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Background: Tracheal intubation and invasive mechanical ventilation initiation is a procedure at high risk for arterial hypotension in intensive care unit. However, little is known about the relationship between pre-existing peripheral microvascular alteration and post-intubation hemodynamic instability (PIHI). Methods: Prospective observational monocenter study conducted in an 18-bed medical ICU. Consecutive patients requiring tracheal intubation were eligible for the study. Global hemodynamic parameters (blood pressure, heart rate, cardiac function) and tissue perfusion parameters (arterial lactate, mottling score, capillary refill time [CRT], toe-to-room gradient temperature) were recorded before, 5 min and 2 h after tracheal intubation (TI). Post intubation hemodynamic instability (PIHI) was defined as any hemodynamic event requiring therapeutic intervention. Results: During 1 year, 120 patients were included, mainly male (59%) with a median age of 68 [57–77]. The median SOFA score and SAPS II were 6 [4–9] and 47 [37–63], respectively. The main indications for tracheal intubation were hypoxemia (51%), hypercapnia (13%), and coma (29%). In addition, 48% of patients had sepsis and 16% septic shock. Fifty-one (42%) patients develop PIHI. Univariate analysis identified several baseline factors associated with PIHI, including norepinephrine prior to TI, sepsis, tachycardia, fever, higher SOFA and high SAPSII score, mottling score ≥ 3, high lactate level and prolonged knee CRT. By contrast, mean arterial pressure, baseline cardiac index, and ejection fraction were not different between PIHI and No-PIHI groups. After adjustment on potential confounders, the mottling score was associated with a higher risk for PIHI (adjusted OR: 1.84 [1.21–2.82] per 1 point increased; p = 0.005). Among both global haemodynamics and tissue perfusion parameters, baseline mottling score was the best predictor of PIHI (AUC: 0.72 (CI 95% [0.62–0.81]). Conclusions: In non-selected critically ill patients requiring invasive mechanical ventilation, tissue hypoperfusion parameters, especially the mottling score, could be helpful to predict PIHI. [ABSTRACT FROM AUTHOR]

To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58–86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45–2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points. In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo. ClinicalTrials.gov Identifier: NCT04325893 (https://clinicaltrials.gov/ct2/show/NCT04325893). [ABSTRACT FROM AUTHOR]

• The treatment of prosthetic joint infections (PJIs) due to Streptococcus agalactiae is associated with a high risk of relapse. • The conservative approach with debridement and implant retention has a poor prognosis. • Debridement, antibiotics and implant retention (DAIR) with polyethylene exchange is probably associated with a higher chance of success. • The one-stage exchange strategy in selected patients has an excellent cure rate. • No antimicrobial treatment seems to be superior for PJIs with streptococcal species. The optimal treatment of streptococcal prosthetic joint infections (PJIs) is unclear. A cohort of streptococcal PJIs was reviewed retrospectively in seven reference centers for the management of complex bone and joint infections, covering the period January 1, 2010 to December 31, 2012. Seventy patients with monomicrobial infections were included: 47 had infections of total hip arthroplasty and 23 had infections of total knee arthroplasty. The median age was 77 years (interquartile range (IQR) 69–83 years), the median Charlson comorbidity score was 4 (IQR 3–6), and 15.6% (n = 11) had diabetes. The most commonly identified streptococcal species were Streptococcus agalactiae and Streptococcus dysgalactiae (38.6% (n = 27) and 17.1% (n = 12), respectively). Debridement, antibiotics and implant retention (DAIR) was performed after a median time of 7 days (IQR 3–8 days), with polyethylene exchange (PE) in 21% of cases. After a minimum follow-up of 2 years, 27% of patients had relapsed, corresponding to 51.4% of DAIR treatment cases and 0% of one-stage (n = 15) or two-stage (n = 17) exchange strategy cases. Rifampicin or levofloxacin in combination therapy was not associated with a better outcome (adjusted p = 0.99). S. agalactiae species and DAIR treatment were associated with a higher risk of failure. On multivariate analysis, only DAIR treatment and S. agalactiae were independent factors of relapse. Compared to DAIR without PE, DAIR with PE was only associated with a trend towards a benefit (odds ratio 0.33, 95% confidence interval 0.06–1.96; adjusted p = 0.44). Streptococcal PJIs managed with DAIR have a poor prognosis and S. agalactiae seems to be an independent factor of treatment failure. [ABSTRACT FROM AUTHOR]

