RESUMO
BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efï¬cacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.
Assuntos
Bacteriúria , Pielonefrite , Infecções Urinárias , Adulto , Humanos , Ertapenem/uso terapêutico , Bacteriúria/tratamento farmacológico , Infecções Urinárias/microbiologia , Antibacterianos , Pielonefrite/tratamento farmacológico , Ciprofloxacina/uso terapêuticoRESUMO
BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.
Assuntos
Ciprofloxacina , Infecções Urinárias , Humanos , Feminino , Ciprofloxacina/uso terapêutico , Infecções Urinárias/microbiologia , Antibacterianos , Lactamas/uso terapêuticoRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression. METHODS: Adults (Nâ =â 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (Nâ =â 246) or placebo equivalent (Nâ =â 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; Pâ =â .78). CONCLUSIONS: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.
Assuntos
Tratamento Farmacológico da COVID-19 , Adulto , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Rivaroxabana/uso terapêutico , SARS-CoV-2 , Resultado do TratamentoRESUMO
BACKGROUND: Urinary tract infections (UTIs), which are usually caused by bacteria in the Enterobacterales family, are a common reason for outpatient visits. Appropriate empiric therapy for UTIs requires an understanding of antibiotic resistance in the community. In this nationwide study, we examined trends in antibiotic resistance in urinary Enterobacterales isolates from ambulatory patients in the United States (US). METHODS: We analyzed the antimicrobial susceptibility profiles (extended-spectrum beta-lactamase [ESBL]-producing phenotype and not susceptible [NS] to beta-lactams, trimethoprim/sulfamethoxazole [TMP/SMX], fluoroquinolones [FQ], or nitrofurantoin [NFT]) of 30-day non-duplicate Enterobacterales isolates from urine cultures tested at ambulatory centers in the BD Insights Research Database (2011-2020). The outcome of interest was the percentage of resistant isolates by pathogen and year. Multi-variable generalized estimating equation models were used to assess trends in resistance over time and by additional covariates. RESULTS: A total of 338 US facilities provided data for > 2.2 million urinary Enterobacterales isolates during the 10-year study. Almost three-quarters (72.8%) of Enterobacterales isolates were Escherichia coli. Overall unadjusted resistance rates in Enterobacterales isolates were 57.5%, 23.1%, 20.6%, and 20.2% for beta-lactams, TMP/SMX, FQ, and NFT, respectively, and 6.9% had an ESBL-producing phenotype. Resistance to two or more antibiotic classes occurred in 16.4% of isolates and 5.5% were resistant to three or more classes. Among isolates with an ESBL-producing phenotype, 70.1%, 59.9%, and 33.5% were NS to FQ, TMP/SMX, and NFT, respectively. In multivariable models, ESBL-producing and NFT NS Enterobacterales isolates increased significantly (both P < 0.001), while other categories of resistance decreased. High rates (≥ 50%) of beta-lactam and NFT resistance were observed in Klebsiella isolates and in non-E. coli, non-Klebsiella Enterobacterales isolates. CONCLUSIONS: Antimicrobial resistance was common in urinary Enterobacterales isolates. Isolates with an ESBL-producing phenotype increased by about 30% between 2011 and 2020, and significant increases were also observed in NFT NS Enterobacterales isolates. Resistance rates for all four antibiotic classes were higher than thresholds recommended for use as empiric therapy. Non-E. coli Enterobacterales isolates showed high levels of resistance to commonly used empiric antibiotics, including NFT. These data may help inform empiric therapy choices for outpatients with UTIs.
Assuntos
Infecções por Escherichia coli , Infecções Urinárias , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Escherichia coli , Infecções por Escherichia coli/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Nitrofurantoína , Estados Unidos/epidemiologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/epidemiologia , Infecções Urinárias/microbiologia , beta-Lactamases/genéticaRESUMO
Dalbavancin is a lipoglycopeptide antibiotic with a prolonged half-life. A phase 1 study assessed dalbavancin levels in epithelial lining fluid (ELF) in 35 healthy adults using ELF bronchial microsampling up to 168 h after administration of 1,500 mg dalbavancin. The penetration of dalbavancin into ELF was 36%. ELF levels of dalbavancin exceeded the MIC90s of Streptococcus pneumoniae and Staphylococcus aureus for ≥7 days.
