Lopinavir pharmacokinetics in COVID-19 patients Gregoire, Matthieu; Le Turnier, Paul; Gaborit, Benjamin J ...
Journal of antimicrobial chemotherapy,
09/2020, Letnik:
75, Številka:
9
Journal Article
Recenzirano
Odprti dostop
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in late 2019. Therapeutic solutions are currently being tested for COVID-19, the SARS-CoV-2-associated ...pneumonia. Ritonavir-boosted lopinavir is included in the investigational therapies. A recent in vitro study reported that lopinavir inhibits SARS-CoV-2 replication with a 50% effective concentration (EC50) of 16 720 ng/mL.1Here we describe lopinavir pharmacokinetics in COVID-19 patients treated with ritonavir-boosted lopinavir at the Nantes University Hospital, France.
A 75-year-old man presented to a French hospital with a 4-day fever after returning from a coronavirus disease-19 (COVID-19) cluster region. A reverse-transcription polymerase chain reaction test was ...positive for severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) using a nasopharyngeal swab sample. After he returned home and a telephone follow-up, he was found deceased 9 days after first showing symptoms. Whole-body, non-enhanced, post-mortem computed tomography (PMCT) and a forensic autopsy were performed approximately 48 h after death, with sanitary precautions. The PMCT showed bilateral and diffuse
crazy-paving
lung opacities, with bilateral pleural effusions. Post-mortem virology studies detected the presence of SARS-CoV-2 (B.1 lineage) in the nasopharynx, plasma, lung biopsies, pleural effusion and faeces confirming the persistence of viral ribonucleic acid 48 h after death. Microscopic examination showed that severe lung damage was responsible for his death. The main abnormality was diffuse alveolar damage, associated with different stages of inflammation and fibrosis. This case is one of the first to describe complete post-mortem data for a COVID-19 death and highlights the ability of PMCT to detect severe involvement of the lungs before autopsy in an apparently natural death. The present pathology results are concordant with previously reported findings and reinforce the disease pathogenesis hypothesis of combined viral replication with an inappropriate immune response.
Abstract
Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory ...T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.
Treg are involved early in immunosuppression during sepsis. The TNFR2pos Treg subset appears to induce a state of immunosuppression and increases the susceptibility to secondary infection. Inhibiting TNFR2pos Treg could represent a prophylactic treatment of pneumonia in the intensive care unit.
...the definite diagnosis of COVID-19 mostly relies on positive RT-PCR on respiratory samples, although discriminant features have been reported on thoracic CT scan.1 However, access to these ...diagnostic tests is limited in the context of this large-scale pandemic. ...the sample size was small and the response rate suboptimal. ...as the diagnosis relied on detection of SARS-CoV-2 by RT-PCR on nasopharyngeal samples, suboptimal sensitivity of this test (as low as 60% in some reports) might have led to misclassification and diagnostic bias.7 However, this preliminary report of an association between hypogeusia or hyposmia and COVID-19 diagnosis in patients with ILI suggests that these symptoms might be a useful tool for initial diagnostic work-up in patients with suspected COVID-19.
Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and ...efficacy of a short course of intravenous ATO in patients with active SLE.
This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS).
Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4).
A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy.
ClinicalTrials.gov, NCT01738360 registered 30 November 2012.
Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical presentation, severity, and mortality ...of PcP has not been adequately evaluated.
Does the underlying disease and immunosuppression causing PcP impact the outcome and clinical presentation of the disease?
In this multicenter retrospective observational study, conducted from January 2011 to December 2021, all consecutive patients admitted with a proven or probable diagnosis of PcP according to the European Organisation for Research and Treatment of Cancer consensus definitions were included to assess the epidemiology and impact of underlying immunosuppressive diseases on overall and 90-day mortality.
