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Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.
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Bacteriófagos , Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Animales , Colitis/terapia , Humanos , Inflamación/terapia , Enfermedades Inflamatorias del Intestino/terapia , Klebsiella pneumoniae , RatonesRESUMEN
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.
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Antibacterianos/farmacocinética , Mucosa Respiratoria/química , Teicoplanina/análogos & derivados , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/análisis , Antibacterianos/sangre , Humanos , Infusiones Intravenosas , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Neumocócica/tratamiento farmacológico , Neumonía Estafilocócica/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Teicoplanina/administración & dosificación , Teicoplanina/análisis , Teicoplanina/sangre , Teicoplanina/farmacocinética , Adulto JovenRESUMEN
Rapid and definitive diagnosis of viral respiratory infections is imperative in patient triage and management. We compared the outcomes for adult patients with positive tests for respiratory viruses at a tertiary care center across two consecutive influenza seasons (winters of 2010-2011 and 2012). Infections were diagnosed by conventional methods in the first season and by multiplex PCR (FilmArray) in the second season. FilmArray decreased the time to diagnosis of influenza compared to conventional methods (median turnaround times of 1.7 h versus 7.7 h, respectively; P = 0.015); FilmArray also decreased the time to diagnosis of non-influenza viruses (1.5 h versus 13.5 h, respectively; P < 0.0001). Multivariate logistic regression found that a diagnosis of influenza by FilmArray was associated with significantly lower odds ratios (ORs) for admission (P = 0.046), length of stay (P = 0.040), duration of antimicrobial use (P = 0.032), and number of chest radiographs (P = 0.005), when controlling for potential confounders. We conclude that the rapid turnaround time, multiplex nature of the test (allowing simultaneous detection of an array of viruses), and superior sensitivity of FilmArray may improve the evaluation and management of patients suspected of having respiratory virus infections.
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Técnicas de Diagnóstico Molecular/métodos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Infecciones del Sistema Respiratorio/diagnóstico , Virosis/diagnóstico , Virus/aislamiento & purificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hospitalización , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/virología , Estudios Retrospectivos , Centros de Atención Terciaria , Factores de Tiempo , Resultado del Tratamiento , Virosis/virología , Virus/clasificación , Virus/genética , Adulto JovenRESUMEN
Background: We assessed the efficacy and safety of dalbavancin, a long-acting lipoglycopeptide with activity against Gram-positive pathogens, for treatment of acute bacterial skin and skin structure infections (ABSSSI) in patients with high body mass index (BMI) and/or diabetes. Methods: Data from two phase 3 trials of dalbavancin (1000â mg intravenous [IV], day 1; 500â mg IV, day 8) versus comparator and one phase 3b trial of single-dose (1500â mg IV, day 1) versus 2-dose (1000â mg IV, day 1; 500â mg IV, day 8) dalbavancin in adults with ABSSSI were pooled and summarized separately by baseline BMI and diabetes status. Clinical success at 48 to 72â hours (≥20% reduction in lesion size), end of treatment ([EOT] day 14), and day 28 was evaluated in the intent-to-treat (ITT) and microbiological ITT (microITT) populations. Safety data were reported in patients who received ≥1 dose of study drug. Results: In the dalbavancin ITT population (BMI, n = 2001; diabetes, n = 2010), at 48 to 72â hours (and EOT) clinical success was achieved in 89.3% (EOT, 90.9%) of patients with normal BMI and 78.9% to 87.6% (EOT, 91.0% to 95.2%) of patients with elevated BMI. Clinical success after dalbavancin treatment was achieved in 82.4% (EOT, 90.8%) of patients with diabetes and 86.0% (EOT, 91.6%) of patients without diabetes. Similar trends were observed for infections due to methicillin-resistant Staphylococcus aureus or methicillin-susceptible S aureus (microITT population). Conclusions: Dalbavancin is effective, with sustained clinical success rates in patients with obesity or diabetes, with a similar safety profile across patient groups.
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Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor.
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Capnocytophaga/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/diagnóstico , Infecciones por Bacterias Gramnegativas/microbiología , Absceso Pulmonar/diagnóstico , Absceso Pulmonar/microbiología , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/secundario , Adulto , Técnicas Bacteriológicas , Broncoscopía , Infecciones por Bacterias Gramnegativas/cirugía , Humanos , Absceso Pulmonar/cirugía , Masculino , Microscopía , Tumores Neuroendocrinos/cirugía , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
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.
