Impact of voriconazole plasma concentrations on treatment response in critically ill patients.

WHAT IS KNOWN AND OBJECTIVE: Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity. METHODS: A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity. RESULTS AND DISCUSSION: A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1-5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C-reactive protein >100 mg/dL was associated with supra-therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity. WHAT IS NEW AND CONCLUSIONS: There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.

Implication of Haemodiafiltration Flow Rate on Amikacin Pharmacokinetic Parameters in Critically Ill Patients.

BACKGROUND: To analyse the effect of haemodiafiltration (CVVHDF) flow rate on amikacin pharmacokinetics and blood concentrations. METHODS: Prospective observational study. Patients receiving CVVHDF and amikacin treatment were included. Pharmacokinetic parameters were calculated using Bayesian analysis. Spearman correlation test was used in order to assess the influence of CVVHDF flux on amikacin minimum concentration (Cmin) and plasma clearance. RESULTS: Thirty patients undergoing CVVHDF procedures were included. The treatment with amikacin started at an initial mean dose of 12.4 (4.1) mg/kg/day. An association between the flow rate and Cmin value (r = 0.261; p = 0.161) and plasma clearance was found (r = 0.268; p = 0.152). Four patients (13.3%) were not able to achieve peak concentration over MIC value higher than 8. In 4 patients, amikacin had to be discontinued due to a high Cmin value. CONCLUSIONS: Amikacin clearance in patients with CVVHDF is affected by the flow rate used. Therefore, CVVHDF dose should be taken into account when dosing amikacin.

Patient safety, what does clinical simulation and teaching innovation contribute?

Clinical simulation in Intensive Care Medicine is a crucial tool to strengthen patient safety. It focuses on the complexity of the Intensive Care Unit, where challenging clinical situations require rapid decision making and the use of invasive techniques that can increase the risk of errors and compromise safety. Clinical simulation, by mimicking clinical contexts, is presented as essential for developing technical and non-technical skills and enhancing teamwork in a safe environment, without harm to the patient. in situ simulation is a valuable approach to practice in realistic environments and to address latent security threats. Other simulation methods as virtual reality and tele-simulation are gaining more and more acceptance. Herein, we provide current data on the clinical utility of clinical simulation related to improved safety in the practice of techniques and procedures, as well as improvements of teamwork performance and outcomes. Finally, we propose the needs for future research.

Isavuconazole Pharmacokinetics in Critically Ill Patients: Relationship with Clinical Effectiveness and Patient Safety.

Isavuconazole is used to treat fungal infections. This study aims to describe isavuconazole pharmacokinetics in critically ill patients and evaluate their relationship with clinical efficacy and patient safety. We conducted a prospective, observational study in patients treated with intravenous isavuconazole. Samples were collected at predose (Cmin), 1 h (Cmax) and 12 h (C50) after the last dose. The plasma concentration was determined by high-performance liquid chromatography. The relationship between plasma concentration and clinical and microbiological outcomes and safety was evaluated. The influence of covariates (age, sex, weight, SAPS3, creatinine, liver enzymes and extracorporeal devices: continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO)) was analysed. Population pharmacokinetic modelling was performed using NONMEN®. A total of 71 isavuconazole samples from 24 patients were analysed. The mean Cmin was 1.76 (1.02) mg/L; 87.5% reached the optimal therapeutic target and 12.5% were below 1 mg/L. Population pharmacokinetics were best described by a one-compartment model with first-order elimination. No factor had a significant impact on the plasma concentration or pharmacokinetic parameters. Thus, isavuconazole could be safely used in a critically ill population, even in those treated with CRRT and ECMO, from a pharmacokinetic standpoint. Therefore, routine therapeutic drug monitoring may not be strictly necessary in daily clinical practice.

Mentoring Programme: Guiding your first steps towards scientific excellence.

SEMICYUC's first Mentoring Programme aims to support the research careers of the Society's youngest members. Added benefits include acquiring new research and/or clinical skills, increasing the ability of critical thought, and fostering the development of the next generation of research leaders. This project would not be possible without the exceptional team of mentors or research experts willing to embark on the journey with the young trainees. This article sets out the foundations of such a programme and proposes future changes for continuous improvement.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients.

INTRODUCTION: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. METHODS: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. RESULTS: The median [p25-p75] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions. CONCLUSION: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities.

