ABSTRACT
Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in â¼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance.
ABSTRACT
QUESTION: There is an increasing prevalence of nontuberculous mycobacteria pulmonary disease (NTM-PD) in the US. Treatment of NTM-PD typically requires multiple medications, which can be associated with unpleasant morbidity and eradication of infection is difficult. Therefore, there is a critical need for novel effective and well-tolerated therapies. Recent in vitro data and case reports have suggested that nitric oxide, inhaled as a gas (gNO), has antimicrobial activity against NTM. We sought to investigate the effect of gNO in patients with NTM-PD in an open-label proof of concept trial. METHODS: Eligible participants had NTM-PD with persistently positive respiratory cultures for NTM even if on antibiotic treatment. Participants were treated with gNO for 50 min three times daily, five days per week, for three weeks (total of 15 treatment days). RESULTS: Ten participants, of whom nine were on long-term NTM antibiotic therapy, were enrolled. All participants completed the regimen without interruption or discontinuation. Small increases in methemoglobin were noted during treatment, and all resolved to baseline within 2 h. Four participants (40%) met the primary outcome measure of negative sputum cultures after three weeks of therapy. Following treatment discontinuation, three of these participants were again culture positive during the 3-month post-treatment monitoring period, although with measures suggesting low bacterial burden. ANSWER: Patients tolerated a 3-week regimen of gNO without safety concerns, and despite highly refractory disease four individuals completed the study with negative cultures, although three were again positive in subsequent months. These data support further investigation of gNO as a potential therapy for NTM-PD.
Subject(s)
Lung Diseases , Mycobacterium Infections, Nontuberculous , Pneumonia , Adult , Humans , Anti-Bacterial Agents/therapeutic use , Lung Diseases/microbiology , Mycobacterium Infections, Nontuberculous/microbiology , Nitric Oxide/therapeutic use , Nontuberculous Mycobacteria , Pneumonia/complications , Retrospective Studies , Proof of Concept StudyABSTRACT
BACKGROUND: Mycobacterial time to positivity (TTP) in liquid culture media has predictive value for longer term outcomes in pulmonary tuberculosis, but has not been thoroughly studied in nontuberculous mycobacterial pulmonary disease. This study sought to evaluate for association between TTP and sputum culture conversion to negative in pulmonary disease caused by Mycobacterium avium complex (MAC). METHODS: Data from the CONVERT trial (NCT02344004) that evaluated efficacy of guideline-based-therapy with or without amikacin liposome inhalation suspension in adults with refractory MAC-PD (Mycobacterium avium complex pulmonary disease) were analyzed. We evaluated TTP measures for sputum obtained prior to study treatment initiation and at monthly visits, assessing reproducibility of measures as well as association of TTP with culture conversion on treatment. RESULTS: Data from 71 participants with at least one screening visit TTP value were analyzed. For participants who provided more than one sputum sample at a given visit, there was moderate between-sample reliability, with median intraclass correlation coefficient 0.62 (IQR 0.50, 0.70). Median TTP at screening was longer in those participants who subsequently achieved vs. did not achieve culture conversion (10.5 [IQR 9.4] days vs. 4.2 [IQR 2.8] days, p = 0.0002). Individuals with culture conversion by study treatment month 6 were more likely to have a screening TTP > 5 days compared to those who did not achieve culture conversion (OR 15.4, 95% CI 1.9, 716.7, p = 0.0037) and had increasing TTPs over time. CONCLUSIONS: TTP prior to and on treatment is associated with microbiological treatment response in patients with MAC-PD.
Subject(s)
Mycobacterium avium Complex , Mycobacterium avium-intracellulare Infection , Adult , Anti-Bacterial Agents/therapeutic use , Humans , Mycobacterium avium-intracellulare Infection/diagnosis , Mycobacterium avium-intracellulare Infection/drug therapy , Mycobacterium avium-intracellulare Infection/microbiology , Reproducibility of Results , Treatment OutcomeABSTRACT
Pseudomonas aeruginosa is a common opportunistic pathogen that can cause chronic infections in multiple disease states, including respiratory infections in patients with cystic fibrosis (CF) and non-CF bronchiectasis. Like many opportunists, P. aeruginosa forms multicellular biofilm communities that are widely thought to be an important determinant of bacterial persistence and resistance to antimicrobials and host immune effectors during chronic/recurrent infections. Poly (acetyl, arginyl) glucosamine (PAAG) is a glycopolymer that has antimicrobial activity against a broad range of bacterial species, and also has mucolytic activity, which can normalize the rheological properties of cystic fibrosis mucus. In this study, we sought to evaluate the effect of PAAG on P. aeruginosa bacteria within biofilms in vitro, and in the context of experimental pulmonary infection in a rodent infection model. PAAG treatment caused significant bactericidal activity against P. aeruginosa biofilms, and a reduction in the total biomass of preformed P. aeruginosa biofilms on abiotic surfaces, as well as on the surface of immortalized cystic fibrosis human bronchial epithelial cells. Studies of membrane integrity indicated that PAAG causes changes to P. aeruginosa cell morphology and dysregulates membrane polarity. PAAG treatment reduced infection and consequent tissue inflammation in experimental P. aeruginosa rat infections. Based on these findings we conclude that PAAG represents a novel means to combat P. aeruginosa infection, and may warrant further evaluation as a therapeutic.
