A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis.

Chronic infection with Pseudomonas aeruginosa is associated with progressive deterioration in lung function in cystic fibrosis (CF) patients. The purpose of this trial was to assess the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients chronically infected with P. aeruginosa. One-hundred and fifteen patients, aged > or = 6 yrs, were randomised to receive either TNS or colistin, twice daily for 4 weeks. The primary end point was an evaluation of the relative change in lung function from baseline, as measured by forced expiratory volume in one second % predicted. Secondary end points included changes in sputum P. aeruginosa density, tobramycin/colistin minimum inhibitory concentrations and safety assessments. TNS produced a mean 6.7% improvement in lung function (p=0.006), whilst there was no significant improvement in the colistin-treated patients (mean change 0.37%). Both nebulised antibiotic regimens produced a significant decrease in the sputum P. aeruginosa density, and there was no development of highly resistant strains over the course of the study. The safety profile for both nebulised antibiotics was good. Tobramycin nebuliser solution significantly improved lung function of patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa, but colistin did not, in this study of 1-month's duration. Both treatments reduced the bacterial load.     

The use of macrolide antibiotics in patients with cystic fibrosis

PURPOSE OF REVIEW: There has been much recent interest in the use of macrolide antibiotics as chronic suppressive therapy in patients with cystic fibrosis. Three recent randomized, placebo-controlled trials have been conducted. RECENT FINDINGS: All three trials used similar regimens of azithromycin, and lung function improved after 3 to 6 months of treatment. The relative change in forced expiratory volume in 1 second predicted improved between 3.6% and 6.2%. Furthermore, the azithromycin treatment groups had improvement in a variety of secondary outcomes related to pulmonary exacerbations, including a reduction in antibiotic use (both intravenous and oral) and hospitalization rate. Furthermore, azithromycin was well tolerated: Only nausea, diarrhea, and wheezing (described as mild to moderate) occurred more frequently in the azithromycin group compared with the placebo group. The evidence for the clinical benefit of azithromycin in cystic fibrosis has been summarized in a Cochrane review in which a meta-analysis confirmed a significant improvement in forced expiratory volume in 1 second among the 286 pooled participants. SUMMARY: Azithromycin has entered the therapeutic armamentarium for patients with cystic fibrosis who are chronically infected with Pseudomonas aeruginosa. Improved lung function, a reduction in pulmonary exacerbations and antibiotic use, and weight gain are potential benefits of this drug. Future studies should address the use of azithromycin in other cystic fibrosis patient populations, including those patients without chronic infection with P. aeruginosa, children younger than 6 years of age, and those infected with Burkholderia cepacia complex. The mechanism of action of macrolide antibiotics in cystic fibrosis remains unknown.     

Bronchial constriction and inhaled colistin in cystic fibrosis

STUDY OBJECTIVE: Inhaled colistin is used for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients despite reports of chest tightness and bronchospasm. The main objective of the study was to assess whether bronchospasm occurred in pediatric CF patients with or without clinical evidence of airway hyperreactivity. DESIGN AND METHODS: A prospective placebo-controlled clinical trial with crossover design was devised using challenge tests with 75 mg colistin in 4 mL saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration. Subjects were recruited as follows: high risk (HR) for bronchospasm due to a personal history of recurrent wheezing, a family history of asthma and/or atopy, or bronchial lability, as demonstrated in pulmonary function tests; or low risk (LR) without these characteristics. RESULTS: The mean FEV(1) (expressed as the mean [+/- SD] fall from baseline) of the HR group (n = 12) fell 12 +/- 9% after placebo was administered, and fell 17 +/- 10% after colistin was administered. For the LR group (n = 8), the mean FEV(1) fell 9 +/- 4% following placebo administration and 13 +/- 8% following colistin administration. There was a greater number of subjects in the HR group compared to the LR group, which had a mean fall in FEV(1) of >/= 15% (p < 0.01) after inhaling colistin. The differences between placebo and colistin therapy in the LR group were not significant. CONCLUSION: The results demonstrated that colistin can cause bronchospasm, particularly in those patients with coexisting CF and asthma.     

Nebulizer choice for inhaled colistin treatment in cystic fibrosis

STUDY OBJECTIVES: To develop practical ways of nebulizing colistin by determining the rate of drug output, total drug output, and particle-size distribution of two commercially available jet nebulizers, the disposable Hudson 1730 Updraft II (Hudson Respiratory Care; Temecula, CA) and the reusable Pari LC Star breath-enhanced nebulizer (Pari Respiratory Equipment; Midlothian, VA). METHODS: The nebulizers contained colistin, 75 mg, in 4 mL of isotonic solution. Particle-size distribution was measured by helium-neon laser diffraction, allowing calculation of the respirable fraction (RF), the mass of aerosol comprised of droplets < 5 microm. RESULTS: The mean (95% confidence interval [CI]) total rate of output of the Updraft II was 2.6 mg/min (2.0, 3.1; n = 4) with 1.3 mg/min (1.0, 1.5) mg/min within the RF. The rate of output of the LC Star increased in a quadratic relationship to the inspiratory flow, delivering 1.8 mg/min (0.7, 2.0; n = 4) with 1.4 mg/min (1.3, 1.6) within the RF, and 6.2 mg/min (5.6, 6.8) with 5.3 mg/min (4.8, 5.7) within the RF, at 0 L/min and 20 L/min inspiratory flows, respectively. Efficiency, as the rate of expected pulmonary deposition divided by rate of total output, was then calculated. The LC Star estimated 56% (51, 61) efficiency, with pulmonary delivery of 29% (26, 32) of the charge of the nebulizer, compared to the Updraft II at 22% (22, 23) efficiency and expected pulmonary deposition of 10% (10, 10) of the dose. CONCLUSIONS: Colistin can be successfully nebulized with both nebulizers tested. This study provides an estimate of in vivo efficiency and expected pulmonary deposition that may be used in future trials.     

