Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis.

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.

New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale.

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

Predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae causing infection among intensive care unit patients with prior colonization.

We investigated the predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) causing infections among intensive care unit patients with prior documented ESBL-PE colonization. Using multivariate analysis, referral from medical ward, nursing home or rehabilitation center [Odds ratio (OR), 2.5; 95 % confidence interval (CI), [1.3-5.0]; p = 0.007], previous fluoroquinolone treatment (OR, 3.4; CI, [1.1-10.5]; p = 0.003), extracorporeal membrane oxygenation (OR, 4.6; CI, [1.3-15.9]; p = 0.02), and absence of prior positive ESBL-PE rectal swab culture (OR, 5.0; CI, [1.6-10.0]; p = 0.0009) were risk factors for ESBL-PE infection. Easily identifiable factors may help with targeting carbapenem prescriptions.

Late dihydroartemisinin-piperaquine treatment failure of P. falciparum malaria attack related to insufficient dosing in an obese patient.

We report the case of an obese patient who experienced late failure on day28 of a well-conducted treatment with artesunate, followed by dihydroartemisinin-piperaquine (DHA-PPQ) for a severe P. falciparum malaria attack. The same P. falciparum strain was evidenced at day0 and day28. Genotypic and phenotypic resistance tests could not explain this treatment failure. The low plasma piperaquine concentration at failure may explain the poor elimination of residual parasites.

Characteristics of deep vein thrombosis in the critically ill COVID-19 patient - an observational cohort study with Doppler ultrasound measurements.

OBJECTIVE: COVID-19 is associated with an increased prevalence of deep venous thrombosis (DVT), mainly in the lower limbs. However, the characteristics and rheological conditions, which contribute to facilitating DVT occurrence have been poorly investigated. We aimed to report DVT characteristics, vein diameters and peak blood flow velocities (PBFV) in the common femoral veins (CFVs) of critically ill COVID-19 patients. PATIENTS AND METHODS: We conducted a prospective single-center cohort study in March-October 2020 including all consecutive mechanically ventilated COVID-19 adults. Doppler ultrasound of the lower limbs was performed systematically during the first week of hospitalization. In DVT-free patients, a second Doppler ultrasound was performed seven days later. Data are expressed as medians (interquartile ranges) or percentages. Comparisons were performed using Mann-Whiney and Wilcoxon signed-rank tests or Fischer's exact tests, as appropriate. RESULTS: Fifty-five patients [age, 63 years (56-74); female/male ratio, 0.62; body-mass index, 29 kg/m2 (26-33); hypertension, 47%; diabetes, 38%; ischemic heart disease, 11%] were included. DVT was diagnosed in 19 patients (35%) including in 5 femoral (9%), 2 popliteal (4%) and 12 below-the-knee sites (22%). CFV diameter was increased to 12.0 mm (11.0-15.0) (normal range, 9.1-12) and PBFV reduced to 11.9 cm/s (8.8-15.8) (normal range, 21.3-49.2) [right-side values]. In four patients who had ultrasound before intubation, CFV diameter increased from 12.5 mm (11.8-13.3) before to 14 mm (13.6-15.3) after intubation (p = 0.008). CONCLUSIONS: DVT in the CFV occurred in 9% of the critically ill COVID-19 patients with an overall 35%-DVT prevalence. Venous return difficulty evidenced by larger than normal CFV diameters and lower than normal PBFVs may have facilitated proximal DVT occurrence.

Imbalance between procoagulant factors and natural coagulation inhibitors contributes to hypercoagulability in the critically ill COVID-19 patient: clinical implications.

