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1.
Transpl Int ; 37: 13022, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39091613

RESUMO

We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.


Assuntos
Aloenxertos , Taxa de Filtração Glomerular , Transplante de Rim , Rim , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Biópsia , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Rim/patologia , Fatores de Tempo , Imunossupressores/uso terapêutico , Rejeição de Enxerto , Terapia de Imunossupressão , Idoso
2.
J Med Chem ; 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39083648

RESUMO

Modification of the R1 and R2 side chain structures has been used as the main strategy to expand the spectrum of cephalosporins and impart resistance to hydrolysis by ß-lactamases. These structural modifications also result in a wide range of plasma protein binding, especially with human serum albumin (HSA). Here, we determined the crystal structures of the HSA complexes with two clinically important cephalosporins, ceftriaxone and cefazolin, and evaluated the binding of cephalosporin to HSA by susceptibility testing and competitive binding assay. Ceftriaxone and cefazolin bind to subdomain IB of HSA, and their cephem core structures are recognized by Arg117 of HSA. Tyr161 of HSA changes its rotamer depending on the cephalosporin, resulting in alterations of the cavity shape occupied by the R2 side chain of cephalosporins. These findings provide structural insight into the mechanisms underlying the HSA binding of cephalosporins.

3.
Antiviral Res ; 229: 105958, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38972603

RESUMO

This exploratory analysis of the double-blind, phase 3, SCORPIO-SR trial assessed the effect of ensitrelvir in preventing post coronavirus disease 2019 (COVID-19) condition (PCC). Patients with mild-to-moderate COVID-19 were randomized (1:1:1) within 120 h of symptom onset; received 5-day oral ensitrelvir 125 mg (375 mg on day 1), 250 mg (750 mg on day 1), or a matching placebo once daily; and were assessed for the severity of typical PCC symptoms using a self-administered questionnaire. In total, 341, 317, and 333 patients were assessed in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively (mean age, 35.6-36.5 years; men, 53.3%-58.3%). On days 85, 169, and 337, ensitrelvir 125-mg treatment showed 32.7% (95% confidence interval [CI]: -30.6, 66.1), 21.5% (95% CI: -37.3, 55.6), and 24.6% (95% CI: -43.7, 60.9) reductions versus placebo, respectively, in the risk of any of the 14 acute-phase COVID-19 symptoms (at least one mild, moderate, or severe symptom with general health not returning to the usual level). Ensitrelvir 250-mg treatment showed 10.9% (95% CI: -67.0, 52.8), 9.5% (95% CI: -56.6, 48.0), and 30.6% (95% CI: -36.2, 65.5) risk reductions versus placebo on days 85, 169, and 337, respectively. Risk reductions were observed in any of the 4 neurological symptoms and were more pronounced among patients with high acute-phase symptom scores at baseline and among those with a baseline body mass index ≥25 kg/m2. Ensitrelvir treatment in the acute phase of COVID-19 may reduce the risk of various symptoms associated with PCC. TRIAL REGISTRATION NUMBER: jRCT2031210350.


Assuntos
Tratamento Farmacológico da COVID-19 , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Método Duplo-Cego , Indazóis , Síndrome de COVID-19 Pós-Aguda/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Resultado do Tratamento , Triazinas , Triazóis
4.
J Infect Dis ; 230(1): 209-220, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39052750

RESUMO

BACKGROUND: Klebsiella pneumoniae carbapenemase-producing K pneumoniae (KPC-Kp) bloodstream infections are associated with high mortality. We studied clinical bloodstream KPC-Kp isolates to investigate mechanisms of resistance to complement, a key host defense against bloodstream infection. METHODS: We tested growth of KPC-Kp isolates in human serum. In serial isolates from a single patient, we performed whole genome sequencing and tested for complement resistance and binding by mixing study, direct enzyme-linked immunosorbent assay, flow cytometry, and electron microscopy. We utilized an isogenic deletion mutant in phagocytosis assays and an acute lung infection model. RESULTS: We found serum resistance in 16 of 59 (27%) KPC-Kp clinical bloodstream isolates. In 5 genetically related bloodstream isolates from a single patient, we noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ. Disruption of wcaJ was associated with decreased polysaccharide capsule, resistance to complement-mediated killing, and surprisingly, increased binding of complement proteins. Furthermore, an isogenic wcaJ deletion mutant exhibited increased opsonophagocytosis in vitro and impaired in vivo control in the lung after airspace macrophage depletion in mice. CONCLUSIONS: Loss of function in wcaJ led to increased complement resistance, complement binding, and opsonophagocytosis, which may promote KPC-Kp persistence by enabling coexistence of increased bloodstream fitness and reduced tissue virulence.


