ABSTRACT
OBJECTIVE: To evaluate microbiological effectiveness, that is, culture negativity of a non-blinded eradication protocol (Rx) compared with observation (Obs) in clinically stable cystic fibrosis participants with newly positive methicillin resistant Staphylococcusaureus (MRSA) cultures. DESIGN: This non-blinded trial randomised participants ages 4-45â years with first or early (≤2 positive cultures within 3â years) MRSA-positive culture without MRSA-active antibiotics within 4â weeks 1:1 to Rx or Obs. The Rx protocol was: oral trimethoprim-sulfamethoxazole or if sulfa-allergic, minocycline plus oral rifampin; chlorhexidine mouthwash for 2â weeks; nasal mupirocin and chlorhexidine body wipes for 5â days and environmental decontamination for 21â days. The primary end point was MRSA culture status at day 28. RESULTS: Between 1 April 2011 to September 2014, 45 participants (44% female, mean age 11.5â years) were randomised (24 Rx, 21 Obs). At day 28, 82% (n=18/22) of participants in the Rx arm compared with 26% (n=5/19) in the Obs arm were MRSA-negative. Adjusted for interim monitoring, this difference was 52% (95% CI 23% to 80%, p<0.001). Limiting analyses to participants who were MRSA-positive at the screening visit, 67% (8/12) in the Rx arm and 13% (2/15) in the Obs arm were MRSA-negative at day 28, adjusted difference: 49% (95% CI 22% to 71%, p<0.001). Fifty-four per cent in the Rx arm compared with 10% participants in the Obs arm remained MRSA-negative through day 84. Mild gastrointestinal side effects were higher in the Rx arm. CONCLUSIONS: This MRSA eradication protocol for newly acquired MRSA demonstrated microbiological efficacy with a large treatment effect. TRIAL REGISTRATION NUMBER: NCT01349192.
Subject(s)
Cystic Fibrosis/microbiology , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Adolescent , Adult , Anti-Bacterial Agents/therapeutic use , Anti-Infective Agents, Local/therapeutic use , Child , Child, Preschool , Chlorhexidine/therapeutic use , Female , Humans , Male , Middle Aged , Minocycline/therapeutic use , Treatment OutcomeABSTRACT
Diffuse lung disease in early childhood due to mutations in the filamin A gene has been recently reported. Clinical outcomes vary among individuals indicating variability in phenotype but a substantial proportion of reported cases in early life have ended up in death or lung transplantation. We recently encountered a school-aged child in whom the diagnosis of a filamin A mutation was delayed and the natural history of emphysematous lung disease was altered by serial lung volume reduction surgeries. She eventually underwent a bilateral lung transplant and we report the natural history of her disease and treatments applied herein.
Subject(s)
Lung Diseases , Pneumonectomy , Child , Female , Filamins/genetics , Humans , Lung Diseases/genetics , Lung Diseases/surgery , Mutation , PhenotypeABSTRACT
OBJECTIVE: To report the rapid onset of adrenal insufficiency and subsequent development of Cushing syndrome precipitated by a CYP3A4-mediated drug-drug interaction that may have been enhanced by the presence of cystic fibrosis (CF)-related liver disease. CASE SUMMARY: A 9-year-old girl with CF and cirrhosis experienced a decline in lung function that led to a diagnosis of asthma. After initiation of asthma therapy with inhaled fluticasone 110 µg/actuation, the patient experienced improvement in lung function to baseline. Seven weeks after the initiation of inhaled fluticasone, she developed vaginal candidiasis and was prescribed fluconazole 100 mg/day, a CYP3A4 inhibitor. Three days after starting fluconazole, she developed polyuria and polydipsia and was found to have severe hyperglycemia, which led to the diagnosis of Cushing syndrome. Fluticasone was discontinued, and the patient's adrenal function normalized. DISCUSSION: Patients with CF are commonly prescribed complex medication regimens that may affect drug metabolism. CYP3A4 inhibitors may significantly decrease metabolic clearance in patients using chronic inhaled corticosteroids. Iatrogenic Cushing syndrome has been reported in patients with CF treated concomitantly, and for extended duration, with inhaled corticosteroids and CYP3A4 inhibitors. This case highlights rapid onset of adrenal insufficiency in a patient with CF-related liver disease treated briefly with a moderate CYP3A4 inhibitor. Use of the Horn drug interaction probability scale indicates that the interaction between fluticasone and fluconazole was probable. CONCLUSIONS: CYP3A4-mediated drug interactions represent a significant risk in patients treated with long-term inhaled corticosteroids. The presence of clinically significant CF-related liver disease may enhance this risk.