Assuntos
Antibacterianos/farmacocinética , Mucosa Respiratória/química , Teicoplanina/análogos & derivados , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/análise , Antibacterianos/sangue , Humanos , Infusões Intravenosas , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Teicoplanina/administração & dosagem , Teicoplanina/análise , Teicoplanina/sangue , Teicoplanina/farmacocinética , Adulto JovemRESUMO
The in vitro activity of sulopenem was assessed against a collection from 2014 to 2016 of 539 urinary isolates of Escherichia coli from Canadian patients by using CLSI-defined broth microdilution methodology. A concentration of sulopenem 0.03 µg/ml inhibited both 50% (MIC50) and 90% (MIC90) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml. The in vitro activity of sulopenem was unaffected by nonsusceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant phenotypes, extended-spectrum ß-lactamases, or AmpC ß-lactamases.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Lactamas/farmacologia , Administração Oral , Canadá , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Escherichia coli/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Fenótipo , Estudos Retrospectivos , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologiaRESUMO
BACKGROUND: Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection. METHODS: We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigator's assessment of outcome. RESULTS: Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success (weighted difference, -0.1 percentage point; 95% confidence interval, -4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator's assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin-linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus. CONCLUSIONS: Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.).
Assuntos
Antibacterianos/administração & dosagem , Dermatopatias Bacterianas/tratamento farmacológico , Teicoplanina/análogos & derivados , Vancomicina/administração & dosagem , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Linezolida , Masculino , Pessoa de Meia-Idade , Oxazolidinonas/administração & dosagem , Oxazolidinonas/efeitos adversos , Teicoplanina/administração & dosagem , Teicoplanina/efeitos adversos , Vancomicina/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Acute bacterial skin and skin structure infections (ABSSSIs) are a cause of significant morbidity and therapy can be a burden to the healthcare system. New antibiotics that simplify treatment and avoid hospitalization are needed. This study compared the safety and efficacy of a single intravenous infusion of 1500 mg of dalbavancin to the 2-dose regimen. METHODS: This study was a randomized, double-blind trial in patients aged >18 years with ABSSSIs. Patients were randomized to dalbavancin 1500 mg either as a single intravenous (IV) infusion or 1000 mg IV on day 1 followed 1 week later by 500 mg IV. The primary endpoint was a ≥20% reduction in the area of erythema at 48-72 hours in the intent-to-treat population. Noninferiority was to be declared if the lower limit of the 95% confidence interval (CI) on the difference in the outcomes was greater than -10%. Clinical outcome was also assessed at days 14 and 28. RESULTS: Six hundred ninety-eight patients were randomized. Demographic characteristics were similar on each regimen, although there were more patients with methicillin-resistant Staphylococcus aureus (MRSA) at baseline on the 2-dose regimen (36/210 [17.1%] vs 61/220 [27.7%]). Dalbavancin delivered as a single dose was noninferior to a 2-dose regimen (81.4% vs 84.2%; difference, -2.9% [95% CI, -8.5% to 2.8%]). Clinical outcomes were also similar at day 14 (84.0% vs 84.8%), day 28 (84.5% vs 85.1%), and day 14 in clinically evaluable patients with MRSA in a baseline culture (92.9% vs 95.3%) in the single- and 2-dose regimens, respectively. Treatment-emergent adverse events occurred in 20.1% of the single-dose patients and 19.9% on the 2-dose regimen. CONCLUSIONS: A single 1500-mg infusion of dalbavancin is noninferior to a 2-dose regimen, has a similar safety profile, and removes logistical constraints related to delivery of the second dose. CLINICAL TRIALS REGISTRATION: NCT02127970.
