Validity of surrogate endpoints assessing central venous catheter-related infection: evidence from individual- and study-level analyses.

OBJECTIVES: The prevention of catheter-related bloodstream infection (CRBSI) has been an area of intense research, but the heterogeneity of endpoints used to define catheter infection makes the interpretation of randomized controlled trials (RCTs) problematic. The aim of this study was to determine the validity of different endpoints for central venous catheter infections. DATA SOURCES: (a) Individual-catheter data were collected from 9428 catheters from four large RCTs; (b) study-level data from 70 RCTs were identified with a systematic search. Eligible studies were RCTs published between January 1987 and October 2018 investigating various interventions to reduce infections from short-term central venous catheters or short-term dialysis catheters. For each RCT the prevalence rates of CRBSI, quantitative catheter tip colonization, catheter-associated infection (CAI) and central line-associated bloodstream infection (CLABSI) were extracted for each randomized study arm. METHODS: CRBSI was used as the gold-standard endpoint, for which colonization, CAI and CLABSI were evaluated as surrogate endpoints. Surrogate validity was assessed as (1) the individual partial coefficient of determination (individual-pR2) using individual catheter data; (2) the coefficient of determination (study-R2) from mixed-effect models regressing the therapeutic effect size of the surrogates on the effect size of CRBSI, using study-level data. RESULTS: Colonization showed poor agreement with CRBSI at the individual-patient level (pR2 = 0.33 95% CI 0.28-0.38) and poor capture at the study level (R2 = 0.42, 95% CI 0.21-0.58). CAI showed good agreement with CRBSI at the individual-patient level (pR2 = 0.80, 95% CI 0.76-0.83) and moderate capture at the study level (R2 = 0.71, 95% CI 0.51-0.85). CLABSI showed poor agreement with CRBSI at the individual patient level (pR2 = 0.34, 95% CI 0.23-0.46) and poor capture at the study level (R2 = 0.28, 95% CI 0.07-0.76). CONCLUSIONS: CAI is a moderate to good surrogate endpoint for CRBSI. Colonization and CLABSI do not reliably reflect treatment effects on CRBSI and are consequently more suitable for surveillance than for clinical effectiveness research.

Association of transcription factor 7-like 2 gene (TCF7L2) polymorphisms with stress-related hyperglycaemia (SRH) in intensive care and resulting outcomes: The READIAB study.

OBJECTIVE: The study aimed to evaluate the impact of the single nucleotide polymorphism (SNP) rs7903146 on the transcription factor 7-like 2 (TCF7L2) gene in stress-related hyperglycaemia (SRH), defined as blood glucose≥11mmol/L in at least two blood samples during the first 3 days in the intensive care unit (ICU), and on 28-day and 1-year mortality, and incidence of type 2 diabetes (T2D) at 6 months and 1 year in patients hospitalized in the ICU. METHODS: This prospective observational (non-interventional) multicentre READIAB study, carried out during 2012-2016 in six French ICUs, involved adult patients admitted to ICUs for at least two organ failures; patients admitted for<48h were excluded. During the 3-day ICU observational period, genetic testing, blood glucose values and insulin treatment were recorded. MAIN RESULTS: The association of rs7903146 with SRH was assessed using logistic regression models. Cox proportional hazards regression models assessed the associations between rs7903146 and mortality and between SRH and mortality, both at 28 days and 1 year. A total of 991 of the 1000 enrolled patients were included in the READIAB-G4 cohort, but 242 (24.4%) had preexisting diabetes and were excluded from the analyses. SRH occurred within the first 3 days in the ICU for one-third of the non-diabetes patients. The association between the rs7903146 polymorphism and SRH did not reach significance (P=0.078): OR(peroneTcopy): 1.24, 95% CI: 0.98-1.58. A significant association was found between rs7903146 and 28-day mortality after adjusting for severity scores (P=0.026), but was no longer significant at 1 year (P=0.61). At 28 days, mortality was increased in patients with SRH (HR: 2.09, 95% CI: 1.43-3.06; P<0.001), and remained significant at 1 year after adjusting for severity scores (HR: 1.73, 95% CI: 1.32-2.28; P<0.001). On admission, non-diabetes patients with SRH had a higher incidence of T2D at 6 months vs. those without SRH (16.0% vs. 7.6%, RR: 2.11, 95% CI: 1.07-4.20; P=0.030). At 1 year, these figures were 13.4% vs. 9.2%, RR: 1.45, 95% CI: 0.71-2.96; P=0.31). Moreover, the rs7903146 polymorphism was not significantly associated with T2D development at either 6 months (P=0.72) or 1 year (P=0.64). CONCLUSION: This study failed to demonstrate any significant association between rs7903146 and SRH. Nevertheless, the issue remains an important challenge, as SRH may be associated with increased rates of both mortality and T2D development.