Subject(s)
Adrenal Cortex Hormones/adverse effects , Adrenal Insufficiency/chemically induced , Asthma/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/complications , Cystic Fibrosis/complications , Cytochrome P-450 CYP3A Inhibitors , Enzyme Inhibitors/adverse effects , Administration, Inhalation , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/therapeutic use , Androstadienes/administration & dosage , Androstadienes/adverse effects , Androstadienes/therapeutic use , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/adverse effects , Anti-Asthmatic Agents/therapeutic use , Antifungal Agents/adverse effects , Antifungal Agents/therapeutic use , Asthma/etiology , Candidiasis, Vulvovaginal/complications , Candidiasis, Vulvovaginal/drug therapy , Child , Cushing Syndrome/chemically induced , Cystic Fibrosis/physiopathology , Drug Interactions , Enzyme Inhibitors/therapeutic use , Female , Fluconazole/adverse effects , Fluconazole/therapeutic use , Fluticasone , Humans , Treatment OutcomeABSTRACT
BACKGROUND: In US cystic fibrosis (CF) patients, methicillin-resistant Staphylococcus aureus (MRSA) rates have tripled in the past 2 decades. Known clinical risk factors include exposure to a healthcare setting, Pseudomonas aeruginosa and CF-related diabetes. Area-level socio-environmental exposures have not been evaluated. We explored the association of area-level deprivation with MRSA prevalence in a pediatric CF Center in the Southeastern United States. METHODS: Patients' residential addresses were geocoded and linked to a composite Area Deprivation Index and Rural-Urban Commuting Area scores. The association of MRSA with Area Deprivation Index and Rural-Urban Commuting Area scores was evaluated using logistic regression with robust standard errors adjusted for sociodemographic covariates (age, sex, race, mother's and father's education and household income), clinical risk factors (P. aeruginosa, CF-related diabetes, hospitalizations and number of clinic visits) and clustering. RESULTS: The study included all pediatric patients (N = 231; mean age 12) at a single CF Center. MRSA was present in 44% of subjects. Higher area-level deprivation was correlated with rural residence, lack of parental college education and lower household income (P < 0.001 for each). In a multiple regression model fully adjusted for patient-level sociodemographic covariates, clinical risk factors and clustering, neighborhood deprivation was associated with more than 2-fold increase in the odds of having MRSA [OR 2.26 (1.14-4.45), P < 0.05]. CONCLUSIONS: Neighborhood deprivation is a risk factor for MRSA in pediatric CF, doubling the odds of infection. Community-level socioeconomic risk factors should be considered when developing prevention strategies and treatment plans for MRSA infection in pediatric patients with CF.
Subject(s)
Cystic Fibrosis/complications , Environment , Residence Characteristics , Staphylococcal Infections/epidemiology , Staphylococcal Infections/etiology , Adolescent , Alabama/epidemiology , Child , Child, Preschool , Cross-Sectional Studies , Cystic Fibrosis/epidemiology , Cystic Fibrosis/microbiology , Female , Humans , Infant , Infant, Newborn , Male , Methicillin-Resistant Staphylococcus aureus , Prevalence , Risk Factors , Rural Population/statistics & numerical data , Urban Population/statistics & numerical data , Young AdultABSTRACT
Diazoxide is commonly used in the treatment of neonatal hyperinsulinism. We describe a one month-old infant who was treated with diazoxide for prolonged neonatal hyperinsulinism. Shortly after starting diazoxide, she was admitted to the hospital for tachypnea with hypoxemia, and was subsequently diagnosed with laryngomalacia and obstructive apnea. During hospitalization, her clinical course worsened due to the development of severe pulmonary hypertension, presumed due to diazoxide toxicity. Lung biopsy revealed a probable toxic vascular drug reaction. After discontinuing diazoxide, her clinical status improved and eventually returned to baseline.
