Incidence of nephrotoxicity associated with intravenous colistimethate sodium administration for the treatment of multidrug-resistant gram-negative bacterial infections.

Colistimethate sodium (CMS) is the inactive prodrug of colistin, CMS has a narrow antibacterial spectrum with concentration-dependent bactericidal activity against multidrug-resistant gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. This study aimed to analyze potential correlations between clinical features and the development of CMS-induced nephrotoxicity. This retrospective cohort study was conducted in a tertiary-care university hospital between 1 January 2015 and 31 December 2019. A total of 163 patients received CMS therapy. 75 patients (46%) developed nephrotoxicity attributable to colistin treatment, although only 14 patients (8.6%) discontinued treatment for this reason. 95.7% of CMS were prescribed as target therapy. Acinetobacter baumannii spp. was the most commonly identified pathogen (72.4%) followed by P. aeruginosa (19.6%). Several risk factors associated with nephrotoxicity were identified, among these were age (HR 1.033, 95%CI 1.016-1.052, p < 0.001), Charlson Index (HR 1.158, 95%CI 1.0462-1.283; p = 0.005) and baseline creatinine level (HR 1.273, 95%CI 1.071-1.514, p = 0.006). In terms of in-hospital mortality, risk factors were age (HR 2.43, 95%CI 1.021-1.065, p < 0.001); Charlson Index (HR 1.274, 95%CI 1.116-1.454, p = 0.043), higher baseline creatinine levels (HR 1.391, 95%CI 1.084-1.785, p = 0.010) and nephrotoxicity due to CMS treatment (HR 5.383, 95%CI 3.126-9.276, p < 0.001). In-hospital mortality rate were higher in patients with nephrotoxicity (log rank test p < 0.001). In conclusion, the nephrotoxicity was reported in almost half of the patients. Its complex management, continuous renal dose adjustment and monitoring creatinine levels at least every 48 h leads to a high percentage of inappropriate use and treatment failure.

Acute kidney injury in cystic fibrosis patients treated with intravenous colistimethate sodium or tobramycin.

OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin. METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI. RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI. CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

Colistimethate sodium-chitosan hydrogel for treating Gram-negative bacterial wound infections.

The drug resistance is higher among Gram-negative bacteria and demands the usage of strong antibiotics which can in turn result in systemic toxicity. In the treatment of the chronic wounds harboring pathogenic Gram-negative bacteria, the demand for an antimicrobial product that can be topically administered has been on the rise. In an effort to address the above issue, we have developed Colistimethate sodium (a high-end antibiotic) loaded chitosan hydrogel and characterized. The prepared hydrogel is very stable and observed to be bio- and hemo-compatible in nature. The antibacterial activity of the prepared hydrogel was studied against both ATCC (American Type Culture Collection) strains and clinical isolates of Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The CMS incorporated hydrogel is also capable of inhibiting the biofilm formation. The developed hydrogel can be potentially being used for the treatment of Gram-negative bacterial infected wounds.

Efficacy of Problem-Solving Intervention to Improve Adherence in Adolescents and Adults with Cystic Fibrosis.

BACKGROUND: Adherence to treatment by adolescents and adults with cystic fibrosis (CF) is often poor. OBJECTIVES: To assess the impact of a focused clinical intervention on adherence in individual patients, including help in problem-solving key barriers to adherence. To implement a patient-centered problem-solving intervention using CF My Way tools. To identify and overcome a selected barrier to adherence. METHODS: Medication possession ratios (MPRs), number of airway clearance sessions, forced expiratory volume (FEV1), body mass index (BMI), and health-related quality of life (HRQoL) were measured before and after the intervention. RESULTS: Sixteen patients with CF, aged 23.4 ± 6.7 years, participated. MPR increased for colistimethate sodium and tobramycin inhalations from a median of 21 (range 0-100) to 56 (range 0-100), P = 0.04 and 20 (range 0-100) to 33.3 (range 25-100), P = 0.03, respectively. BMI standard deviation score rose from -0.37 to -0.21, P = 0.05. No significant improvements were found in FEV1, airway clearance, or HRQoL scores. CONCLUSIONS: The CF My Way problem-solving intervention increased adherence to medical treatments by removing barriers directly related to the needs and goals of young adults with CF.

