colistin and Critical-Illness

Data are limited regarding the clinical effectiveness and safety of intravenous colistin for treatment of infections due to MDR Gram-negative bacilli (GNB) in paediatric ICUs (PICUs).. Systematic review of intravenous colistin use in critically ill paediatric patients with MDR-GNB infection in PubMed, Scopus and EMBASE (up to 31 January 2018).. Out of 1181 citations, 7 studies were included on the use of intravenous colistin for 405 patients in PICUs. The majority of patients were diagnosed with lower respiratory tract infections, Acinetobacter baumannii being the predominant pathogen. Colistin dosages ranged between 2.6 and 18 mg/kg/day, with only one case reporting a loading dose. Emergence of colistin resistance during treatment was reported in two cases. Nephrotoxicity and neurotoxicity were reported in 6.1% and 0.5%, respectively, but concomitant medications and severe underlying illness limited our ability to definitively associate use of colistin with nephrotoxicity. Crude mortality was 29.5% (95% CI = 21.7%-38.1%), whereas infection-related mortality was 16.6% (95% CI = 12.2%-21.5%).. While the reported incidence of adverse events related to colistin was low, reported mortality rates for infections due to MDR-GNB in PICUs were notable. In addition to severity of disease and comorbidities, inadequate daily dosage and the absence of a loading dose may have contributed to mortality. As the use of colistin for treatment of MDR-GNB infections increases, it is imperative to understand whether optimal dosing of colistin in paediatric patients differs across different age groups. Thus, future studies to establish the pharmacokinetic properties of colistin in different paediatric settings are warranted.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intensive Care Units, Pediatric; Male

Due to lack of better therapeutic options, colistin use for extensively drug-resistant Gram-negative organisms was revived in the past two decades, including in patients in intensive-care units (ICU). There are multiple knowledge gaps pertaining to the clinical use and utility of colistin in critically-ill patients, but due to lack of options, it is used in these high risk patients. In this chapter, we critically review the various topics pertaining to colistin use in critically-ill patients, while highlighting the (lack of) controlled evidence supporting common current practices pertaining to colistin use by clinicians.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Intensive Care Units

Colistin, an old cationic polypeptide antibiotic, have been reused due to rising incidence of infections caused by multi-drug resistant (MDR) Gram-negative microorganisms and the lack of new antibiotics. Therefore, we evaluated safety and efficacy of colistin in treatment of these infections. This study included 104 critically ill children with a median age of 55,9 months between January 2011 and January 2016. Nephrotoxicity occurred in 11 (10.5%) patients. Nephrotoxicity occurred between the third and seventh day of treatment in 63% of colistin induced nephrotoxicity episodes. The subgroup analysis between the patients who developed nephrotoxicity during colistin treatment and those that did not, showed no significant difference in terms of age, underlying disease, cause for PICU admission and type of infection required colistin treatment, P values were 0.615, 0.762, 0.621, 0.803, respectively. All patients were receiving a concomitant nephrotoxic agent (P = 0,355). The majority of the patients (52%) were having primary or secondary immune deficiency in treatment failure group and the most common cause of PICU admission was sepsis in treatment failure group, P values were 0.007 and 0.045, respectively. Mortality attributed to colistin failure and crude mortality were 14.4% and 29.8%, respectively. In conclusion, colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children. However, the patients have to be followed for side effects throughout colistin treatment, not for only early stage. And the clinicians should be aware of increase in the rate of nephrotoxicity in patients those have been receiving a concomitant nephrotoxic agent.

Topics: Administration, Intravenous; Child, Preschool; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Immunologic Deficiency Syndromes; Intensive Care Units, Pediatric; Kidney; Referral and Consultation; Retrospective Studies; Sepsis; Treatment Outcome

An optimal therapy for the treatment of pneumonia caused by drug-resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis.. Systematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%.. Twenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41-0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04-0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07-0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19-0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32-0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16-0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL.. This Bayesian network meta-analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order.

Topics: Acinetobacter baumannii; Anti-Infective Agents; Bayes Theorem; Colistin; Critical Illness; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests

Published literature on the pharmacokinetics and effectiveness of colistin loading doses is reviewed.. Colistin is increasingly used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria (GNB). A literature search identified seven reports on studies of colistin loading doses. All reviewed studies involved small samples of critically ill patients, with considerable variation in the colistin products and loading doses used. Pharmacokinetic studies indicated that because of the slow rate of conversion of the prodrug colistimethate sodium to the active drug colistin and the long half-life of colistin, it can take two to three days to attain adequate colistin concentrations without a loading dose. The clinical effectiveness of colistin loading doses was evaluated in two studies, neither involving the use of a comparator group. In one of those studies, clinical cure and bacteriological clearance were reported in 82.1% and 73.9% of cases, respectively; in the other, clinical resolution was reported in 77% of patients. Two studies were conducted to compare clinical outcomes of colistin loading-dose regimens and standard regimens with no loading dose; while use of a loading dose was associated with a higher cure rate (63.0% versus 41.3%, p = 0.04) in one study, no improvement in clinical outcomes was reported in the other study.. Published data on the effectiveness of colistin loading doses are limited. The available evidence suggests that it may be necessary to administer a colistin loading dose in severe and life-threatening infections due to MDR GNB.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Prodrugs; Treatment Outcome

Carbapenem-resistant Enterobacteriaceae (CRE) is a worldwide challenge and associated with a high mortality rate in critically ill patients. This review focused on rapid diagnosis, optimization of antimicrobial therapy, and implication of effective infection control precautions to reduce impact of CRE on vulnerable patients.. Several new diagnostic assays have recently been described for the early diagnosis of CRE. Retrospective studies are supportive for colistin plus meropenem combination for the treatment of CRE infections; however, solid evidence is still lacking. Ceftazidime-avibactam may be an effective therapeutic agent for infections caused by carbapenem-hydrolyzing oxacillinase-48 and Klebsiella pneumoniae carbapenamase-producing Enterobacteriaceae, but not for New Delhi metallo-β-lactamase producers. Gastrointestinal screening may permit early identification of patients with CRE infections. There is not enough evidence to recommend selective digestive decontamination for CRE carriers.. The information for rapid diagnosis of CRE is accumulating. There are new agents with high in-vitro activity against CRE, but clinical experience is limited to case reports. Active surveillance with a high rate of compliance to basic infection control precautions seems to be the best approach to reduce the impact of CRE on vulnerable patients.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Ceftazidime; Colistin; Critical Illness; Drug Combinations; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Retrospective Studies; Thienamycins

Colistin, an "old" polymyxin antibiotic, is increasingly being used as last-line treatment against infections caused by multidrug-resistant gram-negative bacteria. It is administered in patients, parenterally or by inhalation, as its inactive prodrug colistin methanesulfonate (CMS). Scientifically based recommendations on how to optimally dose colistin in critically ill patients have become available over the last decade and are extremely important as colistin has a narrow therapeutic window. A dosing algorithm has been developed to achieve desired plasma colistin concentrations in critically ill patients. This includes the necessary dose adjustments for patients with impaired kidney function and those on renal replacement therapy. Due to the slow conversion of CMS to colistin, a loading dose is needed to generate effective concentrations within a reasonable time period. Therapeutic drug monitoring is warranted, where available; because of the observed high interpatient variability in plasma colistin concentrations. Combination therapy should be considered when the infecting pathogen has a colistin minimum inhibitory concentration above 1 mg/L, as increasing the dose may not be feasible due to the risk for nephrotoxicity. Inhalation of CMS achieves considerably higher colistin concentrations in lung fluids than is possible with intravenous administration, with negligible plasma exposure. Similarly, for central nervous system infections, dosing CMS directly into the cerebrospinal fluid generates significantly higher colistin concentrations at the infection site compared with what can be achieved with systemic administration. While questions remain to be addressed via ongoing research, this article reviews the significant advances that have been made toward optimizing the clinical use of colistin.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Humans

Colistin has been used to treat nosocomial pneumonia (NP) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) via different administration routes. Whether patients may benefit from aerosolised colistin as adjunctive treatment was contradictory. We aimed to clarify the safety and efficacy of administering aerosolised and intravenous (IV-AS) colistin versus intravenous (IV) colistin alone in patients with NP caused by MDR-GNB. Two reviewers independently evaluated and extracted data from PubMed, EMBASE and Cochrane databases. Primary outcomes were clinical response rate, all-cause mortality (ICU or hospital), microbiological eradication and nephrotoxicity. Pooled odds ratios (ORs) were calculated and significance was determined by the Z test. Nine eligible studies involving 672 participants were included. The overall clinical response rate (improvement and cure) was significantly higher in the IV-AS group than that in the IV group [OR=1.81, 95% confidence interval (CI) 1.30-2.53; P=0.0005]. Patients treated with IV-AS colistin showed a higher rate of pathogen eradication (OR=1.66, 95% CI 1.11-2.49; P=0.01) and lower all-cause mortality compared with IV colistin (OR=0.69, 95% CI 0.50-0.95; P=0.02). Nephrotoxicity did not differ significantly between IV-AS and IV groups (five studies; 383 patients) (OR=1.11, 95% CI 0.69-1.80; P=0.67). These data indicate that IV-AS colistin has additional benefits compared with IV colistin alone. Clinicians should be encouraged to give combined administration routes in critically ill patients with NP caused by MDR-GNB.

Topics: Administration, Inhalation; Administration, Intravenous; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Nasal Sprays; Pneumonia, Ventilator-Associated; Treatment Outcome

Teicoplanin and polymyxin E (colistin) are antibiotics consisting of multiple, closely related subcomponents, produced by fermentation. The principal components comprise a complex mixture of chemically related, active substances (teicoplanin A(2-1)-A(2-5) and polymyxin E(1-2), respectively), which might be required to be present in specific ratios to ensure optimal antibacterial and clinical efficacy. These subcomponents differ in their fatty acid and amino acid composition and, as such, the lipophilic and protein binding characteristics differ between components. This has therapeutic implications for critically ill patients, as the volume of distribution of the teicoplanin A2 and polymyxin E analogues at the onset of an intravenous infusion may impact on expected pharmacokinetics and influence outcome.

Topics: Amino Acids; Anti-Bacterial Agents; Bacterial Infections; Colistin; Complex Mixtures; Critical Illness; Drug Approval; Fatty Acids; Fermentation; Humans; Protein Binding; Solubility; Teicoplanin; Treatment Outcome

We sought to evaluate the effectiveness of the antibiotic treatment administered for infections caused by carbapenemase-producing Enterobacteriaceae. The PubMed and Scopus databases were systematically searched. Articles reporting the clinical outcomes of patients infected with carbapenemase-producing Enterobacteriaceae according to the antibiotic treatment administered were eligible. Twenty nonrandomized studies comprising 692 patients who received definitive treatment were included. Almost all studies reported on Klebsiella spp. In 8 studies, the majority of infections were bacteremia, while pneumonia and urinary tract infections were the most common infections in 12 studies. In 10 studies, the majority of patients were critically ill. There are methodological issues, including clinical heterogeneity, that preclude the synthesis of the available evidence using statistical analyses, including meta-analysis. From the descriptive point of view, among patients who received combination treatment, mortality was up to 50% for the tigecycline-gentamicin combination, up to 64% for tigecycline-colistin, and up to 67% for carbapenem-colistin. Among the monotherapy-treated patients, mortality was up to 57% for colistin and up to 80% for tigecycline. Certain regimens were administered to a small number of patients in certain studies. Three studies reporting on 194 critically ill patients with bacteremia showed individually significantly lower mortality in the combination arm than in the monotherapy arm. In the other studies, no significant difference in mortality was recorded between the compared groups. Combination antibiotic treatment may be considered the optimal option for severely ill patients with severe infections. However, well-designed randomized studies of specific patient populations are needed to further clarify this issue.

Topics: Anti-Bacterial Agents; Bacteremia; beta-Lactam Resistance; Carbapenems; Colistin; Critical Illness; Drug Therapy, Combination; Enterobacteriaceae; Humans; Minocycline; Pneumonia, Bacterial; Survival Analysis; Tigecycline; Urinary Tract Infections

There is an alarming global increase in the incidence of nosocomial infections with multidrug-resistant Gram-negative bacteria, which are often only susceptible to colistin. Colistin was developed prior to current methods of establishing dosing using pharmacokinetic-pharmacodynamic relationships. Dosing regimens differ in package inserts from different manufacturers and in different guidelines. It is imperative to avoid under-dosing with colistin in order to limit the development of resistance, as it is the last line of defence.. We conducted a systematic review of the literature to develop guidelines for rational dosing of intravenous colistin, with a particular focus on critically ill patients.. Colistin is administered as the inactive pro-drug colistimethate sodium. Colistin demonstrates concentration-dependent bacterial killing, suggesting that higher doses should be administered less frequently to achieve higher peak concentrations. Dose-related nephrotoxicity occurs, making it impossible to safely achieve concentrations that prevent the selection of resistant mutants or the effective eradication of bacteria with higher minimum inhibitory concentrations. Theoretically, combination therapy should be used to reduce the risk of selection of resistant bacteria. In critically ill patients, a loading dose should be given to rapidly achieve therapeutic concentrations, followed by maintenance doses of 4.5 MU 12-hourly. Maintenance dose adjustment is necessary with renal impairment.. Easier access to colistin is needed in South Africa, where it is not a registered medicine. Further research is needed to better characterise colistin's pharmacokinetic-pharmacodynamic relationships in humans and to establish whether combinations of colistin with other antimicrobials result in improved clinical outcomes or a reduction in selection of resistant bacteria.

Topics: Colistin; Critical Illness; Evidence-Based Medicine; Gram-Negative Bacteria; Humans; Injections, Intravenous

The spread of multidrug-resistant, extensively drug-resistant and pan-drug-resistant pathogens is causing an unprecedented public health crisis. The limited current therapeutic options led to the revival of two 'old' antibiotics - colistin and fosfomycin - for which a better understanding of their pharmacokinetics in the critically ill patient and in specific body compartments is required. Tigecycline's use in clinical practice for nonapproved indication based on its in vitro activity against problematic pathogens requires caution and probably higher doses. Furthermore, all three antibiotics should be used as part of combination regimens in order to prevent resistance and optimize outcomes. The development of new antibacterials in the near future, namely combinations of avibactam, ceftolozane/tazobactam and plazomicin, seems promising; however, they will only partially address current mechanisms of resistance.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Minocycline; Tigecycline

Colistin is a re-emerging old antibiotic that is used as a salvage treatment against multidrug-resistant Gram-negative infections. Because it is administrated as an inactive prodrug, colistin methanesulfonate (CMS) that undergoes rapid hydrolyze to colistin, pharmacokinetic studies using biological assays are unreliable. With the recent development of new assays using high performance liquid chromatography (HPLC) accurate pharmacokinetic of CMS and formed colistin is now available in various populations. This article aims to update previous reports on pharmacodynamics, pharmacokinetics, safety and clinical use of colistin, with a special focus on data useful to treat critically ill patients.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Bacterial; Drug Synergism; Gram-Negative Bacterial Infections; Humans

Increased emergence of bacterial resistance and the decline in newly developed antibiotics have necessitated the reintroduction of previously abandoned antimicrobial agents active against multidrug-resistant bacteria. Having never been subjected to contemporary drug development procedures, these 'old' antibiotics require redevelopment in order to optimize therapy. This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin.. Redevelopment of colistin led to an improved understanding of its chemistry, pharmacokinetics and pharmacodynamics, enabling important steps towards optimizing its clinical use in different patient populations. A scientifically based dosing algorithm was developed for critically ill patients, including those with renal impairment. As nephrotoxicity is a dose-limiting adverse event of colistin, rational combination therapy with other antibiotics needs to be investigated.. The example of colistin demonstrated that state-of-the-art analytical, microbiological and pharmacokinetic/pharmacodynamic methods can facilitate optimized use of 'old' antibiotics in the clinic. Similar methods are now being applied to fosfomycin and fusidic acid in order to optimize therapy. To improve and preserve the usefulness of these antibiotics rational approaches for redevelopment need to be followed.

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Humans

Although colistin has recently played a key role in the treatment of nosocomial infections due to multidrug resistant Gram-negative pathogens, there is a lack of clinical studies examining colistin pharmacokinetics (PKs) in humans. This refers to all routes of colistin administration in clinical practice. Colistin PK data are also limited in critically ill patients.. Literature search took into account data dealing with colistin PK obtained from animal studies performed during previous decades (1970s, 1980s and 1990s) and from recent human studies performed during the last decade.. Valuable information on pharmacodynamics (PD)/PK of colistin used in the treatments of nosocomial infections due to multidrug resistant Gram-negative pathogens, mostly Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. A better understanding of PKs could offer significant improvement of colistin use in humans, especially optimization of colistin doses in different routes of administration in order to maximize clinical efficacy and minimize adverse effects and rate of resistance.. There is a lack of human studies on colistin PK and PD. Significant PD parameters best predicting colistin efficacy and their optimal values such as C(max):MIC ratio, AUC/MIC and T > MIC have not yet been clearly defined. It should be noted that further investigation on colistin PK/PD in vitro and in vivo models is required.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Clinical Trials as Topic; Colistin; Critical Illness; Cross Infection; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Colistin (polymyxin E), an old antibiotic replaced by other less toxic antibiotics in the 1970s, has been increasingly used over the last decade due to multidrug-resistance in Gram-negative bacteria and lack of new antibiotics. However, there is a dearth of information on the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of colistin and its non-active prodrug colistimethate sodium (CMS). Optimised dose regimens have not been established for different types of patients. Additionally, most PK data available in the literature were obtained from concentrations derived from potentially misleading microbiological assays. Therefore, it is urgent to conduct prospective studies to optimise CMS/colistin use in patients, in particular the critically ill. This review summarises recent key clinical studies evaluating the efficacy, toxicity and PK/PD of colistin/CMS.

