Search

Objectives: Limited data are available to guide colistin use in older adults (>65 years old). We aimed to assess the effectiveness and safety of colistin in this population., Methods: Systematic review and meta-analysis of original data from randomized control trials, cohort studies and case-control studies assessing colistin regimens with various comparisons for any infection. Original data were obtained from corresponding authors of original studies. The primary outcome was all-cause 1 month mortality; secondary outcomes included clinical and microbiological outcomes and adverse events, including acute kidney injury. Two independent reviewers screened citations, extracted data and assessed risk of bias. ORs with 95% CIs were pooled., Results: We included 38 publications (41 comparisons) reporting 2857 elderly individuals: 29 studies compared a colistin-based regimen versus another regimen (comparison 1) and 10 compared colistin monotherapy versus colistin combination (comparison 2). No significant difference in 1 month mortality was demonstrated between colistin and comparator (comparison 1, OR 1.13, 95% CI 0.80-1.60; comparison 2, OR 0.99, 95% CI 0.78-1.27). Clinical failure was significantly more likely with colistin-based therapy versus comparator (OR 1.52, 95% CI 1.13-2.06). Acute kidney injury was also significantly more common with colistin-based combinations versus other drugs (OR 3.81, 95% CI 2.14-6.77)., Conclusions: For older adults, colistin-based therapy resulted in no mortality difference, compared with other regimens, for any infection. Clinical failure and acute kidney injury were significantly more common with colistin-based regimens. Close renal function monitoring is needed while using colistin in older adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms., Methods: This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E)., Results: Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475-10.184; P = .006)., Conclusions: Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem., Methods: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin-meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin-meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure., Results: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31-1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22-2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26-1.04) or 14-day mortality (aOR1.09, 95% CI 0.60-1.96)., Discussion: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy., Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality., Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202])., Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy., Clinical Trials Registration: NCT01732250., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria., Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual., Findings: Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5·7%, 95% CI -13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83-1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87-1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury)., Interpretation: Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria., Funding: EU AIDA grant Health-F3-2011-278348., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background:  Optimizing colistin dosing should translate to improved patient outcomes., Methods:  We used data from 2 prospective cohort studies performed between 2006 and 2009 and between 2012 and 2015. In the latter period, a new policy of high-dose colistin (9 million international units [MIU] loading dose followed by 9 MIU daily for normal renal function) was introduced in 2 participating hospitals. We included adult inpatients with invasive infections caused by carbapenem-resistant gram-negative bacteria treated with colistin. Our primary exposure variable was colistin dose, dichotomized to high-dose vs other regimens. The primary outcome was 28-day mortality. We generated a propensity score for high-dose colistin and conducted propensity-adjusted multivariable and matched-cohort analyses for mortality., Results:  Of 529 consecutive patients fulfilling inclusion criteria, 144 were treated with high-dose colistin and 385 with lower-dose colistin regimens. The median daily dose in the high-dose group was 9 MIU (interquartile range [IQR], 9-9) vs 4 MIU (IQR, 3-6) with other regimens. There were 50 of 144 (34.7%) deaths with high-dose colistin vs 165 of 385 (42.9%) with low-dose colistin (P = .1). The propensity-adjusted odds ratio (OR) for mortality was 1.07 (95% confidence interval [CI], .63-1.83) for high-dose colistin. Similar results were obtained when using the study period as the exposure variable, in the subgroup of bacteremic patients (n = 207) and in the propensity-matched cohort (OR, 1.11 [95% CI, .67-1.82]). Nephrotoxicity (RIFLE injury or higher; OR, 2.12 [95% CI, 1.29-3.48]; n = 396) and seizures were significantly more common with high-dose colistin., Conclusions:  In a large cohort, we found no association between high colistin dosing and all-cause mortality. High dosing was associated with more nephrotoxicity., (© 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.)

Introduction: The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification., Methods and Analysis: This is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin-meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilator-associated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patients who met eligibility requirements but were not randomised in order to assess generalisability of findings., Ethics and Dissemination: The study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics., Trial Registration Number: NCT01732250 and 2012-004819-31; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Colistin has re-entered clinical use by necessity. We aimed to assess its effectiveness and safety compared with newer antibiotics., Methods: This was a single-centre, prospective cohort study. Inclusion criteria were microbiologically documented pneumonia, urinary tract infection, surgical site infection, meningitis or bacteraemia treated appropriately with colistin versus imipenem, meropenem or ampicillin/sulbactam (comparators). All consecutive patients were included, only once, between May 2006 and July 2009. The primary outcome was 30 day mortality. Multivariable and Cox regression survival analyses were used to adjust comparisons between groups. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals are reported., Results: Two hundred patients treated with colistin and 295 patients treated with comparators were included. Treatment with colistin was associated with older age, admission from healthcare facilities, mechanical ventilation and lower rate of early appropriate antibiotic treatment. The 30 day mortality was 39% (78/200) for colistin versus 28.8% (85/295) for comparators; unadjusted OR 1.58 (1.08-2.31). In the adjusted analysis the OR was 1.44 (0.91-2.26) overall and 1.99 (1.06-3.77) for bacteraemic patients (n = 220). At the end of follow-up, treatment with colistin was significantly associated with cumulative mortality; adjusted HR 1.27 (1.01-1.60) overall and 1.65 (1.18-2.31) among patients with bacteraemia. Nephrotoxicity at the end of treatment was more frequent with colistin; OR adjusted for other risk factors for nephrotoxicity 3.31 (1.54-7.08). Treatment with colistin was followed by increased incidence of Proteus spp. infections during a 3 month follow-up., Conclusions: The need for colistin treatment is associated with poorer survival. Adjusted analyses suggest that colistin is less effective and more toxic than beta-lactam antibiotics.