A Novel Validated Injectable Colistimethate Sodium Analysis Combining Advanced Chemometrics and Design of Experiments.

Colistimethate sodium (CMS) is widely administrated for the treatment of life-threatening infections caused by multidrug-resistant Gram-negative bacteria. Until now, the quality control of CMS formulations has been based on microbiological assays. Herein, an ultra-high-performance liquid chromatography coupled to ultraviolet detector methodology was developed for the quantitation of CMS in injectable formulations. The design of experiments was performed for the optimization of the chromatographic parameters. The chromatographic separation was achieved using a Waters Acquity BEH C8 column employing gradient elution with a mobile phase consisting of (A) 0.001 M aq. ammonium formate and (B) methanol/acetonitrile 79/21 (v/v). CMS compounds were detected at 214 nm. In all, 23 univariate linear-regression models were constructed to measure CMS compounds separately, and one partial least-square regression (PLSr) model constructed to assess the total CMS amount in formulations. The method was validated over the range 100-220 µg mL-1. The developed methodology was employed to analyze several batches of CMS injectable formulations that were also compared against a reference batch employing a Principal Component Analysis, similarity and distance measures, heatmaps and the structural similarity index. The methodology was based on freely available software in order to be readily available for the pharmaceutical industry.

The first spectrofluorimetric approach for quantification of colistin sulfate and its prodrug colistimethate sodium in pharmaceutical dosage form and human plasma.

A new, accurate, nonextractive, and sensitive fluorimetric approach was proposed and validated for the first time estimation of colistin sulfate and its inactive prodrug colistimethate sodium in its bulk form, pharmaceutical formulations, and human plasma. The approach relied on condensation between acetylacetone/formaldehyde and the primary amino moiety of nonfluorescent colistin in Teorell and Stenhagen buffer (pH 2.8) by the Hantzsch reaction to form a highly fluorescent dihydropyridine derivative. The fluorescent product was measured at 460 nm (λex  = 402 nm). A plot of relative fluorescence intensity (RFI) versus concentration was rectilinear over the range 200-4000 ng ml-1 with excellent correlation (r) and determination (r2 ) coefficients of 0.9999 and 0.9998, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were 40.91 and 123.99 ng ml-1 , respectively. The present procedure was useful for determination of colistin sulfate either in powder form for suspension or in its parenteral prodrug colistimethate sodium in vial formulation. The investigated approach was applied for in vitro quantification of this drug in spiked human plasma, with a per cent mean recovery of 98.24 ± 1.34. The proposed method is reliable, selective, and does not require tedious sample pretreatment steps, expensive instrumentation, or harmful reagents, all of which make it ideally suited for use in quality control laboratories.

Tobramycin and Colistin display anti-inflammatory properties in CuFi-1 cystic fibrosis cell line.

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by 1H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by 1H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics.

Colistimethate Acidic Hydrolysis Revisited: Arrhenius Equation Modeling Using UPLC-QToF MS.

Colistimethate (CMS), the prodrug of polymyxin E (colistin), is an antibiotic widely used as a last-line therapy against multidrug resistant Gram-negative bacteria, but little is known about its pharmacokinetics as its administration has stopped as a result of high neuro- and nephro-toxicity. The measurement of CMS levels in patients' biological fluids is of great importance in order to find the optimal dose regimen reducing the drug toxicity. Until now, CMS assay methods are based on the indirect determination after its hydrolysis to colistin (CS). Herein, the aim is to find the optimal conditions for the complete hydrolysis of CMS to CS. The reaction was studied at accelerated conditions: 40 °C, 50 °C, and 60 °C, and the results were evaluated by assessing the Arrhenius equation and computation employing the Tenua software. A validated analytical methodology based on ultra-performance liquid chromatography (UPLC) coupled to a hybrid quadrupole time of flight (QToF) instrument is developed for the simultaneous measurement of CMS and CS. The current methodology resulted in complete hydrolysis, in contrast with the previously reported one.

Steady-state pharmacokinetic and pharmacodynamic profiling of colistin in critically ill patients with multi-drug-resistant gram-negative bacterial infections, along with differences in clinical, microbiological and safety outcome.

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.

Long-term safety study of colistimethate sodium (Colobreathe®): Findings from the UK Cystic Fibrosis Registry.