Objectives: Cefoxitin and imipenem are the sole recommended β-lactams for the treatment of Mycobacterium abscessus pulmonary infections. Here, we investigated whether one of these drugs displays superiority in terms of killing and intracellular activity. We have also evaluated whether the use of a β-lactamase inhibitor could improve their activity.Methods: The impact of the β-lactamase BlaMab on the activity of β-lactams was assessed by comparing M. abscessus CIP104536 and its β-lactamase-deficient ΔblaMab derivative, as well as by using the β-lactamase inhibitor avibactam. The activity of cefoxitin, imipenem, amoxicillin and ceftaroline, alone and in various combinations including amikacin, was compared based on determination of time-kill curves and of intracellular proliferation in human macrophages.Results: Imipenem was superior to cefoxitin in both the time-kill and macrophage assays. Production of BlaMab limited the activity of imipenem. The combination of imipenem and amikacin was bactericidal against the ΔblaMab mutant. Deletion of blaMab extended the spectrum of β-lactams active against M. abscessus to include amoxicillin and ceftaroline. In the absence of BlaMab, amoxicillin was as active as imipenem. These drugs were more active than ceftaroline and cefoxitin was the least active. Avibactam increased the intracellular activity of ceftaroline, but inhibition of BlaMab was only partial, as previously reported for amoxicillin.Conclusions: Evaluation of the killing and intracellular activities of β-lactams indicates that imipenem is superior to cefoxitin at clinically achievable drug concentrations. Inhibition of BlaMab could improve the efficacy of imipenem and extend the spectrum of drugs potentially useful to treat pulmonary infections. [ABSTRACT FROM AUTHOR]

Objectives: Two β-lactams, cefoxitin and imipenem, are part of the reference treatment for pulmonary infections with Mycobacterium abscessus. M. abscessus has recently been shown to produce a broad-spectrum β-lactamase, BlaMab, indicating that the combination of β-lactams with a BlaMab inhibitor may improve treatment efficacy. The objectives of this study were to evaluate the impact of BlaMab production on the efficacy of β-lactams in vitro and to assess the benefit of BlaMab inhibition on the activity of β-lactams intracellularly and in an animal model. Methods: We analysed the mechanism and kinetics of BlaMab inactivation by avibactam, a non-β-lactam β-lactamase inhibitor currently in Phase III of development, in combination with ceftazidime for the treatment of serious infections due to Gram-negative bacteria. We then deleted the gene encoding BlaMab to assess the extent of BlaMab inhibition by avibactam based on a comparison of the impact of chemical and genetic inactivation. Finally, the efficacy of amoxicillin in combination with avibactam was evaluated in cultured human macrophages and in a zebrafish model of M. abscessus infection. Results: We showed that avibactam efficiently inactivated BlaMab via the reversible formation of a covalent adduct. An inhibition of BlaMab by avibactam was observed in both infected macrophages and zebrafish. Conclusions: Our data identify avibactam as the first efficient inhibitor of BlaMab and strongly suggest that β-lactamase inhibition should be evaluated to provide improved therapeutic options for M. abscessus infections. [ABSTRACT FROM AUTHOR]

Objectives Imipenem and cefoxitin are used to treat Mycobacterium abscessus infections and have moderate activity against this fast-growing mycobacterium (MIC50 of 16 and 32 mg/L, respectively). M. abscessus is highly resistant to most other β-lactams, although the underlying mechanisms have not been explored. Here, we characterized M. abscessus class A β-lactamase (BlaMab) and investigated its role in β-lactam resistance. Methods Hydrolysis kinetic parameters of purified BlaMab were determined by spectrophotometry for various β-lactams and compared with those of related BlaC from Mycobacterium tuberculosis. MICs of β-lactams were determined for M. abscessus CIP104536 and for Escherichia coli producing BlaMab and BlaC. Results BlaMab had a broad hydrolysis spectrum, similar to that of BlaC, but with overall higher catalytic efficiencies, except for cefoxitin. As expected from its in vivo efficacy, cefoxitin was very slowly hydrolysed by BlaMab (kcat/Km = 6.7 M−1 s−1). BlaMab hydrolysed imipenem more efficiently (kcat/Km = 3.0×104 M−1 s−1), indicating that the in vivo activity of this drug might be improved by combination with a β-lactamase inhibitor. β-Lactamase inhibitors clavulanate, tazobactam and sulbactam did not inhibit BlaMab. This enzyme efficiently hydrolysed clavulanate, in contrast to BlaC, which is irreversibly acylated by this inhibitor. BlaMab and BlaC were functional in E. coli and the resistance profiles mediated by these enzymes were in agreement with the kinetic parameters. Conclusions M. abscessus produces a clavulanate-insensitive broad-spectrum β-lactamase that limits the in vivo efficacy of β-lactams. [ABSTRACT FROM PUBLISHER]

