Existing and emerging therapies for the treatment of invasive candidiasis and candidemia.

INTRODUCTION: Invasive candidiasis or candidemia is a severe infection affecting more than 250,000 people worldwide every year. It is present in up to 16% of ICU patients. The prognosis of these infections is unfavorable, with global death estimated around 50,000 per year, which corresponds to up to 40% depending on patient severity and comorbidities. Therapeutic failure is not rare due to the emergence of multiresistant strains and of new species poorly responsive to current therapies like Candida auris. AREAS COVERED: We first review the positioning of antifungal drugs used to treat candidiasis, namely polyenes, azoles, echinocandins and pyrimidine analogues. We then discuss the progresses brought by new formulations, new derivatives within these classes, compounds acting on new targets or repurposed drugs in terms of pharmacokinetic profile, spectrum of activity, potency, safety or risk of drug-drug interactions. EXPERT OPINION: While new formulations (amphotericin B cochleate) improve oral bioavailability of the corresponding drugs, new azoles or echinocandins offer higher potency including against strains resistant to former generations of drugs. Repurposed drugs show synergism with current therapies in vitro. Results from ongoing and future clinical trials will be decisive to establish the interest for these drugs in our arsenal.

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

Creatinine correction to account for fluid overload in children with acute respiratory distress syndrome treated with extracorporeal membrane oxygenation: an initial exploratory report.

BACKGROUND: Creatinine is distributed between the intracellular and extracellular compartments, and as a result, the measurement of its concentration is strongly related to the fluid status of the patient. An interest has been shown in correcting measured serum creatinine levels according to the fluid balance in order to better specify the degree of acute kidney injury (AKI). METHODS: We conducted a retrospective observational study of 33 children, aged 0 to 5 years, admitted to the pediatric intensive care unit for acute respiratory distress syndrome treated by extracorporeal membrane oxygenation. We compared measured and corrected creatinine and assessed the degree of agreement between these values using both Cohen's kappa and Krippendorff's alpha coefficient. RESULTS: In our cohort, 37% of the classifications made according to measured creatinine levels were erroneous and, in the majority of cases, the degree of AKI was underestimated. CONCLUSION: Correction of the measured creatinine value according to the degree of fluid overload may result in more accurate diagnosis of AKI. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Biomarkers for Early Diagnosis of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

Many biomarkers have been proposed for the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in adults, but comparative studies are lacking. We analyzed ferritin, glycosylated ferritin, soluble CD25, CD163 and CD14, IL-6, IFN-γ, IL-18, IL-10, IL-1ß, IL-12p70, IL-17α, IP-10, and CXCL9 levels to differentiate HLH from sepsis in critically ill patients. Of 120 patients, HLH was confirmed for 14 patients. Among the biomarkers tested, ferritin, IL-18, and glycosylated ferritin were the most efficient parameters for early diagnosis of HLH. With a sensitivity set at 85%, ferritin, IL-18, and glycosylated ferritin were the biomarkers with the highest specificity: 84, 79, and 71% respectively. Combining IL-18 with the HScore provided a new score with an increased specificity compared to the HScore alone, 86% compared to 70% with a sensitivity set at 100%. A distinct cytokine pattern was highlighted in patients with malignancy-triggered HLH, with highly increased levels of INF-É£ and CXCL9, compared to HLH secondary to infection. This is the largest study available to date, comparing diagnostic biomarkers for HLH on a cohort of critically ill adult patients. Serum ferritin was the most discriminating parameter for early diagnosis of secondary HLH. IL18*HScore was identified as a highly potential score.

Severe Acute Respiratory Syndrome Coronavirus-2-Associated Acute Kidney Injury: A Narrative Review Focused Upon Pathophysiology.

OBJECTIVE: Severe acute respiratory syndrome coronavirus-2 acute kidney injury is a condition that in many ways resembles classical acute kidney injury. The pathophysiology appears to be multifactorial, and accordingly, our main objective was to review possible components of this form of acute kidney injury. DATA SOURCES: Literature review. DATA SYNTHESIS: Our principal observation was that the various components of severe acute respiratory syndrome coronavirus-2 acute kidney injury appear to be relatively similar to the classical forms. Temporality of injury is an important factor but is not specific to severe acute respiratory syndrome coronavirus-2 acute kidney injury. Several insults hit the kidney at different moments in the course of disease, some occurring prior to hospital admission, whereas others take place at various stages during hospitalization. CONCLUSIONS AND RELEVANCE: Treatment of severe acute respiratory syndrome coronavirus-2 acute kidney injury cannot be approached in a "one-size-fits-all" manner. The numerous mechanisms involved do not occur simultaneously, leading to a multiple hit model that may contribute to the prevalence and severity of acute kidney injury. A personalized approach to each patient with acute kidney injury based on the timing and severity of disease is necessary in order to provide appropriate treatment. Although data from the literature regarding the previous coronavirus infections can give some insights, more studies are needed to explore the different mechanisms of acute kidney injury occurring as a result of severe acute respiratory syndrome coronavirus-2.

Rationale of Blood Purification in the Post-Resuscitation Syndrome following Out-of-Hospital Cardiac Arrest: A Narrative Review.

Even today, little is known about the pathophysiology of the post-resuscitation syndrome. Our narrative review is one of the first summarizing all the knowledge about this phenomenon. We have focused our review upon the potential role of blood purification in attenuating the consequences of the post-resuscitation syndrome. Blood purification can decrease the cytokine storm particularly when using a CytoSorb absorber. Acrylonitrile 69-based oXiris membranes can remove endotoxin and high-mobility group box 1 protein. Blood purification techniques can quickly induce hypothermia. Blood purification can be used with veno-arterial extracorporeal membrane oxygenation to remove excess water. Further trials are needed to provide more concrete data about the use of blood purification in the post-resuscitation syndrome.