Assuntos
Cápsulas Bacterianas , Proteínas do Sistema Complemento , Infecções por Klebsiella , Klebsiella pneumoniae , Fagocitose , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/imunologia , Humanos , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Animais , Cápsulas Bacterianas/imunologia , Cápsulas Bacterianas/genética , Cápsulas Bacterianas/metabolismo , Camundongos , Proteínas do Sistema Complemento/imunologia , Mutação , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sequenciamento Completo do Genoma , Reinfecção/microbiologia , Reinfecção/imunologia , Bacteriemia/microbiologia , Bacteriemia/imunologia , Feminino
5.
Influenza Other Respir Viruses ; 18(6): e13338, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38890511

RESUMO

BACKGROUND: This phase 2b/3, randomized, placebo-controlled trial explored the efficacy and evaluated the safety of ensitrelvir. This trial involved individuals with asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with mild symptoms of coronavirus disease 2019 (COVID-19). METHODS: The trial was conducted at 57 medical institutions in Japan, South Korea, and Vietnam (study period: January 6-August 14, 2022). Eligible participants were randomized (1:1:1) to the ensitrelvir 125-mg, ensitrelvir 250-mg, or placebo group, received the allocated intervention orally, and were followed up until Day 28. Participants self-rated the severity of 14 typical COVID-19 symptoms and recorded the data in an electronic diary. RESULTS: In total, 572 participants (194, 189, and 189 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were included in the intention-to-treat population. Ensitrelvir 125-mg group observed a 77% reduction in the risk of developing any of the 14 COVID-19 symptoms or fever and a 29% reduction in the risk of worsening of such symptoms or fever versus placebo (statistically nonsignificant). The viral RNA, viral titer, and time to infectious viral clearance observed a statistically significant decrease versus placebo. Most treatment-related adverse events (TEAEs) were mild to moderate in severity, and the most common TEAE observed across groups was a decrease in high-density lipoprotein. CONCLUSIONS: Our exploratory results suggest a potential reduction in the risk of development or worsening of COVID-19 symptoms with ensitrelvir. Ensitrelvir showed antiviral efficacy and was well tolerated. TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210350.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Resultado do Tratamento , Infecções Assintomáticas , Vietnã , Japão , Idoso , República da Coreia , Adulto Jovem , Indazóis , Triazinas , Triazóis
7.
J Antimicrob Chemother ; 79(8): 1843-1855, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38842502