Active-site serine D,D-transpeptidases belonging to the penicillin-binding protein family (PBPs) have been considered for a long time as essential for peptidoglycan cross-linking in all bacteria. However, bypass of the PBPs by an L,D-transpeptidase (Ldtfm) conveys high-level resistance to β-lactams of the penam class in Enterococcus faecium with a minimal inhibitory concentration (MIC) of ampicillin >2,000 µg/ml. Unexpectedly, Ldtfm does not confer resistance to β-lactams of the carbapenem class (imipenem MIC = 0.5 µg/ml) whereas cephems display residual activity (ceftriaxone MIC = 128 µg/ml). Mass spectrometry, fluorescence kinetics, and NMR chemical shift perturbation experiments were performed to explore the basis for this specificity and identify β-lactam features that are critical for efficient L,D-transpeptidase inactivation. We show that imipenem, ceftriaxone, and ampicillin acylate Ldtfm by formation of a thioester bond between the active-site cysteine and the β-lactam-ring carbonyl. However, slow acylation and slow acylenzyme hydrolysis resulted in partial Ldtfm inactivation by ampicillin and ceftriaxone. For ampicillin, Ldtfm acylation was followed by rupture of the C5–C6 bond of the β-lactam ring and formation of a secondary acylenzyme prone to hydrolysis. The saturable step of the catalytic cycle was the reversible formation of a tetrahedral intermediate (oxyanion) without significant accumulation of a non-covalent complex. In agreement, a derivative of Ldtfm blocked in acylation bound ertapenem (a carbapenem), ceftriaxone, and ampicillin with similar low affinities. Thus, oxyanion and acylenzyme stabilization are both critical for rapid L,D-transpeptidase inactivation and antibacterial activity. These results pave the way for optimization of the β-lactam scaffold for L,D-transpeptidase-inactivation. [ABSTRACT FROM AUTHOR]

In this prospective study, 50 patients with early-onset spinal implant infections received treatment consisting of debridement surgery with implant retention followed by combination antibiotic therapy for 3 months. Results were not inferior to those previously reported with longer treatments.Background. Optimal duration and modalities of antibiotic therapy for early-onset spinal implant infection (EOSII) remain controversial.Methods. Between November 2004 and November 2007, we conducted a prospective, monocentric study to assess the efficacy of a 3-month course of antibiotics for patients diagnosed with EOSII, as defined by a proven deep infection of the surgical site occurring within 30 days after spinal instrumented surgery. All patients with EOSII underwent surgical debridement with implant retention. Combination antibiotic therapy was administered intravenously for 2 weeks. Treatment was switched orally for the following 10 weeks.Results. 50 patients matched the inclusion criteria and were included in this study. The median age was 68 (interquartile range [IQR]: 51–75) years; the median ASA score was 2 (IQR: 2–2). Emergency spinal surgery had been performed in 18 patients. Staphylococcus aureus was the most frequently isolated pathogen (n = 27), followed by Enterobacteriaceae (n = 22) and coagulase-negative staphylococci (n = 6). Seventeen patients had polymicrobial infections, and 13 patients (26%) had bacteremia. The median time from the first symptoms of infection to debridement surgery was 3 days (IQR: 2–5 days). Three patients underwent 2 debridement surgeries. The median follow-up was 43 (IQR: 34–54) months. The 2-year survival rate for those who did not experience treatment failure was 88% (95% confidence interval [CI]: 75.7%–95.5%). Three patients experienced treatment failure (6%, 95% CI: 1.3%–16.5%), including 1 relapse due to methicillin-susceptible S. aureus and 2 reinfections with another pathogen.Conclusions. In this homogenous cohort of 50 patients with EOSII, treatment consisting of debridement surgery with implant retention followed by combination antibiotic therapy for 3 months appeared safe and effective. [ABSTRACT FROM AUTHOR]

Objectives Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study. Methods Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible. Results One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L). Conclusions Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule. [ABSTRACT FROM AUTHOR]

Background: Lung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may allow early identification of patients who are likely to develop an acute respiratory distress syndrome (ARDS). We hypothesized that L-POCUS performed within the first 48 hours of non-critical patients with suspected COVID-19 would identify those with a high-risk of worsening. Methods: POCUSCO was a prospective, multicenter study. Non-critical adult patients who presented to the emergency department (ED) for suspected or confirmed COVID-19 were included and had L-POCUS performed within 48 hours following ED presentation. The lung damage severity was assessed using a previously developed score reflecting both the extension and the intensity of lung damage. The primary outcome was the rate of patients requiring intubation or who died within 14 days following inclusion. Results: Among 296 patients, 8 (2.7%) met the primary outcome. The area under the curve (AUC) of L-POCUS was 0.80 [95%CI:0.60–0.94]. The score values which achieved a sensibility >95% in defining low-risk patients and a specificity >95% in defining high-risk patients were <1 and ≥16, respectively. The rate of patients with an unfavorable outcome was 0/95 (0%[95%CI:0–3.9]) for low-risk patients (score = 0), 4/184 (2.17%[95%CI:0.8–5.5]) for intermediate-risk patients (score 1–15) and 4/17 (23.5%[95%CI:11.4–42.4]) for high-risk patients (score ≥16). In confirmed COVID-19 patients (n = 58), the AUC of L-POCUS was 0.97 [95%CI:0.92–1.00]. Conclusion: L-POCUS performed within the first 48 hours following ED presentation allows risk-stratification of patients with non-severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: Unique blood culture (UBC) has been proposed to limit the number of venipuncture and to decrease the risk of BC contaminations (BCC) without affecting their yield. We hypothesized that a multi-faceted program based on UBC in the ICU may reduce the rate of contaminants with a similar performance for bloodstream infections (BSI) identification. Methods: In a before and after design, we compared the proportion of BSI and BCC. A first 3-year period with multi-sampling (MS) strategy followed by a 4-month washout period, where staff received education and training for using UBC, and a 32-month period, where UBC was routinely used, while education and feedback were maintained. During the UBC period, a large volume of blood (40 mL) was sampled through a unique venipuncture with additional BC collections discouraged for 48 h. Results: Of the 4,491 patients included (35% female patients, mean age 62 years) 17,466 BC were collected. The mean volume of blood per bottle collected increased from 2.8 ± 1.8 mL to 8.2 ± 3.9 mL between the MS and UBC periods, P < 0.01. A 59.6% reduction (95% CI 56.7–62.3; P < 0.001) of BC bottles collected per week was observed between the MS and UBC periods. The rate of BCC per patient decreased between the two periods from 11.2% to 3.8% (73.4% reduction; P < 0.001) for the MS and UBC periods, P < 0.001. Meanwhile, the rate of BSI per patient remained stable at 13.2% and 13.2% for the MS and UBC periods, P = 0.98. Conclusions: In ICU patients, a strategy based on UBC reduces the contamination rate of cultures without affecting their yield. [ABSTRACT FROM AUTHOR]