Assuntos
Antibacterianos/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Teicoplanina/análogos & derivados , Doença Aguda , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Staphylococcus aureus Resistente à Meticilina , Pessoa de Meia-Idade , Infecções Estafilocócicas/tratamento farmacológico , Teicoplanina/administração & dosagem , Teicoplanina/efeitos adversos , Teicoplanina/uso terapêuticoRESUMO
OBJECTIVES: Dalbavancin, a semi-synthetic lipoglycopeptide, is characterized by a long plasma half-life, which allows weekly dosing. Dalbavancin may be a good treatment option for patients with deep sternal wound infections owing to its improved pharmacokinetic profile and antibacterial activity compared with currently used antibiotics. Here we evaluated the efficacy of 7 or 14 days of treatment with dalbavancin, compared with vancomycin and with saline, in reducing sternal bone MRSA counts in a rat Staphylococcus aureus deep sternal wound infection model. METHODS: A mid-sternal wound was surgically induced in anaesthetized rats. A clinical strain of MRSA was injected into the sternum to establish infection. Rats were treated intraperitoneally for 7 or 14 days with dalbavancin, vancomycin or saline. The number of cfu per gram of sternum or spleen tissue was determined using viable counts. The antibacterial efficacy was determined by the reduction in bacterial counts per gram of sternum or spleen tissue in each treatment group. RESULTS: Treatment with dalbavancin was superior to treatment with saline for 7 days (0.75 log reduction in bone cfu) or 14 days (>3 log reduction in bone cfu) and similar to treatment with vancomycin. Additionally, dalbavancin was also effective in reducing systemic dissemination of MRSA. CONCLUSIONS: Dalbavancin is effective in the treatment of MRSA rat sternal osteomyelitis.
Assuntos
Antibacterianos/uso terapêutico , Mediastinite/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Osteomielite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Teicoplanina/análogos & derivados , Infecção dos Ferimentos/tratamento farmacológico , Animais , Carga Bacteriana , Modelos Animais de Doenças , Masculino , Mediastinite/complicações , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Osteomielite/complicações , Ratos , Baço/microbiologia , Infecções Estafilocócicas/microbiologia , Esterno/microbiologia , Esterno/patologia , Teicoplanina/uso terapêutico , Resultado do Tratamento , Vancomicina/uso terapêutico , Infecção dos Ferimentos/complicaçõesRESUMO
Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC90 for Staphylococcus aureus of 0.06 µg/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 µg/g and 2 weeks later were 4.1 µg/g. A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed.
Assuntos
Antibacterianos/farmacocinética , Osso e Ossos/metabolismo , Cartilagem Articular/metabolismo , Teicoplanina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Área Sob a Curva , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pele/metabolismo , Líquido Sinovial/metabolismo , Teicoplanina/administração & dosagem , Teicoplanina/efeitos adversos , Teicoplanina/farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
In over a decade (2002 to 2012) of Staphylococcus aureus surveillance testing on 62,195 isolates, dalbavancin was demonstrated to be active against isolates that were either susceptible or nonsusceptible to daptomycin, linezolid, or tigecycline. Nearly all (99.8%) multidrug-resistant methicillin-resistant S. aureus isolates were inhibited by dalbavancin at ≤0.12 µg/ml (MIC50/90, 0.06/0.06 µg/ml), the current U.S. Food and Drug Administration (U.S. FDA) breakpoint. Overall, only 0.35% of the monitored S. aureus isolates had a dalbavancin MIC of either 0.25 or 0.5 µg/ml (i.e., were nonsusceptible).
Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Teicoplanina/análogos & derivados , Daptomicina/farmacologia , Farmacorresistência Bacteriana Múltipla , Monitoramento Epidemiológico , Humanos , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Minociclina/análogos & derivados , Minociclina/farmacologia , Teicoplanina/farmacologia , Tigeciclina , Estados UnidosRESUMO
BACKGROUND: Dalbavancin is a lipoglycopepetide antibiotic with activity against gram positive pathogens recently approved for treatment of acute bacterial skin and skin structure infections. Pending the introduction of antimicrobial susceptibility tests, we examined the utility of vancomycin inhibitory concentrations to predict dalbavancin susceptibility in a panel of isolates obtained from phase 3 registration studies. FINDINGS: 99.6% of Staphylococcus aureus and 99.0% of beta-hemolytic streptococci which are susceptible to vancomycin will have an MIC at or below the US FDA susceptibility breakpoint for dalbavancin. CONCLUSION: Vancomycin should be considered as a surrogate for in vitro dalbavancin susceptibility testing.