BACKGROUND: As part of the risk management plan in Europe, a long-term observational study was conducted to monitor the safety of colistimethate sodium dry powder for inhalation (CMS-DPI) compared to other inhaled antibiotics. METHODS: A cohort of CMS-DPI patients and a matched cohort were identified from the UK Cystic Fibrosis Registry (UKCFR) from 2014-2018. The primary outcome was a composite endpoint, defined as adverse events (AEs) or new cystic fibrosis (CF) complications. Other outcomes included pulmonary exacerbations and treatment discontinuations. RESULTS: Of 1466 and 3503 patients in the CMS-DPI and comparator cohorts, respectively, 82.7% and 79.4% had AEs. Among the most common new CF complications were osteopenia, CF-related diabetes, and increased liver enzymes. The adjusted event rate ratio (ERR) for the primary outcome was 1.25 (95% confidence interval [CI]: 1.18-1.33, p<0.001). After excluding new CF complications, there was no difference between cohorts (ERR=1.04, 95% CI: 0.79-1.38, p=0.785). Pulmonary exacerbations were common in CMS-DPI and comparator cohorts (78.0% and 79.9% of patients, respectively), with adjusted ERR of 1.02 (95% CI: 0.95-1.10, p=0.523). Rates of discontinuation were similar in the CMS-DPI and Tobramycin inhalation powder comparator cohorts (37.8% and 39.8% of patients, respectively). CONCLUSIONS: There was no difference in the rate of adverse events between CMS-DPI and comparator cohorts. The safety profile of CMS-DPI is similar to those of other inhaled antibiotics, supporting its long-term safety in people with CF. The UKCFR has developed a successful model for partnership with industry to conduct long-term studies aimed at assessing drug safety.

ColistinDose, a Mobile App for Determining Intravenous Dosage Regimens of Colistimethate in Critically Ill Adult Patients: Clinician-Centered Design and Development Study.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Colistimethate sodium and acute kidney injury: Incidence, risk factors, outcome and prognosis of renal function / Fracaso renal agudo y colistimetato de sodio: incidencia, factores de riesgo, resultados y pronóstico de la función renal

BACKGROUND: Colistimethate sodium (CMS) treatment has increased over the last years, being acute kidney injury (AKI) its main drug-related adverse event. Therefore, this study aimed to evaluate the incidence and risk factors associated with AKI, as well as identifying the factors that determine renal function (RF) outcomes at six months after discharge. MATERIALS AND METHODS: This retrospective study included adult septic patients receiving intravenous CMS for at least 48 h (January 2007-December 2014). AKI was assessed using KDIGO criteria. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD equation. Logistic and linear models were performed to evaluate the risk factors for AKI and chronic kidney disease (CKD). RESULTS: Among 126 patients treated with CMS; the incidence of AKI was 48.4%. Sepsis-severe sepsis (OR 8.07, P = 0.001), sepsis-septic shock (OR 42.9, P < 0.001), and serum creatinine (SCr) at admission (OR 6.20, P = 0.009) were independent predictors. Eighty-four patients survived; the main factors for RF evolution at the 6-month follow-up was baseline eGFR (0.58, P < 0.001) and at discharge (0.34, P < 0.001). Fifty-six percent (34/61) of the patients that developed AKI survived. At six months, 32% had CKD. CONCLUSIONS: The development of AKI in septic patients with CMS treatment was associated with sepsis severity and SCr at admission. Baseline eGFR and eGFR at discharge were and important determinant of the RF at the 6-month follow-up. These predictors may assist in clinical decision making for this patient population

