- Cystic Fibrosis
- Pediatric Pulmonary
Instructor, Pediatrics - Pulmonary Medicine
Residency: Stanford Health Care at Lucile Packard Children's Hospital (2015) CA
Board Certification: American Board of Pediatrics, Pediatric Pulmonary (2018)
Fellowship: Stanford University Pediatric Pulmonary Fellowship (2018) CA
Board Certification: American Board of Pediatrics, Pediatrics (2014)
Medical Education: Joe and Teresa Lozano Long School of Medicine at UT San Antonio (2011) TX
Current Research and Scholarly Interests
Patients with cystic fibrosis suffer from chronic infection in their airways. Pseudomonas aeruginosa is the most common bacteria found in their lungs and is associated with faster decline in lung function and earlier death. We recently discovered a bacteriophage (virus) that infects Pseudomonas, Pf bacteriophage. This virus turns sputum into a thick goop of molecules called a biofilm that makes infection very difficult to treat. In the laboratory we know that Pf phage makes biofilms more viscous, more adherent, and it helps protect Pseudomonas from both antibiotics and immune cells. I am currently studying the role of Pf phage in patients with cystic fibrosis. Pf phage is associated with chronic infection, older age and increased antibiotic resistance in patients with cystic fibrosis.
Dynamic light scattering microrheology for soft and living materials.
We present a method for using dynamic light scattering in the single-scattering limit to measure the viscoelastic moduli of soft materials. This microrheology technique only requires a small sample volume of 12 muL to measure up to six decades in time of rheological behavior. We demonstrate the use of dynamic light scattering microrheology (DLSmuR) on a variety of soft materials, including dilute polymer solutions, covalently-crosslinked polymer gels, and active, biological fluids. In this work, we detail the procedure for applying the technique to new materials and discuss the critical considerations for implementing the technique, including a custom analysis script for analyzing data output. We focus on the advantages of applying DLSmuR to biologically relevant materials: breast cancer cells encapsulated in a collagen gel and cystic fibrosis sputum. DLSmuR is an easy, efficient, and economical rheological technique that can guide the design of new polymeric materials and facilitate the understanding of the underlying physics governing behavior of naturally derived materials.
View details for DOI 10.1039/d0sm01597k
View details for PubMedID 33427280
The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies.
2021; 13 (7)
Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.
View details for DOI 10.3390/v13071268
View details for PubMedID 34209836
Filamentous Bacteriophages and the Competitive Interaction between Pseudomonas aeruginosa Strains under Antibiotic Treatment: a Modeling Study.
Pseudomonas aeruginosa (Pa) is a major bacterial pathogen responsible for chronic lung infections in cystic fibrosis patients. Recent work has implicated Pf bacteriophages, nonlytic filamentous viruses produced by Pa, in the chronicity and severity of Pa infections. Pf phages act as structural elements in Pa biofilms and sequester aerosolized antibiotics, thereby contributing to antibiotic tolerance. Consistent with a selective advantage in this setting, the prevalence of Pf-positive (Pf+) bacteria increases over time in these patients. However, the production of Pf phages comes at a metabolic cost to bacteria, such that Pf+ strains grow more slowly than Pf-negative (Pf-) strains in vitro. Here, we use a mathematical model to investigate how these competing pressures might influence the relative abundance of Pf+ versus Pf- strains in different settings. Our model suggests that Pf+ strains of Pa cannot outcompete Pf- strains if the benefits of phage production falls onto both Pf+ and Pf- strains for a majority of parameter combinations. Further, phage production leads to a net positive gain in fitness only at antibiotic concentrations slightly above the MIC (i.e., concentrations for which the benefits of antibiotic sequestration outweigh the metabolic cost of phage production) but which are not lethal for Pf+ strains. As a result, our model suggests that frequent administration of intermediate doses of antibiotics with low decay rates and high killing rates favors Pf+ over Pf- strains. These models inform our understanding of the ecology of Pf phages and suggest potential treatment strategies for Pf+ Pa infections. IMPORTANCE Filamentous phages are a frontier in bacterial pathogenesis, but the impact of these phages on bacterial fitness is unclear. In particular, Pf phages produced by Pa promote antibiotic tolerance but are metabolically expensive to produce, suggesting that competing pressures may influence the prevalence of Pf+ versus Pf- strains of Pa in different settings. Our results identify conditions likely to favor Pf+ strains and thus antibiotic tolerance. This study contributes to a better understanding of the unique ecology of filamentous phages in both environmental and clinical settings and may facilitate improved treatment strategies for combating antibiotic tolerance.