Assuntos
Antibacterianos/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Teicoplanina/análogos & derivados , Vancomicina/administração & dosagem , Adulto , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Infecções Estafilocócicas/microbiologia , Teicoplanina/administração & dosagemRESUMO
BACKGROUND: Given increasing rates of resistance to existing therapy, new options for treatment and prophylaxis of malaria are needed. METHODS: Two randomised, comparative, non-inferiority studies were conducted in Africa, one double-blinded and one open-label. Adults with fever, a positive peripheral blood smear, and a positive rapid diagnostic test for Plasmodium falciparum were randomised in both studies to either azithromycin (AZ) 1,000 mg plus chloroquine (CQ) 600-mg base (AZCQ 1,000 mg) once daily for three days or mefloquine hydrochloride (MQ) 1,250 mg (split dose). In the first study, an additional regimen of AZ 500 mg plus CQ 600-mg base (AZCQ 500 mg) once daily for three days was included. All study participants were hospitalised until three consecutive daily blood smears were negative for asexual P. falciparum parasitaemia. Study participants were evaluated weekly for 42 days, with Day 28 polymerase chain reaction (PCR)-corrected parasitological clearance rate as primary endpoint. RESULTS: A total of 467 subjects were randomised in the two studies. At 28 days' follow-up, PCR-corrected parasitological clearance rates in the per protocol population in the first study were 101/103 (98%) with AZCQ 1,000 mg compared with 102/103 (99%) with MQ (95% confidence interval [CI]: -5.2, 3.3). The AZCQ 500-mg regimen was stopped during an interim study review (six [86%] clearance of seven evaluable; two lost to follow-up). In the second study, clearance rates were similar: AZCQ 1,000 mg 107/107 (100%) vs MQ 111/112 (99%; 95% CI: -1.8, 3.6). Among the participating countries, in vitro CQ resistance based on pfcrt mutation frequency in the baseline isolates across both studies ranged from 20.8% (Zambia) to 96.1% (Uganda). Serious adverse events (AEs; all causality) were observed more frequently with MQ compared with AZCQ (four vs one, respectively), though discontinuations for AEs were similar (four vs three, respectively). Common AEs in the AZ-containing arms included pruritus, vomiting, dizziness, and headache. CONCLUSIONS: Among adults with symptomatic uncomplicated falciparum malaria in Africa, the combination of AZ 1,000 mg and CQ 600-mg base once daily for three days resulted in Day 28 PCR-corrected parasitological clearance rates of ≥98% and was non-inferior to treatment with MQ. AZCQ was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT00082576 and NCT00367653.
Assuntos
Antimaláricos/administração & dosagem , Azitromicina/administração & dosagem , Cloroquina/administração & dosagem , Malária Falciparum/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Mefloquina/administração & dosagem , Pessoa de Meia-Idade , Parasitemia/diagnóstico , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase , Resultado do Tratamento , Uganda , Adulto Jovem , ZâmbiaRESUMO
BACKGROUND: We conducted a prespecified meta-analysis of two randomized, placebo-controlled trials of rivaroxaban 10 mg daily in prehospital patients with acute coronavirus disease 2019 (COVID-19). Individually, the trials had limited power to detect a treatment effect due to recruitment stopping ahead of plan. MATERIAL AND METHODS: The statistical analysis plan for the meta-analysis was finalized before unblinding of PREVENT-HD, the larger of the two trials. Pooled risk ratios and pooled risk differences along with the two-sided 95% confidence intervals were calculated using random-effect models. RESULTS: Rivaroxaban did not reduce the occurrence of either the primary prespecified endpoint, a composite of symptomatic arterial and venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, all-cause hospitalization, and all-cause mortality (risk difference: 0.0044; 95% confidence interval: -0.0263, 0.0175; p = 0.69 for pooled risk difference) or the secondary endpoint of all-cause hospitalization (p = 0.76). Although thrombotic events were infrequent, pooled analysis did reveal that rivaroxaban reduced arterial and venous thrombotic events (placebo 6 events, rivaroxaban 0 events; pooled risk difference: -0.0068; 95% confidence interval: -0.0132, -0.0006; p = 0.03). In the pooled studies, only one major bleeding event was observed in a rivaroxaban-allocated patient with no critical site or fatal bleeding events. CONCLUSION: Although this meta-analysis does not support antithrombotic prophylaxis with rivaroxaban in a broad prehospital population with acute COVID-19, the prevention of arterial and venous thrombotic events among rivaroxaban-allocated patients is consistent with the known thromboprophylactic effect of the drug in medically ill patients.
