Colistin Therapy Research Articles

The potential role of adjunctive ascorbic acid in the prevention of colistin-induced nephrotoxicity in critically ill patients: A retrospective study

BackgroundColistin is considered a valuable and last-resort therapeutic option for MDR gram-negative bacteria. Nephrotoxicity is the most clinically pertinent adverse effect of colistin. Vivo studies suggest that administering oxidative stress-reducing agents, such as ascorbic acid, is a promising strategy to overcome colistin-induced nephrotoxicity (CIN). However, limited clinical data explores the potential benefit of adjunctive ascorbic acid therapy for preventing CIN. Therefore, this study aims to assess the potential nephroprotective role of ascorbic acid as adjunctive therapy against CIN in critically ill patients. MethodThis was a retrospective cohort study at King Abdulaziz Medical City (KAMC) for all critically ill adult patients who received IV colistin. Eligible patients were classified into two groups based on the ascorbic acid use as concomitant therapy within three days of colistin initiation. The primary outcome was CIN odds after colistin initiation, while the secondary outcomes were 30-day mortality, in-hospital mortality, ICU, and hospital LOS. Propensity score (PS) matching was used (1:1 ratio) based on the patient’s age, SOFA score, and serum creatinine. ResultsA total of 451 patients were screened for eligibility; 90 patients were included after propensity score matching based on the selected criteria. The odds of developing CIN after colistin initiation were similar between patients who received ascorbic acid (AA) as adjunctive therapy compared to patients who did not (OR (95 %CI): 0.83 (0.33, 2.10), p-value = 0.68). In addition, the 30-day mortality, in-hospital mortality, ICU, and hospital LOS were similar between the two groups. ConclusionAdjunctive use of Ascorbic acid during colistin therapy was not associated with lower odds of CIN. Further studies with a larger sample size are required to confirm these findings.

Preferential Selection of Low-Frequency, Lipopolysaccharide-Modified, Colistin-Resistant Mutants with a Combination of Antimicrobials in Acinetobacter baumannii.

ABSTRACTColistin, which targets lipopolysaccharide (LPS), is used as a last-resort drug against severe infections caused by drug-resistant Acinetobacter baumannii. However, A. baumannii possesses two colistin-resistance mechanisms. LPS modification caused by mutations in pmrAB genes is often observed in clinical isolates of multidrug-resistant Gram-negative pathogens. In addition to LPS modification, A. baumannii has a unique colistin resistance mechanism, a complete loss of LPS due to mutations in the lpxACD genes, which are involved in LPS biosynthesis. This study aimed to elucidate the detailed mechanism of the emergence of colistin-resistant A. baumannii using strains with the same genetic background. Various colistin-resistant strains were generated experimentally using colistin alone and in combination with other antimicrobials, such as meropenem and ciprofloxacin, and the mutation spectrum was analyzed. In vitro selection of A. baumannii in the presence of colistin led to the emergence of strains harboring mutations in lpxACD genes, resulting in LPS-deficient colistin-resistant strains. However, combination of colistin with other antimicrobials led to the selection of pmrAB mutant strains, resulting in strains with modified LPS (LPS-modified strains). Further, the LPS-deficient strains showed decreased fitness and increased susceptibility to many antibiotics and disinfectants. As LPS-deficient strains have a higher biological cost than LPS-modified strains, our findings suggested that pmrAB mutants are more likely to be isolated in clinical settings. We provide novel insights into the mechanisms of resistance to colistin and provide substantial solutions along with precautions for facilitating current research and treatment of colistin-resistant A. baumannii infections.IMPORTANCE Acinetobacter baumannii has developed resistance to various antimicrobial drugs, and its drug-resistant strains cause nosocomial infections. Controlling these infections has become a global clinical challenge. Carbapenem antibiotics are the frontline treatment drugs for infectious diseases caused by A. baumannii. For patients with infections caused by carbapenem-resistant A. baumannii, colistin-based therapy is often the only treatment option. However, A. baumannii readily acquires resistance to colistin. Many patients infected with colistin-resistant A. baumannii undergo colistin treatment before isolation of the colistin-resistant strain, and it is hypothesized that colistin resistance predominantly emerges under selective pressure during colistin therapy. Although the concomitant use of colistin and carbapenems has been reported to have a synergistic effect in vitro against carbapenem-resistant A. baumannii strains, our observations strongly suggest the need for attention to the emergence of strains with a modified lipopolysaccharide during treatment.