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney Tubular Necrosis, Acute; Prospective Studies; Retrospective Studies

The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has led to a re-evaluation of the previously discarded antibiotic, colistin. Despite its important role as salvage therapy for otherwise untreatable infections, dosage guidelines for the prodrug colistin methanesulfonate (CMS) are not scientifically based and have led to treatment failure and increased colistin resistance. In this review we summarise the recent progress made in the understanding of the pharmacokinetics of CMS and formed colistin with an emphasis on critically ill patients. The pharmacodynamics of colistin is also reviewed, with special attention given to the relationship between pharmacokinetics and pharmacodynamics and how the emerging data can be used to inform design of optimal dosage regimens. Recent data suggest the current dosage regimens of CMS are suboptimal in many critically ill patients.

Topics: Animals; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Prodrugs

Polymyxin B and colistin are being used increasingly for the treatment of infections caused by gram-negative bacteria that are resistant to all other currently available antibiotics. Although the polymyxins have been available in the clinic for around 50 years, they have never been subjected to the drug development procedures required of modern pharmaceuticals. As a result, the available knowledge on the pharmacokinetics (PK), pharmacodynamics (PD), and toxicodynamics (TD) of the polymyxins is limited. Although significant advances have been made in the last 5 years or so, there are still large gaps in our understanding of the PK, PD, and TD, and of the PK/PD and PK/TD relationships. This information is required to generate recommendations on dosage regimens for various categories of critically ill patients. This paper reviews the growing understanding of the pharmacology of the polymyxins and factors that may impact on the optimization of the dose of these antibiotics in critically ill patients.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Bacterial; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests; Polymyxin B

Intravenous and aerosolized polymyxins are being used increasingly, especially in the critical care setting, for treating patients with infections due to multidrug-resistant Gram-negative bacteria, mainly Acinetobacter baumannii and Pseudomonas aeruginosa. Recent literature suggests that intravenous colistin and polymyxin B have acceptable effectiveness for the treatment of patients with bacteremia, as well as infections of various systems and organs, including pneumonia, bacteremia, skin and soft tissue, and urinary tract infections. Although data from recent studies have suggested that the toxicity of intravenous polymyxins is probably less than reported in the older literature, caution should be taken to monitor the renal function of patients who receive these antibiotics.

Topics: Aerosols; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Polymyxin B; Polymyxins

Selective decontamination of the digestive tract (SDD) is a strategy designed to prevent or minimize the impact of infections by potentially pathogenic micro-organisms in critically ill patients requiring long-term mechanical ventilation. SDD is a four-component protocol to control the three types of infections occurring in intensive care patients: (a) a parenteral antibiotic, cefotaxime, for a few days to prevent primary endogenous infections that generally occur 'early'; (b) the topical antimicrobial drugs colistine (polymyxin E), tobramycin and amphotericin B (together: PTA) used throughout the stay in the intensive care unit (ICU) to prevent secondary endogenous infections developing in general 'late'; (c) a high standard of hygiene to prevent exogenous infections that may occur throughout the ICU stay; (d) surveillance samples of throat and rectum to distinguish between the three types of infection, to monitor compliance and efficacy of treatment and to detect emergence of resistance at an early stage. The most recent and rigorous meta-analysis examined 33 randomized SDD trials involving 5727 patients. It shows significant reductions, in overall mortality by 20% and in the incidence of lower airway infections by 65%. It failed to detect any report on the emergence of resistance and associated superinfections and/or out-breaks in the 33 studies covering a period of more than 10 years. Using the criterion of cost-per-survivor, four recent randomised trials showed that it is cheaper to produce a survivor using SDD than with the traditional approach.

Topics: Amphotericin B; Bacterial Infections; Cefotaxime; Clinical Protocols; Colistin; Critical Care; Critical Illness; Cross Infection; Decontamination; Digestive System; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Male; Survival Rate; Tobramycin

Colistin is a lipopeptide antibiotic administered as an inactive prodrug-colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment.. The COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant.. The study has been approved by the Ethics Committee of St. Anne's University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals.. EudraCT Number 2022-000291-19; NCT05542446.

Topics: Anti-Bacterial Agents; Colistin; COVID-19; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Prospective Studies

The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death.. Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis.. Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen.. The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Topics: Anti-Bacterial Agents; Bacteria; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans

Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone.. This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length.. Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46-1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization.. In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit.. NCT01577862.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Rifampin; Survival Analysis; Tertiary Care Centers; Treatment Outcome

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.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Male; Middle Aged; Young Adult

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Topics: Adult; Aged; Aged, 80 and over; Chromatography, Liquid; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Tandem Mass Spectrometry

The emergence of multidrug-resistant nosocomial pathogens, such as Pseudomonas aeruginosa and Acinetobacter baumannii, has led to the revival of the systemic use of antimicrobial agent colistin in critically ill patients, but only limited data are available to define its pharmacokinetic profile in these patients.. The aim of this study was to assess steady-state serum concentrations of colistin after i.v. administration of colistin methanesulfonate (CMS) in critically ill patients with stable kidney function.. This prospective, open-label, uncontrolled study was conducted at 2 intensive care units in the Athens Trauma Hospital, KAT, Athens, Greece. Adult patients were nonconsecutively enrolled if they were critically ill and had stable kidney function (<0.5 mg/dL change in serum creatinine prior to and until the day of sample collection) and had been receiving CMS as part of a treatment regimen for sepsis irrespective of site of infection with multidrug-resistant, gram-negative bacilli. After i.v. administration of 225-mg CMS (with the exception of 1 patient who received 150 mg) every 8 or 12 hours for at least 2 days, blood samples were collected just before and at 10 minutes and 1, 2, 4, 6, and 8 hours after i.v. infusion (duration, 30 minutes) of the colistin dose on the sampling day.. Fourteen nonconsecutive patients were enrolled in the study (13 male, 1 female; mean [SD] age, 62.0 [19.2] years; mean [SD] estimated weight, 72.5 [8.5] kg; mean [SD] Acute Physiology And Chronic Health Evaluation II score on admission, 17.1 [6.0]). At steady state, mean (SD) colistin maximum and minimum concentrations were 2.93 (1.24) and 1.03 (0.44) mg/L, respectively, while mean (SD) apparent total body clearance, apparent volume of distribution, and t(1/2) were 13.6 (5.8) L/h, 139.9 (60.3) L, and 7.4 (1.7) hours, respectively. Colistin-related nephrotoxicity was not observed in the study patients.. CMS dosage regimens administered to these critically ill adult patients were associated with suboptimal Cmax/MIC ratios for many strains of gram-negative bacilli currently reported as sensitive (MIC, < or = 2 microg/mL).

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Prospective Studies; Pseudomonas Infections; Sepsis

The increasing prevalence of multiresistant Gram-negative strains in intensive care units (ICUs) has recently rekindled interest in colistin, a bactericidal antibiotic that was used in the 1960s for treatment of infections caused by Gram-negative bacilli. We conducted the present observational study to evaluate the efficacy of intravenous colistin in the treatment of critically ill patients with sepsis caused by Gram-negative bacilli resistant to all other antibiotics.. Critically ill patients with sepsis caused by Gram-negative bacilli resistant to all antibiotics with the exception of colistin were treated in the six-bed ICU of a trauma hospital. Diagnosis of infection was based on clinical data and isolation of bacteria, and the bacteria were tested with respect to their susceptibility to colistin. Clinical response to colistin was evaluated.. Twenty-four patients (mean age 44.3 years, mean Acute Physiology and Chronic Health Evaluation II score 20.6) received 26 courses of colistin. Clinical response was observed for 73% of the treatments. Survival at 30 days was 57.7%. Deterioration in renal function was observed in 14.3% of 21 patients who were not already receiving renal replacement therapy, but in only one case did this deterioration have serious clinical consequences.. The lack of a control group in the present study does not allow any definite conclusions to be drawn regarding the clinical effectiveness of colistin. On the other hand, this drug has an acceptable safety profile and its use should be considered in severe infections with multiresistant Gram-negative bacilli.

Topics: Acinetobacter baumannii; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Male; Middle Aged; Pseudomonas aeruginosa; Sepsis

The prevalence of Helicobacter pylori is increased in healthcare workers and in intensive care nurses. Exposure to H. pylori from gastric secretions and faeces are probably the main sources of transmission to healthcare workers. Routine use of selective decontamination of digestive tract (SDD) in an intensive care unit suppresses H. pylori in critically ill patients. It was questioned whether this suppression and the subsequent decreased exposure to H. pylori for intensive care nurses would lead to a lower prevalence of H. pylori infection. Helicobacter pylori infection prevalence in intensive care nurses from a unit routinely using SDD (group I) was compared to that of nurses from a unit not using SDD (group II). Heathcare workers from other departments of the hospital where no SDD was used (group III) served as a control group. Persons using proton pump inhibitors were excluded. Helicobacter pylori was detected by Laser Assisted Ratio Analyser(13)C-urea breath test (UBT) and serology. This could not be performed in three out of 64 in group I, five out of 55 in group II and five out of 55 in group III (total UBTs = 169). The prevalence of H. pylori infection was 11% (7/61) in group I and 25.5% (14/50) in group II (P= 0.027). In group III, the prevalence of H. pylori infection was 16% (8/45), which was not significantly different from both group I and II. Sero-prevalence in group I was 18.6%, 27% in group II (ns) and 24% in group III. Mean age in the three groups was 35.9, 37.8 and 36.6 years, respectively (ns). In conclusion, the prevalence of H. pylori infection among intensive care nurses is lower in nurses from a unit using SDD compared to a non SDD-using unit. Acquisition of H. pylori by transmission from critically ill patients appears to be diminished through SDD use.

Topics: Adult; Amphotericin B; Breath Tests; Colistin; Critical Care; Critical Illness; Cross Infection; Cross-Sectional Studies; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Infection Control; Infectious Disease Transmission, Patient-to-Professional; Nursing Staff, Hospital; Prevalence; Stomach Diseases; Tobramycin

The role of selective decontamination of the digestive tract (SDD) for the prevention of nosocomial infection in critically ill patients remains controversial, and the efficacy of this technique in patients who are already infected on presentation to the intensive care unit has not previously been assessed. We performed a double-blind randomized placebo controlled trial of SDD (parenteral cefotaxime, six-hourly oral and enteral polymyxin E, tobramycin, and amphotericin B vs placebo) for all infected patients presenting to the ICU requiring mechanical ventilation for more than 48 hours and ICU stay of more than 5 days. Daily clinical and microbiological monitoring for secondary infection was undertaken until hospital discharge. In all, 59 selective decontamination and 76 placebo fully comparable patients fulfilled criteria for enrollment and analysis (APACHE II 15.2 vs 15.1). The number of patients receiving SDD who developed nosocomial infections was significantly reduced (P = 0.048), and there were no infections caused by the enterobacteriaceae or Candida spp in this group. No difference in ICU (17.5 vs 18.8 days) or hospital stay (32.7 vs 34.2 days) or mortality (17% vs 22.3%) was shown. Critically ill, primarily infected patients are protected from nosocomial infection by the use of SDD.

Topics: Administration, Oral; Adult; Amphotericin B; Cefotaxime; Colistin; Critical Care; Critical Illness; Cross Infection; Digestive System; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Placebos; Prospective Studies; Respiration, Artificial; Survival Rate; Tobramycin

Topics: Adolescent; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Monitoring; Humans

Colistin remains one of the few available options for the treatment of infections caused by resistant bacteria. Pharmacokinetic (PK) studies have been successful in estimating the appropriate colistin methanesulfonate (CMS) dose to achieve a target colistin concentration. Currently, there is a consensus that the dose of CMS should vary according to the patient renal function since CMS is mainly eliminated by renal route. For this same reason, the loading dose should vary according to the patient's renal capacity; however, this is not the current clinical practice. In this study we develop a framework to determine two key parameters for the loading dose regimen: (1) the optimal dose according to the characteristics (renal function and weight) of the patient; (2) the waiting time before the maintenance dose. Based on a previous PK model, our framework allows a fast parameter sweep so as to select optimal loading dose and waiting time minimizing the deviation between the plasma concentration and a target value. The results showed that patients presenting low creatinine clearance (CrCL) should receive a lower CMS loading dose with longer interval to start maintenance treatment to avoid nephrotoxic colistin concentrations. In cases of high CrCL, the dose should be higher and the interval to the next dose shorter to avoid subtherapeutic concentrations. Optimization of the loading dose should considerably improve colistin therapy, as the target concentration is reached more quickly, without reaching toxic values.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Humans

In this retrospective cohort study, we aimed to evaluate the incidence, risk factors and outcomes of amikacin-induced acute kidney injury (AKI) in critically ill patients with sepsis. A total of 311 patients were included in the study. Of them, 83 (26.7%) had amikacin-induced AKI. In model 1, the multivariable analysis demonstrated concurrent use of colistin (OR 25.51, 95%CI 6.99-93.05, p< 0.001), presence of septic shock during amikacin treatment (OR 4.22, 95%CI 1.76-10.11, p=0.001), and Charlson Comorbidity Index (OR 1.14, 95%CI 1.02-1.28, p=0.025) as factors independently associated with an increased risk of amikacin-induced AKI. In model 2, the multivariable analysis demonstrated concurrent use of at least one nephrotoxic agent (OR 1.95, 95%CI 1.10-3.45; p=0.022), presence of septic shock during amikacin treatment (OR 3.48, 95%CI 1.61-7.53; p=0.002), and Charlson Comorbidity Index (OR 1.12, 95%CI 1.01-1.26; p=0.037) as factors independently associated with an increased risk of amikacin-induced AKI. In conclusion, before amikacin administration, the risk of AKI should be considered, especially in patients with multiple complicated comorbid diseases, septic shock, and those receiving colistin therapy.

Topics: Acute Kidney Injury; Amikacin; Colistin; Critical Illness; Humans; Intensive Care Units; Respiration, Artificial; Retrospective Studies; Risk Factors; Sepsis; Shock, Septic

Colistin is considered as a last resort therapy for multidrug-resistant gram-negative organisms. It is widely used despite the significant risk of nephrotoxicity. Experimental studies showed the nephroprotective effect of dexmedetomidine, a sedative agent, against colistin toxicity. This study was performed to show the possible nephroprotective effect of dexmedetomidine among critically ill patients who received colistin.. Adult (>17 years) patients who were admitted to our surgical and medical intensive care unit (ICU) from March 2018 through March 2021, and who received colistin were included. Patients who receive Colistin therapy or intensive care unit follow-up of <72 h (discharge or death) and Acute kidney injury (AKI) or need hemodialysis prior to colistin therapy at the same hospitalization were excluded. AKI risk factors were examined by grouping patients with and without AKI. Patients, receiving colistin concomitantly with dexmedetomidine were also evaluated.. Of the 139 patients included, 27 (17.8%) patients received dexmedetomidine. Sixty-five patients (47%) had AKI, at a median 5 (4-7) days after the initiation of colistin. Older age, lower baseline estimated glomerular filtration rate, and vasopressor use were associated with a higher risk of AKI, while dexmedetomidine use was associated with a lower risk. In the multivariate regression model, dexmedetomidine use was independently associated with a lower risk of AKI development (OR 0.20 95% CI 0.07-0.59, p = 0.003).. In respect to these findings, dexmedetomidine may provide protection against AKI during colistin therapy in critically ill patients.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Dexmedetomidine; Gram-Negative Bacteria; Humans; Intensive Care Units; Retrospective Studies; Risk Factors

With the difficulties in choosing colistin sulfate and polymyxin B sulfate (PBS) for carbapenem-resistant gram-negative bacteria (CR-GNB), we compared the efficacy and safety of these two old polymyxins in treatment of critically ill patients infected with CR-GNB infection.. One hundred four patients infected with CR-GNB in ICU were retrospectively grouped by PBS (68 patients) or colistin sulfate (36 patients). Clinical efficacy including symptoms, inflammatory parameters, defervescence, prognosis and microbial efficacy were analyzed. Hepatotoxicity, nephrotoxicity, and hematotoxicity were evaluated by TBiL, ALT, AST, creatinine, and thrombocytes.. Demographic characteristics between colistin sulfate and PBS were not significantly different. Most of the CR-GNB were cultured in respiratory tract (91.7% vs 86.8%), and almost all were polymyxin-sensitive (98.2% vs 100%, MIC ≤ 2 μg/ml). The microbial efficacy in colistin sulfate (57.1%) was significantly higher than PBS (30.8%) (p = 0.022), however, no significant difference in clinical success was seen in both groups (33.8% vs 41.7%), as well as mortality, defervescence, imaging remission, days in the hospital, microbial reinfections, and prognosis, and almost all patients defervesce within 7 days (95.6% vs 89.5%).. Both polymyxins can be administrated in critically ill patients infected with CR-GNB and colistin sulfate is superior to PBS in microbial clearance. These results highlight the necessity of identifying CR-GNB patients who may benefit from polymyxin and who are at higher risk of mortality.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Polymyxins; Retrospective Studies

Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most commonly found nosocomial infections in critically ill patients. However, the appropriate treatment period for a specific group of critically ill patients with CRAB infection is currently being debated. Therefore, our study aimed to evaluate the optimal courses of therapy for critically ill patients with CRAB infection by comparing the outcomes of colistin therapy of short duration (<14 days) versus long duration (≥ 14 days).. A retrospective cohort study was conducted at Nakornping Hospital on critically ill patients with CRAB infection who received either a short or long course of colistin treatment between 2015 and 2022. The primary outcome was the 30-day mortality rate while secondary outcomes were clinical response, microbiological response, and nephrotoxicity. Propensity score matching with a 1: 1 ratio was performed to reduce potential biases. Furthermore, a logistic regression model was used to estimate the odds ratio (OR).. A total of 374 patients met the inclusion criteria. Two hundred and forty-eight patients were recruited after utilizing propensity scores to match patients at a 1: 1 ratio. The results from the propensity score matching analysis demonstrated that the long-course therapy group had a lower 30-day mortality rate compared to the short-course therapy group (adjusted OR (aOR) = 0.46, 95% CI: 0.26-0.83, p = 0.009). The clinical response and microbiological response rates were higher in patients who received the long course of colistin therapy compared to those receiving the short course (aOR = 3.24, 95% CI: 1.78-5.92, p = 0.001; aOR = 3.01, 95% CI: 1.63-5.57, p = 0.001). There was no significant different in the occurrence of nephrotoxicity (aOR = 1.28, 95% CI: 0.74-2.22, p = 0.368) between the two treatment groups.. A long course of colistin therapy resulted in a lower 30-day mortality rate in critically ill patients, and better clinical and microbiological outcomes, but similar nephrotoxicity as compared to a short course of colistin therapy. Therefore, a specific subset of critically ill patients who had CRAB infection needed to be considered for a long course of therapy.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Humans; Propensity Score; Retrospective Studies

We aimed to determine the risk factors that may be associated with colistin-induced acute kidney injury (AKI) to promote the safer use of colistin in the treatment of nosocomial infections caused by multidrug-resistant Gram-negative bacteria in intensive care units.. This retrospective observational study was conducted among adult patients who received a minimum of 48 h of intravenous colistin from January 2020 to December 2020 at the intensive care unit of a tertiary care hospital. AKI diagnosis and staging were made based on the Kidney Disease Improving Global Outcome Criteria.. Of 148 patients who received intravenous colistin at a daily dose of 9 million IU, 54 (36%) developed AKI. In the univariate analysis, age, Charlson comorbidity index, APACHE II score, duration of colistin treatment, basal creatinine level, use of vasopressors, and vancomycin were significantly associated with AKI (p < 0.05). The multivariate analysis revealed that the independent predictor of AKI was the use of vasopressors (OR: 3.14; 95% confidence interval: 1.39-97.07; p = 0.06).. The use of vasopressors in critically ill patients was independently associated with AKI developing during colistin treatment.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Humans; Intensive Care Units; Retrospective Studies; Risk Factors; Vancomycin

Colistin is one of the last resort antibiotic options for resistant gram-negative pathogens. Renal injury is the most common side effect of colistin. Characteristics of nephrotoxicity are well described in adults. However, this data is sparse in children.. In this study we evaluated the incidence, severity, time course and risk factors of colistin nephrotoxicity in a pediatric population.. In a prospective study over a 9-month period, children who received intravenous colistin for at least 48 h were evaluated for renal side effect by utilizing Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria. Children receiving renal replacement therapy (RRT) or received a repeated course of colistin were excluded.. Thirty-seven children were included. Median age of participants was 4.5 months. Overall, 48.6% of the cases developed AKI and consisted 56% in the Risk, 33% in the Injury and 11% in the Failure categories of RIFLE criteria. AKI was reversible while colistin continued and no one required RRT. Mean ± SD time to AKI development was 10.94 ± 7.51 days. Multivariate logistic regression analysis demonstrated that total cumulative dose of colistin was an independent predictor of nephrotoxicity (standardized ß = 1.024, P = 0.034).. AKI is a common side effect of colistin therapy in critically ill children developing in nearly half of recipients. However, with the dosage range utilized in this study, in the majority of children, renal injury seemed to be mild to moderate in nature. Given the limited treatment options available in critically ill children with resistant gram-negative pathogens, colistin remains a marvelous therapeutic option. Further studies are required to fully elucidate the risk factors and clinical pictures of colistin-induced nephrotoxicity.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Critical Illness; Humans; Infant; Prospective Studies; Risk Factors

The importance or necessity of a loading dose when prescribing intravenous colistin has not been well established in clinical practice, and approximate one-third to half of patients with carbapenem-resistant gram-negative bacteria (CRGNB) infection did not receive the administration of a loading dose. The aim of this study is to investigate the efficacy and risk of acute kidney injury when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.. This was a multicenter, retrospective study that recruited ICU-admitted patients who had CRGNB-associated nosocomial pneumonia and were treated with intravenous colistin. Then, we classified the patients into colistin loading dose (N = 85) and nonloading dose groups (N = 127). After propensity-score matching for important covariates, we compared the mortality rate, clinical outcome and microbiological eradication rates between the groups (N = 67).. The loading group had higher percentages of patients with favorable clinical outcomes (55.2% and 35.8%, p = 0.037) and microbiological eradication rates (50% and 27.3%, p = 0.042) at day 14 than the nonloading group. The mortality rates at days 7, 14 and 28 and overall in-hospital mortality were not different between the two groups, but the Kaplan-Meier analysis showed that the loading group had a longer survival time than the nonloading group. Furthermore, the loading group had a shorter length of hospital stay than the nonloading group (52 and 60, p = 0.037). Regarding nephrotoxicity, there was no significant difference in the risk of developing acute kidney injury between the groups.. The administration of a loading dose is recommended when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Gram-Negative Bacteria; Humans; Pneumonia, Bacterial; Retrospective Studies

This study intends to compare the clinical characteristics and the prevalence and spectrum of bacterial pathogens in COVID-19 patients admitted to ICU during the first and second waves at a tertiary care, teaching and referral hospital of eastern India.. This is a hospital-based retrospective study which analysed demographic details, clinical profile and bacterial culture results of severe and critically ill COVID-19 patients admitted in intensive care units (ICU) during April -Oct 2020 (1st wave) and April -July 2021 (2nd wave).. The patients admitted during the 2nd wave were comparatively older and had multiple comorbidities compared to the 1st wave. (23.8%) (45/189) and 50% (173/346) of the COVID-19 patients admitted to ICU developed bacterial infection during the 1st and 2nd wave respectively. Overall, there was predominance of multidrug resistant Gram negative bacilli in both the waves. There was increased isolation of intrinsic colistin resistant microorganisms.. Multidrug resistant Gram negative bacterial infections, remain a dreaded complication in severe and critically ill hospitalised COVID-19 patients requiring ICU care and high usage of colistin spirals the emergence and spread of pathogens intrinsically resistant to colistin.

Topics: Anti-Bacterial Agents; Bacteria; Colistin; COVID-19; Critical Illness; Humans; Intensive Care Units; Pandemics; Retrospective Studies; Tertiary Care Centers

Nosocomial pneumonia caused by carbapenem-resistant gram-negative bacteria (CRGNB) is a growing threat due to the limited therapeutic choices and high mortality rate. The aim of this study was to evaluate the prognostic factors for mortality in patients with nosocomial pneumonia caused by CRGNB and the impact of colistin-based therapy on the outcomes of intensive care unit (ICU) patients. We conducted a retrospective study of the ICUs in five tertiary teaching hospitals in Taiwan. Patients with nosocomial pneumonia caused by CRGNB from January 2016 to December 2016 were included. Prognostic factors for mortality were analyzed using multivariate logistic regression. The influence of colistin-based therapy on mortality and clinical and microbiological outcomes were evaluated in subgroups using different severity stratification criteria. A total of 690 patients were enrolled in the study, with an in-hospital mortality of 46.1%. The most common CRGNB pathogens were Acinetobacter baumannii (78.7%) and Pseudomonas aeruginosa (13.0%). Significant predictors (odds ratio and 95% confidence interval) of mortality from multivariate analysis were a length of hospital stay (LOS) prior to pneumonia of longer than 9 days (2.18, 1.53-3.10), a sequential organ failure assessment (SOFA) score of more than 7 (2.36, 1.65-3.37), supportive care with vasopressor therapy (3.21, 2.26-4.56), and escalation of antimicrobial therapy (0.71, 0.50-0.99). There were no significant differences between the colistin-based therapy in the deceased and survival groups (42.1% vs. 42.7%, p = 0.873). In the subgroup analysis, patients with multiple organ involvement (> 2 organs) or higher SOFA score (> 7) receiving colistin-based therapy had better survival outcomes. Prolonged LOS prior to pneumonia onset, high SOFA score, vasopressor requirement, and timely escalation of antimicrobial therapy were predictors for mortality in critically ill patients with nosocomial CRGNB pneumonia. Colistin-based therapy was associated with better survival outcomes in subgroups of patients with a SOFA score of more than 7 and multiple organ involvement.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Cross Infection; Gram-Negative Bacteria; Healthcare-Associated Pneumonia; Humans; Retrospective Studies

Colistin is considered as the last-line antibiotic for the treatment of infections caused by extensively drug-resistant Gram-negative pathogens belonging to the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) group. The present study aimed to explore the colistin resistance mechanisms of a Klebsiella aerogenes (formerly Enterobacter aerogenes) isolate (Kae1177-1bg) obtained from a Bulgarian critically ill patient with septic shock in 2020. Antimicrobial susceptibility testing and whole-genome sequencing using DNA nanoball technology were performed. The resulting read pairs were used for draft genome assembly, MLST analysis and mutation screening in the pmrA/B, phoP/Q, and mgrB genes. Kae1177-1bg demonstrated high-level resistance to colistin, resistance to 3rd generation cephalosporins and susceptibility to all other antibiotics tested. In our strain a CMY-2-type class C cephalosporinase was the only β-lactamase identified. No mobile colistin resistance (mcr) genes were detected. A total of three missense variants in the genes for the two-component PmrA/PmrB system were identified. Two of them were located in the pmrB (pR57K and pN275K) and one in the pmrA gene (pL162M). The pN275K variant emerged as the most likely cause for colistin resistance because it affected a highly conservative position and was the only nonconservative amino acid substitution. In conclusion, to the best of our knowledge, this is the first documented clinical case of a high-level colistin-resistant K. aerogenes in Bulgaria and the first identification of the nonconservative amino acid substitution pN275K worldwide. Colistin-resistant Gram-negative pathogens of ESKAPE group are serious threat to public health and should be subjected to infection control stewardship practices.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bulgaria; Colistin; Critical Illness; Drug Resistance, Bacterial; Enterobacter aerogenes; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Multilocus Sequence Typing; Shock, Septic

Colistin is a narrow-spectrum lipopeptide antimicrobial agent used to treat nosocomial infections caused by multidrug-resistant bacteria, especially in critically ill patients and those with cystic fibrosis. Colistin represents a concentration-time-dependent antibiotic with highly variable pharmacokinetics related to the heterogeneity of the target population and the necessity of bioactivation. Colistin is administered as the inactive prodrug colistimethate sodium. Nephrotoxicity and neurotoxicity are the most frequent adverse effects.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Humans; Renal Insufficiency

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Humans; Longevity; Microbial Sensitivity Tests; Polymyxin B; Polymyxins

Limited data are present regarding the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients suffering from multi-drug-resistant gram-negative bacterial (MDR-GNB) infections. We aimed to profile the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients with MDR-GNB infections, along with determining the predictors that could influence the clinical, microbiological and safety outcome. We recruited 30 critically ill patients suffering from MDR-GNB infections in our prospective open-label study. Intravenous colistimethate sodium (CMS) 2 million IU was administered concurrently with inhalational CMS 1 million IU every 8 hours. Steady-state plasma colistin levels were measured. Logistic regression analysis was used to identify various predictors of clinical, microbiological and safety outcome. A large variability was observed in the steady-state colistin pharmacokinetic/pharmacodynamic parameters, along with the factors that influenced the clinical, microbiological and safety outcome. In conclusion, steady-state colistin pharmacokinetic and pharmacodynamic parameters observed in our study were largely consistent with those reported in previous studies. High acute physiology and chronic health evaluation II scores were associated with poor clinical outcome. Log-transformed colistin maximum concentration, area under the plasma concentration curve for 8 hours, apparent total body clearance and apparent volume of distribution were significantly associated with the safety outcome.

Topics: Administration, Inhalation; Administration, Intravenous; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Patient Safety; Predictive Value of Tests; Prospective Studies; Risk Assessment; Treatment Outcome; Young Adult

To investigate the association between adjunctive nebulized colistin and treatment outcomes in critically ill patients with nosocomial carbapenem-resistant Gram-negative bacterial (CR-GNB) pneumonia.. This retrospective, multi-centre, cohort study included individuals admitted to the intensive care unit with nosocomial pneumonia caused by colistin-susceptible CR-GNB. Enrolled patients were divided into groups with/without nebulized colistin as adjunct to at least one effective intravenous antibiotic. Propensity score matching was performed in the original cohort (model 1) and a time-window bias-adjusted cohort (model 2). The association between adjunctive nebulized colistin and treatment outcomes was analysed.. In total, 181 and 326 patients treated with and without nebulized colistin, respectively, were enrolled for analysis. The day 14 clinical failure rate and mortality rate were 41.4% (75/181) versus 46% (150/326), and 14.9% (27/181) versus 21.8% (71/326), respectively. In the propensity score-matching analysis, patients with nebulized colistin had lower day 14 clinical failure rates (model 1: 41% (68/166) versus 54.2% (90/166), p 0.016; model 2: 35.3% (41/116) versus 56.9% (66/116), p 0.001). On multivariate analysis, nebulized colistin was an independent factor associated with fewer day 14 clinical failures (model 1: adjusted odds ratio (aOR) 0.59, 95% CI 0.37-0.92; model 2: aOR 0.37, 95% CI 0.21-0.65). Nebulized colistin was not associated independently with a lower 14-day mortality rate in the time-dependent analysis in both models 1 and 2.. Adjunctive nebulized colistin was associated with lower day 14 clinical failure rate, but not lower 14-day mortality rate, in critically ill patients with nosocomial pneumonia caused by colistin-susceptible CR-GNB.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Healthcare-Associated Pneumonia; Humans; Pneumonia, Bacterial; Retrospective Studies; Treatment Outcome

Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function.. The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%).. The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Critical Illness; Female; Fosfomycin; Humans; Kidney; Kidney Function Tests; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Tigecycline

Colistin is widely used in the treatment of nosocomial infections caused by carbapenem-resistant gram-negative bacilli (CR-GNB). Colistin-induced nephrotoxicity is one of the major adverse reactions during colistin treatment. Comparisons of colistin-induced nephrotoxicity between different formulations of colistin are rarely reported.. In this retrospective cohort study, we enrolled intensive care unit-admitted patients if they had culture isolates of CR-GNB and underwent intravenous treatment with colistin. The occurrence of acute kidney injury (AKI) during intravenous treatment with colistin was recorded. The occurrence of colistin-induced nephrotoxicity was compared between two formulations of colistin, Locolin®, and Colimycin®. Treatment outcomes associated with the occurrence of colistin-induced nephrotoxicity were also investigated.. Among 195 patients, 95 who were treated with Locolin® and 100 who were treated with Colimycin® were included for analysis. Patients treated with Locolin® had a higher rate of occurrence of stage 2 (46.3% vs. 32%, p = 0.040) and stage 3 (29.5% vs. 13%, p = 0.005) AKI than did those treated with Colimycin®. In multivariate analysis, the presence of septic shock (adjusted odds ratio [aOR] 2.17, 95% confidence interval [CI] 1.10-4.26) and inappropriate colistin dosage (aOR 2.52, 95% CI 1.00-6.33) were clinical factors associated with colistin-induced nephrotoxicity. Treatment with Colimycin® was an independent factor associated with a lower risk of colistin-induced nephrotoxicity (aOR 0.37, 95% CI 0.18-0.77). The mortality rate was comparable between patients with and without colistin-induced nephrotoxicity.. The risk of colistin-induced nephrotoxicity significantly varied in different formulations of colistin in critically ill patients. Colistin-induced nephrotoxicity was not associated with increased mortality rate.