Background Enterococcus faecalis infective endocarditis (EFIE) is characterized by a higher frequency of relapses than other infective endocarditis. The role of the treatment on its occurrence remains poorly understood. The aim of this study was to investigate whether the antibiotic regimen could impact the risk of relapse in EFIE. Materials This was a multicenter retrospective study of patients diagnosed with definite EFIE between 2015 and 2019 in 14 French hospitals. The primary endpoint was the occurrence of relapses within the year following endocarditis diagnosis. As death was a competing risk for relapse, Fine and Gray models were used for studying risk factors and impact of treatment. Results Of the 279 patients included, 83 (29.7%) received the amoxicillin-gentamicin (A-G) combination, 114 (40.9%) amoxicillin-ceftriaxone (A-C), 63 (22.6%) A-G and A-C (A-G/A-C) sequentially, 9 (3.2%) amoxicillin (A), and 10 received other treatments. One-year-relapse rate was 9.3% (26 patients). Relapse occurred after a median delay of 107 days from EFIE diagnosis; 6 occurred after 6 months, and 6 were diagnosed by blood cultures in asymptomatic patients. In multivariate analysis, surgery during treatment was a protective factor against one-year relapse and death. The cumulative incidence of relapse 1 year after endocarditis was 46.2% for patients treated with amoxicillin, 13.4% with A-G, 14.7% with A-C, and 4.3% with A-G/A-C (P ≥.05 in multivariate analysis). Conclusions Relapses after treatment of EFIE are frequent, frequently asymptomatic, and may occur more than 6 months after the initial episode. [ABSTRACT FROM AUTHOR]

Objectives: To describe the clinical features and outcomes of infective endocarditis (IE) in pregnant women who do not inject drugs.Methods: A multinational retrospective study was performed at 14 hospitals. All definite IE episodes between January 2000 and April 2021 were included. The main outcomes were maternal mortality and pregnancy-related complications.Results: Twenty-five episodes of IE were included. Median age at IE diagnosis was 33.2 years (IQR 28.3-36.6) and median gestational age was 30 weeks (IQR 16-32). Thirteen (52%) patients had no previously known heart disease. Sixteen (64%) were native IE, 7 (28%) prosthetic and 2 (8%) cardiac implantable electronic device IE. The most common aetiologies were streptococci (n = 10, 40%), staphylococci (n = 5, 20%), HACEK group (n = 3, 12%) and Enterococcus faecalis (n = 3, 12%). Twenty (80%) patients presented at least one IE complication; the most common were heart failure (n = 13, 52%) and symptomatic embolism other than stroke (n = 4, 16%). Twenty-one (84%) patients had surgery indication and surgery was performed when indicated in 19 (90%). There was one maternal death and 16 (64%) patients presented pregnancy-related complications (11 patients ≥1 complication): 3 pregnancy losses, 9 urgent Caesarean sections, 2 emergency Caesarean sections, 1 fetal death, and 11 preterm births. Two patients presented a relapse during a median follow-up of 3.1 years (IQR 0.6-7.4).Conclusions: Strict medical surveillance of pregnant women with IE is required and must involve a multidisciplinary team including obstetricians and neonatologists. Furthermore, the potential risk of IE during pregnancy should never be underestimated in women with previously known underlying heart disease. [ABSTRACT FROM AUTHOR]

Ventriculitis is a severe complication of CSF drainage; staphylococci and Gram-negative bacilli (including I Pseudomonas aeruginosa i ) being the two main categories of pathogens responsible for this infection.[1],[2] Ventriculitis is a difficult-to-treat infection associated with poor outcomes.[3] Cefiderocol is a new injectable siderophore cephalosporin antibiotic with an extended Gram-negative activity spectrum including carbapenem-resistant bacteria. Iterative CSF analyses were done every 48 h and CSF cultures remained negative while leucocyte count in CSF decreased to 9 cells/mL. The per-surgery CSF culture yielded I P. aeruginosa i with the same antibiotic susceptibility profile, and the patient received a second course of meropenem and ciprofloxacin. [Extracted from the article]