[Infective endocarditis due to Bartonella henselae following a rupture of a cerebral aneurysm]. / Endocardite infectieuse àBartonella henselae précédée par la rupture d'un anévrisme cérébral.

We report a case of severe aortic bicuspid valve endocarditis, revealed by global cardiac failure without fever, in a 38-year-old man who had developed cerebral mycotic aneurysms nine months earlier. PCR analysis of the excised aortic valve and serological tests (even 9 months earlier) were positive for Bartonella henselae. A combination of intravenous then oral doxycyclin at 200mg/day and intravenous gentamycin at 90mg/day was given for 6 and 2 weeks respectively. The evolution was favorable on follow-up, 12 months after completion of the therapy. Only 49 cases of B. henselae endocarditis have been reported to date, none with associated mycotic aneurysm but most often located on the bicuspid aortic valve, and usually with severe valvular damage due to late diagnosis.

Corticosteroids as adjunctive treatment in Austrian's syndrome (pneumococcal endocarditis, meningitis, and pneumonia): report of two cases and review of the literature.

This report describes two cases of Osler's triad of pneumonia, meningitis, and endocarditis, as a result of Streptococcus pneumoniae infection, also called Austrian's syndrome. In the first patient, a 51 year old non-alcoholic man, the aortic valve was affected and needed to be replaced in an emergency operation. The mitral valve was affected in a 70 year old woman without underlying disease, who only benefited from medical treatment. Both patients received corticosteroids, either dexamethasone followed by low doses of hydrocortisone and fludrocortisone, or only hydrocortisone and fludrocortisone, at the onset of the illness, and their outcome was favourable. These case reports focus on the presentation, prognosis, and therapeutic options for this severe syndrome.

Hyperreninemic hypoaldosteronism: a possible etiological factor of septic shock-induced acute renal failure.

OBJECTIVE: Hyperreninemic hypoaldosteronism has been described in critically ill patients. The present study investigated the plasma aldosterone concentration (PAC) in septic shock patients and its relationship with clinical course. DESIGN AND SETTING: Prospective descriptive study in a medical intensive care unit (ICU) of a university hospital. PATIENTS: Forty-six consecutive patients with septic shock as defined by the ACCP/SCCM criteria. INTERVENTION: A corticotropin stimulation test, followed by treatment with low doses of hydrocortisone and fludrocortisone. MEASUREMENTS AND RESULTS: Plasma renin activity, PAC, and cortisol levels were measured before and after the test. PAC measurements were repeated for 1 week. Relevant clinical and laboratory variables were recorded for ICU stay. Patients were divided into two groups according to PAC/renin activity ratio: above 2 (n=24 patients) and below 2 n=22). Patients with PAC/renin activity less than 2 had higher total volume of infused fluid, serum creatinine level, and fractional excretion of sodium values; aldosterone and serum creatinine were negatively correlated. Hypoaldosteronism was reversible within 1 week. Duration of ICU stay (p=0.0026) and the need for renal replacement therapy (p=0.0021) were greater in the group with PAC/renin less than 2. CONCLUSIONS: Transient hyperreninemic hypoaldosteronism is common in patients with septic shock. These abnormal aldosterone levels are associated with greater sodium and fluid depletion and are followed by enhanced incidence of acute renal failure requiring renal replacement therapy and prolonged length of stay in ICU.

Unique blood culture for diagnosis of bloodstream infections in emergency departments: a prospective multicentre study.

Detection of microorganisms by blood cultures (BCs) is essential in managing patients with bacteraemia. Rather than the number of punctures, the volume of blood drawn is considered paramount in efficient and reliable detection of microorganisms. We performed a 1-year prospective multicentre study in adult emergency departments of three French university hospitals comparing two methods for BCs: a unique blood culture (UBC) collecting a large volume of blood (40 mL) and the standard method of multiple blood cultures (MBC). The performances of both methods for bacterial contamination and efficient microbial detection were compared, each patient serving as his own control. Amongst the 2314 patients included, three hundred were positive for pathogens (n=245) or contaminants (n=55). Out of the 245 patients, 11 were positive for pathogens by UBC but negative by MBC and seven negative by UBC but positive by MBC (p 0.480). In the subgroup of 137 patients with only two BCs, UBC was superior to MBC (p 0.044). Seven and 17 patients had contaminated BCs by UBC and MBC only, respectively (p 0.062). Considering the sums of pathogens missed and contaminants, UBC significantly outperformed MBC (p 0.045). Considering the complete picture of cost savings, efficient detection of microorganisms and decrease in contaminations, UBC offers an interesting alternative to MBC.