View details for DOI 10.1128/mSystems.00193-21
View details for PubMedID 34156288
Area Under the Curve Achievement of Once Daily Tobramycin in Children with Cystic Fibrosis during Clinical Care.
BACKGROUND: The area under the concentration-time curve over 24 hours (AUC24 ) is frequently utilized to monitor tobramycin exposure in children with cystic fibrosis (CF). An understanding of exposure target achievement during clinical implementation of an AUC24 based approach in children is limited.METHODS: A retrospective chart review was performed in children with CF treated with once daily tobramycin and drug concentration monitoring at a pediatric CF center. During clinical care AUC24 was estimated using a traditional log-linear regression approach (LLR). AUC24 was also estimated retrospectively using a pharmacokinetic model-based Bayesian forecasting approach (BF). AUC24 achievement after both approaches were compared.RESULTS: In 77 treatment courses (mean age 12.7 ± 5.0 years), a target AUC24 100-125 mg*h/L was achieved after starting dose in 21 (27%) and after initial dose adjustment in 35 (45%). In the first 7 days of treatment, 24 (32%) required ≥3 dose adjustments, and the mean number of drug concentrations measured was 7.1 ± 3.2. Examination of a BF approach demonstrated adequate prediction of measured tobramycin concentrations (median bias -2.1% [95% CI -3.1 to -1.4]; median precision 7.6% [95% CI 7.1 to 8.2%]). AUC24 estimates utilizing the BF approach were higher than the LLR approach with a mean difference of 6.4 mg*h/L (95% CI 4.8 to 8.0 mg*h/L).CONCLUSIONS: Achievement of a narrow AUC24 target is challenging during clinical care, and dose individualization is needed in most children with CF. Implementing a BF approach for estimating AUC24 in children with CF is supported. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/ppul.25037
View details for PubMedID 32827334
Methods for Extraction and Detection of Pf Bacteriophage DNA from the Sputum of Patients with Cystic Fibrosis.
PHAGE (New Rochelle, N.Y.)
2020; 1 (2): 100–108
Background: There is increasing interest in the pulmonary microbiome's bacterial and viral communities, particularly in the context of chronic airway infections in cystic fibrosis (CF). However, the isolation of microbial DNA from the sputum from patients with CF is technically challenging and the optimal protocols for the analysis of viral species, including bacteriophage, from clinical samples remains difficult. Materials and Methods: In this study, we evaluate a set of methods developed for processing and analyzing sputum from patients with CF with the goal of detecting Pf bacteriophage virion-derived nucleic acid. We evaluate the impact of bead beating, deoxyribonuclease digestion, and heating steps in these protocols focusing on the quantitative assessment of Pseudomonas aeruginosa and Pf bacteriophage in sputum. Results: Based on these comparative data, we describe an optimized protocol for processing sputum from patients with CF and isolating DNA for polymerase chain reaction or sequencing-based studies. Conclusion: These studies demonstrate the assessment of a specific bacteriophage and bacteria in sputum from patients with CF.
View details for DOI 10.1089/phage.2020.0003
View details for PubMedID 32626852
View details for PubMedCentralID PMC7327540
Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections.
