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Background: Colistin is one of the last resort therapeutic options for treating carbapenemase-producing Enterobacterales, which are resistant to a broad range of beta-lactam antibiotics. However, the increased use of colistin in clinical and livestock farming settings in Thailand and China, has led to the inevitable emergence of colistin resistance. To better understand the rise of colistin-resistant strains in each of these settings, we characterized colistin-resistant Enterobacterales isolated from farmers, swine, and hospitalized patients in Thailand., Methods: Enterobacterales were isolated from 149 stool samples or rectal swabs collected from farmers, pigs, and hospitalized patients in Thailand between November 2014-December 2017. Confirmed colistin-resistant isolates were sequenced. Genomic analyses included species identification, multilocus sequence typing, and detection of antimicrobial resistance determinants and plasmids., Results: The overall colistin-resistant Enterobacterales colonization rate was 26.2% (n = 39/149). The plasmid-mediated colistin-resistance gene (mcr) was detected in all 25 Escherichia coli isolates and 9 of 14 (64.3%) Klebsiella spp. isolates. Five novel mcr allelic variants were also identified: mcr-2.3, mcr-3.21, mcr-3.22, mcr-3.23, and mcr-3.24, that were only detected in E. coli and Klebsiella spp. isolates from farmed pigs., Conclusion: Our data confirmed the presence of colistin-resistance genes in combination with extended spectrum beta-lactamase genes in bacterial isolates from farmers, swine, and patients in Thailand. Differences between the colistin-resistance mechanisms of Escherichia coli and Klebsiella pneumoniae in hospitalized patients were observed, as expected. Additionally, we identified mobile colistin-resistance mcr-1.1 genes from swine and patient isolates belonging to plasmids of the same incompatibility group. This supported the possibility that horizontal transmission of bacterial strains or plasmid-mediated colistin-resistance genes occurs between humans and swine., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Long-term use of colistin for preventing Gram-negative bacterial infections in food animals was prohibited in Thailand in 2017, but it is permitted for short-term treatment. This study aimed to investigate association between the use of colistin for short-term treatment of infection and the emergence of colistin-resistant Enterobacteriaceae in swine. The current study was conducted at 2 selected swine farms in Thailand. Neither farm has used colistin to prevent infection for longer than 1 year. Rectal swabs were collected from the same 66 pigs at birth, and on days 7, 14, 21, 28, and 60. Colistin was used to treat sick pigs for up to 3 days. Additional rectal swabs were collected during colistin treatment. Rectal swabs were analyzed for colistin-resistant Enterobacteriaceae and the mcr-1 gene. Results revealed that colistin-resistant Enterobacteriaceae were absent at birth. Some pigs at both farms had diarrhea and received colistin treatment during days 2-27. Colistin-resistant Enterobacteriaceae were detected in 13.3-50.0% of sick and healthy pigs. No sick pigs were observed during days 28-60, and colistin was not used during that period. Colistin-resistant Enterobacteriaceae were detected in 2.8-10.0% of healthy pigs on day 28, and in 0-3.4% of healthy pigs on day 60. The mcr-1 gene was detected in 57.6% of colistin-resistant Enterobacteriaceae isolates. Short-term treatment with colistin was found to be associated with the emergence of colistin-resistant Enterobacteriaceae in swine. Colistin-resistant Enterobacteriaceae rapidly emerged after colistin use, and rapidly decreased or disappeared after its discontinuation., Competing Interests: The authors have declared that no competing interests exist.

The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use., (© 2019 Pharmacotherapy Publications, Inc.)