INTRODUCCIÓN: El tratamiento con colistimetato de sodio (CMS) se ha incrementado, siendo su principal complicación el fracaso renal agudo (FRA). El objetivo de este estudio fue determinar la incidencia de FRA y los factores de riesgo asociados, así como identificar los factores que determinan la función renal (FR) a los 6 meses del alta hospitalaria. MATERIALES Y MÉTODOS: Estudio retrospectivo que incluyó pacientes adultos sépticos que recibieron CMS intravenoso durante al menos 48 h (enero 2007-diciembre 2014). El diagnóstico de FRA se realizó según los criterios KDIGO. Se estimó el filtrado glomerular (FG) mediante la ecuación del MDRD-4. Se realizaron modelos logísticos y lineales para evaluar los factores de riesgo para el desarrollo de FRA y enfermedad renal crónica (ERC). RESULTADOS: Ciento veintiséis pacientes fueron incluidos; la incidencia de FRA fue del 48,4%. Sepsis-sepsis severa (OR: 8,07; p = 0,001), sepsis-shock séptico (OR: 42,9; p < 0,001) y la creatinina sérica (CRs) al ingreso (OR: 6,20; p = 0,009) fueron predictores independientes de FRA. Ochenta y cuatro pacientes sobrevivieron; el determinante principal de la evolución de la FR a los 6 meses de seguimiento fue el FGe basal (0,58; p < 0,001) y al alta (0,34; p < 0,001). El 56% (34/61) de los pacientes que desarrollaron FRA sobrevivieron. A los 6 meses, el 32% desarrollo ERC. CONCLUSIONES: El desarrollo de FRA asociado al tratamiento con CMS se asoció con el grado de severidad de la sepsis y la CRs al ingreso. El FGe basal y al alta hospitalaria fueron predictores independientes de la FR a los 6 meses de seguimiento

Generation of a novel human dermal substitute functionalized with antibiotic-loaded nanostructured lipid carriers (NLCs) with antimicrobial properties for tissue engineering.

BACKGROUND: Treatment of patients affected by severe burns is challenging, especially due to the high risk of Pseudomonas infection. In the present work, we have generated a novel model of bioartificial human dermis substitute by tissue engineering to treat infected wounds using fibrin-agarose biomaterials functionalized with nanostructured lipid carriers (NLCs) loaded with two anti-Pseudomonas antibiotics: sodium colistimethate (SCM) and amikacin (AMK). RESULTS: Results show that the novel tissue-like substitutes have strong antibacterial effect on Pseudomonas cultures, directly proportional to the NLC concentration. Free DNA quantification, WST-1 and Caspase 7 immunohistochemical assays in the functionalized dermis substitute demonstrated that neither cell viability nor cell proliferation were affected by functionalization in most study groups. Furthermore, immunohistochemistry for PCNA and KI67 and histochemistry for collagen and proteoglycans revealed that cells proliferated and were metabolically active in the functionalized tissue with no differences with controls. When functionalized tissues were biomechanically characterized, we found that NLCs were able to improve some of the major biomechanical properties of these artificial tissues, although this strongly depended on the type and concentration of NLCs. CONCLUSIONS: These results suggest that functionalization of fibrin-agarose human dermal substitutes with antibiotic-loaded NLCs is able to improve the antibacterial and biomechanical properties of these substitutes with no detectable side effects. This opens the door to future clinical use of functionalized tissues.

Design of experiments guided multivariate calibration for the quantitation of injectable colistimethate sodium by ultra performance liquid chromatography - High resolution mass spectrometry.

Colistimethate sodium (CMS) is a widely administrated old-generation prodrug for the treatment of the life-threatening infections caused by multi-resistant Gram-negative bacteria. Until now, the quality control procedure of the CMS commercial products is based on microbiological assays. The aim of the study is the development of a chemical analysis methodology based on liquid chromatography - mass spectrometry (LC-MS) that could be used for the quality control of CMS products. The careful optimization of the LC and QToF-MS parameters was deemed crucial, as CMS is known to be a very complex mixture. Thus, a two stage Design of Experiments (DoE) pipeline has been followed, aiming towards the separation of the mixture components. According to the DoE results, a baseline-resolved chromatogram revealing more than 20 compounds was achieved. The separation was performed using a Waters Acquity BEH C8 column employing gradient elution. The mobile phase consisted of aq. ammonium formate 0.005 M (pH 6) (solvent A) and methanol/acetonitrile 79/21 (v/v) (solvent B). A second optimization experiment for the MS signal was employed in order to achieve maximum sensitivity. The singly charged signals were monitored for the validation in the positive ion mode. The calibration curve range was 50-110 µg mL-1, corresponding to the 80-120% of the nominal CMS amount in the commercial products. Due to the complexity of the CMS chromatograms and the corresponding spectrum of each chromatographic peak, untargeted and targeted approaches were performed employing the MZmine software. Furthermore, apart from the classical univariate statistical analysis, partial least squares regression (PLS-R) model was also employed, as the variables were more than the observations. The developed methodology has been employed to analyze several batches and inconsistences have been discovered.