OBJECTIVE: Coronavirus Disease-2019 (COVID-19) predisposes patients to thrombosis which underlying mechanisms are still incompletely understood. We sought to investigate the balance between procoagulant factors and natural coagulation inhibitors in the critically ill COVID-19 patient and to evaluate the usefulness of hemostasis parameters to identify patients at risk of venous thromboembolic event (VTE). PATIENTS AND METHODS: We conducted an observational study recording VTEs defined as deep vein thrombosis or pulmonary embolism using lower limb ultrasound (92% of the patients), computed tomography pulmonary angiography (6%) and both tests (2%). We developed a comprehensive analysis of hemostasis. RESULTS: Ninety-two consecutive mechanically ventilated COVID-19 patients (age, 62 years [53-69] (median [25th-75th percentiles]); M/F sex ratio, 2.5; body-mass index, 28 kg/m2 [25-32]; past hypertension (52%) and diabetes mellitus (30%)) admitted to the Intensive Care Unit (ICU) from 03/11/2020 to 5/05/2020, were included. When tested, patients were receiving prophylactic (74%) or therapeutic (26%) anticoagulation. Forty patients (43%) were diagnosed with VTE. Patients displayed inflammatory and prothrombotic profile including markedly elevated plasma fibrinogen (7.7 g/L [6.1-8.6]), D-dimer (3,360 ng/mL [1668-7575]), factor V (166 IU/dL [136-195]) and factor VIII activities (294 IU/dL [223-362]). We evidenced significant discrepant protein C anticoagulant and chromogenic activities, combined with slightly decreased protein S activity. Plasma D-dimer >3,300 ng/mL predicted VTE presence with 78% (95%-confidence interval (95% CI), 62-89) sensitivity, 69% (95% CI, 55-81) specificity, 66% (95% CI, 51-79) positive predictive value and 80% (95% CI, 65-90) negative predictive value [area under the ROC curve, 0.779 (95%CI, 0.681-0.859), p=0.0001]. CONCLUSIONS: Mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway. Plasma D-dimer may be a useful biomarker at the bedside for suspicion of VTE.

Exogenous acquisition of Pseudomonas aeruginosa in intensive care units: a prospective multi-centre study (DYNAPYO study).

BACKGROUND: Pseudomonas aeruginosa remains one of the most common nosocomial pathogens in intensive care units (ICUs). Although exogenous acquisition has been widely documented in outbreaks, its importance is unclear in non-epidemic situations. AIM: To elucidate the role of exogenous origin of P. aeruginosa in ICU patients. METHODS: A chronological analysis of the acquisition of P. aeruginosa was performed using samples collected in 2009 in the DYNAPYO cohort study, during which patients and tap water were screened weekly. Molecular relatedness of P. aeruginosa isolates was investigated by pulsed-field gel electrophoresis. Exogenous acquisition was defined as identification of a P. aeruginosa pulsotype previously isolated from another patient or tap water in the ICU. FINDINGS: The DYNAPYO cohort included 1808 patients (10,402 samples) and 233 water taps (4946 samples). Typing of 1515 isolates from 373 patients and 375 isolates from 81 tap water samples identified 296 pulsotypes. Analysis showed exogenous acquisition in 170 (45.6%) of 373 patients. The pulsotype identified had previously been isolated from another patient and from a tap water sample for 86 and 29 patients, respectively. The results differed according to the ICU. CONCLUSION: Exogenous acquisition of P. aeruginosa could be prevented in half of patients. The overall findings of this survey support the need for studies on routes of transmission and risk assessment approach to better define how to control exogenous acquisition in ICUs.

The tyrosine kinase substrate eps15 is constitutively associated with the plasma membrane adaptor AP-2.

The ubiquitous eps15 protein was initially described as a substrate of the EGF receptor kinase. Its functions are not yet delineated and this work provides evidence for its possible role in endocytosis. A novel anti-eps15 antibody, 6G4, coimmunoprecipitated proteins of molecular mass 102 kD. In human cells, these proteins were identified as the alpha- and beta-adaptins of the AP-2 complex on the basis of their NH2-terminal sequence and their immunoreactivity with anti-alpha- and anti-beta-adaptin antibodies but not with anti-gamma-adaptin antibody. In addition, the anti-eps15 antibody coimmunoprecipitated metabolically labeled polypeptides with molecular mass of 50 and 17 kD, comparable to those of the two other components of the AP-2 complex, mu2 and sigma 2. Constitutive association of eps15 with AP-2 was confirmed by two sets of experiments. First, eps15 was detected in immunoprecipitates of anti-alpha- and anti-beta-adaptin antibodies. Second, alpha- and beta- but not gamma-adaptins were precipitated by a glutathione-S-transferase eps15 fusion protein. The association of eps15 with AP-2 was ubiquitous and conserved between species, since it was observed in human lymphocytes and epithelial cells and in murine NIH3T3 fibroblasts. Our results are in keeping with a recent study showing homology between the NH2-terminal domains of eps15 and the product of the gene END3, involved in clathrin-mediated endocytosis of the pheromone alpha factor in Saccharomyces cerevisiae, and suggest a possible role for eps15 in clathrin-mediated endocytosis in mammals.

[The American opioid overdose crisis: A threat for France?] / La crise des overdoses américaines : une menace pour la France ?