Topics: Acute Kidney Injury; Administration, Intravenous; Aged; Aged, 80 and over; Colistin; Critical Illness; Drug Compounding; Drug Resistance, Bacterial; Female; Hospital Mortality; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Taiwan

Nephrotoxicity is the most important adverse effect of colistin therapy. We investigated the frequency of nephrotoxicity, risk factors related to nephrotoxicity, and its relationship with mortality in patients who received intravenous colistin in intensive care units (ICUs).. We retrospectively reviewed the data of patients who received intravenous colistin in ICUs between 2011 and 2017. Acute kidney injury (AKI) diagnosis and staging were made based on the Kidney Disease Improving Global Outcome criteria.. Higher AKI and mortality rates are observed in patients with diabetes, heart failure, advanced age and the hemodynamically impaired. However, it is a fact that there are no alternative therapies other than colistin in the treatment of multidrug-resistant Gram-negative bacterial infections. Therefore, the development of AKI in this patient group should not be considered a sufficient reason for discontinuing colistin treatment. Understanding the risk factors in this potential nephrotoxic treatment can provide a more careful patient follow-up.

Topics: Acute Kidney Injury; Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; APACHE; Colistin; Critical Illness; Female; Humans; Intensive Care Units; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Time Factors; Turkey

Determining a suitable dose of intravenous colistimethate is challenging because of complicated pharmacokinetics, confusing terminology, and the potential for renal toxicity. Only recently have reliable pharmacokinetic/pharmacodynamic data and dosing recommendations for intravenous colistimethate become available.. The aim of this work was to develop a clinician-friendly, easy-to-use mobile app incorporating up-to-date dosing recommendations for intravenous colistimethate in critically ill adult patients.. Swift programming language and common libraries were used for the development of an app, ColistinDose, on the iPhone operating system (iOS; Apple Inc). The compatibility among different iOS versions and mobile devices was validated. Dosing calculations were based on equations developed in our recent population pharmacokinetic study. Recommended doses generated by the app were validated by comparison against doses calculated manually using the appropriate equations.. ColistinDose provides 3 major functionalities, namely (1) calculation of a loading dose, (2) calculation of a daily dose based on the renal function of the patient (including differing types of renal replacement therapies), and (3) retrieval of historical calculation results. It is freely available at the Apple App Store for iOS (version 9 and above). Calculated doses accurately reflected doses recommended in patients with varying degrees of renal function based on the published equations. ColistinDose performs calculations on a local mobile device (iPhone or iPad) without the need for an internet connection.. With its user-friendly interface, ColistinDose provides an accurate and easy-to-use tool for clinicians to calculate dosage regimens of intravenous colistimethate in critically ill patients with varying degrees of renal function. It has significant potential to avoid the prescribing errors and patient safety issues that currently confound the clinical use of colistimethate, thereby optimizing patient treatment.

Topics: Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Humans; Mobile Applications

To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP).. Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded.. Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12-0.23) and 0.17 (0.11-0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11-0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) and 0.23 (0.11-0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed.. In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Prospective Studies

The objectives of the present study were to identify risk factors for development of acute kidney injury (AKI) during the treatment of bacteraemia due to carbapenem non-susceptible Gram-negative bacteria (CnS-GNB) and its role on mortality. Data of all patients with bacteraemia by CnS-GNB in the intensive care unit of a tertiary hospital from 2012 to 2016 were included. AKI was defined by AKIN criteria. Secondary outcomes were AKI development in patients treated with colistin and predictors of 14-day mortality. Among 285 episodes of bacteraemia due to CnS-GNB, 84 (29.5%) developed AKI. Multivariate analysis revealed that obesity, septic shock, maximum noradrenaline dose and eGFR<60 mL/min/1.73m² upon bacteraemia onset were independently associated with development of AKI. Out of 228 patients receiving colistin, 64 (28.1%) developed AKI. Multivariate analysis found the same factors as before in addition to voriconazole administration. Fourteen-day mortality was 34.2% and was independently associated with bacteraemia by Pseudomonas aeruginosa, AKI during bacteraemia treatment, maximum noradrenaline dose, SAPS II and SOFA scores upon bacteraemia onset, whereas appropriate combination therapy and catheter-related bacteraemia were independently associated with better survival. AKI was a frequent complication of bacteraemia by CnS-GNB and was associated with septic shock and baseline renal function impairment. Mortality was higher among patients that developed AKI due to bacteraemia. Colistin should be considered a safe therapeutic option for treating such infections.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors

Intravenous colistin is increasingly used to treat multidrug-resistant Gram-negative infections. Highly variable nephrotoxicity rates have been reported. Recent PK/PD studies propose a loading dose and a maintenance dose for better efficacy, but data on the renal toxicity of such regimens are rare. This study aimed to evaluate the incidence and risk factors for nephrotoxicity related to colistin after implementation of a new dosing regimen including a loading dose.. This was a prospective observational study that was made between adult patients who received a minimum of 48 hours of intravenous colistin from December 2012 to January 2014 at the medical and surgical intensive care units (ICU) of a university hospital. The severity of acute kidney injury (AKI) was defined by the RIFLE criteria.. Fifty-nine patients met the inclusion criteria, and 31 (52.5%) developed nephrotoxicity. The APACHE-II score was > 15 in 81% of patients. The median time to nephrotoxicity was 7 days. Patients with AKI were in risk (10.2%), injury (16.9%), failure (25.4%), and none of the patients developed permanent renal insufficiency. A logistic regression model identified three predictors of colistin-associated nephrotoxicity: age; the number of days that estimated target plasma concentrations of colistin were ≥ 3.5 mg/L in the first week of therapy; and baseline creatinine level.. In this cohort of severely ill ICU patients, colistin led to a relatively high rate of nephrotoxicity. Further studies are needed to identify the optimal dose for both efficacy and safety.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Female; Humans; Intensive Care Units; Male; Middle Aged; Prospective Studies; Young Adult

In this prospective study, clinical isolates of colistin resistance among. In a total of 142 patients with 136. There is an increase of colistin resistance among clinical isolates of

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Colistin; Critical Illness; Drug Resistance, Microbial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Young Adult

Owing to the emerging problem of MDR bacteria, interest in 'old' antibiotics such as colistin has re-emerged. However, research on the dosing of colistin in patients undergoing renal replacement therapy (RRT), such as prolonged intermittent renal replacement therapy (PIRRT), is scarce.. The aim of this study was to evaluate single- and multiple-dose pharmacokinetics of colistin and its prodrug colistin methanesulfonate in ICU patients with acute kidney injury (AKI) undergoing PIRRT.. We performed a prospective clinical pharmacokinetic single- and multiple-dose study. Eight ICU patients with AKI undergoing treatment with PIRRT and receiving intravenous colistin were studied on day 1 and days 5-9 of treatment, depending on the timing of dialysis. Six million IU (MIU) of colistin methanesulfonate was administered 8 h prior to the PIRRT session followed by 3 MIU every 8 h. The study was registered under clinicaltrails.gov (NCT02556190).. PIRRT removed a considerable amount of colistin and colistin methanesulfonate with a median dialyser plasma CL of 70.1 mL/min (IQR 36.6-96.2) for colistin and 69.3 mL/min (IQR 56.3-318.7) for colistin methanesulfonate. The median amount of colistin in the total collected dialysate was 154 mg (IQR 105-175), corresponding to about 50% of the daily dose. Median colistin peak concentrations accumulated from 5.79 mg/L (IQR 4.14-8.79) on day 1 to 9.49 mg/L (IQR 8.39-10.41) on days 5-9. Cmax was significantly and inversely correlated with body weight.. PIRRT eliminates about half of the daily administered colistin dose. Even a 6 MIU loading dose of colistin methanesulfonate may not ensure immediate sufficient colistin plasma levels in all critically ill patients. However, we measured significant colistin accumulation, suggesting that the dose of colistin methanesulfonate should be adjusted according to body weight and RRT intensity.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Bacterial Infections; Colistin; Critical Illness; Drug Administration Schedule; Drug Monitoring; Female; Humans; Intermittent Renal Replacement Therapy; Male; Middle Aged

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Hospitals, University; Humans; Intensive Care Units; Kidney; Latvia; Male; Middle Aged; Renal Dialysis; Retrospective Studies; Tertiary Healthcare

The desired target steady-state average colistin concentration (C

Topics: Adult; Aged; Aged, 80 and over; Bacteria; Colistin; Critical Illness; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Treatment Outcome; Young Adult

Topics: Aged; Anti-Bacterial Agents; beta-Lactamases; Chromatography, Liquid; Colistin; Critical Illness; Drug Therapy, Combination; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Middle Aged; Serum; Tandem Mass Spectrometry; Tigecycline

Most significant side effect of colistin therapy which is used for the treatment of multi-drug resistant Gram-negative infections is nephrotoxicity. Our aim was to investigate the differences of colistin nephrotoxicity between the geriatric age group (≥65 years) and the younger age group (<65 years) in critically ill medical intensive care unit (ICU) patients.. The medical records of the 76 patients who were taken colistin therapy due to multi-resistant Gram-negative infections between January 2010 and June 2014 in the our medical ICU were retrospectively investigated. Demographic characteristics, reasons for colistin use, daily colistin dose, duration of colistin use were recorded. Colistin-dependent renal dysfunction was evaluated according to the risk, injury, failure, loss and end-stage renal failure (RIFLE) criterias.. The median age of the patients was 65 (65.8% male). Nephrotoxicity was developed in 36 (47.4%) patients. Thirty-nine (51.3%) patients were in geriatric age group, 37 (48.7%) were in younger age group. In geriatric age group, the rates of male gender (53.8 vs 78.4%, p = 0.031), pulmonary (48.7 vs 16.2%, p = 0.003) and cardiac diseases (71.8 vs 29.7%, p < 0.001), post-nephrotoxicity BUN levels (p = 0.023) and urine output during nephrotoxicity (p = 0.016) were higher than younger age group. Nephrotoxicity was developed in 22 (56.4%) patients of geriatric age group, and in 14 (37.8%) patients in younger age group (p = 0.115). The presence of cardiac disease, renal pathology and high creatinin value on admission, daily amount of colistin per body mass, total amount of colistin, use of colistin for pulmonary infection, use of amphotericin and vasopressor on admission were found as risk factors for colistin nephrotoxicity development in all study group; the daily amount of colistin per body mass (risk ratio:0.41; 95% CI 0.19-0.89) and vasopressor use during hospitalization were found independent risk factors (risk ratio:13.54; 95% CI 2.21-83.09).. In our study, in geriatric patient group colistin nephrotoxicity was not different from the younger age group. In the ICU, the age for nephrotoxicity does not appear to be a point to be considered for the initiation of colistin.

Topics: Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Intensive Care Units; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Retrospective Studies; Risk Factors

To assess the association of survival and treatment with colistin and tigecycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii bacteraemia.. An observational cohort study was carried out. Targeted therapy consisted of monotherapy with colistin (9 million UI/day) or combined therapy with colistin and tigecycline (100 g/day). The primary outcome was 30-day crude mortality. The association between combined targeted therapy and mortality was controlled for empirical therapy with colistin, propensity score of combined therapy and other potential confounding variables in a multivariate Cox regression analysis.. A total of 118 cases were analysed. Seventy-six patients (64%) received monotherapy and 42 patients (36%) received combined therapy. The source of bacteraemia was primary in 18% (21/118) of the patients, ventilator-associated pneumonia in 64% (76/118) and other sources in 14% (16/118). The 30-day crude mortality rate was 62% (42/76) for monotherapy and 57% (24/42) for combined therapy. The variables associated with 30-day crude mortality were: Charlson index (hazard ratio (HR) 1.16, 95% CI 1.02-1.32; p 0.028), empirical therapy with colistin (HR 2.25, 95% CI 1.33-3.80; p 0.003) and renal dysfunction before treatment (HR 1.91, 95% CI 1.01-3.61; p 0.045). Combined targeted therapy was not associated with lower adjusted 30-day crude mortality (adjusted HR 1.29, 95% CI 0.64-2.58; p 0.494).. Combined targeted therapy with high-dose colistin and standard dose tigecycline was not associated with lower crude mortality of bacteraemia due to carbapenem-resistant A. baumannii in critically ill patients.. Registered in ClinicalTrials.gov. Identifier: NCT02573064.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Bacteremia; Carbapenems; Cohort Studies; Colistin; Critical Illness; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Propensity Score; Survival Analysis; Tigecycline; Treatment Outcome

Nonclinical studies have suggested that oxidative damage, caspase-mediated apoptosis, and inducible nitric oxide synthase levels may be involved in the pathogenesis of colistin (CST)-associated acute renal failure. MIN inhibits caspase 1, caspase 3, and inducible nitric oxide synthase, leading to the hypothesis that coadministration of CST with MIN (CST-MIN) may reduce the incidence of acute renal failure as well as produce additive or synergistic antimicrobial effects. A multicenter retrospective cohort study was conducted using the Premier Research database to examine the impact of CST-MIN on acute renal failure. Inclusion criteria were as follows: age of ≥18 years, intensive care unit admission at CST initiation, primary International Classification of Diseases 9 (ICD-9) diagnosis of pneumonia or sepsis, nondialysis at hospital admission, and discharge between January 2010 and December 2015. ICD-9 code 584.XX or ICD-10 code N17 was used to define acute renal failure. Baseline comparisons, 1:8 propensity score matching, and confirmatory logistic regression analyses were conducted. In total, 4,817 patients received CST and met inclusion criteria; 93 received CST-MIN. Unadjusted frequency of acute renal failure was significantly lower in patients receiving CST-MIN than CST (11.8% versus 23.7%,

Topics: Acute Kidney Injury; Adult; Aged; Cohort Studies; Colistin; Critical Illness; Female; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Minocycline; Patient Readmission; Protective Agents; Retrospective Studies; Treatment Outcome

Colistin is a last resort antibiotic to treat multidrug-resistant Gram-negative bacteria infections. Colistin is administered intravenously in the form of its inactive prodrug colistin methanesulfonate (CMS). For patients with acute kidney impairment and continuous renal replacement therapy high extracorporeal clearance may cause a substantial removal of active colistin from the bloodstream, eventually decreasing its antibacterial efficacy. Currently recommended doses of CMS may therefore be inadequate for these patients. We report on the potential value of a modified regimen that adopts a loading dose of CMS (bolus of 9 MU vs. conventional 3 MU every 8 h), followed by maintenance (3 MU every 8 h). Preliminary pharmacokinetic evidence for the feasibility and efficacy of this regimen is described for 2 patients.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Area Under Curve; Colistin; Critical Illness; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Prognosis; Pseudomonas aeruginosa; Renal Dialysis; Renal Replacement Therapy; ROC Curve

Topics: Acute Kidney Injury; Colistin; Critical Illness; Humans; Minocycline; Retrospective Studies

A matched 1:2 case-control study was conducted among critically ill patients in order to identify the risk factors of colistin or tigecycline-resistant carbapenemase-producing Klebsiella pneumoniae (ColR-Kp, TigR-Kp) bacteraemia. MIC to colistin and tigecycline were determined by Etest. From 224 bacteraemic patients, 46.4% and 29.5% were resistant to colistin and tigecycline, respectively. PCR revealed that 199 isolates carried the bla

Topics: Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Case-Control Studies; Colistin; Comorbidity; Critical Care; Critical Illness; Drug Resistance, Bacterial; Female; Genotype; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Typing; Tigecycline

Empiric antimicrobial therapy (EAMT) using imipenem/colistin is commonly prescribed as a first line therapy in critically ill patients with severe sepsis. We aimed to assess the appropriateness of prescribing imipenem/colistin as EAMT in ICU patients.. A 3-year observational prospective study included ICU patients that required imipenem/colistin as EAMT. The EAMT was assessed according to microbiological and clinical outcomes. The outcomes were: delay in apyrexia, delay in the decrease of the biological inflammatory parameters (BIP), the requirement for vasoactive agents, bacteriological eradication, length of stay, ventilator days and 30-day mortality.. 79 administrations of EAMT in 70 patients were studied. EAMT was appropriate in 52% of the studied cases. An ICU stay > 6 days was related to inappropriateness, and chronic respiratory failure was associated with appropriateness. In the appropriate EAMT group, we showed: earlier apyrexia, shorter delay in the decrease of the BIP and a reduced significant vasopressors requirement. Furthermore, EAMT improved survival with a median gain of 4 days. Inappropriate EAMT increased the mortality risk by six. The acquisition of NI in ICU was also an independent factor of mortality.. EAMT using imipenem-colistin was appropriate in half of the cases and inappropriateness was associated with an increased ICU mortality risk.