Assessment of colistimethate sodium (COLOBREATHE) risk minimization measures implemented in the European Union: A cross-sectional study.

PURPOSE: To assess the effectiveness of additional risk minimization measures (aRMMs) implemented in Europe for colistimethate sodium (CMS) among healthcare professionals (HCPs) and patients/caregivers following safety concerns regarding incorrect use of CMS delivered via Turbospin inhaler. METHODS: A cross-sectional study was conducted among HCPs and patients/caregivers in Austria, Denmark, France, Germany, The Netherlands, and the United Kingdom between September 2016 and March 2018. Knowledge of the educational materials was assessed regarding common side effects, correct use of CMS and Turbospin inhaler, and capsule breakage. Awareness, receipt, and utilization of the aRMMs were also evaluated. RESULTS: Among 124 HCPs surveyed, the majority acknowledged awareness (86.2%), receipt (91.0%), and utilization (81.6%) of the CMS educational materials and were knowledgeable about the common CMS side effects (93.2%). Most HCPs correctly answered most questions regarding the proper use of CMS (>90%), yet only half knew how to correctly use the Turbospin inhaler (53.2%). Knowledge about capsule breakage was moderate (67.5%). Of the 29 patients/caregivers surveyed, almost half were aware of the educational materials (48.1%); of these, 69.2% received and used the materials. Most patients/caregivers were knowledgeable about the common CMS side effects (81.5%) and proper CMS use (>85%); however, knowledge about correct Turbospin inhaler use and potential for capsule breakage was moderate to low (48.1% and 37.9%, respectively). CONCLUSIONS: HCPs and patients/caregivers have good knowledge about the common side effects associated with CMS. However, knowledge of correct use of the Turbospin inhaler and capsule breakage was moderate to low.

Clinical efficacy and pharmacokinetics of colistimethate sodium and colistin in critically ill patients in an Indian hospital with high endemic rates of multidrug-resistant Gram-negative bacterial infections: A prospective observational study.

BACKGROUND: Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (PD) data to guide dosing. AIM: To evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function. MATERIALS AND METHODS: Twenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium - at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later - were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). RESULTS: Among the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 ± 1.1 mg/L (1.75-5.14) and 2.37 ± 1.2 mg/L (1.52-5.54) for 'cure' and 'failure' groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 ± 1.3 mg/L and 1.78 ± 1.1 mg/L in 'cure' and 'failure' groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD. CONCLUSIONS: Subtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing.

In vitro and in vivo antimicrobial activity of sodium colistimethate and amikacin-loaded nanostructured lipid carriers (NLC).

Sodium colistimethate (SCM) and amikacin (AMK) are among the few antibiotics effective against resistant P. aeruginosa, K. pneumoniae and A. baumannii; however, their toxicity severely limits their use. Enclosing antibiotics into nanostructured lipid carriers (NLC) might decrease drug toxicity and improve antibiotic disposition. In this work, SCM or AMK was loaded into different NLC formulations, through high pressure homogenization, and their in vitro and in vivo effectiveness was analyzed. The encapsulation process did not reduce drug effectiveness since in vitro SCM-NLC and AMK-NLC drug activity was equal to that of the free drugs. As cryoprotectant, trehalose showed better properties than dextran. Instead, positive chitosan coating was discarded due to its limited cost-efficiency. Finally, the in vivo study in acute pneumonia model revealed that intraperitoneal administration was superior to the intramuscular route and confirmed that (-) SCM-NLC with trehalose, was the most suitable formulation against an extensively drug-resistant A. baumannii strain.

Colistimethate sodium and acute kidney injury: Incidence, risk factors, outcome and prognosis of renal function.

