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On 22 March 2023, the FDA approved rezafungin (Rezzayo) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a day 30 all-cause mortality primary end point and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in nonhuman primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other Food and Drug Administration-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options. Clinical Trials Registration . NCT02734862 and NCT03667690.
Assuntos
Antifúngicos , Candidemia , Candidíase Invasiva , Aprovação de Drogas , Equinocandinas , Humanos , Equinocandinas/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Antifúngicos/uso terapêutico , Candidemia/tratamento farmacológico , Adulto , Estados Unidos , United States Food and Drug Administration , Animais , Ensaios Clínicos Fase III como AssuntoRESUMO
Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.
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For treatment of severe malaria, the World Health Organization recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe the Food and Drug Administration's rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.
Assuntos
Antimaláricos , Malária Falciparum , Malária , Antimaláricos/uso terapêutico , Artemisininas , Artesunato/uso terapêutico , Peso Corporal , Criança , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Estados Unidos , United States Food and Drug AdministrationRESUMO
Effective bacterial infection eradication requires not only potent antibacterial agents but also proper dosing strategies. Current practices generally utilize point estimates of the effects of therapeutic agents, even though the actual kinetics of exposure are much more complex and relevant. Here, we use a full time course of the observed in vitro effects to develop a semimechanistic pharmacokinetic-pharmacodynamic model for eravacycline against multiple Gram-negative bacterial pathogens. This model incorporates components such as pharmacokinetics, bacterial life cycle, and drug effects to quantitatively describe the time course of antibacterial killing and the emergence of resistance. Model discrimination was performed by comparing goodness of fit, convergence diagnostics, and objective function values. Models were validated by assessing their abilities to describe bacterial count time courses in visual predictive checks. The final model describes 576 bacterial counts (expressed in log10 CFU per milliliter) from 144 in vitro time-kill experiments with low residual error and high precision. We characterize antibacterial susceptibility as a function of the MIC and adaptive resistance. In doing so, we show that the MIC is proportional to initial susceptibility at 0 h and the development of resistance over the course of 16 h. Altogether, this model may be useful in supporting dose selection, since it incorporates in vitro pharmacodynamics and clinically observed individual drug susceptibilities.
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Antibacterianos , Anti-Infecciosos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , TetraciclinasRESUMO
Acute lung injury (ALI) is a clinical syndrome characterized by acute respiratory failure and is associated with substantial morbidity and mortality. Rhesus θ-defensin (RTD)-1 is an antimicrobial peptide with immunomodulatory activity. As airway inflammation and neutrophil recruitment and activation are hallmarks of ALI, we evaluated the therapeutic efficacy of RTD-1 in preclinical models of the disease. We investigated the effect of RTD-1 on neutrophil chemotaxis and macrophage-driven pulmonary inflammation with human peripheral neutrophils and LPS-stimulated murine alveolar macrophage (denoted MH-S) cells. Treatment and prophylactic single escalating doses were administered subcutaneously in a well-established murine model of direct endotoxin-induced ALI. We assessed lung injury by histopathology, pulmonary edema, inflammatory cell recruitment, and inflammatory cytokines/chemokines in the BAL fluid. In vitro studies demonstrated that RTD-1 suppressed CXCL8-induced neutrophil chemotaxis, TNF-mediated neutrophil-endothelial cell adhesion, and proinflammatory cytokine release in activated murine alveolar immortalized macrophages (MH-S) cells. Treatment with RTD-1 significantly inhibited in vivo LPS-induced ALI by reducing pulmonary edema and histopathological changes. Treatment was associated with dose- and time-dependent inhibition of proinflammatory cytokines (TNF, IL-1ß, and IL-6), peroxidase activity, and neutrophil recruitment into the airways. Antiinflammatory effects were demonstrated in animals receiving RTD-1 up to 12 hours after LPS challenge. Notably, subcutaneously administered RTD-1 demonstrates good peptide stability as demonstrated by the long in vivo half-life. Taken together, these studies demonstrate that RTD-1 is efficacious in an experimental model of ALI through inhibition of neutrophil chemotaxis and adhesion, and the attenuation of proinflammatory cytokines and gene expression from alveolar macrophages.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Defensinas/uso terapêutico , Infiltração de Neutrófilos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Adesão Celular/imunologia , Quimiocinas/biossíntese , Células Endoteliais/patologia , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Macaca mulatta , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Peroxidases/antagonistas & inibidores , Pneumonia/patologia , Edema Pulmonar/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT>MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT>1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT>MIC, 50%) of >0.9 for MICs of ≤16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.).