Background: Gut colonization by ESBL-producing Enterobacteriaceae (ESBL-PE) is widespread and is promoted by antibiotic exposure. Higher fecal abundance of ESBL-PE promotes the dissemination of the bacteria in the environment and is associated with increased risk of infection. Ceftriaxone and temocillin are commonly used antibiotics with a different activity on gut flora. Their impact on fecal abundance of ESBL-producing Enterobacteriaceae has not been studied. The objective of this study was to compare the propensity of ceftriaxone and temocillin to modify the abundance of ESBL-producing Escherichia coli in feces of colonized mice. Methods: Mice received broad-spectrum antibiotics in order to disrupt their normal gut flora. A CTX-M-type ESBL-producing E. coli clinical isolate was then administered orally, leading to durable colonization. Thirty days later, mice received either temocillin or ceftriaxone with drinking water at a concentration simulating human intestinal exposure. Third-generation-cephalosporin resistant (3GCR) E. coli were enumerated in feces on selective medium before, 2 days and 10 days after the end of antibiotic exposure. The experiment was performed with two E. coli isolates with different temocillin minimum inhibitory concentrations. Results: Exposure to ceftriaxone induced an increase in the fecal abundance of 3GCR E. coli. In contrast, temocillin had no effect or transiently decreased the number of 3GCR E. coli. Results obtained with the two strains were similar. Conclusion: Contrary to ceftriaxone, temocillin does not promote expansion of ESBL-producing E. coli in feces of colonized mice. Thus temocillin may be a therapeutic of choice when a temocillin-susceptible strain infection is suspected or proven to prevent the expansion of ESBL-PE in a previously colonized patient. [ABSTRACT FROM AUTHOR]

Background: With the lack of effective therapy, chemoprevention, and vaccination against SARS-CoV-2, focusing on the immediate repurposing of existing drugs gives hope of curbing the COVID-19 pandemic. A recent unbiased genomics-guided tracing of the SARS-CoV-2 targets in human cells identified vitamin D among the three top-scoring molecules manifesting potential infection mitigation patterns. Growing pre-clinical and epidemiological observational data support this assumption. We hypothesized that vitamin D supplementation may improve the prognosis of COVID-19. The aim of this trial is to compare the effect of a single oral high dose of cholecalciferol versus a single oral standard dose on all-cause 14-day mortality rate in COVID-19 older adults at higher risk of worsening.Methods: The COVIT-TRIAL study is an open-label, multicenter, randomized controlled superiority trial. Patients aged ≥ 65 years with COVID-19 (diagnosed within the preceding 3 days with RT-PCR and/or chest CT scan) and at least one worsening risk factor at the time of inclusion (i.e., age ≥ 75 years, or SpO2 ≤ 94% in room air, or PaO2/FiO2 ≤ 300 mmHg), having no contraindications to vitamin D supplementation, and having received no vitamin D supplementation > 800 IU/day during the preceding month are recruited. Participants are randomized either to high-dose cholecalciferol (two 200,000 IU drinking vials at once on the day of inclusion) or to standard-dose cholecalciferol (one 50,000 IU drinking vial on the day of inclusion). Two hundred sixty participants are recruited and followed up for 28 days. The primary outcome measure is all-cause mortality within 14 days of inclusion. Secondary outcomes are the score changes on the World Health Organization Ordinal Scale for Clinical Improvement (OSCI) scale for COVID-19, and the between-group comparison of safety. These outcomes are assessed at baseline, day 14, and day 28, together with the serum concentrations of 25(OH)D, creatinine, calcium, and albumin at baseline and day 7.Discussion: COVIT-TRIAL is to our knowledge the first randomized controlled trial testing the effect of vitamin D supplementation on the prognosis of COVID-19 in high-risk older patients. High-dose vitamin D supplementation may be an effective, well-tolerated, and easily and immediately accessible treatment for COVID-19, the incidence of which increases dramatically and for which there are currently no scientifically validated treatments.Trial Registration: ClinicalTrials.gov NCT04344041 . Registered on 14 April 2020 TRIAL STATUS: Recruiting. Recruitment is expected to be completed in April 2021. [ABSTRACT FROM AUTHOR]