In Vitro Activity of Single and Combined Antibiotics against Carbapenem Resistant Enterobacteriaceae Clinical Isolates in Relation to their Resistance Genes

Background: Mortality due to infection with carbapenem-resistant Enterobacteriaceae (CRE) is reported globally and carbapenemase production is the main mechanism of resistance in these isolates. The detection and treatment of carbapenemase-producing Enterobacteriaceae (CPE) is a major challenge in health care facilities.
 Objectives: The aim of the current study was to evaluate the in-vitro effect of different single and combined antibiotic agents against CRE clinical isolates.
 Methodology: Fifty CRE isolates were detected using disk diffusion test as a screening test. Species identification and antibiotic susceptibility testing was done using Vitek 2 system. Carbapenemase enzyme production was confirmed by Carba NP test. Multiplex PCR was done to detect carbapenem resistance genes. Antibiotics were tested in the form of single agents (colistin and tigecycline) and combined (tigecycline/ colistin, doripenem/ colistin and dual carbapenem therapy (ertapenem and doripenem) against CRE isolates using E-test method.
 Results: Most of the CRE isolates were K. pneumoniae, 68%, followed by E. coli, 22%, S. marcescens, 4%, E. cloacae, 4% and C. freundii, 2%. CPE was confirmed in 46 isolates by multiplex PCR; blaNDM-like was the main carbapenem resistance gene in (84%) of the isolates, followed by blaOXA-48-like (6%) and blaKPC-like (2%). Carba NP test detected 90% of CPE isolates. Single use of colistin and tigecycline showed 100% sensitivity against all tested CRE isolates except in blaNDM-like (83%). Combination of colistin/tigecycline showed synergetic activity in 18% of CRE that was correlated to their carbapenemase R genes showing a significant increase in blaOXA-48-like and blaKPC-like positive isolates (100%) compared to blaNDM-like (7%). Other combinations showed indifferent effect whereas antagonism was not detected in any of the tested combinations.
 Conclusions: blaNDM-like is the main carbapenemase-producing gene detected among our CPE isolates followed by blaOXA-48-like. Colistin and tigecycline are still effective when used as single agents, and may offer effective treatment options when used in combination for CRE infections. Characterization of carbapenemases is crucial in determining treatment options. There is urgent demand for the development of novel therapeutic agents against NDM-producing CPE isolates.

Colistin Monotherapy versus Colistin plus Meropenem Combination Therapy for the Treatment of Multidrug-Resistant Acinetobacter baumannii Infection: A Meta-Analysis

(1) Introduction: Colistin combination therapy with other antibiotics is a way to enhance colistin activity. The purpose of this meta-analysis was to compare the efficacy and safety of treatment with colistin monotherapy versus colistin plus meropenem combination therapy in patients with drug-resistant Acinetobacter baumannii infection. (2) Methods: All studies were included if they reported one or more of the following outcomes: clinical improvement, complete microbiological response, 14-day mortality, hospital mortality, or nephrotoxicity. (3) Results: Three randomized controlled trials and seven retrospective studies were included in the meta-analysis. Colistin monotherapy has similar rates of clinical improvement, 14-day mortality, hospital mortality, and nephrotoxicity as colistin plus meropenem combination therapy. Regarding complete microbiological response, the colistin plus meropenem combination was better than colistin monotherapy. (4) Discussion: Previous meta-analyses demonstrated heterogeneity in study quality and a lack of evidence supporting the use of colistin-based combination therapy. Our meta-analysis clearly showed that colistin combined with meropenem was not superior to colistin monotherapy for the treatment of Acinetobacter baumannii infection. (5) Conclusions: The efficacy and safety of treatment with colistin monotherapy and that of colistin plus meropenem combination therapy in patients with drug-resistant Acinetobacter baumannii infection were comparable. The majority of the evidence was obtained from nonrandomized studies, and high-quality randomized controlled trials are needed to confirm the role of colistin plus meropenem combination therapy in the treatment of multidrug-resistant Acinetobacter baumannii infection.