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BACKGROUND: Staphylococcus aureus bacteremia is a life-threatening infection and leading cause of infective endocarditis, with mortality rates of 15-50%. Treatment typically requires prolonged administration of parenteral therapy, itself associated with high costs and potential catheter-associated complications. Dalbavancin is a lipoglycopeptide with potent activity against Staphylococcus and a long half-life, making it an appealing potential therapy for S. aureus bacteremia without the need for durable central venous access. METHODS: DOTS is a phase 2b, multicenter, randomized, assessor-blinded, superiority, active-controlled, parallel-group trial. The trial will enroll 200 adults diagnosed with complicated S. aureus bacteremia, including definite or possible right-sided infective endocarditis, who have been treated with effective antibiotic therapy for at least 72 h (maximum 10 days) and with subsequent clearance of bacteremia prior to randomization to study treatment. Subjects will be randomized 1:1 to complete their antibiotic treatment course with either two doses of dalbavancin on days 1 and 8, or with a total of 4-8 weeks of standard intravenous antibiotic therapy. The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at day 70 for patients randomized to dalbavancin versus standard of care. Key secondary endpoints include quality of life outcomes and pharmacokinetic analyses of dalbavancin. DISCUSSION: The DOTS trial will establish whether dalbavancin is superior to standard parenteral antibiotic therapy for the completion of treatment of complicated S. aureus bacteremia. TRIAL REGISTRATION: US National Institutes of Health ClinicalTrials.gov NCT04775953 . Registered on 1 March 2021.
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Bacteriemia , Endocarditis , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Adulto , Antibacterianos/efectos adversos , Bacteriemia/diagnóstico , Bacteriemia/tratamiento farmacológico , Endocarditis/tratamiento farmacológico , Humanos , Estudios Multicéntricos como Asunto , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Teicoplanina/análogos & derivados , Resultado del TratamientoRESUMEN
INTRODUCTION: Dalbavancin is a lipoglycopeptide antibiotic approved as a single- and two-dose regimen for adults with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive organisms. We present nephrotoxicity rates for patients with ABSSSI who received dalbavancin in three pivotal clinical trials and compare the rates with vancomycin. METHODS: In a phase 3b clinical trial (DUR001-303), patients were randomized to dalbavancin single-dose (1500 mg intravenous [IV]) or two-dose regimen (1000 mg IV on day 1, 500 mg IV on day 8). In two phase 3 clinical trials (DISCOVER 1 and DISCOVER 2), patients were randomized to dalbavancin (two-dose regimen) or vancomycin 1 g (or 15 mg/kg) IV every 12 h for at least 3 days with an option to switch to orally administered linezolid 600 mg every 12 h for 10-14 days. Patients on dalbavancin with a creatinine clearance below 30 mL/min not on regular dialysis received a reduced dose of 1000 mg (single-dose arm) or 750 mg IV on day 1, 375 mg IV on day 8 (two-dose arm). Nephrotoxicity was defined as a 50% increase from baseline serum creatinine (SCr) or an absolute increase in SCr of 0.5 mg/dL at any time point. P values were obtained using the Cochran-Mantel-Haenszel test. RESULTS: In dalbavancin-treated patients, rates of nephrotoxicity were low. The safety population with available creatinine values included 1325/1347 patients on any regimen of dalbavancin, and 54/651 patients who received vancomycin intravenously for at least 10 days and were not switched to orally administered linezolid. Patients on any regimen of dalbavancin had a lower rate of nephrotoxicity compared with patients receiving vancomycin intravenously for at least 10 days (3.7% vs 9.3%, respectively; P = 0.039). CONCLUSIONS: Nephrotoxicity rates were lower in patients on dalbavancin relative to vancomycin for at least 10 days. On the basis of this experience, dalbavancin may be less nephrotoxic than intravenously administered vancomycin.
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INTRODUCTION: A small percentage of patients with skin infections later develop necrotizing fasciitis (NF). Diagnostic testing is needed to identify patients with skin infections at low risk of NF who could be discharged from the emergency department (ED) after antibiotic initiation. Elevated lactate has been associated with NF; existing estimates of the frequency of NF are based on retrospective reviews, and cases often lack testing for lactate. We present the incidence of patients with skin infections who developed NF and their baseline lactates. METHODS: In four phase-3 trials, 2883 adults with complicated or acute bacterial skin and skin structure infections were randomized to dalbavancin or comparator, with early and late follow-up visits through Day 28. We prospectively collected baseline plasma lactates in one trial to assess an association with NF. RESULTS: NF was diagnosed in 3/2883 patients (0.1%); all three survived. In the study with prospectively collected baseline lactates (n = 622), 15/622 (2.4%) had a lactate ≥4 millimoles per liter (mmol/L), including 3/622 (0.5%) with a lactate ≥7 mmol/L. NF was not seen in patients with a lactate <4 mmol/L; NF was seen in 1/15 (6.7%) with a lactate ≥4 mmol/L, including 1/3 (33.3%) with lactate ≥7 mmol/L. CONCLUSIONS: NF incidence within 72 hours of antibiotic initiation in patients with complicated or acute bacterial skin and skin structure infections was extremely low (0.1%) and occurred in 6.7% with a lactate ≥4 mmol/L. Lactate <4 mmol/L can be used to identify patients at low risk of NF who could be safely discharged from the ED after antibiotic initiation.