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Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacocinética , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/farmacocinética , Ceftazidima/uso terapêutico , Fibrose Cística/patologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Adulto , Idoso , Antibacterianos/farmacocinética , Combinação de Medicamentos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Estudos Prospectivos , Pseudomonas aeruginosa/isolamento & purificação , Infecções Respiratórias/microbiologia , Adulto Jovem , Inibidores de beta-Lactamases/farmacocinéticaRESUMO
Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease. We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models. We evaluated RTD-1's effects on basal and Pseudomonas aeruginosa-induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety, and tolerance studies were performed in naive mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burdens and airway inflammation using an established model of chronic P. aeruginosa endobronchial infection in CF (ΔF508) mice. RTD-1 directly reduces metalloprotease activity, as well as inflammatory cytokine secretion from CF airway leukocyte and bronchial epithelial cells. Intrapulmonary safety, tolerability, and stability data support the aerosol administration route. RTD-1 reduced the bacterial lung burden, airway neutrophils, and inflammatory cytokines in CF mice with chronic P. aeruginosa lung infection. Collectively, these studies support further development of RTD-1 for treatment of CF airway disease.
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Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Defensinas/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Adulto , Animais , Fibrose Cística/fisiopatologia , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/microbiologia , Feminino , Humanos , Inflamação , Leucócitos/microbiologia , Pulmão/microbiologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutrófilos/microbiologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/imunologia , Organismos Livres de Patógenos Específicos , Escarro/microbiologiaRESUMO
OBJECTIVES: Chronic endobronchial infections with Pseudomonas aeruginosa contribute to bronchiectasis and progressive loss of lung function in patients with cystic fibrosis. This study aimed to evaluate the therapeutic potential of a novel macrocyclic peptide, rhesus θ-defensin-1 (RTD-1), by characterizing its in vitro antipseudomonal activity and in vivo efficacy in a murine model of chronic Pseudomonas lung infection. METHODS: Antibacterial testing of RTD-1 was performed on 41 clinical isolates of P. aeruginosa obtained from cystic fibrosis patients. MIC, MBC, time-kill and post-antibiotic effects were evaluated following CLSI-recommended methodology, but using anion-depleted Mueller-Hinton broth. RTD-1 was nebulized daily for 7 days to cystic fibrosis transmembrane conductance regulator (CFTR) F508del-homozygous mice infected using the agar bead model of chronic P. aeruginosa lung infection. In vivo activity was evaluated by change in lung bacterial burden, airway leucocytes and body weight. RESULTS: RTD-1 exhibited potent in vitro bactericidal activity against mucoid and non-mucoid strains of P. aeruginosa (MIC90â=â8 mg/L). Cross-resistance was not observed when tested against MDR and colistin-resistant isolates. Time-kill studies indicated very rapid, concentration-dependent bactericidal activity of RTD-1 with ≥3 log10 cfu/mL reductions at concentrations ≥4× MIC. No post-antibiotic effect was observed. In vivo, nebulized treatment with RTD-1 significantly decreased lung P. aeruginosa burden (mean difference of -1.30 log10 cfu; Pâ=â0.0061), airway leucocytes (mean difference of -0.37 log10; Pâ=â0.0012) and weight loss (mean difference of -12.62% at day 7; Pâ<â0.05) when compared with controls. CONCLUSIONS: This study suggests that RTD-1 is a promising potential therapeutic agent for cystic fibrosis airway disease.
