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BACKGROUND: Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans. METHODS: A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 104 (low dose), 105 (medium dose), or 106 (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00. FINDINGS: Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months. INTERPRETATION: The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use. FUNDING: The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.
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OBJECTIVES: Prudent handling of reported antibiotic allergies is an important aspect of antibiotic stewardship. The Dutch Working Party on Antibiotic Policy (SWAB) constituted a multidisciplinary expert committee to provide evidence-based recommendations for bedside decision-making in antibiotic therapy in patients that report an antibiotic allergy. METHODS: The guideline committee generated 12 key questions, most of which were population, intervention, comparison, and outcome questions relevant to both children and adults with suspected antibiotic allergies. For each question, a systematic literature search was performed and reviewed for the best available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The quality of evidence was graded from very low to high, and recommendations were formulated in structured discussions as strong or weak. RESULTS: Sixty recommendations were provided for suspected allergy to ß-lactam antibiotics (BLAs) and non-ß-lactam antibiotics. Owing to the absence of randomized controlled trials in this field, the underlying evidence was predominantly graded as low or very low. Available data support that a detailed allergy history should always be performed and critically appraised. When cross-allergy between BLA groups is not to be expected due to the absence of molecular similarity of the side chains, the patient can be safely exposed to the alternative BLA. An exception to this rule is severe delayed-type reactions in which re-exposure to a BLA should only be considered after consultation with a multidisciplinary team. CONCLUSIONS: Accumulated scientific data now support a more liberal approach that better balances the benefits of treatment with first choice and usually smaller spectrum antibiotics with appropriate avoidance of antibiotics in case of a truly high risk of a (severe) allergic reaction. In The Netherlands, a formal guideline was developed that provides recommendations for the approach toward suspected allergy to BLA and frequently used non-ß-lactam antibiotics, thereby strongly supporting antimicrobial stewardship.
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Programas de Optimización del Uso de los Antimicrobianos , Hipersensibilidad a las Drogas , Hipersensibilidad , Adulto , Niño , Humanos , Antibacterianos/efectos adversos , beta-Lactamas/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad/tratamiento farmacológicoRESUMEN
Instructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory FE (eFE) evaluation is often incorporated into the first-in-human (FIH) studies in patients to inform food condition of later clinical studies. However, the design aspects of such exploratory assessments are generally under-reported and barely described, and yet complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we review literature of eFE assessment study design in oncology in patients, and present the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies from 2014 to 2021. Based on this, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs in patients, including a framework for common study design options with a focus on study- and patient-level timing for typical scenarios. We also provide a broad spectrum of decision-making factors which should be evaluated to drive the design and implementation of eFE assessment, spanning from clinical development strategy, FIH study design, to compound-specific features.
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Oncología Médica , Proyectos de Investigación , Humanos , Atención a la SaludRESUMEN
BACKGROUND: Approximately 2% of patients in primary care practice and up to 25% of hospital patients are registered as being allergic to an antibiotic. However, up to 90% of these registrations are incorrect, leading to unnecessary prescription of 2nd choice antibiotics with the attendant loss of efficacy, increased toxicity and antibiotic resistance. To improve registration, a better understanding is needed of how incorrect labels are attributed. OBJECTIVE: To investigate the quality of antibiotic allergy registration in primary care and identify determinants to improve registration of antibiotic allergies. DESIGN: Registration of antibiotic allergies in primary care practices were analysed for 1) completeness and 2) correctness. To identify determinants for improvement, semi-structured interviews with healthcare providers from four healthcare domains were conducted. PARTICIPANTS: A total of 300 antibiotic allergy registrations were analysed for completeness and correctness. Thirty-four healthcare providers were interviewed. MAIN MEASURES: A registration was defined as complete when it included a description of all symptoms, time to onset of symptoms and the duration of symptoms. It was defined as correct when the conclusion was concordant with the Salden criteria. Determinants of correct antibiotic allergy registrations were divided into facilitators or obstructers. KEY RESULTS: Rates of completeness and correctness of registrations were 0% and 29.3%, respectively. The main perceived barriers for correct antibiotic allergy registration were insufficient knowledge, lack of priority, limitations of registration features in electronic medical records (EMR), fear of medical liability and patients interpreting side-effects as allergies. CONCLUSIONS: The quality of antibiotic allergy registrations can be improved. Potential interventions include raising awareness of the consequences of incomplete and the importance of correct registrations, by continued education, and above all simplifying registration in an EMR by adequate ICT support.