Topics: Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Female; Humans; Imipenem; Intensive Care Units; Male; Middle Aged; Prospective Studies; Sepsis

Few studies have compared nebulized and intravenous (IV) colistin for multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa pneumonia. This study compared the nephrotoxicity and clinical outcomes for these two delivery routes.. This study retrospectively compared 95 critically ill surgical patients who were diagnosed with Acinetobacter baumannii ventilator associated pneumonia and received colistin between March 2013 and January 2016.. The most common diagnoses were brain hemorrhage (27.4%), traumatic brain injury (20%), traumatic thoracic injury (15.8%), and secondary peritonitis (11.6%). Compared to the IV group, the nebulizer group was significantly older (60.0 vs. 67.5years, p=0.010), had higher APACHE II scores (16.3 vs. 19.9, p=0.001), and more frequently had diabetes mellitus (6.8% vs. 21.6%, p=0.043). Nephrotoxicity was more common in the IV group (60.5% vs. 15.7%, p<0.0001). Both groups had similar microbiological and clinical outcomes (p=0.921 and p=0.719, respectively). Patients with nephrotoxicity exhibited prolonged IV or nebulized colistin treatment and more frequent combination with vancomycin. Nephrotoxicity was independently associated with IV delivery (odds ratio: 8.48, 95% confidence interval: 2.95-24.39, p<0.0001).. Nebulized colistin may have less nephrotoxicity and provide similar clinical results, compared to IV colistin.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aged; Anti-Bacterial Agents; APACHE; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Ventilator-Associated; Retrospective Studies; Treatment Outcome

The aim of this study was to assess the safety and efficacy of colistin use in critically ill neonates.. This was a case-control study that included newborn infants with proven or suspected nosocomial infections between January 2012 and October 2015, at two centers in Diyarbakir, Turkey. The clinical and laboratory characteristics and outcomes of patients who received colistin therapy were reviewed and compared to patients who were treated with antimicrobial agents other than colistin during the same period.. Forty-seven cases who received intravenous colistin (colistin group) and 59 control patients (control group) were included. There were no significant differences between the groups regarding outcomes and nephrotoxicity, including acute renal failure. Colistin therapy was associated with significantly reduced serum magnesium (1.38 ± 0.39 mg/dL vs. 1.96 ± 0.39 mg/dL, p < 0.001) and hypokalemia (46.8% vs. 25.4%, p = 0.026). The patients who received colistin also had longer hospital stays (43 (32-70) days vs. 39 (28-55) days, p = 0.047), a higher rate of previous carbapenem exposure (40.4% vs. 11.9%, p = 0.001), and a higher age at the onset of infection (13 (10-21) days vs. 11 (9-15) days, p = 0.03).. This study showed that colistin was both effective and safe for treating neonatal infections caused by multidrug-resistant gram-negative bacteria. However, intravenous colistin use was significantly associated with hypomagnesemia and hypokalemia.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Case-Control Studies; Colistin; Critical Illness; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant, Newborn; Male

Optimal dosing for nebulized colistin methanesulfonate (CMS), the prodrug of colistin, is unknown. We describe the pulmonary and systemic pharmacokinetics of CMS and colistin following nebulization of 0.5 million IU (MIU) of CMS in ventilated patients.. Twelve critically ill patients received 0.5 MIU of CMS administered every 8 h as 30 min nebulizations. Blood samples were collected immediately before and until 8 h after first nebulization; mini-bronchoalveolar lavage (mini-BAL) was performed at 1 and 5 h or 3 and 8 h (six patients each) post-dose. Pharmacokinetic analysis was performed for CMS and colistin plasma concentrations using a non-compartmental method. ClinicalTrials.gov: NCT01060891.. After nebulization, CMS concentrations in epithelial lining fluid (ELF) were much higher (100- to 1000-fold) than those in plasma. Concentrations of colistin in ELF should be considered with caution because when <6 mg/L in BAL, colistin bound to mini-BAL devices. Nevertheless, CMS and colistin concentrations in ELF were much lower than expected from previous results with a 2 MIU dose. From CMS plasma pharmacokinetics it was shown that CMS systemic bioavailability was only slightly decreased for the 0.5 MIU dose compared with 2 MIU.. This study shows that CMS concentrations were much higher (100- to 1000-fold) in ELF than in plasma after a 0.5 MIU aerosol of CMS, but much lower (10-fold) than expected from previous results with a 2 MIU dose. Therefore, until new pharmacokinetic and pharmacodynamic assessments of the treatment of ventilator-associated pneumonia with nebulized CMS are performed, the 2 MIU dose should be preferred to the 0.5 MIU dose.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Administration Schedule; Female; Gram-Negative Bacterial Infections; Hospitalization; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Ventilator-Associated

Acinetobacter species are not considered skin commensals and under-treatment is an overriding concern when caring for critically-ill patients who are mostly at risk of extensively drug-resistant Acinetobacter baumannii (XDRAB) infections. Hence even a single blood culture yielding XDRAB will tend to prompt intervention. However, field observations suggest that patients with single-positive blood cultures had milder disease and were more likely to be recruited in interventional studies than those with multiple-positive blood cultures, yet no distinction is made in current clinical or trial recruitment practices. To our knowledge, this is the first study to compare the clinical characteristics and outcomes of patients with single-positive versus multiple-positive blood cultures for XDRAB. In this multicenter prospective cohort study of XDRAB bacteremic patients from July 2010 to June 2015, only patients with at least two simultaneously drawn blood cultures were included. The patients were classified as having single-positive or multiple-positive blood cultures according to the number of positive blood cultures yielding XDRAB. The primary end-point was the 28-day mortality. Of a total of 155 patients enrolled, 69 had a single-positive and 86 had multiple-positive blood cultures. Leukopenia (37.2% vs. 16.2%; P = 0.004), thrombocytopenia (56.0% vs. 26.5%; P < 0.001), higher Pitt bacteremia scores (6.6 vs. 5.5, P = 0.03) and higher 28-day mortality rates (70.9% vs. 43.5%; P = 0.001) distinguished patients with multiple-positive from those with single-positive cultures. Multivariate logistic regression showed that multi-positivity independently predicted 28-day mortality (adjusted odds ratio, 2.34; 95% confidence interval (CI), 1.03-5.28; P = 0.04) and the Cox regression confirmed that multi-positivity (adjusted hazard ratio, 1.80; 95% CI, 1.13-2.85; P = 0.01) predicted rapid mortality. Patients with multiple versus single positive blood cultures yielding XDRAB had greater morbidity and mortality. Investigators and clinicians should be aware that the blood culture positivity rate impacts outcomes of XDRAB bacteremia.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Blood Culture; Carbapenems; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Humans; Intensive Care Units; Leukopenia; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Severity of Illness Index; Survival Analysis; Thrombocytopenia

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.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Creatinine; Critical Illness; Female; Humans; Male; Middle Aged

Topics: Colistin; Critical Illness; Humans

Topics: Administration, Intravenous; Colistin; Critical Illness; Humans

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia.. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria.. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy.. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia; Retrospective Studies

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Synergism; Drug Therapy, Combination; Female; Gentamicins; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Minocycline; Thienamycins; Tigecycline

Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment.

Topics: Adolescent; Amikacin; Anti-Bacterial Agents; Armed Conflicts; Bacterial Infections; Child; Child, Preschool; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Hospitalization; Humans; Infant; Infant, Newborn; Israel; Male; Meropenem; Multiple Trauma; Syria; Thienamycins

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Administration Schedule; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lung; Male; Microbial Sensitivity Tests; Middle Aged; Renal Dialysis; Respiratory Tract Infections

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Critical Care; Critical Illness; Drug Resistance, Multiple, Bacterial; Humans

Tigecycline has in vitro activity against multidrug-resistant and extensively drug-resistant Acinetobacter baumannii (MDR/XDRAB), and may constitute an alternative therapy for treating pneumonia caused by MDR/XDRAB. The aim of this study was to compare the efficacy of tigecycline-based therapy with colistin-based therapy in patients with MDR/XDRAB pneumonia. Between January 2009 and December 2010, patients in the intensive care unit who were diagnosed with MDR/XDRAB pneumonia and treated with either tigecycline or colistin mono-/combination therapy were reviewed. A total of 70 patients were included in our analysis. Among them, 30 patients received tigecycline-based therapy, and 40 patients received colistin-based therapy. Baseline characteristics were similar in the two groups. Clinical success rate was 47% in the tigecycline group and 48% in the colistin group (P = 0.95). There were no differences between the groups with regard to other clinical outcomes, with the exception that nephrotoxicity was observed only in the colistin group (0% vs. 20%; P = 0.009). Clinical and microbiological success rates were numerically higher, and mortality rates were numerically lower in combination therapy group than in the monotherapy group. Multivariate analysis indicated that monotherapy was independently associated with increased clinical failure (aOR, 3.96; 95% CI, 1.03-15.26; P = 0.046). Our results suggest that tigecycline-based therapy was tolerable and the clinical outcome was comparable to that of colistin-based therapy for patients with MDR/XDRAB pneumonia. In addition, combination therapy may be more useful than monotherapy in treatment of MDR/XDRAB pneumonia.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Middle Aged; Minocycline; Pneumonia, Bacterial; Retrospective Studies; Tigecycline; Treatment Outcome

Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Treatment Outcome; Young Adult

In this study, we sought to evaluate the pharmacokinetics of colistin after intravenous administration of colistimethate sodium (CMS) in the critically ill neonates with Gram-negative bacterial infections. A single intravenous dose of CMS [approximately 150,000 IU/kg, equivalent to 5 mg/kg colistin base activity (CBA)] was administered to 7 critically ill neonates. Mean (±SD) maximum plasma colistin concentration and area under the time-concentration curve from 0 to infinity were 3.0 ± 0.7 µg/mL and 25.3 ± 10.4 µg·h/mL, respectively. Time to maximum concentration, half-life, apparent volume of distribution and clearance were 1.3 ± 0.9 hours, 9.0 ± 6.5 hours, 7.7 ± 9.3 L/kg and 0.6 ± 0.3 L/h/kg, respectively. After a dose regimen of 5 mg/kg CBA every 24 hours, the average concentration expected at steady state is 1.1 ± 0.4 µg/mL. In critically ill neonates, a single intravenous dose of 5 mg CBA/kg (approximately 150,000 IU/kg of CMS) resulted in suboptimal plasma concentrations of colistin. According to our pharmacokinetics data, the dosage of CMS currently used in critically ill neonates is insufficient.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Bacteremia; Colistin; Critical Illness; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Pneumonia, Bacterial; Prospective Studies

Traditionally, reduced daily doses of colistin methanesulphonate (CMS) in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF) have resulted in suboptimal colistin concentrations. The necessity of a loading dose (LD) at treatment initiation has been proposed. A LD of 9 million IU (MU) [ca. 270 mg of colistin base activity (CBA)] was administrated with a maintenance dose of 4.5 MU (ca. 140 mg CBA) every 12 h (q12h) to eight critically ill patients receiving renal replacement therapy. Blood samples were collected immediately before and at different time intervals after the LD and the fourth dose, whilst pre-filter and post-filter blood samples were also collected. CMS and colistin concentrations were determined using an LC-MS/MS assay. Median maximum observed concentrations after the LD were 22.1 mg/L for CMS and 1.55 mg/L for colistin, whereas during maintenance dosing the corresponding values were 12.6 mg/L and 1.72 mg/L, respectively. CVVHDF clearance was determined as 2.98 L/h for colistin, equivalent to 62% of total apparent colistin clearance in CVVHDF patients. Both CMS and colistin were cleared by CVVHDF. Application of a LD of 9 MU CMS resulted in more rapid achievement of the target colistin concentration. Following implementation of a predicted pharmacokinetic model on plasma CMS/colistin concentrations, a LD of 12 MU CMS appears more appropriate, whilst a CMS maintenance dosage of at least 6.5-7.5 MU q12h is suggested in patients undergoing CVVHDF. However, further clinical studies are warranted to assess the safety of a LD of 12 MU CMS in patients receiving CVVHDF.

Topics: Adult; Aged; Anti-Bacterial Agents; Chromatography, Liquid; Colistin; Critical Illness; Female; Hemodiafiltration; Humans; Male; Middle Aged; Models, Statistical; Plasma; Tandem Mass Spectrometry

Limited data exist regarding prognostic factors and optimal antimicrobial treatment of infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). This retrospective cohort study included 93 adult patients who developed ventilator-associated pneumonia (VAP) due to XDR-AB in the ICU of the University Hospital of Heraklion, Greece, from October 2012 to April 2015. XDR-AB isolates were mainly susceptible to colistin (93.5%) and tigecycline (25.8%), whereas 6 (6.5%) were pandrug-resistant. Prior to infection, patients had long durations of mechanical ventilation and hospital stay and multiple exposures to antibiotics. Median Charlson co-morbidity and APACHE II scores were 2 and 17, respectively. Mortality at 28 days of infection onset was high (34.4%) despite high rates of in-vitro-active empirical (81.7%) and definitive (90.3%) treatment. Active colistin-based combination therapy (n = 55) and monotherapy (n = 29) groups had similar 28-day mortality (27.6% vs. 30.9%, respectively) and Kaplan-Meier survival estimates over time. In multivariable Cox regression, advanced age (aHR = 1.05 per year increase, 95% CI 1.02-1.09), rapidly fatal underlying disease (aHR = 2.64, 95% CI 0.98-9.17) and APACHE II score (aHR = 1.06 per unit increase, 95% CI 0.99-1.14) were identified as independent predictors of 28-day mortality, but no difference in mortality hazards between the active colistin-based combination therapy and monotherapy groups was produced (aHR = 0.88, 95% CI 0.35-2.38). These results support the use of colistin as a first-line agent against VAP in settings where XDR-AB is endemic, but oppose the introduction of colistin-based combination therapy as standard treatment.

Topics: Acinetobacter baumannii; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Greece; Hospitals, University; Humans; Male; Middle Aged; Pneumonia, Ventilator-Associated; Prognosis; Retrospective Studies; Survival Analysis; Young Adult

There has been increased incidence and high mortality in cases with ventilator-associated pneumonia (VAP) caused by colistin-only-susceptible Acinetobacter baumannii (COS-AB). Colistin has emerged as a therapeutic option for VAP caused by multidrug-resistant Gram-negative organisms including COS-AB. A retrospective study was conducted to examine the impact of early versus late initiation of colistin on 30-day mortality of critically ill patients with VAP caused by COS-AB.. Critically ill patients with VAP caused by COS-AB who received colistin were enrolled. The receiver operating characteristic (ROC) curve was used to identify the temporal breakpoint that maximized the difference in 30-day mortality.. A total of 56 patients (34 men and 22 women) were included in the study. About 86% of all cases were late-onset VAP. The 30-day mortality was 46.4%. The rate was higher among patients with admission Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 18 and patients with a delay of more than four days in initiating colistin treatment. The mortality rate was 26.9% among patients with treatment delay of four or fewer days and 63.3% for patients with a treatment delay of more than four days.. A delay of four days or more in initiating colistin in patients with VAP caused by COS-AB significantly increases mortality. Colistin should be considered in the empirical protocols in late-onset VAP cases when COS-AB is highly suspected.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Male; Middle Aged; Pneumonia, Ventilator-Associated; Retrospective Studies; Survival Analysis; Time Factors; Young Adult

Colistin pharmacokinetics data are scarce regarding patients undergoing renal replacement therapy (RRT), or even absent as in patients treated with sorbent technologies potentially capable of removing colistin by extensive absorption on many polymeric materials.. Twelve septic shock patients with acute kidney injury (AKI) undergoing RRT [continuous venovenous hemodiafiltration (CVVHDF) n = 7, coupled-plasma filtration adsorption-HF (CPFA-HF) n = 4, hemoperfusion n = 1] treated with colistin methanesulfonate at a dose of 4.5 × 10(6) U bid were studied. Colistin A (Col-A) and colistin B (Col-B) concentrations on plasma and effluent at time 0, 0.2, 1, 3, 6, 12, 24 and 48 h were determined by the liquid chromatography-tandem mass spectrometry method.. With CVVHDF the sieving coefficient was lower for Col-A, peaked early (0.40 for Col-A at 10 min, and 0.59 for Col-B at 3 h) and declined after 48 h (0.22 and 0.30 for Col-A and Col-B, respectively). Colistin's filter clearance showed a similar pattern, with the highest clearance value of 18.7 ml/min for Col-B at 1 h. With CPFA-HF after the cartridge the Col-A and Col-B levels were negligible (<0.2 mg/l) or not detectable. The sum of the effluent and cartridge clearances reached values of 30 and 40 ml/min for Col-A and Col-B, respectively. With hemoperfusion the postcartridge concentrations for Col-A and Col-B were about 30 % lower than those determined precartridge.. During CPFA-HF and CVVHDF, the extent of colistin removal is high, and patients should receive an unreduced dosage. However, due to risk of accumulation in long-term administration colistin plasma levels determination is recommended.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Chromatography, Liquid; Colistin; Critical Illness; Female; Follow-Up Studies; Hemodiafiltration; Humans; Male; Mass Spectrometry; Middle Aged; Shock, Septic; Sorption Detoxification

There has been a growing need for colistin as a key drug for the treatment of MDR-GNB infection. Information on colistin use in Asian population is limited.. A retrospective observational study was conducted to assess the efficacy and nephrotoxicity in critically ill adult patients who received intravenous colistin for MDR-GNB infection in the intensive care unit (ICU) at Bach Mai Hospital in Hanoi, Vietnam. Colistin was administered according to the dosing guideline that was based on pharmacokinetic, pharmacodynamic and toxicodynamic principles, adjusted by body weight and creatinine clearance.. Twenty-eight eligible patients were included. The mean patient age was 60±20.4 years. The mean body weight was 53±8.6kg. The mean daily dose of colistin was 4.1±1.6 MIU, and the mean cumulative dose of colistin was 48.2±22.8 MIU. Colistin therapies were classified as clinically effective in 19 (67.9%) cases. Six (21.4%) patients developed nephrotoxicity during the study period according to RIFLE criteria.. A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Intensive Care Units; Kidney; Male; Middle Aged; Retrospective Studies; Thinness; Vietnam; Young Adult

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple; Female; Humans; Kidney; Male; Pseudomonas Infections

The objective of this study was to compare the safety and efficacy of inhaled plus intravenous (IV) colistin with that of IV colistin alone in critically ill children with ventilator-associated pneumonia (VAP) due to colistin-only susceptible (COS) Gram-negative bacteria (GNB).. This retrospective cohort study included critically ill children aged 1 month to 18 years with culture-documented monomicrobial VAP due to COS GNB.. Fifty patients were included, and 32 patients received IV colistin alone, whereas 18 patients received inhaled plus IV colistin. No between-cohort differences were observed in clinical (p = 0.49) and microbiological outcomes (p = 0.68), or VAP-related mortality (p = 0.99). Although the bacterial eradication rates did not differ in either treatment group, the median time to bacterial eradication (TBE) was significantly shorter in the inhaled plus IV colistin group than in the IV colistin group. The additional use of inhaled colistin was the only independent factor associated with TBE, and it shortened the median TBE by 3 days. Only one patient in the IV colistin group developed reversible nephrotoxicity. Mild bronchoconstriction was observed in three patients at the time of administration of the first doses of inhaled colistin, which did not require discontinuation of treatment.. The present study has demonstrated that the addition of inhaled colistin to IV colistin led to a shorter TBE in critically ill children with VAP due to COS GNB. However, it did not lead to a significant difference in the clinical and microbiological outcomes of VAP.