Introduction. Treatment of Haemophilus influenzae (Hi) pneumonia is on concern because resistance to amoxicillin is largely diffused. This study describes the evolution of resistance to amoxicillin and amoxicillin/clavulanic acid (AMC) in Hi isolates and characteristics of patients with Hi severe pneumonia. Methods. A monocentric retrospective observational study including patients from 2008 to 2017 with severe pneumonia hospitalized in ICU. Evolution of amoxicillin and AMC susceptibility was showed. Characteristics of patients with Hi pneumonia were compared to characteristics of patients with Streptococcus pneumoniae (Sp) pneumonia, as reference. Risk factors for amoxicillin resistance in Hi were investigated. Results. Overall, 113 patients with Hi and 132 with Sp pneumonia were included. The percentages of AMC resistance among Hi strains decreased over the years (from 10% in 2008-2009 to 0% in 2016-2017) while resistance to amoxicillin remained stable at 20%. Also, percentages of Sp resistant strains for amoxicillin decreased over years (from 25% to 3%). Patients with Hi pneumonia experienced higher prevalence of bronchitis (18% vs. 8%, p = 0.02 , chronic obstructive pulmonary disease (43% vs. 30% p = 0.03), HAP (18% vs. 7%, p = 0.01 , ventilator-associated pneumonia (27% vs. 17%, p = 0.04 , and longer duration of mechanical ventilation (8 days vs. 6 days, p = 0.04) than patients with Sp pneumonia. Patients with Sp pneumonia had more frequently local complications than patients with Hi pneumonia (17% vs. 7%, p = 0.03). De-escalation of antibiotics was more frequent in patients with Sp than in patients with Hi (67% vs. 53%, p = 0.03). No risk factors were associated with amoxicillin resistance among patients with Hi pneumonia. Conclusions. Amoxicillin resistance was stable over time, but no risk factors were detected. AMC resistance was extremely low, suggesting that AMC could be used for empiric treatment of Hi pneumonia, as well as other molecules, namely, cephalosporins. Patients with Hi pneumonia had more pulmonary comorbidities and severe diseases than patients with Sp pneumonia. [ABSTRACT FROM AUTHOR]

Objectives: Metabolic acidosis is commonly observed in critically ill patients. Experimental studies suggested that acidosis by itself could impair vascular function, but this has been poorly investigated in human.Design: Prospective observational study.Setting: Medical ICU in a tertiary teaching hospital.Patients: To assess the relationship between metabolic acidosis severity and microvascular reactivity, we included adult diabetic patients admitted in ICU for ketoacidosis. Microvascular response to acetylcholine iontophoresis was measured at admission (baseline) and after correction of metabolic acidosis (24 hr).Interventions: None.Measurements and Main Results: Thirty-nine patients with diabetic ketoacidosis were included (68% male), with a median age of 43 (31-57) years. At admission, microvascular reactivity negatively correlated with acidosis severity (R = -0.53; p < 0.001). Microvascular response was strongly depressed at pH less than 7.20 (area under the curve, 1,779 [740-3,079] vs 12,944 [4,874-21,596] at pH > 7.20; p < 0.0001). In addition, acidosis severity was significantly correlated with capillary refill time (R = 0.50; p = 0.02). At H24, after rehydration and insulin infusion, clinical and biological disorders were fully corrected. After acidosis correction, microvascular reactivity increased more in patients with severe baseline acidosis (pH < 7.20) than in those with mild baseline acidosis (area under the curve, +453% [213%-1,470%] vs +121% [79%-312%]; p < 0.01).Conclusions: We identified an alteration of microvascular reactivity during metabolic acidosis in critically ill patients with diabetic ketoacidosis. Microvascular hyporeactivity recovered after acidosis correction. [ABSTRACT FROM AUTHOR]

Infections due to Mycobacterium abscessus carry a poor prognosis since this rapidly growing mycobacterium is intrinsically resistant to most antibiotics. Here, we evaluate the in vitro activity of the new oxazolidinone tedizolid against a collection of 44 M. abscessus clinical isolates. The MIC 50 s and MIC 90 s of tedizolid (2 and 8 μg/mL, respectively) were 2- to 16-fold lower than those of linezolid. There was no difference between the 3 M. abscessus subspecies. Time-kill assays did not show any bactericidal activity at 4- and 8-fold the MIC. Combination of tedizolid with clarithromycin was synergistic against 1 out of 6 isolates, while indifferent interactions were observed for tedizolid combined with tigecycline, ciprofloxacin, and amikacin. [ABSTRACT FROM AUTHOR]

Objectives: Mycobacterium tuberculosis and Mycobacterium abscessus produce broad-spectrum class A β-lactamases, BlaC and Bla Mab , which are inhibited by clavulanate and avibactam, respectively. BlaC differs from Bla Mab at Ambler position 132 in the conserved motif SDN (SDG versus SDN, respectively). Here, we investigated whether this polymorphism could account for the inhibition specificity of β-lactamases from slowly and rapidly growing mycobacteria.Methods: Enzyme kinetics were determined to assess the impact of the substitutions G 132 N in BlaC and N 132 G in Bla Mab on β-lactamase inhibition by clavulanate and avibactam. The stability of acylenzymes was evaluated by MS. The impact of the substitutions on the antibacterial activity of drug combinations was determined based on production of the β-lactamases in Escherichia coli .Results: The substitution G 132 N increased 140-fold the efficacy of BlaC inhibition by avibactam and abolished clavulanate inhibition due to acylenzyme hydrolysis. Bla Mab efficiently hydrolysed clavulanate, but the substitution N 132 G led to a 5600-fold reduction in the hydrolysis rate constant k cat due to stabilization of Bla Mab -clavulanate covalent adducts. The N 132 G substitution also led to a 610-fold reduction in the efficacy of Bla Mab carbamylation by avibactam. Testing resistance to the amoxicillin/clavulanate and amoxicillin/avibactam combinations revealed that modifications in the catalytic properties of the β-lactamases resulted in opposite shifts from susceptibility to resistance and vice versa.Conclusions: G 132 N and N 132 G had opposite effects on the inhibition of BlaC and Bla Mab , indicating that these substitutions might lead to acquisition of resistance to either of the β-lactamase inhibitors, but not to both of them. [ABSTRACT FROM AUTHOR]