Development and evaluations of the Rapid Polymyxin NP test for detection of colistin resistance in Enterobacteriaceae have been recently reported. In this study, we evaluated the performance of the test using a larger number of Enterobacteriaceae, and a larger proportion of isolates with a colistin MIC close to the breakpoint. Out of 339 isolates, the Rapid Polymyxin NP test detected colistin resistance in 13 isolates of Escherichia coli, 213 isolates of Klebsiella pneumoniae, 9 isolates of Enterobacter aerogenes, and 10 isolates of the other Enterobacteriaceae species. Sensitivity and specificity of the test for detecting colistin resistance were 100% and 95.9%, respectively. Positive predictive value and negative predictive value were 98.3% and 100%, respectively., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Colistin has been used for therapy of carbapenem-resistant Gram-negative infections in Thailand, especially carbapenem-resistant A. baumannii and P. aeruginosa , for more than 10 years. However, the prevalence of colistin-resistant A. baumannii or P. aeruginosa is still less than 5%. Colistin-resistant Enterobacteriaceae has been increasingly reported globally over the past few years and the use of colistin in food animals might be associated with an emergence of colistin resistance in Enterobacteriaceae. This study aimed to determine the effect of colistin exposure in hospitalized patients who received colistin on development of colistin-resistant (CoR) Escherichia coli (EC) or Klebsiella pneumoniae (KP) colonization and infection., Methods: A prospective observational study was performed in adult hospitalized patients at Siriraj Hospital who received colistin for treatment of infections during December 2016 and November 2017. The surveillance culture samples were collected from the stool and the site of infection of each patient who received colistin at the study enrollment, days 3 and 7 after the study enrollment, and once a week thereafter for determination of CoR EC and CoR KP. CoR EC and CoR KP were also tested for a presence of mcr-1 gene., Results: One hundred thirty-nine patients were included. Overall prevalence of CoR EC or CoR KP colonization was 47.5% among 139 subjects. Prevalence of CoR EC or CoR KP colonization was 17.3% of subjects at study enrollment, and 30.2% after study enrollment. Use of fluoroquinolones, aminoglycosides, and colistin was found to be significantly associated with CoR EC or CoR KP colonization. The mcr-1 gene was detected in 13.0% of CoR EC or CoR KP isolates, and in 27.3% of subjects with CoR EC or CoR KP colonization. CoR EC or CoR KP colonization persisted in 65.2% of the subjects at the end of the study. Five patients with CoR KP infections received combination antibiotics and they were alive at hospital discharge., Conclusions: Prevalence of CoR EC or CoR KP colonization in hospitalized patients receiving colistin was high and it was associated with the use of colistin. Therefore, patients who receive colistin are at risk of developing CoR EC or CoR KP colonization and infection., Competing Interests: The study protocol was approved by the Siriraj Institutional Review Board, and written informed consent was obtained from all subjects.Not applicable.The authors declare that they have no competing interestsSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acute kidney injury (AKI) occurs in a substantial proportion of critically ill patients receiving intravenous colistin. In the pharmacokinetic/toxicodynamic analysis reported here, the relationship of the occurrence of AKI to exposure to colistin and a number of potential patient factors was explored in 153 critically ill patients, none of whom were receiving renal replacement therapy. Tree-based modeling revealed that the rates of AKI were substantially higher when the average steady-state plasma colistin concentration was greater than ∼2 mg/liter., (Copyright © 2017 American Society for Microbiology.)

Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii . The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities., Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactam-resistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations., Results: Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg of >2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth., Conclusions: To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (C ss,avg ) of 2mg/L., Methods: Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/min; 29 receiving renal replacement therapy (RRT)) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based upon the relationship between the dose of colistimethate that would be needed to achieve a desired C ss,avg and creatinine clearance. The increase in colistin clearance when patients were on RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for C ss,avg ≥2 and <30% for C ss,avg ≥4mg/L., Results: When algorithm doses were applied back to individual patients not on RRT (including patients prescribed intermittent dialysis on a non-dialysis day), >80% of patients with creatinine clearance <80mL/min achieved C ss,avg ≥2mg/L; but for patients with creatinine clearance ≥80mL/min target attainment was <40%, even with the maximum allowed daily dose of 360mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained C ss,avg ≥4mg/L., Conclusions: The project has generated clinician-friendly dosing algorithms and pointed to circumstances where intravenous monotherapy may be inadequate., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To monitor the effectiveness and safety of colistin for therapy in resistant Gram-negative bacterial infections at Siriraj Hospital 10 years after colistin was first introduced in Thailand at Siriraj Hospital in 2005., Material and Method: Study subjects were hospitalized adult patients with documented Gram-negative bacterial infections that received parenteral colistin (Colistate) for longer than 48 hours between October 2014 and June 2015. Patient information regarding demographics, characteristics of infections, antibiotic therapy, clinical outcomes, microbiological responses, and nephrotoxicity were identified and retrieved from patient medical records. The data were analyzed using descriptive statistics., Results: One hundred thirty eight patients were included in the study. Many of the patients were elderly males. The most common type of infection was pneumonia and A. baumannii was the most common cause of infection. Nearly all isolates of A. baumannii and P. aeruginosa were resistant to carbapenems. A loading dose of colistin (300 mg) was given in 94.9% of patients. Only 19.6% of patients received colistin alone. Most patients received concomitant antibiotics, especially carbapenems, and piperacillin-tazobactam. Favorable clinical outcome was observed in 71.7% of patients at the end of colistin therapy. Patient mortality at the end of colistin therapy and at 30 days after colistin therapy was completed was 23.2% and 39.9%, respectively. Microbiological eradication of target bacteria at the end of colistin therapy was found in 50.0% of patients. Overall incidence of acute kidney injury was 39.9%, with most cases classified as either risk (20.3%) or injury (13%). Colistin-related renal dysfunction was reversible in most cases., Conclusion: Colistin remains the principal antibiotic in carbapenem-resistant Gram-negative bacterial infections. Colistin's effectiveness and safety is still rated as moderate for therapy in difficult-to-treat resistant Gram-negative bacterial infections.