RESUMO

BACKGROUND: Stenotrophomonas maltophilia is a carbapenem-resistant Gram-negative pathogen increasingly responsible for difficult-to-treat nosocomial infections. OBJECTIVES: To describe the contemporary clinical characteristics and genome epidemiology of patients colonized or infected by S. maltophilia in a multicentre, prospective cohort. METHODS: All patients with a clinical culture growing S. maltophilia were enrolled at six tertiary hospitals across Japan between April 2019 and March 2022. The clinical characteristics, outcomes, antimicrobial susceptibility and genomic epidemiology of cases with S. maltophilia were investigated. RESULTS: In total, 78 patients were included representing 34 infection and 44 colonization cases. The median age was 72.5 years (IQR, 61-78), and males accounted for 53 cases (68%). The most common comorbidity was localized solid malignancy (39%). Nearly half of the patients (44%) were immunosuppressed, with antineoplastic chemotherapy accounting for 31%. The respiratory tract was the most common site of colonization (86%), whereas bacteraemia accounted for most infection cases (56%). The 30 day all-cause mortality rate was 21%, which was significantly higher in infection cases than colonization cases (35% versus 9%; adjusted HR, 3.81; 95% CI, 1.22-11.96). Susceptibility rates to ceftazidime, levofloxacin, minocycline and sulfamethoxazole/trimethoprim were 14%, 65%, 87% and 100%, respectively. The percentage of infection ranged from 13% in the unclassified group to 86% in genomic group 6A. The percentage of non-susceptibility to ceftazidime ranged from 33% in genomic group C to 100% in genomic groups 6 and 7 and genomic group geniculate. CONCLUSIONS: In this contemporary multicentre cohort, S. maltophilia primarily colonized the respiratory tract, whereas patients with bacteraemia had the highest the mortality from this pathogen. Sulfamethoxazole/trimethoprim remained consistently active, but susceptibility to levofloxacin was relatively low. The proportions of cases representing infection and susceptibility to ceftazidime differed significantly based on genomic groups.


Assuntos
Antibacterianos , Infecções por Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Stenotrophomonas maltophilia , Humanos , Stenotrophomonas maltophilia/genética , Stenotrophomonas maltophilia/efeitos dos fármacos , Stenotrophomonas maltophilia/isolamento & purificação , Stenotrophomonas maltophilia/classificação , Masculino , Idoso , Japão/epidemiologia , Feminino , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecção Hospitalar/microbiologia , Infecção Hospitalar/epidemiologia , Genoma Bacteriano , Bacteriemia/microbiologia , Bacteriemia/epidemiologia , Epidemiologia Molecular , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
8.
J Antimicrob Chemother ; 79(8): 1929-1937, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38863337

RESUMO

BACKGROUND: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE). OBJECTIVES: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents. METHODS: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures. RESULTS: The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%-56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group. CONCLUSIONS: Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections.


Assuntos
Antibacterianos , Enterobacteriáceas Resistentes a Carbapenêmicos , Ceftazidima , Infecções por Enterobacteriaceae , Ertapenem , Humanos , Ertapenem/uso terapêutico , Ertapenem/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Masculino , Feminino , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/mortalidade , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Ceftazidima/uso terapêutico , Ceftazidima/farmacologia , Meropeném/uso terapêutico , Meropeném/farmacologia , Combinação de Medicamentos , Compostos Azabicíclicos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana Múltipla , Adulto , Enterobacteriaceae/efeitos dos fármacos
9.
Microbiol Spectr ; 12(5): e0426023, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38587390

RESUMO

Streptococcus pyogenes causes a variety of human infections, and hospital outbreaks with this pathogen have also been reported. The purpose of this study is to describe the clinical characteristics of an outbreak of S. pyogenes involving 15 patients and four healthcare workers (HCWs), as well as the molecular characteristics of the causative isolates. The course and response to the outbreak were reviewed, and information on the characteristics of the patients was extracted retrospectively from the medical records. Whole-genome sequencing of the 16 causative isolates (14 from patients and two from HCWs) was also performed. All 15 patients were postoperative of head and neck cancer with tracheotomy, and 12 had invasive infections, primarily surgical site infections, all of which resolved without causing serious illness. All but the first case was detected more than 7 days after admission. S. pyogenes was detected in two patients after empiric antimicrobial administration was performed on all inpatients and HCWs, and the outbreak was finally contained in approximately 2 months. All isolates detected in patients and HCWs belonged to emm89/clade 3, a hypervirulent clone that has emerged worldwide and was classified as sequence type 646. These isolates had single nucleotide polymorphism (SNP) differences of zero to one, indicating clonal transmission. This study demonstrated an outbreak of S. pyogenes emm89/clade 3 in a ward of patients with head and neck cancer. The global emergence of hypervirulent isolates may increase the risk of outbreaks among high-risk patients. IMPORTANCE: This study describes an outbreak of Streptococcus pyogenes that occurred in a ward caring for patients with head and neck cancer and tracheostomies. Many cases of invasive infections occurred in a short period, and extensive empiric antimicrobial administration on patients and healthcare workers was performed to control the outbreak. Whole-genome sequencing analysis of the causative strains confirmed that it was a monoclonal transmission of strains belonging to emm89/clade 3. The epidemiology and clinical characteristics of S. pyogenes infections have changed with the replacement of the prevalent clones worldwide. In the 1980s, there was a reemergence of S. pyogenes infections in high-income countries due to the spread of hypervirulent emm1 strains. emm89/clade 3 has recently been spreading worldwide and shares common features with emm1, including increased production of two toxins, NADase, and streptolysin O. The outbreak reported here may reflect the high spreading potential and virulence of emm89/clade 3.