Subject(s)
Diazoxide/adverse effects , Hyperinsulinism/drug therapy , Hypertension, Pulmonary/chemically induced , Hypoglycemia/drug therapy , Hypoglycemic Agents/adverse effects , Female , Humans , Hyperinsulinism/complications , Hypertension, Pulmonary/therapy , Hypoglycemia/etiology , Infant , Infant, Newborn , Infant, Small for Gestational Age/blood , Treatment OutcomeABSTRACT
OBJECTIVE: The clinical benefit of newborn screening (NBS) for cystic fibrosis (CF) has been primarily nutritional, with less overt respiratory impact. Identification of risk factors for infant CF lung disease could facilitate targeted interventions to improve pulmonary outcomes. METHODS: This retrospective study evaluated socioeconomic information, clinical data, and results from routine infant pulmonary function testing (iPFT) of infants diagnosed with CF through NBS (N = 43) at a single CF center over a 4-year period (2008-2012). A five-item composite clinical score was developed and combined with socioeconomic indicators to facilitate identification of CF infants at increased risk of early-onset respiratory impairment. RESULTS: Paternal education was positively associated with lung function (P = 0.02). Clinical score <7 (on a scale of 0-10) predicted diminished pulmonary measure (P < 0.005). Retrospective risk stratification by clinical score and paternal education identified CF infants at low, intermediate, or high risk of pulmonary disease. Forced expiratory volume (FEV0.5 %, mean ± SD) averaged 115 ± 19% in the low-risk group, 97 ± 17% in the intermediate-risk group, and 90 ± 8% in the high-risk group (P < 0.005). Results were similar for mid-expiratory flows (FEF25-75 %). Multiple regression analysis confirmed the predictive value of this risk stratification model of CF infant pulmonary health. CONCLUSION: We combined socioeconomic and clinical data to risk-stratify CF infants for early-onset lung disease as quantified by iPFT. Our model showed significant differences in infant pulmonary function across risk groups. The developed tool offers an easily available, inexpensive, and non-invasive way to assess risk of respiratory decline in CF infants and identify those meriting targeted therapeutic attention. Pediatr Pulmonol. 2016;51:1168-1176. © 2016 Wiley Periodicals, Inc.
Subject(s)
Cystic Fibrosis/diagnosis , Lung Diseases/diagnosis , Lung/physiopathology , Neonatal Screening , Cystic Fibrosis/physiopathology , Female , Forced Expiratory Volume , Humans , Infant , Infant, Newborn , Lung Diseases/physiopathology , Male , Models, Theoretical , Respiratory Function Tests/methods , Retrospective Studies , Risk Assessment , Risk FactorsABSTRACT
RATIONALE: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type. OBJECTIVES: We hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health care-associated" (SCCmec II) versus "community-associated" (SCCmec IV) MRSA strains. METHODS: To determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from patients not more than 18 years old at seven CF centers were typed and the association of potential risk factors and subsequent clinical course was assessed, using data provided by the CF Patient Registry. MEASUREMENTS AND MAIN RESULTS: Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%) had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IV PVL(+) strains. SCCmec IV, compared with SCCmec II, increased during the study period, 1996-2010 (P = 0.03). SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95% confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics were prescribed more frequently in those with SCCmec II strains and increased hospitalizations occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(+) strains (adjusted difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior. CONCLUSIONS: Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA detection regardless of SCCmec type.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis , Methicillin-Resistant Staphylococcus aureus , Pseudomonas aeruginosa/isolation & purification , Staphylococcal Infections , Adolescent , Bacterial Toxins/analysis , Child , Child, Preschool , Coinfection , Cystic Fibrosis/complications , Cystic Fibrosis/diagnosis , Cystic Fibrosis/epidemiology , Cystic Fibrosis/microbiology , DNA, Bacterial/analysis , Exotoxins/analysis , Female , Genotyping Techniques , Humans , Leukocidins/analysis , Male , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Pseudomonas Infections/complications , Pseudomonas Infections/diagnosis , Registries , Respiratory Function Tests , Risk Factors , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Staphylococcal Infections/etiology , United States/epidemiology , Virulence Factors/analysisABSTRACT