Background: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations., Methods: Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of ≥0.5, ≥1, ≥2, and ≥4 mg/L were determined for each creatinine clearance category (≥80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min)., Results: For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations., Conclusions: The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints., Clinical Trials Registration: NCT00235690., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Objectives: Colistin, administered intravenously as its inactive prodrug colistin methanesulphonate (CMS), is being increasingly used. However, there is very limited information available on the impact of haemodialysis (HD) on the pharmacokinetics of CMS and formed colistin., Patients and Methods: A single 30 min intravenous dose of CMS (150 mg of colistin base activity) was administered to 10 patients undergoing HD. HD was performed from 1.5 to 5.5 h after the start of the CMS infusion. Serial blood samples were collected over 50 h, additional blood samples pre- and post-dialysis membrane at three timepoints during HD, dialysate samples at four timepoints during HD, and a cumulative urine sample over 24 h. CMS and colistin were determined by HPLC. Population modelling and determination of HD clearance by multiple methods was conducted., Results: The average amount of CMS recovered in the dialysate was 30.6% of the dose administered. The concentrations of CMS and colistin in the plasma and the amounts of CMS recovered in the dialysate were well described by the population disposition model. The clearance of CMS by dialysis as estimated by population analysis based on systemic plasma concentrations and amounts in the dialysate was 4.26 L/h (26% coefficient of variation). The dialysis clearance determined from the pre- and post-membrane plasma concentrations was 5.67 L/h (21%) for CMS and 3.99 L/h (44%) for colistin. Thus, CMS clearance by dialysis from trans-cartridge extraction was ∼30% higher than when calculated based on the amount in dialysate, suggesting adsorption to the membrane., Conclusions: Due to the extensive removal of CMS by dialysis, HD should be conducted at the end of a dosing interval and a supplemental dose should be administered., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Nephrotoxicity is a dose-limiting factor of colistin, a last-line therapy for multidrug-resistant Gram-negative bacterial infections. An earlier animal study revealed a protective effect of ascorbic acid against colistin-induced nephrotoxicity. The present randomized controlled study was conducted in 28 patients and aimed to investigate the potential nephroprotective effect of intravenous ascorbic acid (2 g every 12 h) against colistin-associated nephrotoxicity in patients requiring intravenous colistin. Thirteen patients received colistin plus ascorbic acid, whereas 15 received colistin alone. Nephrotoxicity was defined by the RIFLE classification system. Additionally, urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-d-glucosaminidase (NAG) were measured as markers of renal damage, and plasma colistin concentrations were quantified. The baseline characteristics, clinical features, and concomitant treatments of the patients in the two groups were comparable. The incidences of nephrotoxicity were 53.8% (7/13) and 60.0% (9/15) in the colistin-ascorbic acid group and the colistin group, respectively (P = 0.956; relative risk [RR], 0.9; 95% confidence interval, 0.47 to 1.72). In both groups, the urinary excretion rates of NGAL and NAG on day 3 or 5 of colistin treatment and at the end of colistin treatment were significantly higher than those at the respective baselines (P < 0.05). However, the urinary excretion rates of these biomarkers at the various times during colistin treatment did not differ significantly between the groups (P > 0.05). The plasma colistin concentrations in the two groups were not significantly different (P > 0.28). The clinical and microbiological outcomes and mortality of the patients in the two groups were not significantly different. This preliminary study suggests that ascorbic acid does not offer a nephroprotective effect for patients receiving intravenous colistin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01501968.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Ninety-four patients infected with carbapenem-resistant Acinetobacter baumannii were randomized to receive colistin alone or colistin plus fosfomycin for 7 to 14 days. The patients who received combination therapy had a significantly more favorable microbiological response and a trend toward more favorable clinical outcomes and lower mortality than those who received colistin alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01297894.)., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objective: To determine in vitro activity of colistin plus sulbactam against extensive-drug-resistant (XDR) Acinetobacter baumannii., Material and Method: Checkerboard method was used to determine in vitro activity of colistin plus sulbactam against 11 clinical isolates of XDR A. baumannii. The concentrations of colistin and sulbactam used in the study were 0.025 to 128 mg/ 1 and 4 to 256 mg/l, respectively. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of colistin, sulbactam and colistin plus sulbactam at various concentrations were determined. Fractional inhibitory concentration index (FICI) was calculated. The antibiotic combination is considered synergistic if FICI < 0.5, indifferent if FICI 0.5 to 4.0, and antagonistic if FICI > 4.0., Results: Ten isolates of XDR A. baumannii were susceptible to colistin (MIC < 2 mg/l) and one isolate was resistant to colistin (MIC 8 mg/l). There were no antagonistic effects of colistin plus sulbactam against all study isolates. For 10 isolates of colistin-susceptible XDR A. baumannii, some MIC values of the combinations were lower than those of single antibiotics. However no synergistic effect of colistin and sulbactam was observed in colistin-susceptible XDR A. baumannii isolates. The synergistic effect of colistin and sulbactam was detected in some concentrations of colistin and sulbactam against colistin-resistant XDR A. baumannii isolate., Conclusion: The combination of colistin and sulbactam showed an indifferent effect against colistin-susceptible XDR A. baumannii. The combination of colistin and sulbactam showed synergistic effect at some concentrations of colistin and sulbactam against a clinical isolate of colistin-resistant XDR A. baumannii. In vitro time-kill method should be performed to confirm the aforementioned observations.