National Survey: How Do We Approach the Patient at Risk of Clinical Deterioration outside the ICU in the Spanish Context?

BACKGROUND: Anticipating and avoiding preventable intrahospital cardiac arrest and clinical deterioration are important priorities for international healthcare systems and institutions. One of the internationally followed strategies to improve this matter is the introduction of the Rapid Response Systems (RRS). Although there is vast evidence from the international community, the evidence reported in a Spanish context is scarce. METHODS: A nationwide cross-sectional research consisting of a voluntary 31-question online survey was performed. The Spanish Society of Intensive, Critical and Coronary Care Medicine (SEMICYUC) supported the research. RESULTS: We received 62 fully completed surveys distributed within 13 of the 17 regions and two autonomous cities of Spain. Thirty-two of the participants had an established Rapid Response Team (RRT). Common frequency on measuring vital signs was at least once per shift but other frequencies were contemplated (48.4%), usually based on professional criteria (69.4%), as only 12 (19.4%) centers used Early Warning Scores (EWS) or automated alarms on abnormal parameters. In the sample, doctors, nurses (55%), and other healthcare professionals (39%) could activate the RRT via telephone, but only 11.3% of the sample enacted this at early signs of deterioration. The responders on the RRT are the Intensive Care Unit (ICU), doctors, and nurses, who are available 24/7 most of the time. Concerning the education and training of general ward staff and RRT members, this varies from basic to advanced and specific-specialized level, simulating a growing educational methodology among participants. A great number of participants have emergency resuscitation equipment (drugs, airway adjuncts, and defibrillators) in their general wards. In terms of quality improvement, only half of the sample registered RRT activity indicators. In terms of the use of communication and teamwork techniques, the most used is clinical debriefing in 29 centers. CONCLUSIONS: In terms of the concept of RRS, we found in our context that we are in the early stages of the establishment process, as it is not yet a generalized concept in most of our hospitals. The centers that have it are in still in the process of maturing the system and adapting themselves to our context.

Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study.

OBJECTIVES: To describe the effectiveness of the Surviving Sepsis Campaign bundles with regard to both implementation and outcome in patients with septic shock and to determine the contribution of the various elements of the bundles to the outcome. DESIGN: Quasi-experimental study with a historical comparison group. SETTING: The three medical-surgical intensive care units of an academic tertiary care center. PATIENTS: A total of 384 adult patients in septic shock were enrolled after the educational intervention (September 2005-August 2008) and 96 patients in the historical group (June 2004-May 2005). INTERVENTION: A hospital-wide quality improvement program based on the implementation of the Surviving Sepsis Campaign guidelines performed between June 2005 and August 2005. MEASUREMENTS AND RESULTS: In-hospital mortality was reduced from 57.3% in the historical group to 37.5% in the intervention group (p = .001). This difference remained significant after controlling for confounding factors (odds ratio, 0.50; 95% confidence interval, 0.28-0.89). The intervention group had also lower length of stay for survivors in the hospital (36.2 +/- 34.8 days vs. 41.0 +/- 26.3 days; p = .043) and in the intensive care units (8.4 +/- 9.8 days vs. 11.0 +/- 9.5 days; p = .004). Improvements in survival were related to the number of bundle interventions completed (p for trend <.001). Compliance with six or more interventions of the 6-hr resuscitation bundle was an independent predictor of survival (adjusted odds ratio, 0.30; 95% confidence interval, 0.17-0.53; p <.001). The only single intervention with impact on mortality was the achievement of ScvO2 > or =70% (adjusted odds ratio, 0.62; 95% confidence interval, 0.38-0.99; p = .048). CONCLUSIONS: The implementation of the Surviving Sepsis Campaign guidelines was associated with a significant decrease in mortality. The benefits depend on the number of interventions accomplished within the time limits. The 6-hr resuscitation bundle showed greater compliance and effectiveness than the 24-hr management bundle.

Effect of pharmacokinetic/pharmacodynamic ratio on tigecycline clinical response and toxicity in critically ill patients with multidrug-resistant Gram-negative infections.