Topics: Administration, Inhalation; Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Cohort Studies; Colistin; Critical Illness; Female; Humans; Infant; Male; Pneumonia, Ventilator-Associated; Retrospective Studies; Treatment Outcome

Recent studies suggested that high doses of colistin are necessary in the treatment of serious infections. However, few studies have evaluated such treatment. The objective of this study was to evaluate the effectiveness and nephrotoxicity of high-dose colistin in critically ill patients with respiratory infections associated with carbapenem-resistant Acinetobacter baumannii (CRAB).. This was a retrospective cohort study of critically ill cancer patients who received high-dose intravenous colistin for treatment of CRAB-related respiratory infections. Patients received colistimethate sodium 9 million IU/day or an equivalent dose, adjusted for renal function. Treatment effectiveness was evaluated by determining the microbiological clearance, recurrent and new CRAB-related infections, and mortality in the intensive care unit (ICU). Nephrotoxicity was defined according to the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.. A total of 89 patients met the inclusion criteria. Microbiological clearance was observed in 51 (66.2%) subjects who had at least 2 follow-up cultures (n = 77). In patients who achieved microbiological clearance, recurrent and new CRAB-related infections occurred in 3 (5.9%) and 9 (17.6%) subjects, respectively. Fifty-seven patients (64%) died in the ICU. Thirty-five (39.3%) subjects developed nephrotoxicity according to the RIFLE criteria, which was classified as risk in 4 (11.4%) subjects, injury in 8 (22.8%) subjects, and failure in 21 (60%) subjects.. In critically ill cancer patients, high-dose colistin was associated with microbiological clearance in about two-thirds of the subjects with CRAB-related respiratory infections but mortality was high. A significant portion of patients developed nephrotoxicity while receiving colistin therapy.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Female; Humans; Intensive Care Units; Male; Middle Aged; Neoplasms; Respiratory Tract Infections; Retrospective Studies; Treatment Outcome

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple; Female; Humans; Kidney; Male; Pseudomonas Infections

Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy.. A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach.. Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001).. In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antidotes; Ascorbic Acid; Blighia; Colistin; Critical Illness; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Sepsis; Young Adult

Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Chromatography, Liquid; Colistin; Creatinine; Critical Illness; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Models, Statistical; Tandem Mass Spectrometry

Fosfomycin is active in vitro against extensively drug-resistant (XDR) and pandrug-resistant (PDR) Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing strains; however, the in vivo effectiveness against such pathogens is almost unknown. A multicentre, observational, prospective case-series study was performed in 11 ICUs. All consecutive fosfomycin-treated patients suffering from XDR or PDR fosfomycin-susceptible, microbiologically documented infections were recorded. Clinical and microbiological outcomes were assessed. A safety analysis was performed. In total, 68 patients received fosfomycin during the study period, 48 of whom were considered suitable for effectiveness analysis based on predefined criteria. Bacteraemia and ventilator-associated pneumonia were the main infections. Carbapenemase-producing K. pneumoniae and P. aeruginosa were isolated in 41 and 17 cases, respectively. All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition. Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at Day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. All-cause mortality at Day 28 was 37.5%. Bacterial eradication was observed in 56.3% of cases. Fosfomycin resistance developed in three cases. The main adverse event was reversible hypokalaemia. In conclusion, fosfomycin could have a place in the armamentarium against XDR and PDR Gram-negative infections in the critically ill. Resistance development during therapy, which has been a matter of concern in previous studies, did not occur frequently. The necessity of combination with other antibiotics requires further investigation.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline; Treatment Outcome

Colistin is a 50-year-old antibiotic, the use of which was ceased in the 70s and recently resumed as a "salvage therapy" against multidrug-resistant gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii. The narrow therapeutic range of colistin makes the choice of its correct dosage crucial, and monitoring of blood concentration is occasionally necessary for critically ill patients, including intensive care patients subjected to continuous renal replacement therapy.. Two LC-MS/MS methods were developed and fully validated for the quantitative determination of colistins A and B in plasma and dialysis ultrafiltrate (UF) samples, ultimately arising from 4 patients undergoing continuous venovenous hemodiafiltration (CVVHDF).. The developed methods proved to be both specific and selective. They showed good fit and linearity over the entire range of interest. Trueness and accuracy proved satisfactory. Both methods have excellent intraassay precision (percent coefficient of variations were lower than 10%) and limit of detection values in the range 20-100 ng/mL, about 1-2 orders of magnitude below the concentrations commonly detected in real samples. The mean sieving coefficient (SC) values, measured after 10 minutes of CVVHDF, were 0.42 for colistin A and 0.48 for colistin B. SC values proved to be quite stable for 24 hours, but then declined to 0.24 for colistin A and 0.32 for colistin B, respectively, after 48 hours. At the median blood flow and effluent flow rate of 120 and 28 mL/min, clearance values for colistin B were higher than 15 mL/min. During the entire duration of CVVHDF sessions, the SC and clearance values for colistin A were significantly lower than colistin B.. Two simple methods for the simultaneous determination of colistins A and B have been developed and validated. Their application in the clinical setting demonstrates that CVVHDF treatment lasting 48 hours produces a relatively constant and efficient removal of the drug.

Topics: Anti-Bacterial Agents; Chromatography, Liquid; Colistin; Critical Illness; Hemodiafiltration; Humans; Limit of Detection; Mass Spectrometry; Sensitivity and Specificity

A colistin-glycopeptide combination (CGC) has been shown in vitro to be synergistic against multidrug-resistant Gram-negative bacteria (MDR GNB), especially Acinetobacter baumannii, and to prevent further resistance. However, clinical data are lacking. We carried out a retrospective multicenter study of patients hospitalized in intensive care units (ICUs) who received colistin for GNB infection over a 1-year period, to assess the rates of nephrotoxicity and 30-day mortality after treatment onset among patients treated with and without CGC for ≥48 h. Of the 184 patients treated with colistin, GNB infection was documented for 166. The main causative agents were MDR A. baumannii (59.6%), MDR Pseudomonas aeruginosa (18.7%), and carbapenem-resistant Klebsiella pneumoniae (14.5%); in 16.9% of patients, a Gram-positive bacterium (GPB) coinfection was documented. Overall, 68 patients (40.9%) received CGC. Comparison of patients treated with and without CGC showed significant differences for respiratory failure (39.7% versus 58.2%), ventilator-associated pneumonia (54.4% versus 71.4%), MDR A. baumannii infection (70.6% versus 52%), and GPB coinfection (41.2% versus 0%); there were no differences for nephrotoxicity (11.8% versus 13.3%) and 30-day mortality (33.8% versus 29.6%). Cox analysis performed on patients who survived for ≥5 days after treatment onset showed that the Charlson index (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.44; P = 0.001) and MDR A. baumannii infection (HR, 2.51; 95% CI, 1.23 to 5.12; P = 0.01) were independent predictors of 30-day mortality, whereas receiving CGC for ≥5 days was a protective factor (HR, 0.42; 95% CI, 0.19 to 0.93; P = 0.03). We found that CGC was not associated with higher nephrotoxicity and was a protective factor for mortality if administered for ≥5 days.

Topics: Acinetobacter baumannii; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Therapy, Combination; Female; Glycopeptides; Gram-Negative Bacterial Infections; Humans; Kidney; Klebsiella pneumoniae; Male; Middle Aged; Pneumonia, Ventilator-Associated; Proportional Hazards Models; Pseudomonas aeruginosa; Survival Analysis; Treatment Outcome

Colistin is active against most multidrug-resistant, aerobic Gram-negative bacteria. Because of the reported nephrotoxicity during the first years of use of colistin, there were concerns of its use in pediatrics where there was limited experience The aim of this study is to document the clinical characteristics and outcomes of use of colistin in pediatric patients at a pediatric intensive care unit in Turkey.. We reviewed the medical and laboratory records of 29 critically ill children who were treated with colistin for 38 courses between January 2011 and December 2011 at the Department of Pediatric Intensive Care Unit in Ankara University Medical School, Turkey.. The median age was 17 months (range 3-217 months). Male-to-female ratio was 1:1.37. Ventilator-associated pneumonia (21 courses) was the leading diagnosis followed by catheter-related blood stream infection (6 courses), bacteremia (4 courses), ventriculoperitoneal shunt infection, peritonitis and pneumonia (1 course). The most commonly isolated microorganisms were Acinetobacter baumanni, Pseudomonas aeruginosa, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, and Enterobacter cloacae. Two colistin formulations were used. Colimycin (Kocak Farma) was used in 21 colistin treatment episodes. The median dosage of colistin in this group was 5.0 mg/kg/d (2.3-5.6 mg/kg/d). Colomycin (Forest Laboratories) was used in 17 colistin treatment episodes. The median dosage of colistin in the second group was 75,000 International Unit/kg/d (50,000-80,000 International Unit/kg/d). Thirty colistin treatment episodes (79%) had a good or partial clinical response and 8 (21%) had a poor clinical response. Of the 8 colistin treatment episodes with poor clinical response, 3 were in the Colimycin group and 5 were in the Colomycin group. Ten patients died. There was no evidence of neurotoxicity in this study. Nephrotoxicity was observed in 1 patient but was not attributed to colistin because the patient had multiorgan failure at the same time.. This study in a small cohort of patients suggests that the use of colistin in severe nosocomial infections caused by multidrug-resistant Gram-negative bacteria is well-tolerated and efficacious.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant; Intensive Care Units, Pediatric; Male; Prospective Studies; Risk Factors; Treatment Outcome

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Kidney; Male

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Humans; Pseudomonas; Pseudomonas Infections; Treatment Outcome

Emergence of carbapenem-resistant Enterobacteriaceae has become a substantial global health problem. The aim of this study was to analyze carbapenem-resistant isolates of Enterobacter cloacae that have emerged for the first time in the intensive care unit (ICU) at the University Hospital Centre Split, Croatia. The strains were selected in the period between June and August 2012, according to their susceptibility patterns to carbapenems. Resistant isolates were screened for metallo-β-lactamase (MBL) production with the use of the imipenem-EDTA disk synergy test, and positive findings were confirmed by PCR. The type of VIM β-lactamase gene was determined by sequencing of PCR products. The genetic relatedness was evaluated using pulsed-field gel electrophoresis analysis. The demographic and clinical data were retrospectively analyzed from medical records. Five patients were infected and one patient was colonized with a single clone of multidrug-resistant VIM-1-producing E. cloacae susceptible only to colistin. Three cases of lower respiratory tract infections, one case of bacteremia, and one case of intra-abdominal infection were identified. All cases were hospital-acquired after prolonged stay in ICU. All patients had serious underlying diseases and received a broad-spectrum antibiotic. Four patients died and two had unimprovable medical condition at the time of discharge from the hospital. MBL-producing E. cloacae can cause fatal infection in severely ill patients. Monoclonal outbreak highlights the need for continuous surveillance and good infection control practices to prevent further spread since the antibiotic therapy options for infections caused by such strains are strongly limited.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Clone Cells; Colistin; Critical Illness; Croatia; Cross Infection; Disease Outbreaks; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Gene Expression; Hospitals, University; Humans; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; Survival Analysis

Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n = 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients.

Topics: Administration, Inhalation; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biotransformation; Colistin; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Extracellular Fluid; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Half-Life; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Models, Statistical; Pneumonia, Ventilator-Associated

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Biotransformation; Colistin; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Half-Life; Humans; Lung; Male; Microbial Sensitivity Tests; Middle Aged

To evaluate the association between the administration of intravenous (IV) colistin and the emergence of renal dysfunction.. A retrospective medical record review.. A tertiary care academic medical center.. A total of 174 critically ill patients who received at least one dose of IV colistin between 2004 and 2007.. The primary outcome was development of renal dysfunction, defined as an increase in serum creatinine of 50% or more during therapy or the initiation of renal replacement therapy (RRT), in patients who received at least one dose of colistin and were not already on RRT. The severity of renal dysfunction was further categorized by the RIFLE criteria. Demographic and clinical characteristics were analyzed by logistic regression for association with new renal dysfunction. A total of 174 patients were evaluated for renal dysfunction. Of these patients, 84 (48%) experienced renal dysfunction on colistin. On multivariate analysis, age in years (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05) and receipt of concurrent nephrotoxin(s) (OR 3.35, 95% CI 1.34-8.36) significantly increased the risk of developing renal dysfunction.. In this critically ill population, renal dysfunction occurred frequently and was associated with older age and receipt of nephrotoxins.

Topics: Adult; Age Factors; Aged; Anti-Bacterial Agents; APACHE; Colistin; Confidence Intervals; Creatinine; Critical Illness; Female; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Renal Replacement Therapy; Retrospective Studies; Risk; Tertiary Healthcare; Treatment Outcome

Nosocomial infection due to multidrug-resistant Gram-negative pathogens in ICUs is a challenge for clinicians and microbiologists and has led to the resurgence of IV colistin use in the last decade. The aim of this study was to assess the efficacy of IV colistin in the treatment of critically ill children with multidrug-resistant Gram-negative infections.. Retrospective descriptive study conducted in the PICU of Maulana Azad Medical College and associated Chacha Nehru Bal Chikitsalaya, Delhi, India, during the period of January 2010 to December 2011.. The records of critically ill children with multidrug-resistant Gram-negative infections treated with IV colistin were reviewed.. Fifty critically ill children received IV colistin; their median age was 36 months (range: 1 mo-12 yr), with male:female ratio of 3:2. The isolated pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Mean duration of colistin therapy was 14.3 days (range, 7-21). A favorable clinical outcome occurred in 36 children (72%), and 14 children (28%) died due to severe sepsis with multiple-organ dysfunction syndrome. Renal toxicity occurred in five children and was associated with multiple-organ dysfunction syndrome in three and coadministration of vancomycin in two. No neurotoxic adverse effects due to colistin therapy were reported.. Our study suggests that IV colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children, but further prospective and randomized control trials are needed to confirm its efficacy and safety in children.

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Cross Infection; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infusions, Intravenous; Intensive Care Units, Pediatric; Male; Retrospective Studies; Treatment Outcome

Use of colistin has re-emerged for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria, but information on its pharmacokinetics and pharmacodynamics is limited, especially in critically ill patients. Recent data from pharmacokinetic/pharmacodynamic (PK/PD) population studies have suggested that this population could benefit from administration of higher than standard doses of colistimethate sodium (CMS), but the relationship between administration of incremental doses of CMS and corresponding PK/PD parameters as well as its efficacy and toxicity have not yet been investigated in a clinical setting. The objective was to study the PK/PD differences of CMS and colistin between three different CMS dosage regimens in the same critically ill patient. A critically ill patient with nosocomial pneumonia caused by a MDR Acinetobacter baumannii received incremental doses of CMS. During administration of the different CMS dosage regimens, CMS and colistin plasma concentrations were determined and PK/PD indexes were calculated. With administration of the highest CMS dose once daily (720 mg every 24h), the peak plasma concentration of CMS and colistin increased to 40.51 mg/L and 1.81 mg/L, respectively, and the AUC0-24/MIC of colistin was 184.41. This dosage regimen was efficacious, and no nephrotoxicity or neurotoxicity was observed. In conclusion, a higher and extended-interval CMS dosage made it possible to increase the exposure of CMS and colistin in a critically ill patient infected by a MDR A. baumannii and allowed a clinical and microbiological optimal response to be achieved without evidence of toxicity.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Cross Infection; Drug Resistance, Multiple, Bacterial; Humans; Male; Microbial Sensitivity Tests; Plasma; Pneumonia, Bacterial

Nephrotoxicity was assessed in 173 critically ill patients receiving intravenous colistin or polymyxin B; it occurred in 60.4% and 41.8%, respectively. Further investigation is necessary to elucidate the reason for the difference in nephrotoxicity observed between the groups and to assess the impact of severity of illness and dosing/administration.