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.

With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m(2). Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥ 1.0 mg/liter.

Background: Cases of ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa are common in hospitalized patients at Siriraj Hospital, Bangkok, Thailand. Parenteral colistimethate sodium (CMS) has been used for therapy of VAP caused by MDR A. baumannii and P. aeruginosa at Siriraj Hospital over the past few years, with modest favourable outcomes. Objectives To determine whether nebulized CMS as adjunctive therapy of Gram-negative VAP was safe and beneficial., Methods: This was a randomized controlled study in 100 adults who developed Gram-negative VAP (clinical trial registration number: NCT00920270). All patients received systemic antibiotics according to the decisions of their responsible physicians. The patients were randomized to receive an additional 4 mL of nebulized sterile normal saline (NSS) (n = 49) or nebulized CMS equivalent to 75 mg of colistin base in 4 mL of NSS (n = 51) every 12 h until systemic antibiotic therapy of VAP was ended., Results: The baseline characteristics of the patients and conventional therapy of VAP in both groups were comparable. Most of the cases of VAP were caused by MDR A. baumannii and/or P. aeruginosa. All isolates of Gram-negative bacteria were susceptible to colistin. Favourable clinical outcome was 51.0% in the CMS group and 53.1% in the control group (P = 0.84). Patients in the CMS group had significantly more favourable microbiological outcome when compared with patients in the control group (60.9% versus 38.2%, P = 0.03). Bronchospasm was observed in 7.8% of patients in the CMS group and in 2.0% of patients in the control group (P = 0.36). Renal impairment was observed in 25.5% of patients in the CMS group and in 22.4% of patients in the NSS group (P = 0.82)., Conclusions: Nebulized CMS as adjunctive therapy of Gram-negative VAP seems to be safe. However, a beneficial effect on clinical outcomes of adjunctive nebulized CMS for therapy of Gram-negative VAP was not ascertained.

Objective: To determine the efficacy and safety of colistin (colistimethate sodium) produced by a local pharmaceutical company in Thailand for the treatment of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter baumannii., Methods: Patients hospitalized at Siriraj Hospital between January 2005 and April 2006, who had infections caused by MDR P. aeruginosa or A. baumannii, were enrolled in the study. Colistin (colistimethate sodium) at a dosage of 5 mg/kg/day was given intravenously in two divided doses. Primary outcomes were the clinical response and 30-day mortality; secondary outcomes were microbiological response and adverse events., Results: Ninety-three patients infected with MDR P. aeruginosa and A. baumannii were enrolled. Seventy-eight patients (71 with A. baumannii and seven with P. aeruginosa) received colistin, whereas 15 patients (12 with A. baumannii and three with P. aeruginosa) received other antibiotics. The mean age, gender, underlying conditions and severity of illness of the patients in both groups were not significantly different. In the colistin group, 63 patients (80.8%) had a favorable clinical response and 94.9% had a microbiological response. The overall mortality of the patients in the colistin group was 46.2% and that in the non-colistin group was 80%. Nephrotoxicity was found in 24 patients (30.8%) in the colistin group and 17 of them had predisposing factors contributing to their renal dysfunction. No neurotoxicity was observed among the 78 patients., Conclusion: Locally produced colistin appears to be safe and effective for the treatment of infections caused by MDR P. aeruginosa and A. baumannii in Thai adult patients.