INTRODUCTION: The information about the pharmacokinetics and optimal dose of tigecycline in critically ill patients with severe underlying diseases is limited and controversial. In this study, we evaluate the pharmacokinetic parameters of tigecycline in critically ill patients with multidrug-resistant Gram-negative infection and explore the association between the pharmacokinetic/pharmacodynamic ratio and treatment response. METHODS: A prospective study was designed including critically ill patients treated with tigecycline for multidrug-resistant Gram-negative infections. Blood samples were collected at day 3-5 of treatment, and pharmacokinetics parameters were evaluated using NONMEM® software. Relationship between area under the free concentration-time curve and minimum inhibitory concentration ratio (fAUC/MIC) and treatment failure was evaluated. Association between tigecycline fAUC and hepatobiliary toxicity was also investigated. RESULTS: Twenty-five critically ill patients were included in the study. In the pharmacokinetic model, weight and total bilirubin level were found to be significant predictors of tigecycline clearance. Fifteen (60.0%) patients achieved an fAUC/MIC ratio >4.5, seven (28.0%) an fAUC/MIC > 6.96 and only three (12.0%) an fAUC/MIC > 17.9. No differences in fAUC/MIC ratio were obtained between those patients with and without clinical failure (5.28 (IC95%: 2.57-7.94) vs 8.71 (3.57-13.84)). fAUC values were higher in those patients who suffered hepatobiliary disorders (7.63 (3.93-11.34) vs 17.63 (7.85-26.28) mg/L/h). CONCLUSION: An important percentage of critically ill patients with multidrug-resistant Gram-negative infection treated with tigecycline do not achieve an appropriate pharmacokinetic/pharmacodynamic value. Tigecycline fAUC seems to be associated with hepatobiliary disorders in this study population. The effect of fAUC/MIC ratio on clinical response remains unclear.

Ceftolozane/Tazobactam Dosing Requirements Against Pseudomonas aeruginosa Bacteremia.

OBJECTIVES: To assess the probability of reaching adequate pharmacokinetic/pharmacodynamics values for ceftolozane/tazobactam at different doses and degrees of renal functions in patients with Pseudomonas aeruginosa bacteremia. METHODS: Six dosing regimens were evaluated: 0.5/0.25 g, 1/0.5 g, and 2/1 g every 8 hours given as 1 hour or 3 hours infusions. Pharmacokinetic data were obtained from the literature. Susceptibility data to ceftolozane were collected from patients with P aeruginosa infection treated with ceftolozane-tazobactam. Probability of reaching a fraction of time (fT) >40% minimum inhibitory concentration (MIC) and fT >100%MIC value for ceftolozane at 3 different renal clearance values was evaluated. For tazobactam, the probability of reaching an fT >40% and >70% for 3 limit values was calculated. RESULTS: Thirty-seven strains were included. For ceftolozane, the probability of reaching a fT >40%MIC was greater than 90% for any degree of renal function. The probability of reaching a fT >100%MIC for 1 g dose infused over 1 hour and 3 hours was 82.2% and 86.4% for a creatinine clearance (ClCr) >90 mL/min. Using a 2 g dose, the probability was greater than 90% for both infusions rates. For tazobactam, the probability of reaching a value of fT >50% of the limit concentrations was greater than 90% for a ClCr of 70 mL/min. In the case of a ClCr >90 mL/min and limit concentration values ≥ 0.25 mg/mL, only extended infusions showed a probability >90%. CONCLUSIONS AND RELEVANCE: The standard doses of ceftolozane/tazobactam achieve an adequate fT >40%MIC value. However, doses of 2 g in extended infusion is necessary to reach a value of fT >100%MIC, especially in patients with an increased renal clearance and high levels of beta-lactamases expression.

Vasopressin antagonist efficacy and safety in volume-overloaded critically ill patients: a new therapeutic alternative.

Objectives: To assess tolvaptan's efficacy and safety in critical care patients with volume overload. Methods: Prospective observational study. Twenty-eight patients in the recovery phase from multiple organ failure and with volume overload refractory to conventional therapy treated with tolvaptan were included. Results: Patients received an initial daily dose of 3.75 (n=1), 7.5 (n=8) and 15 (n=19) mg of tolvaptan. Median treatment duration was 2 days (range: 1 to 12). All patients presented an increase in 24 hours diuresis after the first dose (median increase from baseline (IQR)=1114 (285-1943) mL), with a median net daily fluid loss of 1007 mL (456-2380) mL after 24 hours. High diuretic efficacy (daily fluid loss higher than 0.5 L with tolvaptan first dose) was detected in 18 patients (64.3%). Initial hyponatraemia was present in 16 (57.1%) patients, while overly rapid correction with tolvaptan treatment occurred in two patients without clinical consequences. Two patients presented hypophosphataemia after treatment. Conclusion: Tolvaptan is an effective therapeutic option in critically ill patients with volume overload refractory to conventional diuretics. Further studies are required to evaluate its safety profile and its effect on short-term outcomes and mortality.