Overall, 481 patients were included in the study; 180 (37.4%) were defined as proven PcP and 301 (62.6%) were defined as probable PcP. Patients with immune-mediated inflammatory diseases (IMIDs) or solid tumors had a statistically poorer prognosis than other patients with PcP at day 90. In multivariate analysis, among the HIV-negative population, solid tumor underlying disease (OR, 5.47; 95% CI, 2.16-14.1; P < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; P = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; P = .045), cysts in sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; P = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; P < .001) were independently associated with 90-day mortality. Prior corticotherapy was the only immunosuppressant associated with 90-day mortality (OR, 1.67; 95% CI, 1.03-2.71; P = .035), especially for a prednisone daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; P = .010).
Among patients who were HIV-negative, long-term corticosteroid prior to PcP diagnosis was independently associated with increased 90-day mortality, specifically in patients with IMIDs. These results highlight both the needs for PcP prophylaxis in patients with IMIDs and to early consider PcP curative treatment in severe pneumonia among patients with IMIDs.
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Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical presentation, severity, and mortality ...of PcP has not been adequately evaluated.
Does the underlying disease and immunosuppression causing PcP impact the outcome and clinical presentation of the disease?
In this multicenter retrospective observational study, conducted from January 2011 to December 2021, all consecutive patients admitted with a proven or probable diagnosis of PcP according to the European Organisation for Research and Treatment of Cancer consensus definitions were included to assess the epidemiology and impact of underlying immunosuppressive diseases on overall and 90-day mortality.
Overall, 481 patients were included in the study; 180 (37.4%) were defined as proven PcP and 301 (62.6%) were defined as probable PcP. Patients with immune-mediated inflammatory diseases (IMIDs) or solid tumors had a statistically poorer prognosis than other patients with PcP at day 90. In multivariate analysis, among the HIV-negative population, solid tumor underlying disease (OR, 5.47; 95% CI, 2.16-14.1; P < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; P = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; P = .045), cysts in sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; P = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; P < .001) were independently associated with 90-day mortality. Prior corticotherapy was the only immunosuppressant associated with 90-day mortality (OR, 1.67; 95% CI, 1.03-2.71; P = .035), especially for a prednisone daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; P = .010).
Among patients who were HIV-negative, long-term corticosteroid prior to PcP diagnosis was independently associated with increased 90-day mortality, specifically in patients with IMIDs. These results highlight both the needs for PcP prophylaxis in patients with IMIDs and to early consider PcP curative treatment in severe pneumonia among patients with IMIDs.
Abstract
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.
Ludwig’s angina: A diagnostic and surgical priority Vallée, Maxime; Gaborit, Benjamin; Meyer, Jérémy ...
International journal of infectious diseases,
April 2020, 2020-Apr, 2020-04-00, 2020-04-01, Letnik:
93
Journal Article
Recenzirano
Odprti dostop
•Ludwig’s angina is a frequently fatal rapidly progressive necrotizing cellulitis of the floor of the mouth, the throat and the neck.•Ludwig’s angina should not be confused with Lemierre’s syndrome, ...different in terms of pathophysiology and therapeutic.•We present four cases of severe necrotizing cervical cellulitis notably associated to concomitant self-medication with NSAIDs.•To treat anaerobic bacteria and streptococci, B-lactams(penicillin with βLase inhibitors) +/- combination with clindamycin, should be used.
Ludwig’s angina has been known for two centuries as a rapidly and frequently fatal progressive gangrenous cellulitis or necrotizing fasciitis of the neck and the floor of the mouth. The management of the usually young patients affected requires a trained team combining medical skills in surgery, antibiotic therapy, and resuscitation. The prognosis is directly related to early surgical debridement and the experience of the team managing these patients. We present four cases of severe necrotizing cervical cellulitis notably associated with concomitant self-medication with non-steroidal anti-inflammatory drugs. Through these cases, we conclude that several surgical steps could be required, combined with broad-spectrum antibiotic therapy. An optimal surgery, draining all collections and excising all necrotic tissues, seems to be a condition needed for antibiotic efficacy and finally healing.
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