Use of polymyxins for carbapenem-resistant infections in children and adolescents.

BackgroundPolymyxins are still used in children in some regions due to limited availability of newer antibiotics.ObjectivesTo describe our experience in a cohort of children who received polymyxins for suspected or confirmed carbapenem-resistant bacterial infections (CRI), and explore potential factors associated with therapeutic success.MethodsRetrospective, observational study in children and adolescents <18 years who received IV polymyxin B or colistin therapy for suspected or culture-documented CRI and were admitted to a high complexity clinic in Cali, Colombia between 1 September 2016 and 22 June 2020. Patients’ demographic, clinical and microbiological characteristics were collected and analysed; associations with therapeutic success were explored using univariate and multivariate models.ResultsThere were 40 episodes of polymyxin use (polymyxin B, n = 34; colistin, n = 6) in 34 patients with a median age of 10 years (IQR 7–15); 65% were male. There were 17 adverse events: 3 (17.6%) neurotoxic and 14 (82.4%) nephrotoxic. Therapeutic success was achieved in 28 episodes (70%), of which 32% (9/28) had adverse events. Therapeutic success decreased by 35% with each additional year of age (OR 0.65; 95% CI 0.49–0.80) and by 7% for every hour that elapsed between the onset of fever and the start of appropriate antibiotic therapy (OR 0.93; 95% CI 0.8–0.97) and increased with concomitant non-carbapenem treatment (OR 6.87; 95% CI 1.04–71.01) and the use of adequate empirical therapy (OR 121.36; 95% CI 2.90–1147.95).ConclusionsSeveral factors were associated with the therapeutic success of polymyxins, however, more than half of episodes had therapeutic failure or adverse events. Antibiotics with greater efficacy and safety are needed in regions with high rates of CRI.

Colistin Therapy, Survival and Renal Replacement Therapy in Burn Patients: A 10-Year Single-Center Cohort Study.

PurposeColistin is still a therapeutic cornerstone against multidrug-resistant gram-negative bacteria (MDRGN), mostly when other antibiotics do not gain adequate activity on these strains. In the present study, we evaluated in a cohort of burn patients the relationship between colistin therapy, survival and requirement of renal replacement therapy (CRRT).Patients and MethodsRetrospective study of 133 burn patients treated with iv colistimethate sodium (loading dose 9.0 × 106 IU, maintenance dose 4.5 × 106 IU BID) and 35 treated with other antibiotics for MDRGN infection including Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae between January 2008 and December 2017. Multivariate analysis with logistic regression was used to determine the effect of the predictors such as age, total body surface area (TBSA), third-degree burn areas, Revised Baux score, Charlson comorbidity score, length of stay, colistin dose and duration of treatment, mechanical ventilation, and need of CRRT on in-hospital mortality. To investigate the relationship between colistin and renal function, we focused on survivor patients as the completion of the therapeutic course of colistin represented the basic requirement to analyze its impact on the kidney.ResultsOut of 133 colistin- and 35 other antibiotics-treated patients, 83 (62.4%) and 31 (88.6%) survived, and 53 (39.8%) and 3 (9.7%) required CRRT, respectively. The severity of burns, as well as CRRT requirement and mortality, was significantly higher in colistin-treated patients than in other antibiotics-treated patients. Age and TBSA% were the significant predictors of mortality. Out of 83 colistin-treated survivors, 19 (22.9%) required CRRT (9 before and 10 after the start of colistin), and 64 (77.1%) had a normal renal function. No difference about the colistin dose and baseline characteristics, but the revised Baux score was found between the 9 patients requiring CRRT before the colistin course and the 10 patients after. Similarly, among the 64 patients not undergoing CRRT, no difference was found between the patients treated with the cumulative dose of colistin <99.0 × 106 IU (n = 33, median daily dose of 4.0 × 106 IU) and >99.0 × 106 IU (n = 31, median daily dose of 9.0 × 106 IU) about the baseline characteristics and the daily median plasma creatinine over 24 days of therapy.ConclusionColistin therapy was associated with more severe burns, mortality, and CRRT requirement. A short course therapy, at appropriate cumulative dosage, can lead to clinical success without a significant association with severe renal impairment.

Pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following nebulisation of CMS among patients with ventilator-associated pneumonia

There has been accumulating interest in nebulised colistin methanesulfonate (CMS) for the treatment of ventilator-associated pneumonia (VAP). In this study, pulmonary and systemic pharmacokinetics following nebulisation of CMS at a dose of 3 MIU and 5 MIU, using a vibrating mesh nebuliser, for VAP caused by extensively drug-resistant Gram-negative pathogens was assessed. Blood samples and mini-bronchoalveolar lavage (mini-BAL) was performed post-dose at 1, 4 and 8 h. Concentrations of CMS and formed colistin in mini-BAL and plasma were determined by liquid chromatography–tandem mass spectrometry, and pharmacokinetic analysis was conducted using a population approach. The study population included three groups (n = 10 per group): (A) intravenous CMS and concomitantly nebulised CMS at a dose of 3 MIU (30 min duration); (B) nebulised CMS at a dose of 3 MIU (30 min duration) as monotherapy; and (C) nebulised CMS 5 MIU (45 min duration) as monotherapy. Mean plasma formed colistin concentrations were <1 mg/L following CMS nebulisation as monotherapy (groups B and C). Predicted trough concentrations of formed colistin in the epithelial lining fluid (ELF) following 24-h dosing of 3 MIU and 5 MIU nebulised CMS were 120.4 mg/L and 200.7 mg/L, respectively. The model predicted that concomitant intravenous CMS (group A) had minimal impact on the formed colistin concentration in ELF. This study demonstrated high ELF formed colistin concentrations following nebulised CMS (constantly above colistin MICs), while plasma concentrations were lower than those associated with nephrotoxicity. Our results provide important information for optimisation of nebulised colistin therapy.

Colistin-induced pulmonary toxicity involves the activation of NOX4/TGF-β/mtROS pathway and the inhibition of Akt/mTOR pathway

Colistin therapy can cause pulmonary toxicity, however, our understanding of the underlying molecular mechanism remains incomplete. This study aimed to investigate the molecular mechanism of colistin-induced pulmonary toxicity in vitro and in vivo. Our results showed that intraperitoneal colistin treatment significantly increased the expression of TGF-β and NOX4 protein and mRNA, then triggers oxidative stress, mitochondrial dysfunction, and apoptosis in the lung tissue of mice and A549 cells. Moreover, colistin treatment significantly increased levels of mitochondrial ROS (mtROS) and autophagy flux in A549 cells. Inhibition of NOX4 protected A549 cells against colistin-induced mtROS and apoptosis. Colistin treatment also down-regulated the expression of p-Akt and p-mTOR proteins (all P < 0.05 or 0.01) in lung tissues of mice or A549 cells. Inhibition of autophagy or Akt pathways by chloroquine (CQ), 3-Methyladenine (3-MA) or LY294002 promoted colistin-induced mitochondrial damage, and caspase-dependent cellular apoptosis. Whereas, activation of autophagy by rapamycin pretreatment of A549 cells partly abolished colistin-induced cytotoxicity, mitochondrial dysfunction, and apoptosis. This is first study to show that colistin-induced pulmonary toxicity involves the activation of TGF-β/NOX4/mtROS pathway and the inhibition of Akt/mTOR pathway in lung tissues of mice and highlights the key protective role of autophagy activation.

Efficacy and safety of Colistin-Imipenem/Cilastatin combination Therapy for Multidrug-Resistant Gram-Negative Bacteria Infections in Critically Ill Pediatric Patients

Purpose: The aim of this study was to ensure the safety and efficacy of intravenous administration of colistin-imipenem/cilastatin combination to critically ill pediatrics suffering from multidrug-resistant gram-negative sepsis. Patients and methods: The study was designed to give sixty patients in Al-Demerdash hospital pediatric intensive care units (PICU), Ain Shams University, Cairo, Egypt, either imipenem/cilastatin as a monotherapy (thirty patients) or colistin-imipenem/cilastatin intravenously as a combination (thirty patients). The interventional prospective randomized study was performed with focusing on patients' hemodynamic parameters, vital signs, sepsis markers and microbiological response. Results: Thirty patients received intravenous colistin-imipenem/cilastatin combination; with median age of 8.5 months (range: 1-36 months). The isolated bacteria were Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. Klebsiella pneumoniae was the most common isolate (51.7%) of the overall examined sixty patients. Patient who received the combination therapy, was associated with improving in vital signs and hemodynamic parameters with significant p = 0.001, and microbiological responses were represented by the recorded cultures. No patients were defined by renal impairment or neurological toxicity as a side effect to colistin therapy. However, non-significant differences in fatality was found among the two groups with p = 0.108. Conclusion: Colistin combination therapy resulted in better clinical outcomes of PICU patients, which were represented by eradication of the multidrug-resistant gram-negative bacteria without noticeable nephrotoxicity.