Assuntos
Infecção Hospitalar , Surtos de Doenças , Neoplasias de Cabeça e Pescoço , Infecções Estreptocócicas , Streptococcus pyogenes , Humanos , Streptococcus pyogenes/genética , Streptococcus pyogenes/isolamento & purificação , Streptococcus pyogenes/classificação , Streptococcus pyogenes/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/microbiologia , Neoplasias de Cabeça e Pescoço/cirurgia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Estudos Retrospectivos , Sequenciamento Completo do Genoma , Adulto , Polimorfismo de Nucleotídeo Único , Infecção da Ferida Cirúrgica/microbiologia , Infecção da Ferida Cirúrgica/epidemiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Idoso de 80 Anos ou mais , Pessoal de Saúde/estatística & dados numéricos
10.
Am J Respir Cell Mol Biol ; 71(2): 207-218, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38656811

RESUMO

Pseudomonas aeruginosa causes chronic lung infection in cystic fibrosis (CF), resulting in structural lung damage and progressive pulmonary decline. P. aeruginosa in the CF lung undergoes numerous changes, adapting to host-specific airway pressures while establishing chronic infection. P. aeruginosa undergoes lipid A structural modification during CF chronic infection that is not seen in any other disease state. Lipid A, the membrane anchor of LPS (i.e., endotoxin), comprises the majority of the outer membrane of Gram-negative bacteria and is a potent Toll-like receptor 4 (TLR4) agonist. The structure of P. aeruginosa lipid A is intimately linked with its recognition by TLR4 and subsequent immune response. Prior work has identified P. aeruginosa strains with altered lipid A structures that arise during chronic CF lung infection; however, the impact of the P. aeruginosa lipid A structure on airway disease has not been investigated. Here, we show that P. aeruginosa lipid A lacks PagL-mediated deacylation during human airway infection using a direct-from-sample mass spectrometry approach on human BAL fluid. This structure triggers increased proinflammatory cytokine production by primary human macrophages. Furthermore, alterations in lipid A 2-hydroxylation impact cytokine response in a site-specific manner, independent of CF transmembrane conductance regulator function. It is interesting that there is a CF-specific reduction in IL-8 secretion within the epithelial-cell compartment that only occurs in CF bronchial epithelial cells when infected with CF-adapted P. aeruginosa that lacks PagL-mediated lipid A deacylation. Taken together, we show that P. aeruginosa alters its lipid A structure during acute lung infection and that this lipid A structure induces stronger signaling through TLR4.


Assuntos
Fibrose Cística , Lipídeo A , Infecções por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/imunologia , Humanos , Lipídeo A/metabolismo , Lipídeo A/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Líquido da Lavagem Broncoalveolar/imunologia , Pulmão/microbiologia , Pulmão/imunologia , Pulmão/metabolismo
12.
Infect Control Hosp Epidemiol ; : 1-3, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38482594

RESUMO

We evaluated the secondary COVID-19 incidence among uninfected hospitalized patients after nosocomial COVID-19 exposure. An exposure source of SARS-CoV-2 was hospitalized patients or healthcare personnel (HCP) newly diagnosed as having COVID-19. Patients exposed to a COVID-19-infected patient in a shared room more frequently developed COVID-19 than those exposed to an infected HCP.

