Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

The pharmacokinetics and pharmacodynamics of continuous infusion vancomycin in adult people with cystic fibrosis.

BACKGROUND: The American Thoracic Society Guidelines recommend vancomycin as first line option for treatment of methicillin-resistant Staphylococcus aureus. Two studies have described the pharmacokinetics (PK) of intermittent intravenous (IV) vancomycin in adult people with cystic fibrosis (PwCF). Currently, there have not been any studies describing the PK of continuous infusion vancomycin in PwCF. Our study aimed to describe the PK of continuous infusion vancomycin in adult PwCF. METHODS: Included patients were adult PwCF, who were admitted to University of Utah Hospital between May 11, 2014 and August 31, 2020, and received continuous infusion vancomycin for the treatment of an pulmonary exacerbations. The primary outcome was to describe vancomycin clearance rate (CLvanco ) and total daily dose (TDD). Secondary outcomes included rates of acute kidney injury (AKI), liver injury, and infusion-related reactions. RESULTS: Twenty patients were included in this study. The mean CLvanco was 5.08 L/h on Day 3 and 4.58 L/h on Day 7 (p = .04), and the TDD increased from 2444 mg on Day 3 to 2556 on Day 7, although not statistically significant (p = 0.26). Zero patients experienced an AKI, two patients experienced liver injury, and no patients experienced infusion-related reactions. CONCLUSIONS: This study demonstrates that continuous infusion vancomycin PK, namely CLvanco , is similar to previously reported CLvanco for intermittent dosed IV vancomycin in adult PwCF. This study suggests that continuous infusion vancomycin is likely safe to use in adult PwCF.

Pharmacokinetics of intermittent dosed intravenous vancomycin in adult persons with cystic fibrosis.

BACKGROUND: Antibiotics have altered pharmacokinetics (PK) in persons with cystic fibrosis (PwCF) during treatment for an acute pulmonary exacerbation (APE). The Cystic Fibrosis Foundation Pulmonary Guidelines-Treatment of Pulmonary Exacerbations do not provide specific recommendations for treatment of methicillin-resistant Staphylococcus aureus (MRSA) lung infections. However, the American Thoracic Society Guidelines recommend vancomycin as the first-line therapy. Only one study has previously described a single dose of intravenous (IV) vancomycin PK in adult PwCF. Our study aimed to describe intermittent IV vancomycin PK at steady-state in adult PwCF. METHODS: Adult PwCF who were admitted to University of Utah Hospital between May 11, 2014 and August 31, 2020, and received intermittent IV vancomycin for the treatment of an APE were included in this study. The primary outcome was to describe the drug volume of distribution (Vd), drug clearance, elimination half-life, and total daily dose of vancomycin. Secondary outcomes were rates of acute kidney injury (AKI), liver injury, and infusion-related reactions. RESULTS: Thirteen patients were included. The mean Vd was 0.54 L/kg on Day 3 and 0.53L/kg on Day 7. CLvanco was 5.11L/h on Day 3 and 4.69 L/h on Day 7. Zero patients experienced an AKI, two patients experienced liver injury, and no patients experienced infusion-related reactions. CONCLUSIONS: Our results demonstrate that in PwCF intermittent IV vancomycin steady-state PK are similar to previously reported single-dose IV vancomycin. Additionally, CLvanco minimally changes from Day 3 to Day 7, although this study was not powered to detect a difference.

Transcriptional Changes in Chronic Rhinosinusitis with Asthma Favor a Type 2 Molecular Endotype Independent of Polyp Status.

BACKGROUND: Data regarding the inflammatory profile of patients with asthma and chronic rhinosinusitis (CRS-A) with (CRSwNP-A) and without (CRSsNP-A) nasal polyposis remain limited. OBJECTIVE: Define and compare systemic transcriptional changes in patients with CRS-A to those with non-asthma-related CRS with (CRSwNP) and without nasal polyposis (CRSsNP). METHODS: Thirty-four patients with CRS-A (n=19) and CRS (n=15) were prospectively enrolled into an observational study. Demographic information and subjective and objective disease severity measures were recorded. Multiplex gene expression analysis of mRNA extracted from peripheral blood was performed. A total of 594 genes associated with innate/adaptive immunity were analyzed using NanoString technology. Gene expression ratios were reported for genes that were differentially expressed among these cohorts. Linear regression analysis was used to compare the mRNA transcript copy numbers for each gene with disease severity. RESULTS: There was no significant difference in age, gender, nasal polyposis, or health-related quality of life measures between the two groups (p>0.05). HLA class II histocompatibility antigen, DRB3-1 beta chain (HLA-DRB3) was significantly upregulated in the peripheral blood of patients with CRSsNP-A compared to CRSsNP, whereas chemokine (C-C motif) ligands 4 (CCL4) and zinc finger protein helios (IKZF2) were significantly upregulated in CRSwNP-A compared to CRSwNP (p<0.05). CONCLUSION: Patients with CRSsNP-A demonstrate a molecular endotype associated with a Th2-dominant inflammatory profile compared to CRSsNP. Patients with CRSwNP-A similarly demonstrate an overrepresentation of genes associated with Th2-driven inflammation compared to patients with CRSwNP.