Assuntos
Antibacterianos/administração & dosagem , Defensinas/administração & dosagem , Macaca mulatta , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Carga Bacteriana , Peso Corporal , Fibrose Cística/complicações , Defensinas/farmacologia , Modelos Animais de Doenças , Humanos , Contagem de Leucócitos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Resultado do TratamentoRESUMO
A hallmark of cystic fibrosis is the massive recruitment of neutrophils into the lung compartment in response to chronic Pseudomonas aeruginosa infection. The overexuberant neutrophilic response results in release of proteases (e.g. neutrophil elastase and matrix metalloproteinase-9) leading to matrix breakdown, airway remodeling, and progressive loss of lung function. Doxycycline is used clinically for the management of periodontitis due to its potent direct inhibition of matrix metalloproteinases; however, little is known regarding its potential anti-inflammatory properties and clinical utility in the context of cystic fibrosis airway disease. CF (IB3-1) and corrected (S9) bronchial epithelial cell lines were used to determine the cytotoxicity and anti-inflammatory effects of doxycycline in-vitro. Exposure to doxycycline, at low concentrations, resulted in minimal cell death and dose dependent reductions in release of CXCL-8 and MMP-9 protein. To confirm these findings, mechanistic analysis revealed ERK 1/2, p38, and JNK, but not NF-κB p65 dependent cell signaling inhibition with doxycycline treatment. These findings indicate that doxycycline exhibits anti-inflammatory activity in CF lung epithelial cells at concentrations below the cytotoxic potential. These data are encouraging and indicate in-vivo studies are warranted.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Brônquios/efeitos dos fármacos , Fibrose Cística/complicações , Doxiciclina/farmacologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Humanos , Interleucina-8/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Vicious cycles of chronic airway obstruction, lung infections with Pseudomonas aeruginosa, and neutrophil-dominated inflammation contribute to morbidity and mortality in cystic fibrosis (CF) patients. Rhesus theta defensin-1 (RTD-1) is an antimicrobial macrocyclic peptide with immunomodulatory properties. Our objective was to investigate the anti-inflammatory effect of RTD-1 in a murine model of chronic P. aeruginosa lung infection. Mice received nebulized RTD-1 daily for 6 days. Bacterial burden, leukocyte counts, and cytokine concentrations were evaluated. Microarray analysis was performed on bronchoalveolar lavage fluid (BALF) cells and lung tissue homogenates. In vitro effects of RTD-1 in THP-1 cells were assessed using quantitative reverse transcription PCR, enzyme-linked immunosorbent assays, immunoblots, confocal microscopy, enzymatic activity assays, and NF-κB-reporter assays. RTD-1 significantly reduced lung white blood cell counts on days 3 (-54.95%; p = 0.0003) and 7 (-31.71%; p = 0.0097). Microarray analysis of lung tissue homogenates and BALF cells revealed that RTD-1 significantly reduced proinflammatory gene expression, particularly inflammasome-related genes (nod-like receptor protein 3, Mediterranean fever gene, interleukin (IL)-1α, and IL-1ß) relative to the control. In vitro studies demonstrated NF-κB activation was reduced two-fold (p ≤ 0.0001) by RTD-1 treatment. Immunoblots revealed that RTD-1 treatment inhibited proIL-1ß biosynthesis. Additionally, RTD-1 treatment was associated with a reduction in caspase-1 activation (FC = -1.79; p = 0.0052). RTD-1 exhibited potent anti-inflammatory activity in chronically infected mice. Importantly, RTD-1 inhibits inflammasome activity, which is possibly a downstream effect of NF-κB modulation. These findings support that this immunomodulatory peptide may be a promising therapeutic for CF-associated lung disease.