BACKGROUND: Colistimethate sodium (CMS) treatment has increased over the last years, being acute kidney injury (AKI) its main drug-related adverse event. Therefore, this study aimed to evaluate the incidence and risk factors associated with AKI, as well as identifying the factors that determine renal function (RF) outcomes at six months after discharge. MATERIALS AND METHODS: This retrospective study included adult septic patients receiving intravenous CMS for at least 48h (January 2007-December 2014). AKI was assessed using KDIGO criteria. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD equation. Logistic and linear models were performed to evaluate the risk factors for AKI and chronic kidney disease (CKD). RESULTS: Among 126 patients treated with CMS; the incidence of AKI was 48.4%. Sepsis-severe sepsis (OR 8.07, P=0.001), sepsis-septic shock (OR 42.9, P<0.001), and serum creatinine (SCr) at admission (OR 6.20, P=0.009) were independent predictors. Eighty-four patients survived; the main factors for RF evolution at the 6-month follow-up was baseline eGFR (0.58, P<0.001) and at discharge (0.34, P<0.001). Fifty-six percent (34/61) of the patients that developed AKI survived. At six months, 32% had CKD. CONCLUSIONS: The development of AKI in septic patients with CMS treatment was associated with sepsis severity and SCr at admission. Baseline eGFR and eGFR at discharge were and important determinant of the RF at the 6-month follow-up. These predictors may assist in clinical decision making for this patient population.

Quantitative determination of colistin A/B and colistin methanesulfonate in biological samples using hydrophilic interaction chromatography tandem mass spectrometry.

Colistin (polymyxin E) is a polycation antibiotic which is increasingly used (administered as colistin methanesulfonate, CMS) as a salvage therapy in critically ill patients with multidrug resistant Gram-negative infections. Even though colistin has been used for more than 50 years, its metabolic fate is poorly understood. One of the current challenges for studying the pharmacokinetics (PK) is the precise and accurate determination of colistin in in vitro and in vivo studies. In the present study, we developed and validated a series of sensitive and robust liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for analysing biological samples obtained from in vitro and in vivo disposition assays. After a zinc acetate-mediated precipitation, hydrophilic-lipophilic-balanced solid phase extraction (HLB-SPE) was used for the extraction of colistin. The compounds were retained on a hydrophilic interaction liquid chromatography (HILIC) column and were detected by MS/MS. CMS was quantified by determining the produced amount of colistin during acidic hydrolysis. The developed methods are sensitive with lower limits of quantification varying between 0.009 µg/mL and 0.071 µg/mL for colistin A, and 0.002 µg/mL to 0.013 µg/mL for colistin B. The intra- and inter-day precision and accuracy were within ±15%. Calibration curves of colistin were linear (0.063 µg/mL to 8.00 µg/mL) within clinically relevant concentration ranges. Zinc acetate-mediated precipitation and the use of a HILIC column were found to be essential. The developed methods are sensitive, accurate, precise, highly efficient and allow monitoring colistin and CMS in biological samples without the need for an internal standard.

Greater optimisation of pharmacokinetic/pharmacodynamic parameters through a loading dose of intravenous colistin in paediatric patients.

Use of colistin in children is rising in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). In adults, a colistin loading dose is recommended to achieve therapeutic concentrations within 12-24 h. Here we aimed to describe the pharmacokinetic (PK) parameters of a loading dose versus a recommended initial dose of intravenous colistimethate sodium (CMS) in paediatric patients. A prospective, open-label, PK study was conducted in paediatric patients (age 2-18 years) with normal renal function. Patients (n = 20) were randomly assigned to receive either a CMS loading dose (LD group) of 4 mg of colistin base activity (CBA)/kg/dose or a standard initial dose (NLD group) of 2.5 mg (12-h interval) or 1.7 mg (8-h interval) of CBA/kg/dose. Serial blood samples were collected. Plasma concentrations of formed colistin were measured by LC-MS/MS. PK parameters were reported. Acute kidney injury (AKI) was monitored by serum creatinine and urine NGAL. The median (interquartile range) age and body weight were 8.5 (3.5-11.3) years and 21.5 (13.5-20.0) kg. The mean (standard deviation) of first-dose PK parameters of the LD group versus the NLD group were: Cmax, 6.1 (2.4) vs. 4.1 (1.3) mg/L; AUC0-t, 26.5 (12.5) vs. 13.5 (3.6) mg/L·h; Vd, 0.7 (0.4) vs. 0.6 (0.3) L/kg; and t1/2, 2.9 (0.6) vs. 2.6 (0.4) h. No patient developed AKI by serum creatinine criteria. A CMS loading dose is beneficial for improvement of colistin exposure without increased AKI. A higher daily dose of CMS should be considered, especially for MDR-GNB treatment.