Asthma increases long-term revision rates of endoscopic sinus surgery in chronic rhinosinusitis with and without nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with asthma (CRS-A) has a significant impact on patient morbidity and quality of life. Nevertheless, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate revision rates of ESS in CRS-A and identify risk factors associated with increased likelihood for revision surgery compared to those with CRS without asthma (CRS-alone). METHODS: The Utah Population Database was queried for patients age >18 years with CRS who underwent at least 1 ESS between 1996 and 2018. Demographic information and history of ESS were collected and compared between CRS-A and CRS-alone using chi-square tests for categorical variables and t tests for continuous variables. Risk factors for revision surgery were analyzed using Cox proportional hazard models. RESULTS: A total of 33,090 patients (7693 CRS-A and 25,397 CRS-alone) were included in the final analysis. Mean follow up was 9.8 years in CRS-A and 9.1 years in CRS-alone (p < 0.001). The revision rate among patients with CRS-A (21.5%) was twice that of CRS-alone (10.8%) (p < 0.001). Among patients with CRS, a history of allergy (p < 0.001), asthma (p < 0.001), and nasal polyposis (p < 0.001) was independently associated with increased risk of revision ESS. Patients with CRS-A and nasal polyposis were 6 times more likely to require revision surgery than those with CRS-alone (p < 0.010). CONCLUSION: The rate of revision ESS in CRS-A was twice that of CRS-alone; patients with CRS-A and nasal polyposis were 6 times more likely to require revision than those with CRS-alone. ©2021 ARSAAOA, LLC.

Bioengineered lysozyme in combination therapies for Pseudomonas aeruginosa lung infections.

There is increasing urgency in the battle against drug-resistant bacterial pathogens, and this public health crisis has created a desperate need for novel antimicrobial agents. Recombinant human lysozyme represents one interesting candidate for treating pulmonary infections, but the wild type enzyme is subject to electrostatic mediated inhibition by anionic biopolymers that accumulate in the infected lung. We have redesigned lysozyme's electrostatic potential field, creating a genetically engineered variant that is less susceptible to polyanion inhibition, yet retains potent bactericidal activity. A recent publication demonstrated that the engineered enzyme outperforms wild type lysozyme in a murine model of Pseudomonas aeruginosa lung infection. Here, we expand upon our initial studies and consider dual therapies that combine lysozymes with an antimicrobial peptide. Consistent with our earlier results, the charge modified lysozyme combination outperformed its wild type counterpart, yielding more than an order-of-magnitude reduction in bacterial burden following treatment with a single dose.

Glutaredoxin-1 attenuates S-glutathionylation of the death receptor fas and decreases resolution of Pseudomonas aeruginosa pneumonia.

RATIONALE: The death receptor Fas is critical for bacterial clearance and survival of mice after Pseudomonas aeruginosa infection. OBJECTIVES: Fas ligand (FasL)-induced apoptosis is augmented by S-glutathionylation of Fas (Fas-SSG), which can be reversed by glutaredoxin-1 (Grx1). Therefore, the objective of this study was to investigate the interplay between Grx1 and Fas in regulating the clearance of P. aeruginosa infection. METHODS: Lung samples from patients with bronchopneumonia were analyzed by immunofluorescence. Primary tracheal epithelial cells, mice lacking the gene for Grx1 (Glrx1(-/-)), Glrx1(-/-) mice treated with caspase inhibitor, or transgenic mice overexpressing Grx1 in the airway epithelium were analyzed after infection with P. aeruginosa. MEASUREMENTS AND MAIN RESULTS: Patient lung samples positive for P. aeruginosa infection demonstrated increased Fas-SSG compared with normal lung samples. Compared with wild-type primary lung epithelial cells, infection of Glrx1(-/-) cells with P. aeruginosa showed enhanced caspase 8 and 3 activities and cell death in association with increases in Fas-SSG. Infection of Glrx1(-/-) mice with P. aeruginosa resulted in enhanced caspase activity and increased Fas-SSG as compared with wild-type littermates. Absence of Glrx1 significantly enhanced bacterial clearance, and decreased mortality postinfection with P. aeruginosa. Inhibition of caspases significantly decreased bacterial clearance postinfection with P. aeruginosa, in association with decreased Fas-SSG. In contrast, transgenic mice that overexpress Grx1 in lung epithelial cells had significantly higher lung bacterial loads, enhanced mortality, decreased caspase activation, and Fas-SSG in the lung after infection with P. aeruginosa, compared with wild-type control animals. CONCLUSIONS: These results suggest that S-glutathionylation of Fas within the lung epithelium enhances epithelial apoptosis and promotes clearance of P. aeruginosa and that glutaredoxin-1 impairs bacterial clearance and increases the severity of pneumonia in association with deglutathionylation of Fas.

