Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody ...that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease.
In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization.
In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P = 0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively).
Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060.).
Neglected endemic mycoses Queiroz-Telles, Flavio; Fahal, Ahmed Hassan; Falci, Diego R ...
The Lancet infectious diseases,
November 2017, 2017-11-00, 20171101, Letnik:
17, Številka:
11
Journal Article
Recenzirano
Fungi often infect mammalian hosts via the respiratory route, but traumatic transcutaneous implantation is also an important source of infections. Environmental exposure to spores of pathogenic fungi ...can result in subclinical and unrecognised syndromes, allergic manifestations, and even overt disease. After traumatic cutaneous inoculation, several fungi can cause neglected mycoses such as sporotrichosis, chromoblastomycosis, mycetoma, entomophthoramycosis, and lacaziosis. Most of these diseases have a subacute to chronic course and they can become recalcitrant to therapy and lead to physical disabilities, including inability to work, physical deformities, and amputations. For many years, paracoccidioidomycosis was considered the most prevalent endemic systemic mycosis in the Americas, but this situation might be changing with recognition of the worldwide presence of Histoplasma capsulatum. Both paracoccidioidomycosis and histoplasmosis can mimic several infectious and non-infectious medical conditions and lead to death if not recognised early and treated. Cutaneous implantation and systemic mycoses are neglected diseases that affect millions of individuals worldwide, especially in low-income countries where their management is suboptimum because challenges in diagnosis and therapeutic options are substantial issues.
Background. Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. Methods. ...Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography—tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. Results. Twenty-four patients aged 21–87 years received intravenous polymyxin B (0.45–3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10–143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r2 = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. Conclusions. Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.
Polymyxins are valuable antimicrobials for the management of multidrug-resistant Gram-negative bacteria; however, nephrotoxicity associated with these drugs is a very common side effect that occurs ...during treatment. This article briefly reviews nephrotoxic mechanisms and risk factors for polymyxin-associated acute kidney injury (AKI) and discusses dosing strategies that may mitigate kidney damage without compromising antimicrobial activity. Polymyxins have a very narrow therapeutic window and patients requiring treatment with these drugs are frequently severely ill and have multiple comorbidities, which increases the risk of AKI. Notably, there is a significant overlap between therapeutic and toxic plasma polymyxin concentrations that substantially complicates dose selection. Recent dosing protocols for both colistin and polymyxin B have been developed and may help fine tune dose adjustment of these antibiotics. Minimizing exposure to modifiable risk factors, such as other nephrotoxic agents, is strongly recommended. The dose should be carefully selected, particularly in high-risk patients. The administration of oxidative stress-reducing drugs is a promising strategy to ameliorate polymyxin-associated AKI, but still requires support from clinical studies.
Summary
Despite the existence of endemic mycoses in Latin America and the Caribbean, in addition to a large population of patients at risk for invasive mycoses, the capability of medical centres to ...perform a proper diagnosis in mycology has not been studied in the region. Moreover, availability of antifungal drugs in the region is unknown. Here, we report the results of a survey involving 129 centres in 24 countries. Only 9% of centres would have the potential to apply for the minimum standards in mycology, as determined by the European Confederation of Medical Mycology. There is an urgent need to improve diagnostic conditions in Latin America and the Caribbean, as well as providing access to safer and more efficacious antifungal drugs.
The triazole class of antifungal drugs comprises first-line agents for the treatment of several invasive fungal diseases. Isavuconazole is a novel broad-spectrum triazole agent. Here we summarize its ...characteristics and compare it with the currently available antifungal agents. Isavuconazole is administered as a prodrug, and it is water soluble. Oral and intravenous formulations are available. Its intravenous formulation does not contain cyclodextrin, which is an advantage over voriconazole, considering the potential for nephrotoxicity of cyclodextrin. As with other azoles, isavuconazole requires a loading dose. Due to its prolonged half-life, a once-a-day regimen is possible. Considering that isavuconazole shares the same mechanism of action with the other triazoles, cross-resistance is an important concern in the class. Tolerability and safety profiles are favorable, and no serious adverse events have been consistently reported. Significant interactions with drugs metabolized by cytochrome P450 are expected to occur, especially with substrates and inducers of the CYP3A4 enzyme. Isavuconazole has in vitro activity against most medically important fungi, including species of Candida, Aspergillus, and Cryptococcus. It has some activity against the agents of mucormycosis. Clinical data regarding isavuconazole remain limited because ongoing trials have not yet been completed or published. Isavuconazole has the potential to become first-line therapy for invasive aspergillosis. It also has the potential for use in the context of antifungal prophylaxis, salvage therapy, or in combination regimens. Results of clinical trials are ultimately expected in order to adequately position isavuconazole in the current antifungal armamentarium.
