonapeptide was ineffective. The stimulatory effect of PMB was accompanied by upregulation of HGF gene expression. Increase in phosphorylation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) was observed from 0.25h to 6h after the addition of PMB, while increase in phosphorylation of p38 mitogen-activated protein kinase (MAPK) was detected from 24h to 60h after PMB addition. The MAPK/ERK kinase inhibitor PD98059, the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 all potently inhibited PMB-induced HGF production. Lastly, proliferation of human dermal fibroblasts was significantly stimulated by PMB. These results indicate that PMB-induced HGF production and proliferation of human dermal fibroblasts and suggest that activation of MAPKs is involved in the induction of HGF production.

Pharmacokinetics of Colistin in Cerebrospinal Fluid after Intraventricular Administration of Colistin Methanesulfonate

Intraventricular colistin, administered as colistin methanesulfonate (CMS), is the last resource for the treatment of central nervous system infections caused by panresistant Gram-negative bacteria. The doses and daily regimens vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) pharmacokinetics of colistin after intraventricular administration of CMS has never been characterized. Nine patients (aged 18 to 73 years) were treated with intraventricular CMS (daily doses of 2.61 to 10.44 mg). Colistin concentrations were measured using a selective high-performance liquid chromatography (HPLC) assay. The population pharmacokinetics analysis was performed with the P-Pharm program. The pharmacokinetics of colistin could be best described by the one-compartment model. The estimated values (means ± standard deviations) of apparent CSF total clearance (CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and terminal half-life (t(1/2λ)) were 0.033 ± 0.014 liter/h and 7.8 ± 3.2 h, respectively, and the average time to the peak concentration was 3.7 ± 0.9 h. A positive correlation between CL/Fm and the amount of CSF drained (range 40 to 300 ml) was observed. When CMS was administered at doses of ≥5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 μg/ml, and measured values of trough concentration (C(trough)) ranged between 2.0 and 9.7 μg/ml. Microbiological cure was observed in 8/9 patients. Intraventricular administration of CMS at doses of ≥5.22 mg per day was appropriate in our patients, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent.

Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill

A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

Colistin Distribution in the Peritoneal Fluid of a Patient with Severe Peritonitis

Colistin appears more and more frequently as a last-line defense therapy against nosocomial infections due to multiresistant Gram-negative bacteria ([8][1]). For parenteral administration, colistin is used as a prodrug, colistin methanesulfonate (CMS), which is less toxic but inactive and hydrolyzed

Bactericidal Activity of Multiple Combinations of Tigecycline and Colistin against NDM-1-Producing Enterobacteriaceae

The interaction between colistin and tigecycline against eight well-characterized NDM-1-producing Enterobacteriaceae strains was studied. Time-kill methodology was employed using a 4-by-4 exposure matrix with pharmacokinetically achievable free drug peak, trough, and average 24-h serum concentrations. Colistin sulfate and methanesulfonate alone showed good early bactericidal activity, often with subsequent regrowth. Tigecycline alone had poor activity. Addition of tigecycline to colistin does not produce increased bacterial killing; instead, it may cause antagonism at lower concentrations.