Therapeutic Drug Monitoring of Antimicrobials in Critically Ill Obese Patients.

Obesity is a significant global public health concern that is associated with an elevated risk of comorbidities as well as severe postoperative and nosocomial infections. The treatment of infections in critically ill obese patients can be challenging because obesity affects the pharmacokinetics and pharmacodynamics of antibiotics, leading to an increased risk of antibiotic therapy failure and toxicity due to inappropriate dosages. Precision dosing of antibiotics using therapeutic drug monitoring may help to improve the management of this patient population. This narrative review outlines the pharmacokinetic and pharmacodynamic changes that result from obesity and provides a comprehensive critical review of the current available data on dosage adjustment of antibiotics in critically ill obese patients.

How to Use Nebulized Antibiotics in Severe Respiratory Infections.

Difficult-to-treat pulmonary infections caused by multidrug-resistant (MDR) pathogens are of great concern because their incidence continues to increase worldwide and they are associated with high morbidity and mortality. Nebulized antibiotics are increasingly being used in this context. The advantages of the administration of a nebulized antibiotic in respiratory tract infections due to MDR include the potential to deliver higher drug concentrations to the site of infection, thus minimizing the systemic adverse effects observed with the use of parenteral or oral antibiotic agents. However, there is an inconsistency between the large amount of experimental evidence supporting the administration of nebulized antibiotics and the paucity of clinical studies confirming the efficacy and safety of these drugs. In this narrative review, we describe the current evidence on the use of nebulized antibiotics for the treatment of severe respiratory infections.

Drug Regimens of Novel Antibiotics in Critically Ill Patients with Varying Renal Functions: A Rapid Review.

There is currently an increase in the emergence of multidrug-resistant bacteria (MDR) worldwide, requiring the development of novel antibiotics. However, it is not only the choice of antibiotic that is important in treating an infection; the drug regimen also deserves special attention to avoid underdosing and excessive concentrations. Critically ill patients often have marked variation in renal function, ranging from augmented renal clearance (ARC), defined as a measured creatinine clearance (CrCL) ≥ 130 mL/min*1.73 m2, to acute kidney injury (AKI), eventually requiring renal replacement therapy (RRT), which can affect antibiotic exposure. All novel beta-lactam (BLs) and/or beta-lactam/beta-lactamases inhibitors (BL/BLIs) antibiotics have specific pharmacokinetic properties, such as hydrophilicity, low plasma-protein binding, small volume of distribution, low molecular weight, and predominant renal clearance, which require adaptation of dosage regimens in the presence of abnormal renal function or RRT. However, there are limited data on the topic. The aim of this review was therefore to summarize available PK studies on these novel antibiotics performed in patients with ARC or AKI, or requiring RRT, in order to provide a practical approach to guide clinicians in the choice of the best dosage regimens in critically ill patients.

Ensuring target concentrations of antibiotics in critically ill patients through dose adjustment.

INTRODUCTION: Antibiotics are commonly prescribed in critical care, and given the large variability of pharmacokinetic (PK) parameters in these patients, drug PK frequently varies during therapy with the risk of either treatment failure or toxicity. Therefore, adequate antibiotic dosing in critically ill patients is very important. AREAS COVERED: This review provides an overview of the basic principles of PK and pharmacodynamics of antibiotics and the main patient and pathogen characteristics that may affect the dosage of antibiotics and different approaches to adjust doses. EXPERT OPINION: Dose adjustment should be done for aminoglycosides and glycopeptides based on daily drug concentration monitoring. For glycopeptides, in particular vancomycin, the residual concentration (Cres) should be assessed daily. For beta-lactam antibiotics, a loading dose should be administered, followed by three different possible approaches, as TDM is rarely available in most centers: 1) antibiotic regimens should be adapted according to renal function and other risk factors; 2) nomograms or software can be used to calculate daily dosing; 3) TDM should be performed 24-48 h after the initiation of treatment; however, the results are required within 24 hours to appropriately adjust dosage regimens. Drug dosing should be reduced or increased according to the TDM results.

Prediction of Insufficient Beta-Lactam Concentrations in Extracorporeal Membranous Oxygenation Patients.

BACKGROUND: The aim of this study was to identify predictors of insufficient beta-lactam concentrations in patients undergoing extracorporeal membrane oxygenation (ECMO). METHODS: Retrospective analysis of all patients receiving ECMO support and treated with ceftazidime or cefepime (CEF), piperacillin/tazobactam (TZP), or meropenem (MEM). Trough drug concentrations (Cmin) were measured before the subsequent dose, according to the decision of the attending physician. Insufficient drug concentrations were identified if Cmin was below the clinical breakpoint of Pseudomonas aeruginosa. RESULTS: A total of 222 Cmin (CEF, n = 41; TZP, n = 85; MEM, n = 96) from 110 patients were included; insufficient concentrations were observed in 26 (12%) antibiotic assessments; 21 (81%) of those occurred during MEM therapy. Insufficient Cmin were associated with a shorter time from initiation of antibiotics to measurement, a lower single dose of antibiotic, a higher creatinine clearance (CrCL), lower sequential organ failure assessment (SOFA) scores, and less use of continuous renal replacement therapy (CRRT) when compared to others. CONCLUSIONS: Insufficient broad-spectrum beta-lactam concentrations were observed in 12% of drug measurement during ECMO therapy. Higher than recommended drug regimens could be considered in the very early phase of therapy and in those patients with augmented renal clearance and with less severe organ dysfunction.

