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1.
Antibiotics (Basel) ; 11(5)2022 May 21.
Article in English | MEDLINE | ID: covidwho-1917255

ABSTRACT

Given the increase in bacterial resistance and the decrease in the development of new antibiotics, the appropriate use of old antimicrobials has become even more compulsory. Clindamycin is a lincosamide antibiotic approved for adults and children as a drug of choice for systemic treatment of staphylococcal, streptococcal, and gram-positive anaerobic bacterial infections. Because of its profile and high bioavailability, it is commonly used as part of an oral multimodal alternative for prolonged parenteral antibiotic regimens, e.g., to treat bone and joint or prosthesis-related infections. Clindamycin is also frequently used for (surgical) prophylaxis in the event of beta-lactam allergy. Special populations (pediatrics, pregnant women) have altered cytochrome P450 (CYP)3A4 activity. As clindamycin is metabolized by the CYP3A4/5 enzymes to bioactive N-demethyl and sulfoxide metabolites, knowledge of the potential relevance of the drug's metabolites and disposition in special populations is of interest. Furthermore, drug-drug interactions derived from CYP3A4 inducers and inhibitors, and the data on the impact of the disease state on the CYP system, are still limited. This narrative review provides a detailed survey of the currently available literature on pharmacology and pharmacokinetics and identifies knowledge gaps (special patient population, drug-drug, and drug-disease interactions) to describe a research strategy for precision medicine.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315433

ABSTRACT

Background: Drug repurposing is an attractive strategy to rapidly develop affordable therapy against COVID-19. The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 comparable to that of hydroxychloroquine. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized patients with COVID-19 were randomly assigned to receive standard of care with or without itraconazole. The primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. Other outcomes included time to sustained clinical improvement, duration of supplemental oxygen and evolution of nasopharyngeal viral load. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and interim analysis that showed no trends for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19), median time to clinical improvement 10 vs 9 days, hazard ratio 0.94 (95% CI 0.56 to 1.60) for itraconazole vs standard of care. Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. A proof-of-concept clinical study was ended prematurely because of futility. Trial Registration: (EudraCT 2020-001243-15)Funding: Covid-19-Fund KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates FoundationDeclaration of Interests: Initial dug screening and discovery of the antiviral effect of itraconazole was done in collaboration with Johnson & Johnson and described in a separate manuscript. Scientists from Johnson & Johnson also performed drug measurements on hamster samples and provided guidance on the dosing regimens for the preclinical studies. The company had no role in the design, execution, analysis, publication or funding of the clinical trial.Author Conflict of Interests: None to declare.Ethics Approval Statement: The institutional Ethical Committee approved all animal experiments (license P065-2020).The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies.

3.
J Fungi (Basel) ; 7(12)2021 Dec 11.
Article in English | MEDLINE | ID: covidwho-1572540

ABSTRACT

Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a severe fungal infection complicating critically ill COVID-19 patients. Numerous retrospective and prospective studies have been performed to get a better grasp on this lethal co-infection. We performed a qualitative review and summarized data from 48 studies in which 7047 patients had been included, of whom 820 had CAPA. The pooled incidence of proven, probable or putative CAPA was 15.1% among 2953 ICU-admitted COVID-19 patients included in 18 prospective studies. Incidences showed great variability due to multiple factors such as discrepancies in the rate and depth of the fungal work-up. The pathophysiology and risk factors for CAPA are ill-defined, but therapy with corticosteroids and anti-interleukin-6 therapy potentially confer the biggest risk. Sampling for mycological work-up using bronchoscopy is the cornerstone for diagnosis, as imaging is often aspecific. CAPA is associated with an increased mortality, but we do not have conclusive data whether therapy contributes to an increased survival in these patients. We conclude our review with a comparison between influenza-associated pulmonary aspergillosis (IAPA) and CAPA.

5.
Microorganisms ; 9(7)2021 Jul 20.
Article in English | MEDLINE | ID: covidwho-1323313

ABSTRACT

BACKGROUND: Voriconazole is one of the first-line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population. METHODS: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit's binding sites over time. RESULTS: Sixty-nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (<2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO (p = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2-4.7) mg/L under ECMO and 2.5 (1.4-3.9) mg/L without ECMO (p = 0.58). Extensive inter-and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure. CONCLUSIONS: No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.

6.
EBioMedicine ; 66: 103288, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1141720

ABSTRACT

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Itraconazole/pharmacology , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/etiology , COVID-19/transmission , Chlorocebus aethiops , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Itraconazole/administration & dosage , Itraconazole/pharmacokinetics , Itraconazole/therapeutic use , Male , Mesocricetus , Middle Aged , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proof of Concept Study , SARS-CoV-2/drug effects , Treatment Outcome , Vero Cells
7.
Proc Natl Acad Sci U S A ; 117(43): 26955-26965, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-841910

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Hydroxychloroquine/therapeutic use , Pyrazines/therapeutic use , Amides/pharmacokinetics , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cricetinae , Disease Models, Animal , Disease Transmission, Infectious/prevention & control , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Hydroxychloroquine/pharmacokinetics , Lung/drug effects , Lung/pathology , Lung/virology , Pyrazines/pharmacokinetics , SARS-CoV-2 , Treatment Outcome , Vero Cells , Viral Load/drug effects
8.
Intensive Care Med ; 46(8): 1524-1535, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-615887

ABSTRACT

PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung. CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.


Subject(s)
Aspergillus/isolation & purification , Betacoronavirus , Coronavirus Infections/complications , Influenza, Human/complications , Intensive Care Units , Pneumonia, Viral/complications , Pulmonary Aspergillosis , Antifungal Agents/therapeutic use , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/microbiology , COVID-19 , Galactose/analogs & derivatives , Humans , Mannans/analysis , Pandemics , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/etiology , Pulmonary Aspergillosis/prevention & control , SARS-CoV-2
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