13.
Antimicrob Agents Chemother ; 68(5): e0167223, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38517188

RESUMO

Carbapenemase-producing Enterobacterales (CPEs) are one of the top priority antimicrobial-resistant pathogens. Among CPEs, those producing acquired metallo-ß-lactamases (MBLs) are considered particularly problematic as few agents are active against them. Imipenemase (IMP) is the most frequently encountered acquired MBL in Japan, but comprehensive assessment of clinical and microbiological features of IMP-producing Enterobacterales infection remains scarce. Here, we retrospectively evaluated 62 patients who were hospitalized at a university hospital in Japan and had IMP-producing Enterobacterales from a clinical culture. The isolates were either Enterobacter cloacae complex or Klebsiella pneumoniae, and most of them were isolated from sputum. The majority of K. pneumoniae, but not E. cloacae complex isolates, were susceptible to aztreonam. Sequence type (ST) 78 and ST517 were prevalent for E. cloacae complex and K. pneumoniae, respectively, and all isolates carried blaIMP-1. Twenty-four of the patients were deemed infected with IMP-producing Enterobacterales. Among the infected patients, therapy varied and largely consisted of conventional ß-lactam agents, fluoroquinolones, or combinations. Three (13%), five (21%), and nine (38%) of them died by days 14, 30, and 90, respectively. While incremental mortality over 90 days was observed in association with underlying comorbidities, active conventional treatment options were available for most patients with IMP-producing Enterobacterales infections, distinguishing them from more multidrug-resistant CPE infections associated with globally common MBLs, such as New Delhi metallo-ß-lactamase (NDM) and Verona integron-encoded metallo-ß-lactamase (VIM).


Assuntos
Antibacterianos , Proteínas de Bactérias , Enterobacter cloacae , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , beta-Lactamases , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , beta-Lactamases/genética , beta-Lactamases/metabolismo , Humanos , Enterobacter cloacae/genética , Enterobacter cloacae/efeitos dos fármacos , Enterobacter cloacae/isolamento & purificação , Enterobacter cloacae/enzimologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Masculino , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Idoso , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Aztreonam/farmacologia , Aztreonam/uso terapêutico , Japão , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Idoso de 80 Anos ou mais , Adulto
14.
Sci Rep ; 14(1): 5119, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429496

RESUMO

Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15-60 mL/min/1.73 m2. The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13-2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney.


Assuntos
Insuficiência Renal Crônica , Ácido Úrico , Humanos , Ácido Úrico/urina , Estudos Retrospectivos , Rim , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/urina
15.
Clin Pharmacol Ther ; 115(6): 1372-1382, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38441177

RESUMO

With the coronavirus disease 2019 (COVID-19) pandemic, there is growing interest in utilizing adaptive platform clinical trials (APTs), in which multiple drugs are compared with a single common control group, such as a placebo or standard-of-care group. APTs evaluate several drugs for one disease and accept additions or exclusions of drugs as the trials progress; however, little is known about the efficiency of APTs over multiple stand-alone trials. In this study, we simulated the total development period, total sample size, and statistical operating characteristics of APTs and multiple stand-alone trials in drug development settings for hospitalized patients with COVID-19. Simulation studies using selected scenarios reconfirmed several findings regarding the efficiency of APTs. The APTs without staggered addition of drugs showed a shorter total development period than stand-alone trials, but the difference rapidly diminished if patient's enrollment was accelerated during the trials owing to the spread of infection. APTs with staggered addition of drugs still have the possibility of reducing the total development period compared with multiple stand-alone trials in some cases. Our study demonstrated that APTs could improve efficiency relative to multiple stand-alone trials regarding the total development period and total sample size without undermining statistical validity; however, this improvement varies depending on the speed of patient enrollment, sample size, presence/absence of family-wise error rate adjustment, allocation ratio between drug and placebo groups, and interval of staggered addition of drugs. Given the complexity of planning and implementing APT, the decision to implement APT during a pandemic must be made carefully.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Simulação por Computador , Desenvolvimento de Medicamentos , Humanos , Desenvolvimento de Medicamentos/métodos , COVID-19/epidemiologia , Tamanho da Amostra , Pandemias , SARS-CoV-2 , Ensaios Clínicos como Assunto/métodos , Antivirais/uso terapêutico , Ensaios Clínicos Adaptados como Assunto , Projetos de Pesquisa
16.
Int J Antimicrob Agents ; 63(5): 107119, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38417706