Use of Sedatives and Neuromuscular-Blocking Agents in Mechanically Ventilated Patients with COVID-19 ARDS.

OBJECTIVES: To assess differences in the use of analgesics, sedatives and neuromuscular-blocking agents (NMBA) in patients with acute respiratory distress syndrome (ARDS) due to COVID-19 or other conditions. METHODS: Retrospective observational cohort study, single-center tertiary Intensive Care Unit. COVID-19 patients with ARDS (March-May 2020) and non-COVID ARDS patients (2017-2020) on mechanical ventilation and receiving sedation for at least 48 h. RESULTS: A total of 39 patients met the inclusion criteria in each group, with similar demographics at baseline. COVID-19 patients had a longer duration of MV (median 22 (IQRs 16-29) vs. 9 (6-18) days; p < 0.01), of sedatives administration (18 (11-22) vs. 5 (4-9) days; p < 0.01) and NMBA therapy (12 (9-16) vs. 3 (2-7) days; p < 0.01). During the first 7 days of sedation, compared to non-COVID patients, COVID patients received more frequently a combination of multiple sedative drugs (76.9% vs. 28.2%; p < 0.01) and a higher NMBA regimen (cisatracurium: 3.0 (2.1-3.7) vs. 1.3 (0.9-1.9) mg/kg/day; p < 0.01). CONCLUSIONS: The duration and consumption of sedatives and NMBA was significantly increased in patients with COVID-19 related ARDS than in non-COVID ARDS. Different sedation strategies and protocols might be needed in COVID-19 patients with ARDS, with potential implications on long-term complications and drugs availability.

Interleukine-6 in critically ill COVID-19 patients: A retrospective analysis.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) appeared in China in December 2019 and has spread around the world. High Interleukin-6 (IL-6) levels in COVID-19 patients suggest that a cytokine storm may play a major role in the pathophysiology and are considered as a relevant parameter in predicting most severe course of disease. The aim of this study was to assess repeated IL-6 levels in critically ill COVID-19 patients admitted to our Intensive Care Unit (ICU) and to evaluate their relationship with patient's severity and outcome. METHODS: We conducted a retrospective study on patients admitted to the ICU with a diagnosis of COVID-19 between March 10 (i.e. the date of the first admitted patients) and April 30, 2020. Demographic, clinical and laboratory data were collected at admission. On the day of IL-6 blood concentration measurement, we also collected results of D-Dimers, C-Reactive Protein, white blood cells and lymphocytes count, lactate dehydrogenase (LDH) and ferritin as well as microbiological samples, whenever present. RESULTS: Of a total of 65 patients with COVID-19 admitted to our ICU we included 41 patients with repeated measure of IL-6. There was a significant difference in IL-6 levels between survivors and non-survivors over time (p = 0.001); moreover, non survivors had a significantly higher IL-6 maximal value when compared to survivors (720 [349-2116] vs. 336 [195-646] pg/mL, p = 0.01). The IL-6 maximal value had a significant predictive value of ICU mortality (AUROC 0.73 [95% CI 0.57-0.89]; p = 0.01). CONCLUSIONS: Repeated measurements of IL-6 can help clinicians in identifying critically ill COVID-19 patients with the highest risk of poor prognosis.

The Acquisition of Multidrug-Resistant Bacteria in Patients Admitted to COVID-19 Intensive Care Units: A Monocentric Retrospective Case Control Study.

Whether the risk of multidrug-resistant bacteria (MDRB) acquisition in the intensive care unit (ICU) is modified by the COVID-19 crisis is unknown. In this single center case control study, we measured the rate of MDRB acquisition in patients admitted in COVID-19 ICU and compared it with patients admitted in the same ICU for subarachnoid hemorrhage (controls) matched 1:1 on length of ICU stay and mechanical ventilation. All patients were systematically and repeatedly screened for MDRB carriage. We compared the rate of MDRB acquisition in COVID-19 patients and in control using a competing risk analysis. Of note, although we tried to match COVID-19 patients with septic shock patients, we were unable due to the longer stay of COVID-19 patients. Among 72 patients admitted to the COVID-19 ICUs, 33% acquired 31 MDRB during ICU stay. The incidence density of MDRB acquisition was 30/1000 patient days. Antimicrobial therapy and exposure time were associated with higher rate of MDRB acquisition. Among the 72 SAH patients, 21% acquired MDRB, with an incidence density was 18/1000 patient days. The septic patients had more comorbidities and a greater number of previous hospitalizations than the COVID-19 patients. The incidence density of MDRB acquisition was 30/1000 patient days. The association between COVID-19 and MDRB acquisition (compared to control) risk did not reach statistical significance in the multivariable competing risk analysis (sHR 1.71 (CI 95% 0.93-3.21)). Thus, we conclude that, despite strong physical isolation, acquisition rate of MDRB in ICU patients was at least similar during the COVID-19 first wave compared to previous period.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 5: Neurological auto-antibodies, discussion, flow chart, conclusions.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the last of a series of five and deals mainly with onconeural antibodies involved in neurological paraneoplastic syndromes and provides the final discussion.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 2: Hematologic, cutaneous and vascular syndromes.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes associated with lung cancer appears useful. This article is the second of a series of five and deals with hematologic, cutaneous and vascular syndromes.