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Celulitis (Flemón) , Fascitis Necrotizante , Ácido Láctico/sangre , Teicoplanina/análogos & derivados , Adulto , Antibacterianos/administración & dosificación , Celulitis (Flemón)/complicaciones , Celulitis (Flemón)/diagnóstico , Método Doble Ciego , Servicio de Urgencia en Hospital , Fascitis Necrotizante/sangre , Fascitis Necrotizante/diagnóstico , Fascitis Necrotizante/etiología , Fascitis Necrotizante/prevención & control , Femenino , Humanos , Masculino , Pronóstico , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Teicoplanina/administración & dosificaciónRESUMEN
OBJECTIVES: Treatment of acute bacterial skin and skin structure infections (ABSSSIs) in the outpatient setting has potential advantages. We performed a subanalysis of outcomes for patients treated as outpatients versus inpatients with dalbavancin, a long-acting lipoglycopeptide, in a phase 3 clinical trial of ABSSSI. METHODS: The study was a double-blind trial of patients with ABSSSI randomised to receive dalbavancin 1500 mg intravenously as a single dose or two doses (1000 mg followed by 500 mg a week later). The primary endpoint was ≥20% reduction in erythema at 48-72 h after the start of therapy. Patient satisfaction and preference for antibiotic treatment and care setting were measured using the 10-item Skin and Soft Tissue Infection (SSTI) questionnaire at Day 14. RESULTS: A total of 698 patients were randomised (386 treated as outpatients and 312 as inpatients). Outpatients were more likely to be younger and to have major abscess or traumatic wound infection; inpatients were more likely to have cellulitis as the type of ABSSSI, to meet SIRS criteria and to have elevated plasma lactate at baseline. Efficacy and safety outcomes at 48-72 h, Days 14 and 28 were similar between patients treated in the outpatient and inpatient setting with either the single-dose or two-dose regimen. Outpatients reported significantly greater convenience and satisfaction with antibiotic treatment and care setting compared with inpatients (P < 0.001). CONCLUSION: Single-dose dalbavancin is an effective treatment option for outpatients with ABSSSI and is associated with a high degree of patient treatment satisfaction and convenience.
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Antibacterianos/administración & dosificación , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Teicoplanina/análogos & derivados , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Eritema/tratamiento farmacológico , Eritema/microbiología , Eritema/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios/psicología , Satisfacción del Paciente , Enfermedades Cutáneas Bacterianas/microbiología , Enfermedades Cutáneas Bacterianas/psicología , Infecciones de los Tejidos Blandos/microbiología , Infecciones de los Tejidos Blandos/psicología , Teicoplanina/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Osteomyelitis is a challenging infection that can involve 4-6 weeks of intravenous (IV) antibiotics. Dalbavancin, approved for acute bacterial skin and skin structure infections, has potent activity against gram-positive pathogens. This study assessed the efficacy and safety of dalbavancin as a 2-dose regimen for osteomyelitis. METHODS: This study was a randomized, open-label, comparator-controlled trial in adults with a first episode of osteomyelitis defined by clinical symptoms, radiologic findings, and elevated C-reactive protein. Patients were randomized 7:1 to dalbavancin (1500 mg IV on days 1 and 8) or standard of care (SOC) for osteomyelitis (oral or IV) per investigator judgment for 4-6 weeks. The primary endpoint was clinical response at day 42, defined as recovery without need for additional antibiotics in the clinically evaluable (CE) population. Clinical response was also assessed at day 21, 6 months, and 1 year. RESULTS: Eighty patients were randomized to dalbavancin (n = 70) or SOC (n = 10). All had baseline debridement; Staphylococcus aureus was the most common pathogen (60% of patients). Clinical cure at day 42 was seen in 65/67 (97%) and 7/8 (88%) patients in the dalbavancin group and SOC group in the CE population, respectively. Clinical response was similar in the dalbavancin group at day 21 (94%), 6 months, and 1 year (96%). Treatment-emergent adverse events occurred in 10 patients in the dalbavancin group; no patient discontinued treatment due to an adverse event. CONCLUSIONS: A 2-dose regimen of weekly dalbavancin is effective and well tolerated for the treatment of osteomyelitis in adults. CLINICAL TRIALS REGISTRATION: NCT02685033.
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BACKGROUND: Persons who inject drugs (PWID) are at increased risk of acute bacterial skin and skin structure infections (ABSSSIs), a growing healthcare concern. Multiple medical, social, and economic issues, including adherence and comorbidities, complicate the medical care of the PWID population, adversely affecting patient outcomes. METHODS: We assessed demographics and outcomes for the PWID population in a double-blind trial of 698 patients randomized to dalbavancin 1500 mg as a single intravenous (IV) infusion or as a 2-dose regimen (1000 mg IV on day 1; 500 mg IV on day 8) for ABSSSI. The primary endpoint was ≥20% reduction in erythema at 48-72 hours in the intent-to-treat population; clinical status was also assessed at days 14 and 28. RESULTS: There were 212/698 (30.4%) patients with a history of injection drug use in this clinical trial. Dalbavancin efficacy was similar between the single- and 2-dose therapy groups in the PWID and non-PWID populations at all timepoints. Dalbavancin was well tolerated in the PWID population, with similar rates of adverse events as the non-PWID population. CONCLUSION: Dalbavancin as a single-dose or 2-dose regimen had similar efficacy for the treatment of ABSSSI at all timepoints in the PWID and non-PWID populations. A single 30-minute IV infusion would eliminate the need for indwelling IV access. The convenience of a single dose supervised in a health setting may also optimize treatment adherence in the PWID population.