Frontiers in immunology
2020; 11: 244
Pf bacteriophage are temperate phages that infect the bacterium Pseudomonas aeruginosa, a major cause of chronic lung infections in cystic fibrosis (CF) and other settings. Pf and other temperate phages have evolved complex, mutualistic relationships with their bacterial hosts that impact both bacterial phenotypes and chronic infection. We and others have reported that Pf phages are a virulence factor that promote the pathogenesis of P. aeruginosa infections in animal models and are associated with worse skin and lung infections in humans. Here we review the biology of Pf phage and what is known about its contributions to pathogenesis and clinical disease. First, we review the structure, genetics, and epidemiology of Pf phage. Next, we address the diverse and surprising ways that Pf phages contribute to P. aeruginosa phenotypes including effects on biofilm formation, antibiotic resistance, and motility. Then, we cover data indicating that Pf phages suppress mammalian immunity at sites of bacterial infection. Finally, we discuss recent literature implicating Pf in chronic P. aeruginosa infections in CF and other settings. Together, these reports suggest that Pf bacteriophage have direct effects on P. aeruginosa infections and that temperate phages are an exciting frontier in microbiology, immunology, and human health.
View details for DOI 10.3389/fimmu.2020.00244
View details for PubMedID 32153575
View details for PubMedCentralID PMC7047154
- Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis SCIENCE TRANSLATIONAL MEDICINE 2019; 11 (488)
- Cystic fibrosis transmembrane conductance regulator modulators: precision medicine in cystic fibrosis CURRENT OPINION IN PEDIATRICS 2018; 30 (3): 372–77
Pf Phage in Chronic Pseudomonas aeruginosa Wound Infections
WILEY. 2018: A5
View details for Web of Science ID 000430308600016
PF BACTERIOPHAGE IN PATIENTS WITH CYSTIC FIBROSIS (CF) IS ASSOCIATED WITH INCREASED SPUTUM ELASTASE AND PSEUDOMONAS AERUGINOSA LOAD
WILEY. 2017: S350
View details for Web of Science ID 000411113700434
Clinical characteristics and outcomes of pediatric patients with CMV DNA detection in bronchoalveolar lavage fluid.
2017; 52 (1): 112-118
Cytomegalovirus (CMV) infection can cause severe pulmonary disease in immunocompromised patients. There are no standard diagnostic criteria for CMV pulmonary disease beyond histopathology findings on lung tissue, which is challenging to obtain in pediatric patients. Bronchoalveolar lavage (BAL) fluid is easier to obtain. Since CMV remains latent after primary infection and can potentially reactivate due to any inflammatory response, CMV detection in BAL specimen may not indicate acute CMV pulmonary disease. Thus, we describe the clinical manifestations and outcomes of pediatric patients with CMV detection in BAL fluid.We reviewed the clinical, radiologic, and laboratory data of patients <19 years old with a BAL specimen positive for CMV during a 5-year period.Thirty-four encounters in 29 patients were found with CMV detected in their BAL specimen. Half (17/34) of the encounters were in immunocompromised patients. CMV, polymerase chain reaction (PCR) was the most common positive test. Forty-seven percent of the patients had other infections detected in BAL specimens. The majority of patients were never treated for CMV and resolved their acute respiratory illness. Only one patient had probable CMV pulmonary disease.CMV is frequently recovered from BAL specimens but does not usually indicate acute CMV pulmonary disease. We would suggest that other diagnoses be considered first, even if CMV is recovered. Pediatr Pulmonol. 2016; 9999:XX-XX. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ppul.23494
View details for PubMedID 27280337
Molecular and Culture-Based Bronchoalveolar Lavage Fluid Testing for the Diagnosis of Cytomegalovirus Pneumonitis.
Open forum infectious diseases
2016; 3 (1): ofv212-?