RESUMO

OBJECTIVES: Imipenem-relebactam (IMR), a novel ß-lactam/ß-lactamase inhibitor combination, is recommended for infections caused by difficult-to-treat Pseudomonas aeruginosa. This study aimed to investigate the evolution trajectory of IMR resistance under the selection of levofloxacin in P. aeruginosa. METHODS: Antimicrobial susceptibility testing, complete genome sequencing and gene manipulation experiments were performed. Quantitative reverse transcription PCR for specific genes and porin levels were detected. Evolution trajectory was simulated in vitro by induction assay. RESULTS: P. aeruginosa HS347 and HS355 were isolated from abdominal drainage of two neighbouring patients (S and Z) undergoing surgery of colon carcinoma in Shanghai, China, with the latter patient having received levofloxacin. They were closely related ST16 strains, and both carried blaKPC-2 plasmids highly similar to those of P. aeruginosa endemic clones from Zhejiang province, where patient Z had received enteroscopy before this admission. Acquisition of resistance was observed for both IMR and fluoroquinolones in HS355, likely prompted by treatment with levofloxacin. The T274I substitution in MexS (putative oxidoreductase), upregulated efflux pump operon mexEF-oprN and decreased production of porin OprD leading to cross-resistance to fluoroquinolones and IMR, which was also verified by in vitro mutant selection under levofloxacin selection. CONCLUSIONS: The emergence of a rare blaKPC-2-plasmid-bearing ST16 clone implies the horizonal spread and inter-regional dissemination of a high-risk plasmid-clone combination, representing a public health challenge. Levofloxacin exposure can select for mexS inactivating mutation, which in turn leads to IMR resistance phenotype, implicating the role of an unrelated, widely used antimicrobial agent in insidiously triggering the development of cross resistance to a latest ß-lactam/ß-lactamase inhibitor combination.


Assuntos
Antibacterianos , Compostos Azabicíclicos , Imipenem , Levofloxacino , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas , Pseudomonas aeruginosa , beta-Lactamases , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Levofloxacino/farmacologia , Humanos , Compostos Azabicíclicos/farmacologia , Imipenem/farmacologia , beta-Lactamases/genética , Antibacterianos/farmacologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , China , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mutação , Inibidores de beta-Lactamases/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Plasmídeos/genética
17.
JAMA Netw Open ; 7(2): e2354991, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38335000

RESUMO

Importance: Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease. Objective: To assess the efficacy and safety of ensitrelvir in patients with mild to moderate COVID-19. Design, Setting, and Participants: This phase 3 part of a phase 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. Patients (aged 12 to <70 years) with mild to moderate COVID-19 within 120 hours of positive viral test results were studied. Interventions: Patients were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 days. Main Outcomes and Measures: The primary end point was the time to resolution of the composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy and safety were also assessed. Results: A total of 1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the 250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 (12.3) years, and 552 (53.6%) were men. A significant difference was observed between the 125-mg ensitrelvir group and the placebo group (P = .04 with a Peto-Prentice generalized Wilcoxon test). The difference in median time was approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs 192.2 hours; difference, -24.3 hours; 95% CI, -78.7 to 11.7 hours). Adverse events were observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients (53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo group). No treatment-related serious adverse events were reported. Conclusions and Relevance: In this randomized clinical trial, 125-mg ensitrelvir treatment reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in patients treated in less than 72 hours of disease onset; the absolute difference in median time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to populations outside Asia should be confirmed. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2031210350.


Assuntos
COVID-19 , Medicamentos de Ervas Chinesas , Indazóis , Triazinas , Triazóis , Feminino , Humanos , Masculino , Fatores de Risco , SARS-CoV-2 , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso
18.
Clin Exp Nephrol ; 28(7): 629-635, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38402502

RESUMO

BACKGROUND: Volume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium-glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD. METHODS: The EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters. CONCLUSIONS: This trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.