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Señales (Psicología) , Hipersensibilidad a las Drogas , Antibacterianos/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/epidemiología , Farmacorresistencia Microbiana , Registros Electrónicos de Salud , HumanosRESUMEN
BACKGROUND: Lithium remains the first line therapy for treatment of bipolar disorder and is widely used in psychiatry despite its narrow therapeutic window. Cardiac side effects are uncommon, but when they are present, they can vary from benign repolarization changes to life threatening tachyarrhythmias as well as conduction time abnormalities. In extremely rare cases complete atrioventricular block with cardiogenic shock can be seen. METHODS: We report the clinical course and outcome of a 79-year-old patient who presented with bradyarrhythmias and a complete atrioventricular block due to severe lithium intoxication. The patient was admitted to ICU where fluid resuscitation and intermittent haemodialysis were performed. Interestingly, the cardiac ultrasound on ICU showed a diastolic mitral regurgitation which was related to the underlying complete atrioventricular block. RESULTS: After two cycles of haemodialysis lithium blood levels were normalised and 24 h later sinus rhythm was restored without any signs of atrioventricular block. The patient recovered completely. CONCLUSION: Lithium is widely used for the treatment of bipolar disorder and it can rarely lead to complete atrioventricular block. If the physician encounters a patient with a history of lithium use, who also shows cardiac arrhythmias, then lithium intoxication should always be ruled out. Haemodialysis is the treatment of choice in severe lithium intoxication. Diastolic mitral regurgitation can hint towards underlying atrioventricular conduction disturbances.
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Bloqueo Atrioventricular , Insuficiencia de la Válvula Mitral , Humanos , Anciano , Bloqueo Atrioventricular/inducido químicamente , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/terapia , Insuficiencia de la Válvula Mitral/inducido químicamente , Insuficiencia de la Válvula Mitral/diagnóstico , Litio , Arritmias Cardíacas/terapia , DiástoleAsunto(s)
Antineoplásicos/administración & dosificación , Desarrollo de Medicamentos , Descubrimiento de Drogas , Farmacología Clínica/educación , Rol Profesional , Investigadores/educación , Antineoplásicos/efectos adversos , Cálculo de Dosificación de Drogas , Procesos de Grupo , Humanos , Liderazgo , Seguridad del Paciente , Medición de RiesgoRESUMEN
World-wide, emerging triazole resistance increasingly complicates treatment of invasive aspergillosis (IA). In settings with substantial (>10%) prevalence of triazole resistance, empiric combination therapy with both a triazole and liposomal amphotericin B (LAmB) can be considered because of the low yields of susceptibility testing. To avoid toxicity while optimizing outcome, a strategy with monotherapy would be preferable. A newly designed treatment algorithm based on literature and expert consensus provided guidance for empiric monotherapy with either voriconazole or LAmB. Over a four and a half year period, all adult patients in our hospital treated for IA were included and patient data were collected. An independent committee reviewed the attributability of death to IA for each patient. Primary outcomes were 30- and 100-day crude mortality and attributable mortality. In total, 110 patients were treated according to the treatment algorithm. Fifty-six patients (51%) were initially treated with voriconazole and 54 patients (49%) with LAmB. Combined attributable and contributable mortality was 13% within 30 days and 20% within 100 days. Treatment switch to LAmB was made in 24/56 (43%) of patients who were initially treated with voriconazole. Combined contributable and attributable 100-day mortality in this subgroup was 21% and was not increased when compared with patients initially treated with LAmB (P = 0.38). By applying a comprehensive clinical decision algorithm, an antifungal-sparing regime was successfully introduced. Further research is warranted to explore antifungal treatment strategies that account for triazole-resistance. LAY SUMMARY: Due to resistance of Aspergillus against triazoles, combination therapy with liposomal amphotericin B (LAmB) is applied more often as primary therapy against invasive aspergillosis. This study presents the results of a decision tool which differentiated between triazole or LAmB monotherapy.
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Aspergilosis , Infecciones Fúngicas Invasoras , Animales , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/veterinaria , Reglas de Decisión Clínica , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/veterinaria , Triazoles/uso terapéutico , Voriconazol/uso terapéuticoRESUMEN
BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin. METHODS: Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W). RESULTS: Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy. CONCLUSIONS: Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. CLINICAL TRIALS IDENTIFIER: NCT02157792.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Isoxazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Pirazinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Isoxazoles/efectos adversos , Isoxazoles/farmacocinética , Masculino , Persona de Mediana Edad , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. METHODS: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. RESULTS: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. CONCLUSIONS: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. CLINICAL TRIAL IDENTIFIER: NCT02157792.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Isoxazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Pirazinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Isoxazoles/efectos adversos , Isoxazoles/farmacocinética , Masculino , Persona de Mediana Edad , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Análisis de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: The Guillan-Barré syndrome (GBS) is the most common acute disease of the peripheral nervous system, often necessitating ICU care. Although no clear paraneoplastic syndrome has been defined, it has been known to occur together with several types of cancer. METHODS: We present the case of a 35-year-old man with acute flaccid paralysis and cervical lymphadenopathy. RESULTS: the patient was diagnosed with a severe presentation of GBS and papillary thyroid cancer. After surgical treatment for his cancer, his condition improved and he reached a nearly full recovery. CONCLUSION: our case concerns a young man in whom a severe presentation of GBS led to the diagnosis of thyroid cancer. To our knowledge, this represents the first reported case of this association.