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infects â¼25% of patients with cystic fibrosis (CF) in the United States. We hypothesized that health-related outcomes differed between healthcare-associated (staphylococcal cassette chromosome mec [SCCmec] II) vs community-associated (SCCmec IV) MRSA strains in patients chronically infected with CF. METHODS: At 7 CF centers, MRSA isolates were prospectively obtained from patients ≤18 years old with 2 or more positive MRSA cultures within 1 year. Isolates were classified by SCCmec type and Panton-Valentine-leukocidin (PVL) status at a core laboratory, and sites remained blinded to SCCmec type and PVL results. Prospective clinical data including antibiotic use, respiratory symptoms, and pulmonary exacerbations were obtained. RESULTS: Among the 295 cohort participants with typeable MRSA isolates, 69.5% had SCCmec II PVL(-), 13.2% had SCCmec IV PVL(-), and 17.3% had SCCmec IV PVL(+) strains. During follow-up of 287 patients with prospective data after enrollment, the risk for pulmonary exacerbations was significantly higher among participants with SCCmec II than SCCmec IV strains (risk ratio [RR] = 1.13; P = .03) and higher in those with SCCmec IV PVL(-) than SCCmec IV PVL(+) strains (RR = 1.62; P < .0001). Neither decline in lung function nor changes in nutritional outcomes differed by SCCmec type or PVL status during the study period. CONCLUSIONS: Participants harboring chronic SCCmec II MRSA received more antibiotics and may have more lung disease than those with SCCmec IV; PVL(+) isolates were not associated with more advanced disease.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Cystic Fibrosis/complications , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections/complications , Staphylococcal Infections/drug therapy , Adolescent , Anti-Bacterial Agents/adverse effects , Bacterial Toxins , Child , Child, Preschool , Chronic Disease , Cystic Fibrosis/drug therapy , Exotoxins , Female , Humans , Leukocidins , Male , Methicillin-Resistant Staphylococcus aureus/classification , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/etiology , Treatment Outcome , United StatesABSTRACT
BACKGROUND: Accelerated lung function decline in cystic fibrosis (CF) is associated with mucoid Pseudomonas aeruginosa infection. Recent data suggest that mucoid P. aeruginosa may amenable to elimination from the airway. We aim to determine whether the initiation of an aggressive antibiotic eradication regimen upon initial discovery of mucoid P. aeruginosa in the CF airway could be successful in clearing the organism from the CF lung. METHODS: We performed a retrospective analysis of patients with CF who demonstrated new growth of mucoid P. aeruginosa in an airway culture between January 2003 and December 2008. The primary endpoint was clearance of mucoid P. aeruginosa, based upon the Leeds criteria, with no further growth of mucoid P. aeruginosa cultures within 12 months of the initial discovery and treatment. Factors associated with successful clearance were also evaluated. RESULTS: Forty-eight of 355 patients with CF had a new diagnosis of mucoid P. aeruginosa during the study period; 15 patients underwent an eradication attempt, while 33 patients received no increase in therapy. We observed clearance of mucoid P. aeruginosa in 73.3% of patients undergoing an eradication attempt, whereas 36.6% of those that did not undergo attempted eradication cleared the organism at 1 year (P < 0.05). Prolonged mucoid P. aeruginosa airway clearance (>24 months) for mucoid P. aeruginosa was seen in 60.0% in subjects undergoing eradication compared to 21.2% (P = 0.02) in control patients. At the study conclusion, lung function was greater in subjects who underwent an eradication attempt than in patients who did not undergo an eradication attempt (FEV(1) %: 91.7% vs. 75.0%, P = 0.04). CONCLUSIONS: Clearance of initial mucoid P. aeruginosa from the airways of select patients with CF is possible with current antibiotic regimens, and the attempt may be associated with improved lung function.