Molecular and Phenotypic Characterization of a Multidrug-Resistant Escherichia coli Coproducing OXA-232 and MCR-1.1 in Argentina

The spread of carbapenem-resistant Enterobacterales has raised concern in clinical settings due to the limited therapeutic options available. OXA-48-like enzymes are still sporadic in South America. The aim of this study was to characterize a multidrug-resistant Escherichia coli isolate from a hospitalized patient in Buenos Aires city. The isolate was characterized phenotypically by determination of its susceptibility pattern, synergistic and colorimetric tests, and molecularly, by PCR, whole genome sequencing, and plasmid analysis. It belonged to ST-744, phylogroup A, and serotype O162/O89: H9. It remained susceptible to ceftazidime, meropenem, aminoglycosides, trimethoprim/sulfamethoxazole, and tigecycline. The presence of blaOXA-232 harbored by a nonconjugative plasmid ColKp3, and blaCTX-M-14, mcr-1.1, and fosL1 in 2 conjugative plasmids, together with their genetic environment, was revealed. To the best of our knowledge, this is the first report of the coproduction of the enzyme OXA-232 and the mcr-1.1 gene in an E. coli clinical isolate in South America in a patient who had not received colistin therapy.

Intrathecal/Intraventricular Colistin for Antibiotic-Resistant Bacterial CNS Infections in Pediatric Population: A Systematic Review.

Central nervous system (CNS) infections constitute a life-threatening condition, especially in children. Treatment limitations exist for drug-resistant CNS bacterial infections. Inadequate CNS penetration and intravenous (IV) antibiotic treatment failure represent a major clinical challenge. However, patients with antibiotic-resistant bacterial CNS infections may benefit from intrathecal (IT) or intraventricular (IVT) colistin. The authors aimed to assess the safety and effectiveness of IT/IVT colistin therapy in the pediatric population, with or without other antibiotics, for the treatment of antibiotic-resistant CNS infections. A comprehensive literature search was conducted using the electronic databases of PubMed, Ovid, and Embase for relevant articles using the following terms: “Colistin”, “CNS infection”, and “Outcome”, as well as their combinations. The retrieved articles were filtered by age (Child), language (English), route of administration (IT/IVT), and species (Humans). The present systematic review comprised 20 articles that included 31 children (19; 61.2% were boys) with multidrug-resistant CNS infection. Their ages ranged from less than one month to 18 years (median: 9 months). Acinetobacter baumannii was the main causative organism in 22 patients (70.9%), and infection occurred mainly after neurosurgical interventions (83.8%). An external ventricular drain was inserted to administer colistin into the ventricular system in 29 cases (93.5%). The median duration for colistin therapy was 18 days. Twenty-three patients (74%) recovered, while five patients (16%) had residual disability, and three patients (10%) died. The authors concluded that IT/IVT colistin therapy is safe and effective as either the primary or adjunct treatment for antibiotic-resistant cases with CNS infection.

Asymptomatic Eosinophilia Induced by Systemic Colistin Therapy: A Brief Case Report

Colistin is a polymyxin group antibiotic, and colistimethate-sodium is the prodrug form of colistin and is inactive. Colistin is often the last optional drug for nosocomial infections caused by multidrug-resistant gram-negative microorganisms. We present a case of asymptomatic eosinophilia due to systemic colistin therapy. The increasing trend of absolute eosinophil counts appeared with recurrent colistin therapy and decreased when colistin was discontinued. The Naranjo Adverse Drug Reaction Probability Scale score was 7, and this score was classified as 'probable' for this case. Clinicians should consider this drug reaction in a patient with eosinophilia and avoid unnecessary laboratory tests and treatments.

