Use Of Colistin In Patients Research Articles

Inhaled Colistimethate Sodium in the Management of Patients with Bronchiectasis Infected by Pseudomonas aeruginosa: A Narrative Review of Current Evidence.

International guidelines on the treatment of bronchiectasis indicate that the use of inhaled antibiotics is effective, especially in symptomatic chronic bronchial infection (CBI) due to Pseudomonas aeruginosa (PA). To date, however, no such treatment has been approved by regulatory agencies. Of the inhaled antibiotics on the market, colistimethate sodium (colistin) is one of the most used in many countries, either in its nebulized presentation or as dry powder. Among the characteristics of this antibiotic, it is worth noting that its main target is the lipopolysaccharide in the outer membrane of the cell wall of gram-negative bacteria and that it has a low rate of resistance to PA (<1%). Most observational studies have shown that the use of colistin in patients with bronchiectasis and CBI due to PA results in a decrease in both the number and severity of exacerbations, an improvement in quality of life, a decrease in sputum volume and purulence, and a high rate of PA eradication, although there are no clear differences with respect to other inhaled antibiotics. However, the lack of randomized clinical trials (RCT) with positive results for its main variable (exacerbations) in an intention-to-treat analysis has prevented its approval by regulatory agencies as a formal indication for use in bronchiectasis. The PROMIS program, made up of two RCT with identical methodology, is currently underway. The first of these RCT (already concluded) has demonstrated a clearly positive effect on the group randomized to colistin in its main variable (number of annual exacerbations), while the results of the second are still pending. This review presents exhaustive information on the pharmacological and microbiological characteristics of colistin, the results of the studies carried out to date, and the future challenges associated with this treatment.

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m2 for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45–95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2–2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

Colistin Use in Patients with Extreme Renal Function: From Dialysis to Augmented Clearance

Background and objectives: Colistin is used for the treatment of multidrug-resistant (MDR) Gram-negative bacteria infection in critically ill patients. It is recommended to adjust the dose in cases of renal impairment but not in cases of augmented renal clearance (ARC). The aim of this study was to determine colistin use pattern in patients with different renal functional states. Materials and Methods: Adult patients admitted to intensive care units of single Latvian hospitals in the years 2015–2017 with an MDR Gram-negative bacterial infection and at least 72 h colistin therapy were included in this study. Data were collected retrospectively from medical notes. Colistin use pattern and outcomes were analyzed in patients with different renal function prior to colistin therapy: normal, ARC, impaired, and on renal replacement therapy (RRT). Results: 100 cases of colistin use met the inclusion criteria. The study group was heterogeneous, and patients had different renal function states prior to colistin therapy-from continuous RRT (18 cases) to ARC (16 cases). The standard colistin dose of 9 million units (MU) daily was the most common dose among the patients. In many cases (43%), colistin dose adjustment did not follow the recent recommendations of drug manufacturers-this was mainly in patients with renal impairment prior to colistin therapy. Eighteen cases of colistin acute kidney injury (AKI) were detected, mostly (10 cases) in patients with normal renal function and without ARC prior to colistin therapy. No patients with colistin AKI needed RRT. Conclusions: Colistin doses varied greatly among patients, and in patients with renal function impairment it was commonly not in accordance with the summary of product characteristics (SPC). Patients with ARC mostly received a standard colistin daily dose of 9 MU daily, but the cumulative dose had a tendency to be higher and duration of colistin therapy was longer in comparison with other patient groups. ARC’s role in the development of colistin nephrotoxicity is still unclear.

Patterns of Infection and Mortality Associated with Intensive AML Induction Therapy: 10 Year Experience from a Tertiary Cancer Centre in India

Introduction: The treatment of acute myeloid leukaemia (AML) with intensive induction regimens remains a challenge in low and middle incomes countries. Early induction related deaths particularly due to infectious complications are a major problem. This is in stark contrast to high-income countries where induction mortality has declined significantly over the last 2 decades with improved antibiotic use and supportive care. In this study we assess induction mortality (all cause and infection related) in AML patients who received intensive induction therapy in a tertiary cancer centre in India over a 10-year period (2008-2017).Methods: We included patients with newly diagnosed AML treated at Cancer Institute, Chennai in South India who received intensive induction therapy. Intensive therapy was defined as use of any anthracycline with cytarabine (3+7/ADE/others). We assessed baseline demographics including age, gender, cytogenetic risk status, and type of induction regimen used. We also assessed key clinical outcomes including patterns of antimicrobial prophylaxis and treatment, infectious complications, cause of death, ICU stay, and length of hospital stay. Induction mortality was defined as deaths occurring within 45 days of initiating treatment for AML or start of 2nd induction.Results: Between January 2008 and December 2017, 510 patients with AML were evaluated at Cancer Institute, Chennai and accepted for treatment. Excluding 51 patients with APML and 55 patients who were unfit for intensive induction, 404 patients received treatment with an intensive induction regimen. Median age was 23 years (Range: 1-74 years) and 219 (54.2%) were male patients. 165(40.8%) patients were less than 18 years of age. Among those who had cytogenetic and/ molecular data for risk stratification [N=341 (84.7%)], 101 (29.6%) were low risk, 166 (48.7%) intermediate risk and 74 (21.7%) high risk. Therapy details: 318 (78.7%) patients received daunorubicin and cytarabine (‘3+7‘), 52 (12.9%) received ADE, and 38 (8.4%) received other combinations ofdaunorubicin and cytarabine.87(21.5%) of the cases had infection at the time of presentation. 389(96.8%) had an episode of febrile neutropenia with 184(45.5%) requiring management in Intensive Care Unit (ICU). Focus of infection could be identified in 294(72.7%) of the patients with 207(51.2%) having a positive culture.The overall incidence of induction mortality over the entire study period was 15.6%(n=63)and 14.8% for the most recent year included (2017). The majority of the deaths (n=53; 84.1%) were due to infectious complications (fig1). Median time to death from start of induction was 19 days. The incidence of fungal pneumonia significantly reduced since 2012 when thethe antifungal prophylaxis was switched from fluconazole to voriconazole (p=0.03). Starting in 2012, an increase in the incidence of multi-drug resistance (MDR) gram negative septicaemia and mortality (MDR: carbapenem resistant enterobacteriaceasensitive only to colistin and tigecycline) was noted. This led to proactive use of colistin in patients with febrile neutropenia and septic shock, a GI focus or baseline stool colonisation by MDR gram negative organisms.Despite this, during the last 4 years(2014-2017), there has been a significant rise in the incidence of sepsis and death due to MDR gram negative organisms (fig2). The proportion of deaths attributable to MDR sepsis is 23.8%. The early use of colistin, tigecycline and carbapenems did not significantly decrease the mortality.Conclusions: The induction mortality remains high at 15.6% and is in contrast to the declining induction mortality in high-income countries. While the morbidity and mortality due to specific infections (specifically fungal pneumonia) have changed over time, there is no signfiicant decline in infectious or all cause induction mortality over the 10 years. In the last four years, MDR gram negative sepsis has been a major cause of morbidity and mortality. The early and increased use of broad spectrum antibiotics like tigecycline, colistin and carbapenems has not led to a decrease in MDR gram negative sepsis. Overall, despite improvements in supportive care and early use of broad spectrum antimicrobial agents, infection related morbidity and mortality remains a substantial challenge in treating acute myeloid leukaemia in low- and middle-income countries. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Colistin Use in Patients With Reduced Kidney Function.