Background: Third-generation cephalosporins (3GCs) are recommended for empirical antibiotic therapy of community-acquired pneumonia (CAP) in patients requiring ICU admission. However, their extensive use could promote the emergence of extended-spectrum beta-lactamases-producing Enterobacteriaceae. Our aim was to assess whether the use of 3GCs in patients with CAP requiring ICU admission was justified. Methods: We assessed all patients with CAP who required ICU admission during a 7-year period. We recorded empirical and definitive antibiotic therapies and susceptibility of causative pathogens. Amoxicillin, amoxicillin/clavulanate (A/C) susceptibilities as well as amikacin susceptibility of A/C-resistant strains were recorded. Results: From January 2007 to March 2014, 391 patients were included in the study. Empirical 3GCs were used in 215 patients (55%). Among 267 patients with microbiologically documented CAP (68%), 241 received a beta-lactam as definitive therapy, and of those, 3CGs were chosen for 43 patients (18%). Amoxicillin or A/C was active against isolated pathogens in 159 patients (66%), while 39 patients (16%) required a beta-lactam with a broader spectrum than 3GCs. Ninety-four per cent of A/C-resistant strains were amikacin susceptible. Conclusions: In ICU patients with CAP, 3GCs given on an empirical basis are changed, according to microbiological documentation, for another beta-lactam in 82% of cases especially to A/C in the absence of resistance risk factor. In patients evidencing risk factors for A/C-resistant strains infection, 3GCs or antipseudomonal beta-lactams including carbapenem associated with amikacin in the most severe patients seem a relevant empirical antibiotic therapy. This strategy could decrease 3GCs' use. [ABSTRACT FROM AUTHOR]

Fungal infections remain hardly treatable because of unstandardized diagnostic tests, limited antifungal armamentarium, and more specifically, potential toxic interactions between antifungals and immunosuppressants used during anti-inflammatory therapies, such as those set up in critically ill COVID-19 patients. Taking into account pre-existing difficulties in treating vulnerable COVID-19 patients, any co-occurrence of infectious diseases like fungal infections constitutes a double debacle for patients, healthcare experts, and the public economy. Since the first appearance of SARS-CoV-2, a significant rise in threatening fungal co-infections in COVID-19 patients has been testified in the scientific literature. Better management of fungal infections in COVID-19 patients is, therefore, a priority and requires highlighting common risk factors, relationships with immunosuppression, as well as challenges in fungal diagnosis and treatment. The present review attempts to highlight these aspects in the three most identified causative agents of fungal co-infections in COVID-19 patients: Aspergillus , Candida , and Mucorales species. [ABSTRACT FROM AUTHOR]

Background: Microcirculatory disorders leading to tissue hypoperfusion play a central role in the pathophysiology of organ failure in severe sepsis and septic shock. As microcirculatory disorders have been identified as strong predictive factors of unfavourable outcome, there is a need to develop accurate parameters at the bedside to evaluate tissue perfusion. We evaluated whether different body temperature gradients could relate to sepsis severity and could predict outcome in critically ill patients with severe sepsis and septic shock. Method: We conducted a prospective observational study in a tertiary teaching hospital in France. During a 10-month period, all consecutive adult patients with severe sepsis or septic shock who required ICU admission were included. Six hours after initial resuscitation (H6), we recorded the hemodynamic parameters and four temperature gradients: central-to-toe, central-to-knee, toe-to-room and knee-to-room. Results: We evaluated 40 patients with severe sepsis (40/103, 39 %) and 63 patients with septic shock (63/103, 61 %). In patients with septic shock, central-to-toe temperature gradient was significantly higher (12.5 [9.2; 13.8] vs 6.9 [3.4; 12.0] °C, P < 0.001) and toe-to-room temperature gradient significantly lower (1.2 [−0.3; 5.2] vs 6.0 [0.6; 9.5] °C, P < 0.001) than in patients with severe sepsis. Overall ICU mortality rate due to multiple organ failure (MOF) was 21 %. After initial resuscitation, toe-to-room temperature gradient was significantly lower in patients dead from MOF than in the survivors (−0.2 [−1.1; +1.3] °C vs +3.9 [+0.5; +7.2] °C, P < 0.001) and the difference in gradients increased during the first 24 h. Furthermore, toe-to-room temperature gradient was related to tissue perfusion parameters such as arterial lactate level ( r = −0.54, P < 0.0001), urine output ( r = 0.37, P = 0.0002), knee capillary refill time ( r = −0.42, P < 0.0001) and mottling score ( P = 0.001). Conclusions: Toe-to-room temperature gradient reflects tissue perfusion at the bedside and is a strong prognosis factor in critically ill patients with severe infections. [ABSTRACT FROM AUTHOR]