A multi-state model for kidney disease progression

BackgroundUnderstanding the progression of kidney disease is of great interest among clinicians. The multi-state model is an adequate tool to model the effects of covariates that influence the onset, progression, and regression of kidney function. ObjectiveThe goal of the present study is to propose a stochastic model for kidney disease progression and to demonstrate the application of the same. MethodologyWe proposed a semi-parametric continuous time homogeneous multi-state Markov model for the kidney disease progression data obtained from a retrospective study of 225 patients prescribed with colistin (a re-emerging antibiotic) in a tertiary care hospital in coastal Karnataka. Different stages of kidney disease were defined based on the Kidney Disease Improving Global Outcome (KDIGO) score. The model consists of three transient states, and an absorbing state death. Covariate effects on the bidirectional transition rates were estimated using the multi-state model. ResultsWe used the data of 225 patients to see their kidney disease progression. All the patients were under colistin therapy. The median length of hospital stay was 21 days. A total of 83 (36.89%) patients died in the hospital. The prognostic factors such as gender, hypertension, sepsis, and surgery are significant factors affecting kidney disease in different stages. ConclusionThe findings of the study will be useful for public health policymakers to implement the policies and treatment plans to improve the survival of the patients. Moreover, modelling the disease progression helps in understanding the expected burden of the disease.

Characteristics, Influencing Factors, Predictive Scoring System, and Outcomes of the Patients with Nephrotoxicity Associated with Administration of Intravenous Colistin.

Multidrug-resistant Gram-negative infection is a major global public health threat. Currently, colistin is considered the last-resort treatment despite its nephrotoxicity. The purpose of this study was to estimate the incidence, characteristics, and influencing factors and to develop a prediction model for colistin-associated nephrotoxicity. A retrospective study was conducted in the university hospital in the South of Thailand from December 2015 to June 2019. A total of 381 patients (median age (IQR) of 64 (51–62) years) were analyzed. Overall, 282 (74%) had nephrotoxicity according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification. In-hospital, 30-day mortality rates and cost of hospital admission were significantly higher among those with nephrotoxicity. Age > 60 years, comorbidities, serum albumin less than 3.5 g/dL, and concomitant nephrotoxic use were significantly associated with colistin-associated nephrotoxicity with adjusted OR (95% CI) 2.01 (1.23–2.45), 1.85 (1.18–3.6), 1.68 (1.09–2.99), and 1.77 (1.10–2.97), respectively. The prediction model for high-risk colistin-associated nephrotoxicity was identified with good overall performance (specificity of 79.6% (95% CI 70.3–87.1) and positive predictive value of 92.1% (95% CI 88.0–95.1)). In conclusion, the incidence of colistin-associated nephrotoxicity was high and incurred significant morbidity, mortality, and economic burden. Our predictive scoring system is relatively simple and useful for optimizing colistin therapy.

Outcomes and Risk Factors of Critically Ill Patients with Hematological Malignancy. Prospective Single-Centre Observational Study.

Background and Objectives: Oncohematological patients have a high risk of mortality when they need treatment in an intensive care unit (ICU). The aim of our study is to analyze the outcomes of oncohemathological patients admitted to the ICU and their risk factors. Materials and Methods: A prospective single-center observational study was performed with 114 patients from July 2017 to December 2019. Inclusion criteria were transfer to an ICU, hematological malignancy, age >18 years, a central line or arterial line inserted or planned to be inserted, and a signed informed consent form. Univariate and multivariable logistic regression models were used to evaluate the potential risk factors for ICU mortality. Results: ICU mortality was 44.74%. Invasive mechanical ventilation in ICU was used for 55.26% of the patients, and vasoactive drugs were used for 77.19% of patients. Factors independently associated with it were qSOFA score ≥2, increase of SOFA score over the first 48 h, mechanical ventilation on the first day in ICU, need for colistin therapy, lower arterial pH on arrival to ICU. Cut-off value of the noradrenaline dose associated with ICU mortality was 0.21 μg/kg/min with a ROC of 0.9686 (95% CI 0.93–1.00, p < 0.0001). Conclusions: Mortality of oncohematological patients in the ICU is high and it is associated with progression of organ dysfunction over the first 48 h in ICU, invasive mechanical ventilation and need for relatively low dose of noradrenaline. Despite our findings, we do not recommend making decisions regarding treatment limitations for patients who have reached cut-off dose of noradrenaline.