Colistin (polymyxin E) is a mainly concentration-dependent bactericidal antimicrobial active against multidrug-resistant Gram-negative bacteria. After being abandoned over the past 30 years due to its neuro- and nephrotoxicity, colistin has been reintroduced recently as a last-resort drug for the treatment of multidrug-resistant Gram-negative bacteria infections in combination with other antimicrobials. Unfortunately, although renal toxicity is a well-known dose-related adverse effect of colistin, relatively few studies are currently available on its peculiar pharmacodynamic/pharmacokinetic properties in clinical settings at high risk for drug accumulation, such as acute or chronic kidney disease. In these specific contexts, the risk for underdosing is also substantial because colistin can be easily removed by dialysis/hemofiltration, especially when the most efficient modalities of renal replacement therapy (RRT) are used in critically ill patients. For this reason, recent recommendations in patients undergoing RRT have shifted toward higher dosing regimens, and therapeutic drug monitoring is advised. This review aims to summarize the main issues related to chemical structure, pharmacodynamics/pharmacokinetics, and renal toxicity of colistin. Moreover, recent data and current recommendations concerning colistin dosing in patients with reduced kidney function, with special regard to those receiving RRT such as dialysis or hemofiltration, are also discussed.

Risk Factors for Colistin-Associated Acute Kidney Injury: A Multicenter Study from Turkey.

The aim of this study was to investigate the incidence of acute kidney injury (AKI) and risk factors due to colistin use in patients infected with multidrug-resistant pathogens. This multicenter, retrospective, observational study was conducted in Turkey, at 5 different research and university hospitals. Cox regression analyses were performed, to determine independent predictors of AKI. From April 2012 to July 2014, a total of 216 patients aged between 18-94 years, treated with colistimethate sodium (CMS) were included in the study. The mean age of the patients was 60.3 ± 20.1 years. The overall incidence of AKI was 34.3% (74/216) at any time during treatment. Concomitant use of loop diuretics, baseline creatinine level, and CMS dosage were independently associated with AKI. According to our results, patients with higher baseline creatinine levels, or patients who had to use concomitant loop diuretics may need to be monitored more closely, and dose adjustment should be done promptly. More comprehensive studies are, however, still needed to evaluate the efficacy of low-dose colistin since higher doses tend to increase the risk of AKI.

Resurgence of colistin use

The role of colistin in the treatment of infections caused by multidrug-resistant gram-negative microorganisms is discussed. Colistin is structurally and pharmacologically related to polymyxin B, the other commercially available drug from the polymyxin class. Colistin is bactericidal in nearly all strains of gram-negative bacilli. As with all antibiotics, resistance is of paramount concern. Resistance to colistin has not been frequently documented. Colistin must be administered parenterally, as it is not absorbed from the gastrointestinal tract, mucous membranes, or intact or denuded skin. Parenteral colistin has been replaced by less-toxic antibiotics and should be reserved for life-threatening infections caused by organisms resistant to preferred drugs. A number of published studies and case reports have reevaluated the safety and efficacy of parenteral colistin use in patients with multidrug-resistant infections. In three case series, 58-74% of patients exhibited a clinical response to colistin. Although colistin was previously viewed as reasonably effective but highly nephrotoxic, recent studies have suggested that nephrotoxicity may not be as severe as once thought. Frequent renal function monitoring is necessary in patients receiving colistin, since adverse renal effect may occur, regardless of the dosage given. The recommended dosage of parenteral colistin for adults and children with normal renal function is 2.5-5 mg/kg/day, administered as two to four divided doses. Doses must be adjusted for renal impairment, and dosing recommendations for patients undergoing renal replacement therapy have not been well established. With vigilant monitoring of renal function and the avoidance of concomitant neurotoxic medications, colistin can be used safely and effectively with minimal adverse outcomes.

The clinical use of colistin in patients with cystic fibrosis

Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled colistin therapy to identify sensitized individuals. Judicious use of colistin where the benefits have been clearly documented will retain this as a useful agent in the management of P. aeruginosa infections in patients with cystic fibrosis.