Membrane-Based Therapeutic Plasma Exchange in Intensive Care.

The principles and use of plasmapheresis are often little understood by intensivists. We propose to review the principles, the main indications, and the methods of using this technique.

Extracorporeal CO2 Removal Integrated within a Continuous Renal Replacement Circuit Offers Multiple Advantages.

Extracorporeal CO2 removal within a continuous renal replacement therapy circuit offers multiple advantages for the regulation of the CO2 extraction. The authors review the impact of the dialysate solution, the buffer, and the anticoagulation on CO2 removal. They propose a theoretical model of the ideal circuit for the optimization of CO2 extraction.

Feasibility of Citrate Dialysis in Hyponatremia: A Case Series.

BACKGROUND: Correcting hyponatremia too quickly can lead to osmotic demyelination syndrome. During citrate dialysis, a significant sodium load is brought to the prefilter. We reviewed the impact of this sodium load on the evolution of sodium levels in patients undergoing continuous renal replacement therapy with citrate anticoagulation. MATERIALS AND METHODS: The medical records of 5 patients with hyponatremia who received dialysis with citrate anticoagulation, over a 10-year period, were reviewed. The sodium of the dialysate and of the reinjection fluid was adapted according to the serum sodium level recommended by the guidelines of the time. Data from the first 24 h after initiation of dialysis was evaluated. RESULTS: The difference in serum sodium levels between day 1 and day 2 was statistically significant, with a rise of 7.8 ± 3.7 mmol/L. DISCUSSION: The mean serum sodium increase in our series of patients did not exceed the increase of 10-12 mEq/L/day permitted by the guidelines. The excess sodium was absorbed by the filter. CONCLUSION: In this small series of patients, with adjustment of the sodium concentration of dialysate and reinjection fluid, the use of citrate was found to be safe.

ECCO2R therapy in the ICU: consensus of a European round table meeting.

BACKGROUND: With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO2 removal (ECCO2R). However, current evidence in these indications is limited. A European ECCO2R Expert Round Table Meeting was convened to further explore the potential for this treatment approach. METHODS: A modified Delphi-based method was used to collate European experts' views to better understand how ECCO2R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus. RESULTS: Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO2R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO2R therapy (n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO2R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO2 levels. Driving pressure (≥ 14 cmH2O) followed by plateau pressure (Pplat; ≥ 25 cmH2O) was considered the most important criteria for ECCO2R initiation. Key treatment targets for patients with ARDS undergoing ECCO2R included pH (> 7.30), respiratory rate (< 25 or < 20 breaths/min), driving pressure (< 14 cmH2O) and Pplat (< 25 cmH2O). In ae-COPD, there was consensus that, in patients at risk of non-invasive ventilation (NIV) failure, no decrease in PaCO2 and no decrease in respiratory rate were key criteria for initiating ECCO2R therapy. Key treatment targets in ae-COPD were patient comfort, pH (> 7.30-7.35), respiratory rate (< 20-25 breaths/min), decrease of PaCO2 (by 10-20%), weaning from NIV, decrease in HCO3- and maintaining haemodynamic stability. Consensus was reached on weaning protocols for both indications. Anticoagulation with intravenous unfractionated heparin was the strategy preferred by the group. CONCLUSIONS: Insights from this group of experienced physicians suggest that ECCO2R therapy may be an effective supportive treatment for adults with ARDS or ae-COPD. Further evidence from randomised clinical trials and/or high-quality prospective studies is needed to better guide decision making.

Hyperammonemia, the Last Indication of High-Volume Hemodiafiltration in Adult and Children: A Structured Review.

Ammonia is a neurotoxic molecule that causes cerebral edema and encephalopathy. Ammonia is either produced in excess or poorly purified during severe hepatic insufficiency, poisoning, infection, and inborn errors of metabolism. During continuous renal replacement therapy, ammonia clearance is determined by the dialysate flow rate and the dialyzer surface area. Extra-renal blood purification for ammonia clearance has been studied in neonates with urea cycle disorders. Prognostic factors affecting patient outcome are thought to be the duration of coma, the patient's clinical status prior to dialysis, and the ammonia removal rate. In this review, we discuss the various dialytic modalities used for ammonia clearance as well as the thresholds for initiating dialysis and the better strategy ensures rapid patient protection from cerebral edema and herniation induced by hyperammonemia.

Angiotensin converting enzyme inhibitor intoxication: Naloxone to the rescue? Naloxone for ACE inhibitor intoxication.

We report here the case of a patient with perindopril intoxication inducing severe bradycardia together with a profound hypotension. Initiation of a naloxone infusion completely resolved those symptoms. As a consequence, we could recommend as a first step the use of naloxone in order to prevent the use of more invasive therapeutic tools.

An update on membranes and cartridges for extracorporeal blood purification in sepsis and septic shock.

PURPOSE OF REVIEW: This review aims to summarize the most recent advances on different membranes and cartridges used for extracorporeal blood purification in critically ill patients with sepsis or septic shock. RECENT FINDINGS: Despite positive signals from experimental, cases and small clinical studies, blood purification showed no distinct morbidity and mortality benefit in large clinical trials. SUMMARY: None of the discussed specific membranes or cartridges can currently be recommended as sole adjunctive treatment in sepsis and septic shock. Any available technique should be timely initiated and adapted to the patient's status. Sickest patients seem to benefit more from blood purification. Patient selection is thus of crucial importance and may be optimized by focusing on disease severity and degree of organ failure. Measurement of endotoxin activity and plasma procalcitonin levels can support the selection process but ideal cutoff values need to be defined. Well-designed prospective randomized clinical trials assessing or comparing the various available membranes and cartridges are eagerly awaited.