Assuntos
Estudos Cross-Over , Glucosídeos , Diálise Peritoneal , Inibidores do Transportador 2 de Sódio-Glicose , Ultrafiltração , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Método Duplo-Cego , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Cardíaca , Estudos Multicêntricos como Assunto , Soluções para Diálise , Resultado do Tratamento
19.
Nat Microbiol ; 9(3): 631-646, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38409256

RESUMO

The antibiotic cefiderocol hijacks iron transporters to facilitate its uptake and resists ß-lactamase degradation. While effective, resistance has been detected clinically with unknown mechanisms. Here, using experimental evolution, we identified cefiderocol resistance mutations in Pseudomonas aeruginosa. Resistance was multifactorial in host-mimicking growth media, led to multidrug resistance and paid fitness costs in cefiderocol-free environments. However, kin selection drove some resistant populations to cross-protect susceptible individuals from killing by increasing pyoverdine secretion via a two-component sensor mutation. While pyochelin sensitized P. aeruginosa to cefiderocol killing, pyoverdine and the enterobacteria siderophore enterobactin displaced iron from cefiderocol, preventing uptake by susceptible cells. Among 113 P. aeruginosa intensive care unit clinical isolates, pyoverdine production directly correlated with cefiderocol tolerance, and high pyoverdine producing isolates cross-protected susceptible P. aeruginosa and other Gram-negative bacteria. These in vitro data show that antibiotic cross-protection can occur via degradation-independent mechanisms and siderophores can serve unexpected protective cooperative roles in polymicrobial communities.


Assuntos
Antibacterianos , Sideróforos , Humanos , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Sideróforos/metabolismo , Sideróforos/farmacologia , Cefiderocol , Ferro/metabolismo , Enterobacteriaceae/metabolismo , Pseudomonas aeruginosa/metabolismo
20.
J Antimicrob Chemother ; 79(4): 801-809, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38334390

RESUMO

OBJECTIVES: To investigate the genomic diversity and ß-lactam susceptibilities of Enterococcus faecalis collected from patients with infective endocarditis (IE). METHODS: We collected 60 contemporary E. faecalis isolates from definite or probable IE cases identified between 2018 and 2021 at the University of Pittsburgh Medical Center. We used whole-genome sequencing to study bacterial genomic diversity and employed antibiotic checkerboard assays and a one-compartment pharmacokinetic-pharmacodynamic (PK/PD) model to investigate bacterial susceptibility to ampicillin and ceftriaxone both alone and in combination. RESULTS: Genetically diverse E. faecalis were collected, however, isolates belonging to two STs, ST6 and ST179, were collected from 21/60 (35%) IE patients. All ST6 isolates encoded a previously described mutation upstream of penicillin-binding protein 4 (pbp4) that is associated with pbp4 overexpression. ST6 isolates had higher ceftriaxone MICs and higher fractional inhibitory concentration index values for ampicillin and ceftriaxone (AC) compared to other isolates, suggesting diminished in vitro AC synergy against this lineage. Introduction of the pbp4 upstream mutation found among ST6 isolates caused increased ceftriaxone resistance in a laboratory E. faecalis isolate. PK/PD testing showed that a representative ST6 isolate exhibited attenuated efficacy of AC combination therapy at humanized antibiotic exposures. CONCLUSIONS: We find evidence for diminished in vitro AC activity among a subset of E. faecalis IE isolates with increased pbp4 expression. These findings suggest that alternate antibiotic combinations against diverse contemporary E. faecalis IE isolates should be evaluated.


Assuntos
Endocardite Bacteriana , Endocardite , Infecções por Bactérias Gram-Positivas , Humanos , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Enterococcus faecalis , Ampicilina/farmacologia , Ampicilina/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Endocardite Bacteriana/tratamento farmacológico , Endocardite Bacteriana/microbiologia , Endocardite/tratamento farmacológico , Testes de Sensibilidade Microbiana , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Quimioterapia Combinada
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