Colistin induced acute kidney injury in critically ill children: a prospective study utilizing RIFLE criteria.

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 48h 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 4.5months. 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 ± 7.51days. 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.

Evaluation of mortality and acute kidney injury by KDIGO and RIFLE in patients treated with colistin in the intensive care unit

Introduction: Multidrug-resistant bacterial infections such as pseudomonas aeruginosa, acinetobacter baumannii, klebsiella pneumoniae are common in Intensive Care Units. Colistin is preferred today due to limited treatment options sensitive to these pathogens. However, colistin has a high potential for nephrotoxicity. Some classifications (KDIGO, RIFLE, AKIN) are used for the diagnosis of Acute Kidney Injury (AKI). The incidence of AKI varies according to these classifications. In our study, we aimed to evaluate and compare the development of Acute Kidney Injury according to KDIGO criteria and RIFLE classification in patients followed up in the intensive care unit and started colistin therapy. &#x0D; Materials and Methods: The data of 145 patients who started colistin treatment in the Internal Medicine Intensive Care Unit between January 2016 and December 2019 were retrospectively reviewed. Patients were grouped as those with Acute Kidney Injury and those without. Acute Kidney Injury evaluation was made according to RIFLE classification and KDIGO criteria. &#x0D; Results: In patients who received colistin treatment, 75 patients were evaluated as AKI when KDIGO criteria were used for the AKI diagnosis, and 54 patients were evaluated as AKI when the RIFLE classification was used. While the number of KDIGO Stage 1 patients was 44, the number of patients in the RIFLE classification risk group was determined as 23. The mean SOFA score was calculated as 7.91±2.8 and the mean APACHE II score as 22.77±5.3. The duration of stay in the ICU was 22.60±9.04. The duration of stay in the ICU was shorter in the group who developed AKI. 44.8% of the patients included in the study died. 52% of patients who developed AKI and 37.1% of those who did not develop AKI died. 30-day mortality in patients with AKI was significantly higher than both KDIGO staging and RIFLE classification (p=0.03, p=0.005, respectively). Mortality rate increased 1.42 times in KDIGO Stage 1, 2.79 times in KDIGO Stage 2 and 2.10 times in KDIGO Stage 3. When evaluated by the RIFLE classification, the mortality rate increased 2.32 times in the Risk group, 3.12 times in the Injury group, 2.06 times in the Failure group and 2.15 times in the Loss group.&#x0D; Conclusion: We observed an increase in the frequency of AKI in patients using colistin in the ICU, both according to KDIGO criteria and the RIFLE classification. This situation also increases the 30-day mortality. We think that the KDIGO criteria are more sensitive to diagnose AKI in these patients.

Incidence and risk factors of nephrotoxicity associated with intravenous colistin use in the intensive care unit

Background/Aim: The most serious side effect of colistin therapy is nephrotoxicity. This study aimed to investigate the incidence of nephrotoxicity (NT) due to intravenous colistin and determine the associated risk factors in critically ill patients in the intensive care unit (ICU). Methods: This retrospective cohort study was conducted by examining the files of 100 patients who were hospitalized in the ICU and received intravenous colistin therapy. According to the RIFLE criteria, the patients were divided into two groups as those with and without nephrotoxicity. The clinical characteristics of the patients were compared between the groups and the risk factors associated with nephrotoxicity were determined by multivariate linear logistic regression analysis. Results: The mean age, mean length of stay in the ICU, and mortality rate of 44 patients included in the study were 68±16.36 years, 77.14 (83.03) days, and 56.8%, respectively. NT developed in 22 (50%) patients during colistin therapy. In those with NT, diabetes mellitus, chronic obstructive pulmonary disease, and coronary artery disease were significantly more common (P<0.05 for all), the mean age (P<0.001), Charlson age-adjusted comorbidity index (CACI) scores, APACHE scores (P=0.010) were higher and albumin level was lower (P=0.001). High CACI scores (B=0.532, P=0.002) and low albumin levels (B=-0.323, P=0.023) were significant risk factors for colistin NT according to the regression analysis. Conclusion: Nephrotoxicity is significantly common among critically ill patients receiving colistin therapy. Patients with high CACI scores and hypoalbuminemia should be followed up closely for nephrotoxicity.