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation.

BACKGROUND: Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. OBJECTIVES: We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. METHODS: We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. RESULTS: We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV(1) and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC(20), 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4(+) T cells increased significantly. CONCLUSIONS: Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.

Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice.

Bone marrow-derived mesenchymal stromal cells (BMSCs) mitigate inflammation in mouse models of acute lung injury. However, specific mechanisms of BMSC actions on CD4 T lymphocyte-mediated inflammation in vivo remain poorly understood. Limited data suggests promotion of Th2 phenotype in models of Th1-mediated diseases. However, whether this might alleviate or worsen Th2-mediated diseases such as allergic asthma is unknown. To ascertain the effects of systemic administration of BMSCs in a mouse model of Th2-mediated allergic airways inflammation, ovalbumin (OVA)-induced allergic airways inflammation was induced in wild-type C57BL/6 and BALB/c mice as well as in interferon-γ (IFNγ) receptor null mice. Effects of systemic administration during antigen sensitization of either syngeneic or allogeneic BMSC on airways hyperreactivity, lung inflammation, antigen-specific CD4 T lymphocytes, and serum immunoglobulins were assessed. Both syngeneic and allogeneic BMSCs inhibited airways hyperreactivity and lung inflammation through a mechanism partly dependent on IFNγ. However, contrary to existing data, BMSCs did not affect antigen-specific CD4 T lymphocyte proliferation but rather promoted Th1 phenotype in vivo as assessed by both OVA-specific CD4 T lymphocyte cytokine production and OVA-specific circulating immunoglobulins. BMSCs treated to prevent release of soluble mediators and a control cell population of primary dermal skin fibroblasts only partly mimicked the BMSC effects and in some cases worsened inflammation. In conclusion, BMSCs inhibit Th2-mediated allergic airways inflammation by influencing antigen-specific CD4 T lymphocyte differentiation. Promotion of a Th1 phenotype in antigen-specific CD4 T lymphocytes by BMSCs is sufficient to inhibit Th2-mediated allergic airways inflammation through an IFNγ-dependent process.

Hemolytic phospholipase C inhibition protects lung function during Pseudomonas aeruginosa infection.

RATIONALE: The opportunistic pathogen Pseudomonas aeruginosa causes both acute and chronic lung infections and is particularly problematic in patients with cystic fibrosis and those undergoing mechanical ventilation. Decreased lung function contributes significantly to morbidity and mortality during P. aeruginosa infection, and damage inflicted by P. aeruginosa virulence factors contributes to lung function decline. OBJECTIVES: We sought to describe direct contribution of a bacterial phospholipase C/sphingomyelinase, PlcHR, to alteration of host lung physiology and characterize a potential therapeutic for protection of lung function. METHODS: We infected C57Bl/6 mice with P. aeruginosa wild-type or isogenic plcHR deletion strains and measured lung function using computer-controlled ventilators. For in vivo testing, miltefosine was delivered intraperitoneally 1 hour after infection. Infection and respiratory endpoints were at 24 hours after infection. MEASUREMENTS AND MAIN RESULTS: P. aeruginosa wild-type infection caused significant lung function impairment, whereas the effects of a ΔplcHR strain infection were much less severe. Surfactometry analysis of bronchoalveolar lavage fluid indicated that PlcHR decreased pulmonary surfactant function. Miltefosine has structural similarity to the PC and sphingomyelin substrates of PlcHR, and we found that it inhibits the cleavage of these choline-containing lipids in vitro. Miltefosine administration after P. aeruginosa infection limited the negative effects of PlcHR activity on lung function. CONCLUSIONS: We have directly linked production of a single virulence factor in P. aeruginosa with effects on lung function, and demonstrated that the inhibitor miltefosine protects lung function from PlcHR-dependent surfactant dysfunction.

Mixed bacterial-fungal infections in the CF respiratory tract.

Cystic fibrosis (CF) is a common genetic disease whose major clinical manifestations include repeated episodes of airway infection and inflammation that ultimately result in premature death from respiratory failure. The consequences of infection by individual bacteria have been well studied and the evidence is building that fungal pathogens may be playing an important role in lung disease progression. In contrast, though many CF patients have airway infections characterized by the presence of both bacteria and fungi, our understanding of the impact of such polymicrobial infections on the host is limited. In this review, we discuss what is currently known about incidence of mixed bacterial-fungal infections, and the potential consequences of these mixed infections on the progression of CF lung disease.