Topics: Acute Kidney Injury; Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Female; Humans; Incidence; Male; Middle Aged; Polymyxin B; Retrospective Studies; Tertiary Care Centers

Use 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.. The 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.. The 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.. In 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.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Female; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Prospective Studies; Retrospective Studies; Risk Factors; Sepsis

This study was conducted in response to the rising incidence of drug resistance observed in the intensive care unit (ICU) of King Fahad Medical City.. A retrospective observational study was conducted in the ICU of King Fahad Medical City between October 2003 and April 2012. Data were collected using a structured data sheet.. Nine episodes of infection with colistin-resistant Enterobacteriacae were recorded in seven patients. Five were females with an average age of 59.75 years. All patients had multiple co-morbidities; five had diabetes mellitus. In five of the episodes, Klebsiella pneumoniae was responsible, Serratia marcescens was reported in two, while Enterobacter aerogenes and Providencia stuartii were responsible for one episode of infection each. Prior colistin use was documented in all but one patient. Colistin resistance was defined by a minimum inhibitory concentration (MIC) of > 4 µg/mL according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint for Enterobacteriacae. Various antibiotics were used to treat the patients, with mortality reported in two.. Infection due to colistin-resistant Enterobacteriacae is a rising challenge in Saudi Arabia; colistin use is thought to be associated with these infections. This calls for a stricter antimicrobial stewardship program and improved infection control measures to curb the rising trend of antibiotic resistance.

Topics: Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Cross-Sectional Studies; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Saudi Arabia

A potent synergy of a glycopeptide-colistin combination against Acinetobacter baumannii has recently been described. We set out to assess the efficacy and safety of this combination in a retrospective study including episodes of ventilator-associated pneumonia or bacteremia caused by carbapenem-resistant A. baumannii. We compared 29 patients (group I) treated with colistin plus vancomycin with 28 patients treated with colistin alone (group II). Group I received vancomycin (for empirical or targeted therapy) at the onset of colistin administration and both antimicrobials coincided for at least 5 days. Baseline characteristics, clinical cure, microbiological eradication, and mortality were similar in both groups but the rate of acute kidney injury was higher in group I (55.2 vs. 28%; p = 0.04). In critically ill patients with carbapenem-resistant A. baumannii infections, clinical outcomes do not differ in patients treated with colistin plus vancomycin from those receiving colistin without vancomycin. This combination significantly increases the risk of renal failure.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Treatment Outcome; Vancomycin

To identify risk factors for the first episode of Klebsiella Pneumonia resistant to carbapenems (KPRC) infection in critically ill patients.. This prospective cohort study was conducted in a 12-bed general Intensive Care Unit (ICU) in a University Hospital on ICU patients who required mechanical ventilation (MV) for >48 hours during a 12-month period. Clinical and microbiologic data were studied. Characteristics of KPRC patients were compared with those of critically ill patients who presented nonmultidrug resistant (MDR) bacterial infections or no documented infection at all.. Twenty-five patients presented KPRC infection, 18 presented non-MDR bacterial infection, and 39 patients presented no infection. Compared to patients without documented infection or infected by non MDR bacteria, patients with KPRC infection had received more frequently or for longer duration antibiotics against Gram-negative bacteria (carbapenems, colistin P < 0.05). Duration of colistin administration prior to KPRC isolation was independently associated with increased frequency of KPRC infection (odds ratio, 1.156 per day; 95% confidence interval, 1.010 to 1.312; P = 0.025). KPRC patients stayed longer in the ICU and received mechanical ventilation and sedation for longer periods and presented increased mortality (P < 0.05).. KPRC infection is an emerging problem which might be more common in patients with previous use of antibiotics and especially colistin.

Topics: Adult; Aged; Carbapenems; Colistin; Critical Illness; Drug Resistance, Microbial; Female; Humans; Intensive Care Units; Klebsiella pneumoniae; Male; Middle Aged; Pneumonia; Prospective Studies; Risk Factors

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.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Colistin; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Female; Hemodiafiltration; Humans; Male; Microbial Sensitivity Tests; Middle Aged

Recently, colistin has become a salvage therapy in the treatment of serious Intensive Care Unit infections owing to the emergence of extensively drug-resistant (XDR) bacterial isolates. This study aimed to show the effectiveness of colistin in critically ill patients with renal failure. A prospective case-control study of 94 patients admitted to medical intensive care units of a university hospital from December 2008 to June 2010 was conducted. All patients had infections with XDR Acinetobacter baumannii or Pseudomonas aeruginosa and received colistin. Cases comprised 39 patients with chronic renal failure (CRF) and controls were other patients without CRF. Apart from the male dominancy in the CRF group, there was no statistical difference between the two groups regarding demographic characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and site and type of infection. In patients who completed colistin therapy, bacteriological cure was seen in 87% of patients with CRF and 95% of patients without CRF (P=0.890). Mortality in patients with CRF was similar to that in patients without CRF (44% and 42%, respectively) (P=0.999). Nephrotoxicity developed in 23.6% of patients in the control group. Concomitant nephrotoxic agents and total defined daily dose of colistin did not affect the development of nephrotoxicity. The mortality rate was 38% in patients with nephrotoxicity, similar to the mortality rate in patients without nephrotoxicity (36%) (P=0.999). In conclusion, in critically ill patients with CRF, colistin therapy, although used at a reduced dosage, was as effective as in patients without CRF.

Topics: Acinetobacter baumannii; Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; APACHE; Bacterial Infections; Case-Control Studies; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Hospitals, University; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Pseudomonas aeruginosa; Survival Analysis; Treatment Outcome

Gram-negative bacteria susceptible only to colistin (COS) are emerging causes of severe nosocomial infections, reviving interest in the use of colistin. However, consensus on the most effective way to administer colistin has not yet been reached.. All patients who had sepsis due to COS gram-negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded.. Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment.. Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Cross Infection; Female; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Sepsis; Treatment Outcome

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.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Female; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Protein Binding; Pseudomonas aeruginosa

Available data on colistin pharmacokinetics in patients undergoing continuous renal replacement therapy (CRRT) are limited. Our aim was to study colistin pharmacokinetics in critically ill patients treated with colistin methane sulphonate for Gram-negative sepsis and undergoing continuous venovenous haemodiafiltration for acute renal failure.. Three patients were studied. The colistin methane sulphonate dose administered was at the discretion of the attending physician and was in all cases lower than that recommended for individuals with intact renal function. Colistin methane sulphonate was administered intravenously over 30 min, and blood samples were collected from each patient pre- and post-filter for the HPLC determination of colistin levels in serum before infusion, at 10, 60, 120, 240, 360, 480 and 600 min from the end of infusion, and immediately before the next dose. Concurrently, spot samples of effluent from the haemofilter were also collected and analysed. Both colistin total extracorporeal clearance and clearance in the effluent were calculated.. Extracorporeal clearance resulted in substantial removal of colistin (43%-59% of total colistin clearance). Total colistin clearance was found to be reduced (varying between 3.3 and 4.5 L/h), compared with patients with normal renal function. Colistin methane sulphonate dosage resulted in clearly suboptimal colistin steady-state concentrations.. In spite of substantial extracorporeal clearance, total colistin clearance was reduced, compared with patients with normal renal function. Colistin adsorption by the haemofilter contributed to its extracorporeal clearance to a large extent. Studies on other patients receiving colistin methane sulphonate and undergoing CRRT are required before more appropriate dosage regimens can be recommended.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Colistin; Critical Illness; Gram-Negative Bacterial Infections; Hemodiafiltration; Humans; Infusions, Intravenous; Intensive Care Units; Male; Metabolic Clearance Rate; Middle Aged; Sepsis; Serum; Time Factors

Topics: Bronchoalveolar Lavage Fluid; Colistin; Critical Illness; Humans; Injections, Intravenous; Pneumonia, Ventilator-Associated

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Humans; Pneumonia, Ventilator-Associated

To analyze the efficacy of nebulized colistin in the microbiological eradication and clinical improvement of patients with pulmonary infection by multi-resistant Acinetobacter baumannii (MAB).. A retrospective study.. Intensive Care Unit of a Tertiary hospital.. Hospitalized patients on invasive mechanical ventilation with positive MAB cultures of the airway.. All received treatment with colistin (CL). Nosocomial pneumonia (NP) or Tracheobronchitis (TB) was determined according to routine criteria and colonization (CO) was determined in the case of a positive culture in the absence of infection criteria. Three groups of patients were defined: those treated with nebulized CL, those treated with IV CL and those treated with IV CL plus nebulized CL.. Baseline characteristics. Microbiological eradication and clinical recovery were evaluated according to routine criteria.. 83 patients were studied, 54 of whom were treated, with the following diagnoses: 15 (27.8%) with NP, 16 (29.6%) with TB and 23 patients (42.6%) with CO. Nebulized CL was used in 36 patients (66.7%): 66.7% of which for CO, 33.3% in treatment for TB and in no case of NP. In 61.1% of the patients, IV CL was used: 22.2% of which for CO, 38.9% for TB and 38.9% in NP. The combination of IV CL and nebulized CL was used in 15 patients (27.8%): 5 patients (33.3%) CO, 2 patients (13.3%) TB and 8 patients (53.3%) NP. Microbiological eradication was achieved in 32 patients (59.3%), with the following distribution: 8 (47.1%) with IV CL, 15 (83.3%) with nebulized CL and 9 patients (69.2%) with a combination of IV CL and nebulized CL. Clinical recovery was achieved in 42 patients (77.8%): 12 (80%) with IV CL, 18 (94.7%) with nebulized CL and 12 (85.7%) with a combination of nebulized and IV CL. These differences were not significant. In the group of patients with infection due to TB and NP (31 patients, 57.4%), microbiological eradication was achieved in 5 patients (100%) treated with nebulized CL and in 6 of the 9 patients (42.9%) treated with IV CL, the difference being significant (P<.05). Clinical recovery in this group was 100% (6 patients) treated with nebulized CL and 75% (9 of the 12 patients) in the IV CL group. This difference was not significant.. Our study suggests that treatment with colistin in patients with pulmonary infection with multi-resistant Acinetobacter baumannii could be more efficient if it were to be administrated solely nebulized or in combination with IV colistin rather than administered solely intravenously.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Adult; Aged; Bronchitis; Colistin; Critical Illness; Cross Infection; Dose-Response Relationship, Drug; Drug Evaluation; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Retrospective Studies; Tracheitis; Tracheotomy

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Female; Humans; Male

In recent years there has been renewed interest in colistin for the treatment of infections by multidrug-resistant Gram-negative bacteria, causing concern that increasing use may be accompanied by the emergence of resistance. This is a retrospective cohort study of colonization and infection by colistin-resistant (CR) gram-negative bacteria in critically ill patients. Colonization data were based on surveillance culture results. Among 150 patients, 78 (52%) were colonized by CR Gram-negative bacteria. Among them, 30 (20%) were colonized by Klebsiella pneumoniae isolates and 51 (34%) were colonized by intrinsically resistant to colistin (CIR) enterobacteriaceae. Seven cases of infection were caused by CR K. pneumoniae and 12 cases by CIR strains. The main risk factor for colonization by CR pathogens was colistin treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Young Adult

To determine the frequency of nephrotoxicity associated with colistin therapy by using a standardized definition and to identify risk factors for colistin-induced nephrotoxicity in critically ill patients.. Single-center, retrospective cohort analysis.. University-affiliated tertiary care center.. Forty-nine adults admitted to an intensive care unit who received intravenous colistin for at least 48 hours between July 2007 and July 2009.. Nephrotoxicity was determined by using the standardized RIFLE criteria: risk, injury, failure, loss, and end-stage renal disease. Patients who had end-stage renal disease or required renal replacement therapy before initiation of colistin were excluded. Of the 49 patients included in the analysis, 15 (31%) developed nephrotoxicity, and only two patients (4%) had irreversible cases. Patients with chronic kidney disease (40% in the group with nephrotoxicity vs 3% in the group without nephrotoxicity, p=0.002) and hypertension (87% vs 56%, p=0.037) at baseline had a higher risk of developing nephrotoxicity. In addition, patients with nephrotoxicity were more likely to have received intravenous contrast material (33% vs 0%, p=0.002). The risk of developing nephrotoxicity was 6.5 times higher in patients who had been given at least two concomitant nephrotoxic agents compared with no other nephrotoxic agents (p=0.034).. The frequency and severity of colistin-induced nephrotoxicity in critically ill patients was consistent with previous reports in non-critically ill patients. Most cases of nephrotoxicity demonstrated in this study were mild and reversible. Patients receiving colistin therapy who have hypertension or chronic kidney disease should be monitored closely, and administration of additional nephrotoxic agents should be avoided in all patients when possible. Large, prospective trials are warranted to confirm these results.

Topics: Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Female; Humans; Hypertension; Injections, Intravenous; Intensive Care Units; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Risk Factors; Severity of Illness Index

In recent reports polymyxins have been considered an effective and safe treatment option for the management of multidrug-resistant (MDR) Gram-negative bacterial infections. Here we report our clinical experience with the use of intravenous colistin sulfate in critically ill patients hospitalized from January 2006 to October 2008, as a last treatment resort in China, and assess its effectiveness and adverse effects. Fifteen patients who suffered from severe infections caused by MDR or pandrug-resistant (PDR) Gram-negative bacteria (13 isolates of Acinetobacter baumannii, 4 isolates of Pseudomonas aeruginosa and 2 isolates of Klebsiella pneumoniae), unresponsive to the initial empirical regimens, were treated with colistin sulfate (daily dose of 1.28 +/- 0.25 million IU and duration of 22.3 +/- 6.2 days), based on sensitivity results. The treatment resulted in a good clinical response in 73.3%, microbiological clearance in 60% and mortality in 20%. Possible nephrotoxicity occurred in 1 patient and no patients developed neurotoxicity. In conclusion, intravenous colistin sulfate is a safe and viable alternative for the treatment of severe infections due to sensitive MDR Gram-negative bacteria.

Topics: Adult; Aged; Anti-Bacterial Agents; Central Nervous System Diseases; China; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Critical Illness; Cross Infection; Humans; Infusions, Intravenous; Male; Plasma; Renal Insufficiency

Infections caused by multidrug-resistant gram-negative bacteria have caused a resurgence of interest in colistin. To date, information about pharmacokinetics of colistin is very limited in critically ill patients, and no attempts have been made to evaluate its concentration in BAL.. In this prospective, open-label study, 13 adult patients with ventilator-associated pneumonia caused by gram-negative bacteria were treated with colistin methanesulfonate (CMS) IV, 2 million International Units (174 mg) q8h, a usually recommended dose, for at least 2 days. Blood samples were collected from each patient at time intervals after the end of infusion. BAL was performed at 2 h. Colistin was measured by a selective, sensitive high-performance liquid chromatography-based method. Pharmacokinetic parameters were determined by noncompartmental analysis.. Patients received 2.19 ± 0.38 mg/kg (range, 1.58-3.16) of CMS per dose. At steady state, mean ± SD plasma colistin maximum (Cmax) and trough (Ctrough) concentrations were 2.21 ± 1.08 and 1.03 ± 0.69 μg/mL, respectively. Mean ± SD area under the plasma concentration-time curve from 0 to 8 h (AUC(0-8)), apparent elimination half-life, and apparent volume of distribution were 11.5 ± 6.2 μg × h/mL, 5.9 ± 2.6 h, and 1.5 ± 1.1 L/kg, respectively. Cmax/minimum inhibitory concentration (MIC) ratio and AUC(0-24)/MIC ratio (MIC = 2 μg/mL) were 1.1 ± 0.5 and 17.3 ± 9.3, respectively. Colistin was undetectable in BAL. Nephrotoxicity was not observed.. Although the pharmacodynamic parameters that better predict the efficacy of colistin are not known in humans, in critically ill adult patients the IV administration of CMS 2 million International Units (174 mg) q8h results in apparently suboptimal plasma concentrations of colistin, which is undetectable in BAL. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen.

Topics: Adult; Aged; Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Pneumonia, Ventilator-Associated; Prospective Studies; Survival Rate; Treatment Outcome; Young Adult

Although colistin methanesulfonate (CMS) has been used extensively in critically ill patients infected with multidrug-resistant organisms, the optimum dosing regimen remains to be determined. Herein, we examined the pharmacokinetics of three different dosing regimens of CMS, 3 million units every 8 h (regimen A), 4.5 million units every 12 h (regimen B), 9 million units every 24 h (regimen C) and evaluated the bactericidal activity of serum containing various concentrations of colistin against Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) of 1 microg/ml. the means +/- SE serum C(max )of colistin for regimens A, B, and C were 3.34+/-0.35, 2.98+/-0.27, and 5.63+/-0.87 microg/ml, respectively. All serum samples containing colistin >4 microg/ml (serum concentration/MIC >4) eliminated P. aeruginosa whereas only 40% of samples containing colistin <4 microg/ml resulted in complete bacterial killing. these findings indicate that the currently used dosing regimens might not provide the most effective therapy with CMS and justify administering larger dosages in longer intervals.