Safety and efficacy of colistin and fluoroquinolone in neonatal persistent late-onset sepsis

Growing resistance of microorganisms to antibiotics for the treatment of late-onset sepsis (LOS) in premature infants has led physicians to use antibiotics that are not well studied in neonatal populations. We aimed to determine the efficacy and safety of colistin and fluoroquinolone for the treatment of persistent LOS. We retrospectively reviewed infants with gram-negative LOS, who received either colistin or fluoroquinolone therapy, to determine if there was a significant difference in kidney and liver function tests and electrolyte levels before, during, and at the end of the treatment. Infants who received colistin and fluoroquinolone had 17 and 34 positive cultures with gram-negative organisms, respectively. Multi-drug resistant organisms were more common in infants who received colistin than in those who received fluoroquinolone. Microbiological clearance was found to be higher in infants treated with fluoroquinolone than in those treated with colistin. In both the groups, the median levels of kidney and liver function tests and electrolytes showed a significant increase during the treatment. The prescription of colistin and fluoroquinolones should be reserved for cases with no other safe and effective alternatives.

A comparative evaluation of mikrolatest kit broth microdilution and VITEK2 in assessing colistin susceptibility to Gram-negative bacterial isolates

Introduction and Aim: The increasing resistance in colistin is a major concern. The aim of the study was to compare the methods to identify the prevalence of colistin resistance and antibiotic susceptibility patterns of colistin resistant strains isolates from blood, urine and sputum samples at all ICUs including NICU and PICU and wards.&#x0D; &#x0D; Materials and Methods: A total of 1458 consecutive Gram-negative isolates were tested for colistin susceptibility by standard broth microdilution method, Mikrolatest method and VITEK 2 automation system. Intrinsically colistin resistant organisms including Proteus sps, Providencia sps, Serratia sps., and Morganella morganii were excluded. Enterobacteriaceae (e.g., Escherichia coli, Klebsiella), Pseudomonas aeruginosa and Acinetobacter baumanii were included. The sensitivity, specificity, positive predictive value, negative predictive value of Vitek-2, BMD and Mikrolatest methods were compared. &#x0D; &#x0D; Results: Sixteen (1.09%) colistin?resistant isolates were reported over 24 months. K. pneumoniae constituted 8(50%), E. coli 6 (37.5%) and Enterobacter cloacae 2 (12.5%) of the 16 resistant isolates. The sensitivity, specificity, positive predictive value, negative predictive value of Mikrolatest compared with that of VITEK2 were 87.5% vs 56.25%, 90.84% vs 82.65%, 9.58% vs 3.47%and 99.8% vs 99.3%, respectively for resistant isolates. Mikrolatest shared good Category agreement of 1.24% with BMD Essential agreement was 1.5%. Comparing MICs of BMD with other tests, essential agreement was the lowest for the VITEK2, while the Mikrolatest MIC showed essential agreement greater than 1.5%. No errors and 100% categorical agreement (for E. coli, K. pneumoniae) were observed while comparing colistin susceptibility test results of the Mikrolatest MIC and BMD tests. The difference between the two methods in assessing colistin resistance were not statistically significant (P=0.89). Blood[37.5%] and pus[37.5%] samples recorded as the common sources of the isolate, followed by Urine [12.5%], and respiratory [12.5%) samples.&#x0D; &#x0D; Conclusion: Automated VITEK, Mikrolatest MIC methods give variable susceptibility results and colistin should be prescribed only after Mikrolatest and BMD. K. pneumoniae and E. coli, the Mikrolatest showed better performance for isolates with ? 0.5 or ? 16 µg/mL MICs. For P. aeruginosa isolates, colistin resistant isolates must be confirmed Colistin resistance among Gram-negative bacteria, especially K. pneumoniae, is emerging in Indian hospitals. Re-evaluation is required of the methods available to address the numerous technical challenges associated with colistin susceptibility testing, and to determine which method yields the most meaningful results. These studies will provide critical information on the appropriate selection of colistin therapy, as well as evaluating novel and upcoming compounds with structure and properties similar to the Polymyxin.