Background Highly active antiretroviral therapy (HAART) has reduced HIV-related morbidity and mortality at all stages of infection and reduced transmission of HIV. Currently, the immediate start of ...HAART is recommended for all HIV patients, regardless of the CD4 count. There are several concerns, however, about starting treatment in critically ill patients. Unpredictable absorption of medication by the gastrointestinal tract, drug toxicity, drug interactions, limited reserve to tolerate the dysfunction of other organs resulting from hypersensitivity to drugs or immune reconstitution syndrome, and the possibility that subtherapeutic levels of drug may lead to viral resistance are the main concerns. The objective of our study was to compare the early onset (up to 5 days) with late onset (after discharge from the ICU) of HAART in HIV-infected patients admitted to the ICU. Methods This was a randomized, open-label clinical trial enrolling HIV-infected patients admitted to the ICU of a public hospital in southern Brazil. Patients randomized to the intervention group had to start treatment with HAART within 5 days of ICU admission. For patients in the control group, treatment should begin after discharge from the ICU. The patients were followed up to determine mortality in the ICU, in the hospital and at 6 months. The primary outcome was hospital mortality. The secondary outcome was mortality at 6 months. Results The calculated sample size was 344 patients. Unfortunately, we decided to discontinue the study due to a progressively slower recruitment rate. A total of 115 patients were randomized. The majority of admissions were for AIDS-defining illnesses and low CD4. The main cause of admission was respiratory failure. Regarding the early and late study groups, there was no difference in hospital (66.7% and 63.8%, p = 0.75) or 6-month (68.4% and 79.2%, p = 0.20) mortality. After multivariate analysis, the only independent predictors of in-hospital mortality were shock and dialysis during the ICU stay. For the mortality outcome at 6 months, the independent variables were shock and dialysis during the ICU stay and tuberculosis at ICU admission. Conclusions Although the early termination of the study precludes definitive conclusions being made, early HAART administration for HIV-infected patients admitted to the ICU compared to late administration did not show benefit in hospital mortality or 6-month mortality. ClinicalTrials.gov, NCT01455688. Registered 20 October 2011,
Immunobiological drugs such as TNF-α inhibitors are valuable in rescue therapy for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), but they increase the risk of ...infectious complications. Histoplasmosis is a significant concern in patients living in endemic regions, however, few studies have assessed the incidence of Histoplasma infection during therapy, and classic estimates may underestimate the risk. This study aimed to produce an updated risk estimate of histoplasmosis in patients on TNF-α blocking therapy.
This is a systematic review and meta-analysis of studies that contain parameters for calculating the risk of histoplasmosis in people who use TNF-α inhibitors, to produce a risk estimate.
We identified 11 studies with the necessary parameters for inclusion in the meta-analysis, most of which were from North America. The incidence rate of histoplasmosis found was 33.52 cases per 100,000 patients treated with TNF-ɑ inhibitors (95% CI 12.28-91.46). Considering only studies evaluating monoclonal antibodies, the calculated incidence was 54.88/100,000 patients treated (95%CI 23.45-128.34). In subgroup analysis, the incidence was much higher in patients with IBD compared to rheumatic diseases. There was significant heterogeneity among the studies.
The risk of histoplasmosis during TNF-α inhibitory therapy may be considerably higher than that found in classical estimates, especially in patients with IBD. There is a lack of studies evaluating histoplasmosis in large endemic areas, such as Central and South America.
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