Topics: Aged; Anti-Bacterial Agents; Blood Bactericidal Activity; Colistin; Critical Illness; Dose-Response Relationship, Drug; Female; Humans; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections

Data regarding the role of inhaled colistin in critically ill pediatric patients without cystic fibrosis are scarce. Three children (one female), admitted to the intensive care unit (ICU) of a tertiary-care pediatric hospital in Athens, Greece, during 2004-2009 received inhaled colistin as monotherapy for tracheobronchitis (two children), and as adjunctive therapy for necrotizing pneumonia (one child). Colistin susceptible Acinetobacter baumannii and Pseudomonas aeruginosa were isolated from the cases' bronchial secretions specimens. All three children received inhaled colistin at a dosage of 75 mg diluted in 3 ml of normal saline twice daily (1,875,000 IU of colistin daily), for a duration of 25, 32, and 15 days, respectively. All three children recovered from the infections. Also, a gradual reduction, and finally total elimination of the microbial load in bronchial secretions was observed during inhaled colistin treatment in the reported cases. All three cases were discharged from the ICU. No bronchoconstriction or any other type of toxicity of colistin was observed. In conclusion, inhaled colistin was effective and safe for the treatment of two children with tracheobronchitis, and one child with necrotizing pneumonia. Further studies are needed to clarify further the role of inhaled colistin in pediatric critically ill patients without cystic fibrosis.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Albuterol; Anti-Bacterial Agents; Bronchitis; Bronchodilator Agents; Case-Control Studies; Child; Child, Preschool; Colistin; Critical Care; Critical Illness; Cystic Fibrosis; Female; Hospitals, Pediatric; Humans; Infant; Ipratropium; Male; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Tracheitis; Treatment Outcome

Ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) Acinetobacter baumannii in critically ill patients presents an emerging challenge to clinicians. Administration of aerosolized colistin as an adjunctive therapy is one therapeutic option mentioned in limited evidence-based studies. This study aimed to evaluate the effectiveness of adjunctive aerosolized colistin treatment for VAP due to MDR pathogens.. We retrospectively reviewed the medical records of patients who had received aerosolized colistin for treatment of VAP due to MDR A. baumannii in our hospital from August to December 2008.. Forty-five patients were enrolled in our study. The mean age was 71 +/- 15 years. The mean Acute Physiological and Chronic Health Evaluation II (APACHE II) scores on the day of intensive care unit admission and on the first day of aerosolized colistin administration were 22.5 +/- 6.7 and 18.9 +/- 5.7, respectively. The mean duration of intensive care unit stay was 34 +/- 16 days. The mean daily dosage of aerosolized colistin was 4.29 +/- 0.82 million IU, and the mean duration of administration was 10.29 days. Seventeen patients (37.8%) had a favorable microbiological outcome and 26 (57.8%) showed a clinical response. Mortality due to all causes was 42.2%. No adverse effects related to inhaled colistin were recorded.. Aerosolized colistin may be considered as an adjunct to intravenous treatments in patients with VAP due to colistin-susceptible MDR A. baumannii in critically ill patients.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Hospitals; Humans; Male; Middle Aged; Pneumonia, Ventilator-Associated; Retrospective Studies; Taiwan; Treatment Outcome

We sought to evaluate the safety and feasibility of inhaled aminoglycosides or colistin in cancer patients with ventilator-associated pneumonia (VAP) due to Gram-negative bacteria (GNB). A retrospective case-matched study was obtained after obtaining IRB approval in patients at the intensive care unit at our NCI-designated comprehensive cancer center between 1999 and 2005. Sixteen patients with GNB-VAP who received inhaled aminoglycosides or colistin were compared with 16 patients who had received these antibiotics intravenously alone. Eligible patients were required to have received at least six doses of inhaled therapy, or 3 or more days of intravenous therapy. Clinical Pulmonary Infection Scores were used to assess pneumonia severity. Standard ATS criteria were used to define VAP. Patients treated with inhaled antibiotics were less likely to have received corticosteroids (13% vs 50%; P < 0.02) and had a higher median baseline creatinine level (0.85 vs 0.6 mg/dL; P < 0.02) than patients treated intravenously. Pseudomonas aeruginosa (69%) was the most common cause of VAP. There were no serious adverse events associated with inhaled antibiotics. Patients who received these antibiotics intravenously developed renal dysfunction (31%); none of the patients treated with inhaled antibiotics developed nephrotoxicity (P < or = 0.04). Patients treated with inhaled antibiotics were more likely to have complete resolution of clinical (81% vs 31% in the intravenous antibiotic group; P < 0.01) and microbiologic infection (77% vs 8% in the intravenous antibiotic group: P < 0.0006). In a multivariate analysis adjusted for corticosteroid use, inhaled antibiotic therapy was predictive of complete clinical resolution (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.1, 37.6; P < 0.04) and eradication of causative organisms (OR 36.7; 95% CI, 3.3, 412.2; P < 0.003). In critically ill cancer patients with Gram-negative VAP, inhaled aminoglycosides were tolerated without serious toxicity and may lead to improved outcome.

Topics: Administration, Inhalation; Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Case-Control Studies; Colistin; Critical Illness; Drug Resistance; Female; Gram-Negative Bacterial Infections; Humans; Immunologic Factors; Male; Middle Aged; Neoplasms; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Retrospective Studies; Severity of Illness Index; Steroids; Treatment Outcome

The increasing frequency of infections caused by multidrug-resistant (MDR) Gram-negative bacteria has led to the reappraisal of colistimethate use.. We present a case series of critically ill pediatric patients without cystic fibrosis who received intravenous colistimethate treatment. All available relevant medical records were reviewed.. Seven children without cystic fibrosis (mean age 7.7 years; 2 female), admitted to the intensive care unit of a tertiary-care pediatric hospital in Athens, Greece, were identified to have received intravenous colistimethate during October 2004 to May 2008. MDR Acinetobacter baumannii, Pseudomonas aeruginosa, and/or Klebsiella pneumoniae were isolated from blood and/or bronchial secretions specimens in 6 of 7 reported patients. All isolates were susceptible to colistin. All 7 patients received intravenous colistimethate in a dosage of 5 mg/kg daily (divided in 3 equal doses, administered every 8 hours). Five children received colistimethate for 10 days and the remaining 2 for 2 and 23 days, respectively. The infections caused by MDR Gram-negative bacteria were improved in 6 children with microbiologically documented infections. Five of the 7 children were discharged from the ICU. The remaining 2 children died (1 of them had received colistimethate for 2 days); their death was not attributed to MDR Gram-negative infection. No nephrotoxicity or other type of toxicity of colistimethate was noted in this case-series.. Although the small number of included cases precludes any firm conclusions, our study suggests that colistimethate may have a role for the treatment of infections caused by MDR Gram-negative bacteria in critically ill pediatric patients.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Injections, Intravenous; Male

To determine clinical and microbiologic success in patients receiving adjunctive aerosolized antibiotics for the treatment of ventilator-associated pneumonia (VAP).. Retrospective medical record review.. Level I trauma intensive care unit of a large academic medical center.. Forty-nine patients (mean +/- SD age 42 +/- 19 yrs) who received aerosolized antibiotics for the treatment of a total of 60 episodes of VAP caused by Pseudomonas aeruginosa and/or Acinetobacter baumannii between January 2001 and July 2007.. Patients were identified by using an existing database of patients with documented VAP at the study center. To receive a diagnosis of VAP, patients had to have bacterial growth of 10(5) or more colony-forming units/ml from a bronchoscopic bronchoalveolar lavage and new or changing infiltrate on chest radiograph, plus at least two of the following: abnormal body temperature (> 38 degrees C or < 36 degrees C), abnormal white blood cell count (> 10 or < 4 x 10(3)/mm(3), or > 10% immature bands), or macroscopically purulent sputum. By reviewing patient data, we evaluated clinical and microbiologic success using standard definitions. The median (interquartile range) Injury Severity Score and admission Acute Physiology and Chronic Health Evaluation II score were 40 (29-45) and 17 (9-21), respectively. Pseudomonas aeruginosa, A. baumannii, or both were isolated in 45, 14, and 1 episode(s), respectively. Eighteen VAP episodes included additional bacteria. Aerosolized tobramycin, amikacin, and colistimethate were used in 44, 9, and 9 episodes, respectively. Systemic antibiotics were used in 59 (98%) of the 60 episodes. Clinical success was achieved in 36 (73%) of the 49 first episodes of VAP, 8 (73%) of 11 subsequent episodes, 17 (85%) of 20 episodes that were failing intravenous monotherapy, and 30 (79%) of 38 episodes with multidrug-resistant P. aeruginosa or A. baumannii. Microbiologic success was achieved in 29 (71%) of 41 evaluable episodes. Six patients died from VAP.. Treatment with adjunctive aerosolized antibiotics was associated with a good response rate in critically ill trauma patients with VAP due to nonfermenting gram-negative bacilli. It is noteworthy that episodes of VAP that followed intravenous therapy failure and/or that were due to multidrug-resistant organisms responded well.

Topics: Acinetobacter baumannii; Adult; Aerosols; Amikacin; Anti-Bacterial Agents; APACHE; Colistin; Critical Illness; Drug Resistance, Multiple; Female; Glasgow Coma Scale; Gram-Negative Bacteria; Humans; Male; Middle Aged; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Retrospective Studies; Tobramycin; Treatment Outcome

Tracheotomy is considered to be an independent risk factor for ventilator-associated pneumonia (VAP). Antimicrobial prophylaxis, in particular with coverage of Pseudomonas aeruginosa, is presently advocated. Selective decontamination of the digestive tract (SDD) aims to prevent VAP in critically ill patients, including those after tracheotomy. We determined the incidence and microbial spectrum of VAP after tracheotomy in a SDD-setting.. Retrospective analysis of 231 tracheotomized patients during a 2-year period.. Thirteen patients (5.6%) developed VAP. The median [IQR] day of onset was 8.0 [3.0-10.5] days after tracheotomy. The most predominant causative pathogen was Methicillin-sensitive Staphylococcus aureus (MSSA). Timing of tracheotomy was not different between patients developing VAP and those who did not. The type of tracheotomy (percutaneous or surgical, 84.6% versus 15.4%) had no significant influence on the incidence of VAP.. The incidence of VAP after tracheotomy in a SDD-setting is low, with MSSA as the predominant causative pathogen. Accordingly, if antimicrobial prophylaxis is considered, it may be advisable to cover MSSA in an SDD-setting.

Topics: Administration, Buccal; Adult; Aged; Amphotericin B; Anti-Bacterial Agents; Antibiotic Prophylaxis; Colistin; Critical Illness; Cross Infection; Decontamination; Enteral Nutrition; Female; Gastrointestinal Tract; Humans; Incidence; Intensive Care Units; Male; Methicillin; Microbial Sensitivity Tests; Middle Aged; Netherlands; Pneumonia, Ventilator-Associated; Retrospective Studies; Risk Factors; Staphylococcus aureus; Tobramycin; Tracheotomy

We sought to approach a practical question: Should polymyxins be used in the initial empirical antibiotic regimen in the intensive care unit (ICU) patient with fever that is thought to be due to infection? By retrieving data from the literature and the WHONET Greece, we formulated a mathematical model to estimate the probability (Ptotal) that a gram-negative bacterium susceptible only to polymyxins is isolated from an ICU patient. Ptotal = P1 * P2 * P3 * P4, where Ptotal = total probability; P1 = probability that fever is due to infection; P2 = probability that infection is due to gram-negative bacteria; P3 = probability that the gram-negative bacterium is Acinetobacter baumannii, Pseudomonas aeruginosa, or Klebsiella pneumoniae; and P4 = probability that A. baumannii, P. aeruginosa, or K. pneumoniae is susceptible only to polymyxins. Using the information from our data sources, we estimated that P1 (before physician input in differential diagnosis) = 0.5, P2 = 0.523, P3 = 0.79, and P4 = 0.567, thus Ptotal = P1 * P2 * P3 * P4 = 0.5 * 0.523 * 0.79 * 0.567 = 0.117 = 11.7%. Based on this information and combining it with data regarding the attributable mortality of inappropriate empirical antimicrobial treatment, 4 to 5 patients in every 100 ICU patients will die if physicians do not include polymyxins in the initial empirical regimen in the ICU setting for an episode of fever due to infection. Polymyxins should probably be included in the empirical antibiotic regimen in the ICU setting in hospitals, where the observed probability that a gram-negative bacterium (A. baumannii, P. aeruginosa, or K. pneumoniae) is polymyxin-only-susceptible is close to that (50%) used in our model (based on the individual hospital data).

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Critical Care; Critical Illness; Decision Support Techniques; Fever; Gram-Negative Bacteria; Humans; Polymyxin B; Polymyxins; Probability; Sensitivity and Specificity; Shock

Multi-drug resistant (MDR) organisms in intensive care units (ICUs) are a growing concern. The emergence of several infections with MDR Acinetobacter baumannii prompted a review of cases and evaluation of the efficacy of intervention.. To determine the rate of clinical cure, the incidence of drug resistance, and the mortality rate associated with A. baumannii infection.. Retrospective review of A. baumannii infections in three surgical ICUs between January, 2004 and November, 2005. Infection was identified in 291 patients, 20 of whom were excluded because of incomplete documentation. Of the remaining 271 patients, 71% were male, and the mean age was 47 +/- 18 years (range 13-90 years).. Patients had a mean length of stay in the ICU of 14 days (range 0-136 days) before infection. The initial positive cultures were from bronchoalveolar lavage fluid (BAL) in 72.3%, blood in 16.2%, a catheter tip in 6.3%, urine in 1.8%, wound in 2.2%, and abscess in 1.1%. In 46.9% of patients, the first culture was polymicrobial. The Acinetobacter isolates were resistant or intermediate-resistant to imipenem-cilastatin in 81.2% of cases; 19.9% were resistant to all drugs except colistin, and two were resistant to all tested drugs. Colistin was used in 75.6% of patients (intravenous 61.5%, nebulized 38.5%). The mean duration of treatment was 13 +/- 8.9 days (range 0-56 days), and clinical cure was achieved in 73.8% of patients. Recurrent infection after initial cure was found in 19.2% of patients. There was no significant difference in clinical cure rates between patients treated with colistin and those treated with other culture-directed drugs (75.1% vs. 69.7%), or between patients treated with intravenous vs. nebulized colistin (72.4% vs. 79.5%). The mortality rate was 26.2% for the entire group and was significantly higher in the subgroup of transplant patients (n = 31) (64.5% vs. 21.4%; p < 0.001).. The majority of A. baumannii isolates were MDR, and a significant proportion were sensitive only to colistin. Treatment of A. baumannii infection with colistin is effective by both intravenous and nebulized routes of administration. However, infection with A. baumannii in critically ill surgical patients is associated with a high mortality rate, particularly in transplant patients.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Florida; Hospital Mortality; Humans; Immunosuppression Therapy; Incidence; Intensive Care Units; Male; Middle Aged; Organ Transplantation; Retrospective Studies

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Rifampin; Treatment Outcome

Topics: Colistin; Critical Illness; Female; Hemodiafiltration; Humans; Middle Aged; Pseudomonas aeruginosa

To evaluate the efficiency of intratracheal colistin in preventing nosocomial bronchopneumonia (BPN) in the critically ill.. Study evaluating the clinical incidence of nosocomial BPN in 2 groups of critically ill patients who receive or did not receive intratracheal colistin. BPN was assessed clinically in survivors and histologically in non-survivors.. A 14-bed surgical intensive care unit.. 598 consecutive critically ill patients were studied during a prospective non-randomized study over a 40-month period.. 251 patients--31 non-survivors and 220 survivors--did not receive intratracheal colistin and 347-42 non-survivors and 305 survivors--received intratracheal colistin for a 2-week period (1,600,000 units per 24 h).. The incidence of nosocomial BPN was evaluated clinically in survivors, using repeated protected minibronchoalveolar lavages, and histologically in non-survivors via an immediate postmortem pneumonectomy (histologic and semi-quantitative bacteriologic analysis of one lung). The clinical incidence of nosocomial BPN was of 37% in coli (-) survivors and of 27% in coli (+) survivors (p < 0.01). This result was histologically confirmed in non-survivors, where the incidence of histologic BPN was of 61% in coli (-) patients and of 36% in coli (+) patients (p < 0.001). Emergence of BPN due to colistin-resistant micro-organisms was not observed. Because colistin was successful in preventing Gram-negative BPN and did not change the absolute number of Gram-positive BPN, the proportion of BPN caused by staphylococcus species was higher in group coli (+) patients (33% vs 16%). Mortality was not significantly influenced by the administration of colistin.. This study suggests that the administration of intratracheal colistin during a 2-week period significantly reduces the incidence of Gram-negative BPN without creating an increasing number of BPN due to colistin-resistant micro-organisms.

Topics: Aged; Bronchoalveolar Lavage Fluid; Colistin; Critical Illness; Cross Infection; Drug Evaluation; Drug Resistance, Microbial; Female; Gram-Negative Bacterial Infections; Humans; Incidence; Instillation, Drug; Intubation, Intratracheal; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonectomy; Pneumonia; Prospective Studies; Respiration, Artificial; Survival Rate