Subject(s)
Cystic Fibrosis , Pseudomonas Infections , Animals , Anti-Bacterial Agents/pharmacology , Biofilms , Cystic Fibrosis/microbiology , Glucosamine/pharmacology , Glucosamine/therapeutic use , Humans , Lung/microbiology , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/physiology , RatsABSTRACT
Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginyl) glucosamine (PAAG), a polycationic biopolymer suitable for human use, interacts directly with mucins in a Ca2+-sensitive manner to reduce CF mucus viscoelasticity and improve its transport. Notably, PAAG induced a linear structure of purified MUC5B and altered its sedimentation profile and viscosity, indicative of proper mucin expansion. In vivo, PAAG nebulization improved mucociliary transport in CF rats with delayed mucus clearance, and cleared mucus plugging in CF ferrets. This study demonstrates the potential use of a synthetic glycopolymer PAAG as a molecular agent that could benefit patients with a broad array of mucus diseases.
Subject(s)
Cystic Fibrosis/drug therapy , Glucosamine/analogs & derivatives , Mucin-5B/metabolism , Mucociliary Clearance/drug effects , Mucus/drug effects , Polymers/pharmacology , Animals , Cystic Fibrosis/genetics , Cystic Fibrosis/pathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Models, Animal , Ferrets , Glucosamine/pharmacology , Glucosamine/therapeutic use , Humans , Mice , Mice, Inbred CFTR , Mucin-5B/chemistry , Mucus/metabolism , Polymers/therapeutic use , Protein Structure, Quaternary/drug effects , Rats , Respiratory Mucosa/drug effects , Respiratory Mucosa/pathology , Viscosity/drug effectsABSTRACT
BACKGROUND: Infection with Burkholderia cepacia complex (Bcc) results in a heterogeneous clinical course ranging from asymptomatic colonization of the airways to fulminant respiratory failure in patients with cystic fibrosis (CF). Early eradication of Pseudomonas aeruginosa improves clinical outcomes. The efficacy and clinical outcomes following implementation of an eradication protocol for Bcc are less well understood. METHODS: We developed and implemented a single center Bcc eradication protocol that included an intensive combination of intravenous, inhaled, and oral antibiotic therapies based on in vitro sensitivities. We conducted a retrospective cohort analysis of clinical outcomes compared to patients with chronic Bcc infection. RESULTS: Six patients were identified as having a newly acquired Bcc colonization and were placed on the eradication protocol. Sequential sputum samples after completion of the protocol demonstrated sustained clearance of Bcc in all patients. Lung function and nutritional status remained stable in the year following eradication. CONCLUSION: Clearance of Bcc from sputum cultures using a standardized protocol was successful at one year and was associated with clinical stability.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Burkholderia Infections/drug therapy , Burkholderia cepacia complex , Cystic Fibrosis/therapy , Pneumonia, Bacterial/drug therapy , Administration, Inhalation , Administration, Intravenous , Administration, Oral , Adult , Azithromycin/administration & dosage , Burkholderia Infections/complications , Ceftazidime/administration & dosage , Clinical Protocols , Cohort Studies , Consolidation Chemotherapy , Cystic Fibrosis/complications , Drug Therapy, Combination , Female , Humans , Induction Chemotherapy , Male , Middle Aged , Pneumonia, Bacterial/complications , Retrospective Studies , Tobramycin/administration & dosage , Treatment Outcome , Trimethoprim, Sulfamethoxazole Drug Combination/administration & dosage , Young AdultABSTRACT
Acute fibrinous organizing pneumonia (AFOP) is a distinct histopathologic pattern of lung injury with the hallmark feature of intra-alveolar fibrin deposits with associated organizing pneumonia, type II pneumocyte hyperplasia, and a patchy lymphohistiocytic proliferation. We describe the case of a previously healthy 47-year-old man who presented with a 4-day history of worsening dyspnea, cough, and nocturnal fevers and miliary nodules on chest imaging. Subsequently, there was an indication of AFOP when he underwent open lung biopsy. AFOP has been associated with a variety of underlying conditions including rheumatologic diseases, medications, and infections, and several cases were idiopathic. This case highlights the importance for radiologists to be aware of this uncommon pattern of lung injury and to consider it in the differential when encountering bilateral miliary infiltrates on chest imaging.
Subject(s)
Cryptogenic Organizing Pneumonia/pathology , Biopsy , Cryptogenic Organizing Pneumonia/diagnostic imaging , Humans , Lung/pathology , Male , Middle Aged , RadiographyABSTRACT
Corticosteroids are the mainstay of treatment of inflammatory pseudotumor (IPT) of the head and neck; however, involvement of the skull base and mandible can be unresponsive to steroids and require surgical resection. IPT is known to usually contain a CD20+ lymphocyte subgroup. Rituximab, a chimeric anti-CD20 antibody, has been successfully utilized in the treatment of other CD20+ diseases, including the similar idiopathic orbital inflammatory disease. This is the first report to describe successful treatment with Rituximab of a recurrent IPT of the mandible with trigeminal spread and leptomeningeal involvement with clinical and radiologic evidence demonstrating a sustained response to therapy.