Since the 2000s, a concerning increase in opioid-analgesic-related overdoses and deaths has been reported in the United States. In contrast with opioid overdoses reported in the 80-90s mostly involving heroin, currently it is the misuse of opioid analgesics that is mainly responsible for opioid overdoses. This crisis is related to factors (not limited to the US) which occurred during the 90s and which have led to a broad prescription of opioids in non-cancer pain. In Europe and France, there is (but to a much lesser extent) an increase in strong opioid consumption and in opioid prescription related morbi-mortality. This situation, which can be described as "worrying" today, requires awareness among the French medical community, both upstream (rational prescription of opioids) and downstream (optimal management of opioid poisoning) from the opioid prescription.

[The serotonin syndrome: An updated literature review]. / Le syndrome sérotoninergique : une revue actualisée de la littérature.

The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome.

A 2-year multicenter, observational, prospective, cohort study on extracorporeal CO2 removal in a large metropolis area.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) is a promising technique for the management of acute respiratory failure, but with a limited level of evidence to support its use outside clinical trials and/or data collection initiatives. We report a collaborative initiative in a large metropolis. METHODS: To assess on a structural basis the rate of utilization as well as efficacy and safety parameters of 2 ECCO2R devices in 10 intensive care units (ICU) during a 2-year period. RESULTS: Seventy patients were recruited in 10 voluntary and specifically trained centers. The median utilization rate was 0.19 patient/month/center (min 0.04; max 1.20). ECCO2R was started under invasive mechanical ventilation (IMV) in 59 patients and non-invasive ventilation in 11 patients. The Hemolung Respiratory Assist System (Alung) was used in 53 patients and the iLA Activve iLA kit (Xenios Novalung) in 17 patients. Main indications were ultraprotective ventilation for ARDS patients (n = 24), shortening the duration of IMV in COPD patients (n = 21), preventing intubation in COPD patients (n = 9), and controlling hypercapnia and dynamic hyperinflation in mechanically ventilated patients with severe acute asthma (n = 6). A reduction in median V T was observed in ARDS patients from 5.9 to 4.1 ml/kg (p <0.001). A reduction in PaCO2 values was observed in AE-COPD patients from 67.5 to 51 mmHg (p< 0.001). Median duration of ECCO2R was 5 days (IQR 3-8). Reasons for ECCO2R discontinuation were improvement (n = 33), ECCO2R-related complications (n = 18), limitation of life-sustaining therapies or measures decision (n = 10), and death (n = 9). Main adverse events were hemolysis (n = 21), bleeding (n = 17), and lung membrane clotting (n = 11), with different profiles between the devices. Thirty-five deaths occurred during the ICU stay, 3 of which being ECCO2R-related. CONCLUSIONS: Based on a registry, we report a low rate of ECCO2R device utilization, mainly in severe COPD and ARDS patients. Physiological efficacy was confirmed in these two populations. We confirmed safety concerns such as hemolysis, bleeding, and thrombosis, with different profiles between the devices. Such results could help to design future studies aiming to enhance safety, to demonstrate a still-lacking strong clinical benefit of ECCO2R, and to guide the choice between different devices. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT02965079 retrospectively registered https://clinicaltrials.gov/ct2/show/NCT02965079.

Snake Bites by Bothrops lanceolatus in Martinique.

Bothrops lanceolatus, a member of the Viperidae family and Crotalinae subfamily, is the only snake causing envenomation in Martinique, which is the only place it exists in the world. Any bite by this snake may result in severe thrombotic complications including cerebral, pulmonary, and myocardial infarction and affecting the patient's vital or functional prognosis. The exact composition of the venom as well as the mechanisms of toxicity involved are still debated today. The first specific antivenom immunotherapy (AVI), Bothrofav1, manufactured in 1991, reduced mortality and morbidity significantly. In 2004, however, an increase in the number of cases of Bothrops lanceolatus envenomation-induced ischemic strokes despite early AVI administration, raised questions about its effectiveness and encouraged the development of a second AVI, Bothrofav2, which became available in February 2011. Causes of the failures with the first AVI remain hypothetical, and the effectiveness of the second is under evaluation. This article reviews the published data available on this rare envenomation, present in one of our French overseas departments and discusses its fascinating scientific and medical issues.

Paraquat poisoning in Western French Guyana: a public health problem persisting ten years after its withdrawal from the French market.