Combinations of β-lactams of the carbapenem class, such as meropenem, with clavulanate, a β-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual β-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum β-lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the β-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide-alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable β-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the l,d-transpeptidase LdtMt1 target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of LdtMt1 and reduced hydrolysis by BlaC. [ABSTRACT FROM AUTHOR]

Abstract: The efficacy of fosfomycin alone or combined with cefoxitin was investigated in vitro and in a murine model of urinary tract infection due to susceptible Escherichia coli CFT073-RR and its transconjugant CFT073-RR Tc (pbla CTX-M-15) harbouring a plasmid carrying the bla CTX-M-15 gene. In vitro, the combination of cefoxitin and fosfomycin was synergistic and bactericidal and prevented the emergence of fosfomycin-resistant mutants of CFT073-RR and CFT073-RR Tc (pbla CTX-M-15) that were selected with fosfomycin alone. In vivo, the combination conferred an advantage in terms of kidney sterilisation of mice infected with either strain compared with fosfomycin monotherapy. [Copyright &y& Elsevier]

The article describes the case of autoimmune vasculitis in a context of persistent Coxiella burnetii infection in a 73-year-old man. Highlights include mild inflammatory syndrome revealed by blood tests, treatment with doxycycline and hydroxychloroquine for a planned duration of 18 months, and a pauci-immune extracapillary crescentic glomerulonephritis demonstrated by renal biopsy.

Peptidoglycan is predominantly cross-linked by serine dd-transpeptidases in most bacterial species. The enzymes are the essential targets of β-lactam antibiotics. However, unrelated cysteine ld-transpeptidases have been recently recognized as a predominant mode of peptidoglycan cross-linking in Mycobacterium tuberculosis and as a bypass mechanism conferring resistance to all β-lactams, except carbapenems such as imipenem, in Enterococcus faecium. Investigation of the mechanism of inhibition of this new β-lactam target showed that acylation of the E. faecium enzyme (Ldtfm) by imipenem is irreversible. Using fluorescence kinetics, an original approach was developed to independently determine the catalytic constants for imipenem binding (k1 = 0.061 μm-1 min-1) and acylation (kinact = 4.5 min-1). The binding step was limiting at the minimal drug concentration required for bacterial growth inhibition. The Michaelis complex was committed to acylation because its dissociation was negligible. The emergence of imipenem resistance involved substitutions in Ldtfm that reduced the rate of formation of the non-covalent complex but only marginally affected the efficiency of the acylation step. The methods described in this study will facilitate development of new carbapenems active on extensively resistant M. tuberculosis. [ABSTRACT FROM AUTHOR]

• For IgG detection >14 days after symptoms onset was 100.0 % for all assays. • Specificity for IgG was greater than 98 % for CLIA and LFIA compared to ELISA. • LFIA (NG-Test®) is reliable and accurate to diagnose SARS-CoV-2 infection. • Best agreement was observed between CLIA and LFIA assays (97 %; k = 0.936). The emergence of new SARS-CoV-2 has promoted the development of new serological tests that could be complementary to RT-PCR. Nevertheless, the assessment of clinical performances of available tests is urgently required as their use has just been initiated for diagnose. The aim of this study was to assess the performance of three immunoassays for the detection of SARS-CoV-2 antibodies. Two automated immunoassays (Abbott SARS-CoV-2 CLIA IgG and Euroimmun Anti-SARS-CoV-2 ELISA IgG/IgA assays) and one lateral flow immunoassay (LFIA NG-Test® IgG-IgM COVID-19) were tested. 293 specimens were analyzed from patients with a positive RT-PCR response, from patients with symptoms consistent with COVID-19 but exhibiting a negative response to the RT-PCR detection test, and from control group specimens. Days since symptoms onset were collected from clinical information sheet associated with respiratory tract samples. Overall sensitivity for IgG was equivalent (around 80 %) for CLIA, ELISA and LFIA. Sensitivity for IgG detection, >14 days after onset of symptoms, was 100.0 % for all assays. Overall specificity for IgG was greater for CLIA and LFIA (more than 98 %) compared to ELISA (95.8 %). Specificity was significantly different between IgA ELISA (78.9 %) and IgM LFIA (95.8 %) (p < 0.05). The best agreement was observed between CLIA and LFIA assays (97 %; k = 0.936). Excellent sensitivity for IgG detection was obtained >14 days after onset of symptoms for all immunoassays. Specificity was also excellent for IgG CLIA and IgG LFIA. Our study shows that NG-Test® is reliable and accurate for routine use in clinical laboratories. [ABSTRACT FROM AUTHOR]