In vitro study of antimicrobial activity on Klebsiella Pneumoniae biofilms in endotracheal tubes.

Effective treatment approaches for biofilms in endotracheal tubes (ETTs) are lacking. In this study, we evaluated the in vitro effects of five antimicrobials against biofilms formed by Klebsiella pneumoniae in ETTs. K. pneumoniae was added to minimal mucin medium prior to inoculation in microtiter plates containing ETT fragments. Biofilm susceptibility was assessed by crystal violet staining. At 24 h, the antimicrobials significantly reduced biofilm formation. At 48 h, all of the antimicrobial agents exhibited significant reductions in biofilm formation, even at concentrations above the minimum inhibitory concentration (MIC). Tigecycline and fosfomycin showed the greatest inhibition capacity, with good activity at concentrations twofold greater than the MIC. K. pneumoniae exhibited excellent biofilm formation ability, with formation in the first 24 h and significantly reduced antimicrobial activity. These results contribute to the establishment of new antibiotic breakpoints for the adequate management of infections associated with biofilm formation. Abbreviations ETT Endotracheal tube MIC Minimum inhibitory concentration MBIC Minimum biofilm inhibitory concentration OD Optical density PBS Phosphate-buffered saline VAP Ventilator-associated pneumonia.

Vancomycin and daptomycin minimum inhibitory concentrations as a predictor of outcome of methicillin-resistant Staphylococcus aureus bacteraemia.

OBJECTIVES: The aim of this study was to determine the persistence of the adverse prognostic effect of elevated vancomycin minimum inhibitory concentration (MIC) in methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in a setting with low vancomycin use. METHODS: A retrospective study focusing on episodes of bacteraemia due to MRSA diagnosed from January 2010 through December 2015 was designed. The main outcome measures were 30-day mortality and treatment failure. Multivariate logistic regression analysis was used to identify variables associated with patient mortality and treatment outcome. RESULTS: In total, 79 MRSA bacteraemia episodes were included. The vancomycin MIC was >1.0µg/mL in 53 episodes (67.1%). The presence of high vancomycin MIC was not associated with a higher mortality rate or treatment success. A daptomycin MIC≥0.5µg/mL was present in 16 (26.2%) of 61 episodes for which the daptomycin MIC was obtained and was associated with 30-day mortality in the multivariate analysis (odds ratio=4.72, 95% confidence interval 1.19-18.71). None of the antimicrobials used were associated with a lower risk of treatment failure or mortality. CONCLUSIONS: The pernicious effect of high vancomycin MIC disappears in the absence of a predominant use of this antibiotic. However, a high daptomycin MIC in MRSA bacteraemia is associated with higher mortality in patients with bacteraemia, irrespective of antimicrobial treatment choice.

Impact of amikacin pharmacokinetic/pharmacodynamic index on treatment response in critically ill patients.

OBJECTIVES: This study evaluated the association between the pharmacokinetic/pharmacodynamic index and treatment response to amikacin in critically ill patients. METHODS: An observational prospective study was designed. Critically ill adult patients with infection due to amikacin-sensitive Gram-negative bacteria treated with amikacin were included. Amikacin maximum (Cmax) and minimum (Cmin) plasma concentration samples were taken during the first 48-96h after the beginning of treatment. The impact of Cmax/MIC ratio and area under the concentration-time curve (AUC)/MIC ratio on early and final clinical response, microbiological eradication, development of resistant strains and renal toxicity was analysed using a multivariate model. RESULTS: A total of 85 patients received amikacin treatment, of whom 71 (83.5%) achieved a Cmax/MIC >6, 66 (77.6%) a Cmax/MIC >8, 64 (75.3%) a Cmax/MIC >10 and 72 (84.7%) an AUC/MIC >65. Clinical response at the end of treatment was significantly greater in patients with Cmax/MIC >6 [OR=5.48 (95% CI 1.28-11.40)], Cmax/MIC >8 [OR=6.01 (2.41-12.2)] and Cmax/MIC >10 [OR=8.02 (2.21-14.2)]. Cmax/MIC >10 was associated with a non-significant increase in microbiological eradication [OR=2.84 (0.76-10.61)]. Achieving Cmax/MIC >6 was associated with a lower proportion of patients with selection of resistant strains or with an increase in amikacin MIC (27.8% vs. 10.2%). Amikacin AUC was associated with development of nephrotoxicity [ROC curve 0.77 (0.66-0.87)]. CONCLUSIONS: The Cmax/MIC ratio of amikacin in critically ill patients is directly related to the response to treatment and the selection of resistant strains.