Background. Cytomegalovirus (CMV) is a major cause of morbidity and mortality in immunocompromised patients, with CMV pneumonitis among the most severe manifestations of infection. Although bronchoalveolar lavage (BAL) samples are frequently tested for CMV, the clinical utility of such testing remains uncertain. Methods. Retrospective analysis of adult patients undergoing BAL testing via CMV polymerase chain reaction (PCR), shell vial culture, and conventional viral culture between August 2008 and May 2011 was performed. Cytomegalovirus diagnostic methods were compared with a comprehensive definition of CMV pneumonitis that takes into account signs and symptoms, underlying host immunodeficiency, radiographic findings, and laboratory results. Results. Seven hundred five patients underwent 1077 bronchoscopy episodes with 1090 BAL specimens sent for CMV testing. Cytomegalovirus-positive patients were more likely to be hematopoietic cell transplant recipients (26% vs 8%, P < .0001) and less likely to have an underlying condition not typically associated with lung disease (3% vs 20%, P < .0001). Histopathology was performed in only 17.3% of CMV-positive bronchoscopy episodes. When CMV diagnostic methods were evaluated against the comprehensive definition, the sensitivity and specificity of PCR, shell vial culture, and conventional culture were 91.3% and 94.6%, 54.4% and 97.4%, and 28.3% and 96.5%, respectively. Compared with culture, PCR provided significantly higher sensitivity and negative predictive value (P ≤ .001), without significantly lower positive predictive value. Cytomegalovirus quantitation did not improve test performance, resulting in a receiver operating characteristic curve with an area under the curve of 0.53. Conclusions. Cytomegalovirus PCR combined with a comprehensive clinical definition provides a pragmatic approach for the diagnosis of CMV pneumonitis.
View details for DOI 10.1093/ofid/ofv212
View details for PubMedID 26885542
Eosinophilic Pneumonitis As Initial Presentation Of Acute Lymphoblastic Leukemia
AMER THORACIC SOC. 2016
View details for Web of Science ID 000390749607630
- Index of suspicion. Pediatrics in review 2014; 35 (10): 439-446
Case 3 Lactic Acidosis and Cardiovascular Collapse in a Teen With Ulcerative Colitis
PEDIATRICS IN REVIEW
2014; 35 (10): 444–46
View details for Web of Science ID 000421128400006
The impact of the central venous catheter on the diagnosis of infectious endocarditis using Duke criteria in children with Staphylococcus aureus bacteremia
PEDIATRIC INFECTIOUS DISEASE JOURNAL
2008; 27 (7): 636-639
Infective endocarditis (IE) is a known complication of Staphylococcus aureus bacteremia in pediatric patients. We sought to evaluate the impact of prolonged bacteremia associated with a retained central venous catheter (CVC) in the diagnosis of IE using Duke criteria.We conducted a 13-year retrospective review of hospitalized patients with blood cultures positive for S. aureus from 1993 to 2005. Subjects were identified from the microbiology database and medical records. To identify patients with IE we retrospectively applied the Duke criteria by recording the number of positive blood cultures, time to sterilization, presence of congenital heart disease, fever >38.5 degrees C, and echocardiographic findings.During the study period, 344 events of S. aureus bacteremia were identified in 316 pediatric patients. S. aureus bacteremia attributable mortality was 1.7% (n = 6), all among patients with comorbid conditions. By applying the Duke criteria to the 206 (60%) patients who received echocardiographic evaluation, 78 (37.9%) patients were given a diagnosis of IE (7 definite; 71 possible). The incidence of definite IE in patients with CVC is 3.4% and the incidence in patients without CVC is 3.4% (P = 0.6305). The incidence of possible IE in patients with CVC is 42.9%, whereas the incidence in patients without CVC is 23% (P = 0.002).Evaluation for IE is inconsistently done. The presence of a CVC may skew the diagnosis of IE by prolonging the bacteremic state. We believe that a major microbiologic criteria should not be assumed unless cultures remain positive after removal of CVC.
View details for DOI 10.1097/INF.0b013e31816b78c8
View details for Web of Science ID 000257176600010
View details for PubMedID 18520969