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Síndrome de Guillain-Barré , Síndromes Paraneoplásicos , Neoplasias de la Tiroides , Enfermedad Aguda , Adulto , Síndrome de Guillain-Barré/complicaciones , Síndrome de Guillain-Barré/diagnóstico , Humanos , Masculino , Cáncer Papilar Tiroideo/diagnóstico , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugíaRESUMEN
PURPOSE: Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia-telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability. METHODS: A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18-480 mg/m2). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated. RESULTS: PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) IC50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine. CONCLUSIONS: There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemo-combinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date. CLINICAL TRIAL INFORMATION: NCT02157792, EudraCT 2013-005100-34.
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Isoxazoles/farmacocinética , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazinas/farmacocinética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Concentración 50 Inhibidora , Isoxazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazinas/administración & dosificaciónRESUMEN
Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen.
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Atención Ambulatoria/métodos , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Farmacorresistencia Fúngica , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Mucormicosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Adulto JovenRESUMEN
PURPOSE: Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. PROCEDURES: Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. RESULTS: The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. CONCLUSIONS: Hypoxia modulation may play a role in nal-IRI's mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response.
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Hipoxia de la Célula/fisiología , Irinotecán/administración & dosificación , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Animales , Femenino , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Liposomas/administración & dosificación , Liposomas/química , Estudios Longitudinales , Ratones , Ratones Endogámicos NOD , Ratones SCID , Nitroimidazoles/química , Nitroimidazoles/farmacocinética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Radiofármacos/química , Radiofármacos/farmacocinética , Inhibidores de Topoisomerasa I/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Background: From a stewardship perspective it is recommended that antibiotic guidelines are adjusted to the local setting, accounting for the local epidemiology of pathogens. In many settings the prevalence of Gram-negative pathogens with resistance to empiric sepsis therapy is increasing. How and when to escalate standard sepsis therapy to a reserve antimicrobial agent, is a recurrent dilemma. The study objective was to develop decision strategies for empiric sepsis therapy based on local microbiological and clinical data, and estimate the number needed to treat with a carbapenem to avoid mismatch of empiric therapy in one patient (NNTC). Methods: We performed a nested case control study in patients (> 18 years) with Gram-negative bacteremia in 2013-2016. Cases were defined as patients with Gram-negative bacteremia with in vitro resistance to the combination 2nd generation cephalosporin AND aminoglycoside (C-2GC + AG). Control patients had Gram-negative bacteremia with in vitro susceptibility to cefuroxime AND/OR gentamicin, 1:2 ratio. Univariate and multivariable analysis was performed for demographic and clinical predictors of resistance. The adequacy rates of empiric therapy and the NNTC were estimated for different strategies. Results: The cohort consisted of 486 episodes of Gram-negative bacteremia in 450 patients. Median age was 66 years (IQR 56-74). In vitro resistance to C-2GC + AG was present in 44 patients (8.8%). Independent predictors for resistance to empiric sepsis therapy were hematologic malignancy (adjusted OR 4.09, 95%CI 1.43-11.62, p < 0.01), previously cultured drug resistant pathogen (adjusted OR 3.72. 95%CI 1.72-8.03, p < 0.01) and antibiotic therapy during the preceding 2 months (adjusted OR 12.5 4.08-38.48, p < 0.01). With risk-based strategies, an adequacy rate of empiric therapy of 95.2-99.3% could be achieved. Compared to treating all patients with a carbapenem, the NNTC could be reduced by 82.8% (95%CI 78.5-87.5%) using the targeted approaches. Conclusions: A risk-based approach in empiric sepsis therapy has the potential to better target the use of reserve antimicrobial agents aimed at multi-resistant Gram-negative pathogens. A structured evaluation of the expected antimicrobial consumption and antibiotic adequacy rates is essential to be able to weigh the costs and benefits of potential antibiotic strategies and select the most appropriate approach.