RESUMO
Antimicrobial resistance (AMR) can complicate effective management of urinary tract infections. We conducted a retrospective study of AMR in Enterobacterales urine isolates from ambulatory and hospitalized adult patients from 2018-2020 (BD Insights Research Database) to evaluate regional differences in isolates with an extended-spectrum beta-lactamase-producing phenotype and those not susceptible to beta-lactams, fluoroquinolone (FQ), nitrofurantoin (NFT), trimethoprim/sulfamethoxazole (TMP/SMX), or multiple antibiotic classes (≥ 2 or ≥ 3). Our analyses included 349,741 Enterobacterales urine isolates from 321 inpatient facilities and 980,354 isolates from 338 ambulatory care facilities. In multivariable analyses, the highest rate of resistance was to beta-lactams (60.8% and 55.8% for inpatient and ambulatory settings, respectively), followed by FQ (27.5%), NFT (27.0%), and TMP/SMX (25.4%) for inpatients and by TMP/SMX (22.4%), FQ (21.6%), and NFT (21.6%) for ambulatory patients. Isolates with an extended-spectrum beta-lactamase-producing phenotype (13.2% and 8.6% for inpatient and ambulatory settings, respectively) and multidrug resistance (inpatient and ambulatory rates of 23.4% and 17.7% for ≥ 2 drugs; 9.9% and 6.4% for ≥ 3 drugs) were also prevalent. Statistically significant differences by geographic region (P ≤ 0.005) were observed for AMR classes in both inpatient and ambulatory settings, but the rates remained above the thresholds recommended for empiric urinary tract infection therapy across most regions.
Assuntos
Farmacorresistência Bacteriana , Enterobacteriaceae , Infecções Urinárias , Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Fluoroquinolonas/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Estados Unidos/epidemiologia , Infecções Urinárias/epidemiologia , Infecções Urinárias/microbiologia , beta-Lactamases/genética , beta-Lactamas/farmacologiaRESUMO
INTRODUCTION: Dalbavancin is a long-acting, bactericidal, lipoglycopeptide antibiotic approved by the US Food and Drug Administration and the European Medicines Agency for treatment of acute bacterial skin and skin structure infections in adults, with potent activity against Gram-positive pathogens, including methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Here we describe the clearance and clinical outcomes of patients with S. aureus bacteremia in five clinical trials of skin and skin structure infections or catheter-related bloodstream infections that evaluated the efficacy and safety of dalbavancin. METHODS: Patients with uncomplicated S. aureus bacteremia identified in blood cultures drawn at baseline (before study drug) with at least one follow-up blood culture are described from four phase 3 trials in skin and skin structure infections and one phase 2 catheter-related infection study. Dalbavancin was administered as a single-dose (1500 mg intravenous [IV]) or a two-dose regimen (1000 mg IV on day 1, 500 mg IV on day 8). Comparators included vancomycin IV or linezolid IV/oral for 10-14 days. RESULTS: All 39 patients (100%) who received dalbavancin, including 8 patients on the single-dose regimen, had clearance of bacteremia versus 19/20 patients (95%) treated with comparators (vancomycin or linezolid). At end of treatment, 33/36 dalbavancin-treated patients (92%) achieved clinical success versus 18/23 patients (78%) treated with comparators. CONCLUSIONS: All 39 patients with uncomplicated S. aureus bacteremia treated with dalbavancin (single- or two-dose regimen) and with follow-up blood cultures had clearance of their bloodstream infection. Clinical response rates were similar to daily comparator therapy for 10-14 days. TRIAL REGISTRATION: DISCOVER 1, NCT01339091; DISCOVER 2, NCT01431339; DUR001-303, NCT02127970; VER001-9; VER001-4, NCT00057369.
RESUMO
Antimicrobial resistance in Enterobacterales has made empiric therapy for hospitalized patients with urinary tract infections (UTIs) more challenging. We analyzed the antibiotic susceptibility of nonduplicate Enterobacterales isolates from urine cultures tested at US hospitals in the BD Insights Research Database (2011-2020). Multivariable generalized estimating equation models were used to assess resistance trends over time. A total of 322 US hospitals provided data on 876,507 urinary Enterobacterales isolates (62.4% Escherichia coli). Enterobacterales antibiotic resistance rates were 64.6%, 29.3%, 27.6%, and 26.3% for beta-lactams, fluoroquinolones, nitrofurantoin, and trimethoprim/sulfamethoxazole, respectively, and 12.4% had an extended-spectrum beta-lactamase (ESBL) phenotype. In multivariable models, rates of ESBL isolates and isolates resistant to ≥3 drug classes increased significantly between 2011 and 2020, while other categories of resistance generally decreased. We conclude that antimicrobial resistance is common in urinary Enterobacterales isolates. Management of UTIs should be guided by urine culture data and may benefit from new therapies.