OBJECTIVE: Paraquat poisoning has almost disappeared from metropolitan France following its ban from the European market ten years ago. However, due to neighboring countries still authorizing paraquat use, French Guyana seems in a different situation. Here we aimed to report a series of paraquat-poisoned patients admitted to the emergency department of the Western French Guyana Hospital in Saint-Laurent du Maroni, to raise awareness of national health authorities on this persistent major issue. PATIENTS AND METHODS: We conducted a retrospective observational study describing the clinical features, the prognostic factors and the final outcome of paraquat-poisoned patients admitted to the emergency department between January 2008 and August 2014. RESULTS: Twenty-six paraquat-poisoned patients were included in the study. The median estimated paraquat dose intentionally ingested was 105 mg/kg (interquartile range, IQR: 359). Eighteen patients were treated with the cyclophosphamide/dexamethasone combination and seventeen with N-acetylcysteine in addition to the usual supportive care. Six patients survived and twenty died within a median 36h delay after admission (IQR: 130). Death was associated with cardiovascular (65%) and respiratory (35%) failure. Based on a bivariate analysis, predictive factors of death included (p≤0.05): advanced age, higher ingested paraquat dose, altered renal function, hypokalemia, acidosis, and dark blue dithionite test, observed on hospital admission. CONCLUSIONS: Paraquat poisoning still persists in French Guyana despite its withdrawal from the market. It is possible to determine the probability of death on patient admission based on routine clinical and biological parameters. There is an urgent need to request neighboring countries to ban paraquat with the aim of eradicating this dramatically life-threatening poisoning.

Severe atypical pneumonia in critically ill patients: a retrospective multicenter study.

BACKGROUND: Chlamydophila pneumoniae (CP) and Mycoplasma pneumoniae (MP) patients could require intensive care unit (ICU) admission for acute respiratory failure. METHODS: Adults admitted between 2000 and 2015 to 20 French ICUs with proven atypical pneumonia were retrospectively described. Patients with MP were compared to Streptococcus pneumoniae (SP) pneumonia patients admitted to ICUs. RESULTS: A total of 104 patients were included, 71 men and 33 women, with a median age of 56 [44-67] years. MP was the causative agent for 76 (73%) patients and CP for 28 (27%) patients. Co-infection was documented for 18 patients (viruses for 8 [47%] patients). Median number of involved quadrants on chest X-ray was 2 [1-4], with alveolar opacities (n = 61, 75%), interstitial opacities (n = 32, 40%). Extra-pulmonary manifestations were present in 34 (33%) patients. Mechanical ventilation was required for 75 (72%) patients and vasopressors for 41 (39%) patients. ICU length of stay was 16.5 [9.5-30.5] days, and 11 (11%) patients died in the ICU. Compared with SP patients, MP patients had more extensive interstitial pneumonia, fewer pleural effusion, and a lower mortality rate [6 (8%) vs. 17 (22%), p = 0.013]. According MCA analysis, some characteristics at admission could discriminate MP and SP. MP was more often associated with hemolytic anemia, abdominal manifestations, and extensive chest radiograph abnormalities. SP-P was associated with shock, confusion, focal crackles, and focal consolidation. CONCLUSION: In this descriptive study of atypical bacterial pneumonia requiring ICU admission, mortality was 11%. The comparison with SP pneumonia identified clinical, laboratory, and radiographic features that may suggest MP or CP pneumonia.

Acute lower limb ischemia is a frequent complication of severe diabetic hyperosmolarity.

AIM: To describe the outcome of intensive care unit (ICU) patients admitted with a hyperglycaemic hyperosmolar non-ketotic syndrome (HHNS), with a specific analysis of precipitating conditions and complications including lower limb ischemia. METHODS: Retrospective review of patients admitted in a university-hospital ICU for HHNS. RESULTS: Seventeen consecutive patients (9F/8M, age: 75 years [57-81] (median [25-75% percentiles], Glasgow Coma score: 13 [12-14]) were admitted for HHNS over an 8-year period (1998-2005). On admission, the blood glucose level was 40.0 mmol/l [26.3-60.8], the corrected serum sodium concentration 167 mmol/l [158-174], and the calculated plasma osmolarity 384 mosmol/l [365-405]. All the patients presented with renal failure due to severe dehydration. An infection was identified as the precipitating factor in 8/17 cases. Three (18%) patients died in the ICU. Non-survivors were significantly older than survivors (P=0.02). Using univariate analysis, no other parameter measured on admission was related to mortality. Four patients (24%) presented with lower limb ischemia. They had a significantly more elevated blood urea nitrogen (P=0.03), creatinine phosphokinase level (P=0.04), and leukocyte count (P=0.02). The bilateral, symmetrical, and distal extremity involvement suggested diminished blood flow due to hyperviscosity, hypotension, vasoconstrictors, or cholesterol emboli rather than a proximal arterial obstruction as causative mechanisms. No patient was treated surgically. Ischemia reversed with fluid loading and resulted in toe dry digital necrosis. CONCLUSION: HHNS is a rare but life-threatening cause of ICU admission. There is a high incidence of lower limb ischemia in HHNS patients, which may be related to dehydration and blood hyperviscosity.