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Antibacterianos/administración & dosificación , Bacteriemia/tratamiento farmacológico , Carbapenémicos/administración & dosificación , Sepsis/prevención & control , Anciano , Aminoglicósidos/administración & dosificación , Bacteriemia/microbiología , Estudios de Casos y Controles , Cefalosporinas/administración & dosificación , Estudios de Cohortes , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Sepsis/microbiologíaRESUMEN
MM-302 is an anti-HER2 antibody-targeted pegylated liposomal doxorubicin designed to deliver doxorubicin specifically to HER2-expressing solid tumors. The delivery and activity of MM-302 were evaluated in orthotopic, transgenic, and intravenous breast cancer models expressing varying levels of HER2 that metastasize to some of the most common sites of dissemination for breast cancer, namely, lung, liver, and brain. Metastatic burden was quantified by gross evaluation, immunohistochemistry (IHC), and bioluminescent imaging. Liposome delivery was quantified by IHC and ex vivo fluorescent imaging. Unlike its non-targeted counterpart, pegylated liposomal doxorubicin (PLD), MM-302 showed activity at controlling both primary and metastatic tumor burden in all models tested. The effect of HER2-targeting was greatest in the lung where lymphatic vessel density and MM-302 delivery were highest. Our data indicate that the therapeutic advantage of actively targeting a nanoliposome with an antibody is influenced by both target expression and the tumor microenvironment.
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Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Inmunoconjugados/química , Liposomas/química , Anticuerpos de Cadena Única/química , Animales , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Femenino , Ratones , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Receptor ErbB-2/metabolismo , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: This phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer. METHODS: Patients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w. RESULTS: Sixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain. CONCLUSION: MM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w.
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Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Doxorrubicina/análogos & derivados , Inmunoconjugados/administración & dosificación , Receptor ErbB-2/genética , Anticuerpos de Cadena Única/administración & dosificación , Trastuzumab/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Encéfalo/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Anticuerpos de Cadena Única/efectos adversos , Anticuerpos de Cadena Única/farmacocinética , Análisis de Supervivencia , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
Triple negative breast cancer (TNBC) represents a significant therapeutic challenge due to its highly aggressive nature and lack of effective treatment options. Liposomal irinotecan (nal-IRI, ONIVYDE) was approved in 2015 (by the Food and Drug Administration, European Medicines Agency, and Therapeutic Goods Administration) and is a topoisomerase inhibitor indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. This study investigates the potential therapeutic benefit of nal-IRI for the treatment of advanced TNBC in a clinically relevant mouse model of spontaneous metastasis (LM2-4). Female SCID mice were orthotopically inoculated with TNBC LM2-4-luc cells in the lower mammary fat pad. Following primary tumor resection, bioluminescence imaging (BLI) was used to monitor both metastasis formation and spread as well as response to treatment with nal-IRI. Weekly treatment with 10 mg/kg of nal-IRI provided a 4.9-times longer median survival compared to both 50 mg/kg irinotecan treated and untreated animals. The survival benefit was supported by a significant delay in the regrowth of the primary tumor, effective control, and eventual regression of metastases assessed using longitudinal BLI, which was confirmed at the study end point with magnetic resonance (MR) imaging and post-mortem observation. This preclinical investigation demonstrates that, at a five-times lower dose compared to the free drug, liposomal irinotecan provides significant survival benefit and effective management of metastatic disease burden in a clinically relevant model of spontaneous TNBC metastases. These findings support the evaluation of nal-IRI in patients with advanced and metastatic TNBC.
Asunto(s)
Irinotecán/química , Irinotecán/uso terapéutico , Liposomas/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Femenino , Imagen por Resonancia Magnética , Ratones , Ratones SCID , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Carga Tumoral/efectos de los fármacosRESUMEN
Deposition of liposomal drugs into solid tumors is a potentially rate-limiting step for drug delivery and has substantial variability that may influence probability of response. Tumor deposition is a shared mechanism for liposomal therapeutics such that a single companion diagnostic agent may have utility in predicting response to multiple nanomedicines. Methods: We describe the development, characterization and preclinical proof-of-concept of the positron emission tomography (PET) agent, MM-DX-929, a drug-free untargeted 100 nm PEGylated liposome stably entrapping a chelated complex of 4-DEAP-ATSC and 64Cu (copper-64). MM-DX-929 is designed to mimic the biodistribution of similarly sized therapeutic agents and enable quantification of deposition in solid tumors. Results: MM-DX-929 demonstrated sufficient in vitro and in vivo stability with PET images accurately reflecting the disposition of liposome nanoparticles over the time scale of imaging. MM-DX-929 is also representative of the tumor deposition and intratumoral distribution of three different liposomal drugs, including targeted liposomes and those with different degrees of PEGylation. Furthermore, stratification using a single pre-treatment MM-DX-929 PET assessment of tumor deposition demonstrated that tumors with high MM-DX-929 deposition predicted significantly greater anti-tumor activity after multi-cycle treatments with different liposomal drugs. In contrast, MM-DX-929 tumor deposition was not prognostic in untreated tumor-bearing xenografts, nor predictive in animals treated with small molecule chemotherapeutics. Conclusions: These data illustrate the potential of MM-DX-929 PET as a companion diagnostic strategy to prospectively select patients likely to respond to liposomal drugs or nanomedicines of similar molecular size.