Pharmacokinetics of Amikacin in Critical Care Patients on Extracorporeal Device.

In this study, we evaluate the effect of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (Levitronix) on the pharmacokinetic of amikacin in critically ill patients. Twelve patients with ECMO and three with Levitronix devices who started treatment with amikacin were included. Amikacin pre (Cmax) and post (Cmin) dose serum concentrations were measured during the first 72-96 hours of treatment initiation. Pharmacokinetic parameters were performed by Bayesian adjustment. The median initial dose was 1,000 mg (range: 600-1,400 mg). Mean plasma concentrations were Cmax 58.6 mg/L (17.0 mg/L); Cmin 9.58 mg/L (7.8 mg/L). Patients with an ECMO device had a higher volume of distribution (0.346 [0.033] vs. 0.288 [0.110] L/kg) and a lower plasma clearance (1.58 [0.21] vs. 3.73 [1.03] L/h) than the control group. This phenomenon was also observed in those patients with simultaneous use of ECMO and hemodilafiltration. For patients with Levitronix system, no significant alterations in the volume of distribution were observed, although a lower plasma clearance was noticed. Placement of ECMO devices alters the pharmacokinetic parameters of amikacin in the critically ill patients and should be considered when selecting the initial dose.

Individualised antimicrobial dosing in critically ill patients undergoing continuous renal replacement therapy: focus on total drug clearance.

BACKGROUND: Continuous renal replacement therapy (CRRT) is common practice in critical care patients with acute renal failure. OBJECTIVES: To evaluate the adequacy of antimicrobial doses calculated based on the total drug clearance and dose recommended by different guides in critically ill patients undergoing CRRT. METHODS: Retrospective observational study. Patients admitted to a critical care unit during May 2014 to May 2016 and subjected to CRRT were included. The recommended dose was established as the product of the usual dose of the drug by total drug clearance. RESULTS: 177 antimicrobial agents, used in 64 patients were analysed; 45 (25.4%) antimicrobials were given in an insufficient dose (<20%) according to the theoretical calculation. Following the recommendations in the revised guidelines, between 10% and 20% of antimicrobials were given in insufficient doses. A higher success rate of treatment in those patients not receiving a low drug dosage was seen (35.2% vs 24.0%). CONCLUSIONS: There is a great disparity between the antimicrobial dose prescribed, recommended and calculated based on drug clearance in critically ill patients undergoing CRRT.

Daily bathing strategies and cross-transmission of multidrug-resistant organisms: Impact of chlorhexidine-impregnated wipes in a multidrug-resistant gram-negative bacteria endemic intensive care unit.

BACKGROUND: Health-care associated infections are a major cause of morbidity and mortality in critical care units. The aim of this study is to evaluate the effectiveness of chlorhexidine gluconate (CHG)-impregnated wipes in the daily bathing of patients in an intensive care unit (ICU) to prevent cross-transmission and colonization by multidrug-resistant organisms (MDROs) METHODS: Prospective cohort study with an intervention of 11 months. The intervention consisted of using CHG-impregnated wipes for the daily bathing of patients on mechanical ventilation or colonized by MDROs. Monthly trends in the number of patients colonized by MDROs and the incidence of nosocomial infections were evaluated. RESULTS: A total of 1,675 patients were admitted to the unit during the intervention period, and 430 (25.7%) were bathed with chlorhexidine wipes. A significant decrease was observed in the incidence of colonization by MDROs over the months (ß = -0.209; r2 = 0.549; P = .027), and in the number of patients colonized compared with the equivalent period of the previous year (22.0% vs 18.4%; P = .01). No significant decrease was observed in the incidence of nosocomial infection between the two periods (4.11% vs 4.57%; P = .355). No dermatologic problems were observed in the treated patients. CONCLUSIONS: The use of CHG-impregnated wipes reduces cross-transmission and colonization by MDROs in the ICUs in an endemic situation because of multidrug-resistant Enterobacteriaceae.