Hospital-wide modification of fluoroquinolone policy and meticillin-resistant Staphylococcus aureus rates: a 10-year interrupted time-series analysis.

In our tertiary university hospital, fluoroquinolones were prohibited during 2001 leading to a 90% reduction in their use. Our objective was to examine the trends in meticillin-resistant Staphylococcus aureus (MRSA) following the reintroduction of fluoroquinolones. We conducted a 10-year time-series analysis of monthly MRSA according to: (i) period of fluoroquinolone restriction (January 2001 to January 2002); (ii) period of fluoroquinolone increase up to pre-restriction levels (January 2002 to December 2004); and (iii) an observational period including the implementation of a hand hygiene campaign with alcohol-based hand rub (January 2005 to June 2009). We used segmented linear autoregression analysis to assess trends between adjacent periods. Fluoroquinolone use increased from 5.2 defined daily doses (DDD) per 1000 patient-days in 2001 to 56.6 DDD per 1000 patient-days in 2005 reaching pre-restriction fluoroquinolone levels (P<0.001) and remained stable during 2005-2010 (P=0.65). The monthly proportion of MRSA decreased during the period of FQ restriction (-0.49 per month, P<0.05). The reintroduction of fluoroquinolones was associated with a significant increase in MRSA (+0.68 per month, P<0.02) compared to the previous period. During period 3, we observed a significant change in MRSA (-5.9, P<0.002) compared to the previous period (-0.32 per month, P<0.001). During the latter period, hand hygiene was promoted and alcohol-based hand-rub consumption increased from 3411 L in 2005 to 14,599 L in 2009. This study reinforces the rationale for a hospital-wide fluoroquinolone formulary policy to control MRSA and suggests that it has an additive effect with a hand hygiene promotion.

[Regulation of the luminal Na+/H+ exchanger NHE3 by intracellular protein trafficking]. / Régulation de l'activité de l'échangeur Na+/H+ apical NHE3 par trafic intracellulaire de la protéine.

The article summarizes some of the recent developments in the understanding of the mechanisms of regulation of the proximal tubule apical membrane Na+/H+ antiporter NHE3. NHE3 antiporter has a major role in HCO3- and NaCl reabsorption in the proximal tubule. NHE3 protein is associated with the regulatory factor NHERF which interacts with ezrin, an actin-binding protein. This multi-protein complex constitutes a link between a membrane protein, NHE3, and actin cytoskeleton. Cytoskeleton organization has a key role to control NHE3 activity under normal conditions. Pharmacological perturbations of actin polymerization interfere with NHE3 activity. Parathyroid hormone-induced NHE3 activity inhibition results first, from a protein kinase A-mediated phosphorylation without protein trafficking, and then from endocytosis involving dynamin. The stimulatory effect of systemic angiotensin II concentrations on NHE3 activity is protein kinase C-dependent and results, at least in part, from exocytic insertion of the protein in luminal membranes. It requires cytoskeleton integrity.

NHE3 activity and trafficking depend on the state of actin organization in proximal tubule.

The present study was addressed to define the contribution of cytoskeleton elements in the kidney proximal tubule Na+/H+ exchanger 3 (NHE3) activity under basal conditions. We used luminal membrane vesicles (LMV) isolated from suspensions of rat cortical tubules pretreated with either colchicine (Colch) or cytochalasin D (Cyto D). Colch pretreatment of suspensions (200 microM for 60 min) moderately decreased LMV NHE3 activity. Cyto D pretreatment (1 microM for 60 min) elicited an increase in LMV NHE3 transport activity but did not increase Na-glucose cotransport activity. Cyto D pretreatment of suspensions did not change the apparent affinity of NHE3 for internal H+. In contrast, after Cyto D pretreatment of the suspensions, NHE3 protein abundance was increased in LMV and remained unchanged in cortical cell homogenates. The effect of Cyto D on NHE3 was further assessed with cultures of murine cortical cells. The amount of surface biotinylated NHE3 increased on Cyto D treatment, whereas NHE3 protein abundance was unchanged in cell homogenates. In conclusion, under basal conditions NHE3 activity depends on the state of actin organization possibly involved in trafficking processes between luminal membrane and intracellular compartment.