Nontuberculous mycobacteria in patients with cystic fibrosis.

The prevalence and clinical implications of colonization with nontuberculous mycobacteria were prospectively studied in 37 patients who had cystic fibrosis. Sputum samples were cultured on Coletsos and L?wenstein-Jensen selective media after decontamination with sodium hydroxide and oxalic acid. Oxalic acid-decontaminated fractions were also cultured in selective liquid medium. Nontuberculous mycobacteria were isolated from 6 patients (16.1%). Mycobacterium chelonae and Mycobacterium avium-intracellulare complex were the most common species. Three patients with positive results of culture had at least 1 positive result by acid-fast smear. Oxalic acid decontamination and culture in liquid medium had the lowest contamination rate (6.7%). Colonization with nontuberculous mycobacteria was associated with humoral response to mycobacteria (immunoglobulin G titers against antigen A60) in patients with samples that tested positive by acid-fast smear. An improvement in pulmonary function was observed in 2 patients after they received a course of antimycobacterial therapy. Screening for nontuberculous mycobacteria in patients with cystic fibrosis will contribute to understanding the relevance of these pathogens with regard to deterioration of pulmonary function in patients with cystic fibrosis.     

Echocardiographic abnormalities in patients with cystic fibrosis.

An echographic study was undertaken to evaluate left (LV) and right ventricular (RV) function in 30 patients with cystic fibrosis. Echographic recording of the pulmonary and aortic valve echogram permitted measurement of the phases of right and left ventricular systole. The ratio of the LV preejection period/LV ejection time (LPEP/LVET) and shortening of the LV internal dimension %SID was employed to reflect LV function, while RV preejection period/RV ejection time (RPEP/RVET) has excellent correlation with pulmonary artery diastolic pressure. RPEP/RVET and two other echographic measurements, right ventricular wall (RVW) and internal dimension (RVD) were compared with pulmonary function tests and clinical scores. RPEP/RVET correlated well with percent vital capacity(%VC), r = -0.73, percent residual volume (%RVol) r = +0.72, and clinical score, r = -0.77. Multilinear regression of RPEP/RVET, RVD, and RVW improved correlation for %VC (r = -0.80), %RVol, r = +0.82, and clinical score, r = -0.84. Patients in overt right heart failure exhibited elevated RPEP/RVET (mean = 0.48) when compared to patients not in right heart failure (mean = .33). Marked diminution of LV function was present in two patients. A variety of cardiovascular abnormalities were demonstrated echographically and were valuable in assessing the degree of cardiac involvement in patients with cystic fibrosis.     

Pharmacokinetics of methicillin in patients with cystic fibrosis.

The disposition of methicillin in normal subjects and in subjects with cystic fibrosis (CF) was studied after administration of single intravenous doses of 15 mg/kg. The area under the serum concentration vs. time curve for CF patients was, on the average, only 75% of that found for normal subjects. The low concentrations in serum were caused by more rapid urinary excretion of the antibiotic, with rates of renal clearance averaging 425 ml/min per 1.73 m2 in the patients with CF and 362 ml/min per 1.73 m2 in the normal subjects. No differences were found in volumes of distribution and metabolic clearance rates of methicillin or in rates of creatinine clearance between the two groups of subjects. These data support previous findings with dicloxacillin which show that patients with CF exhibit unusually rapid, active tubular secretion of certain penicillins that may necessitate use of larger doses of these drugs in treatment of infections.     

Trampoline use as physiotherapy for cystic fibrosis patients

Physicians and physiotherapists who care for CF patients have recommended the use of trampolines as a physiotherapeutic tool for enhancing cardiopulmonary performance, encouraging sputum production, and improving general well-being. Despite some therapeutic and recreational benefits associated with trampoline use, papers in the general pediatric population mostly document an increased incidence of injuries, ranging from minor trauma to spinal cord injuries and even death. The aim of this review is to examine the accumulated published data regarding the use of trampolines, to assess their potential contributions and disadvantages for CF patients, and to define whether trampoline use should be recommended. An extensive search in the published medical literature retrieved approximately 60 articles that primarily dealt with trampolines, out of which only two dealt with CF. The preponderance of these articles are reports pertaining to injuries related to the use of trampolines, with only a few describing the medical, physiologic, and/or psychological benefits of trampolines. Based on the accumulated data, the presumed benefits of trampoline use for CF patients are not proven. Furthermore, the suggested benefits could be acquired using other types of exercise. Weighing the known risks of trampolines against the potential benefits that are not unique to this modality suggests that the use of trampolines for CF should not be recommended.     

Lobectomy in patients with cystic fibrosis

BACKGROUND:

Some patients with cystic fibrosis (CF) develop severe but localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional medical therapies.

METHODS:

The outcomes of lung resection in patients with CF and worsening localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional therapy (n=15) were evaluated by reviewing the medical records of all patients with CF followed at the CF Center at Nationwide Children’s Hospital (Columbus, Ohio, USA), who underwent lobectomy over a 15-year period (1998 to 2012).

RESULTS:

The median age of the 15 patients (93% Caucasian) was 20 years (range two to 41 years) and their mean forced expiratory volume in 1 s (FEV₁) was 59.5% of predicted one year before surgery. Three patients died within two years after lobectomy; all three deaths occurred in patients with an FEV₁ ≤40% of predicted before surgery. There were no significant changes in mean height, weight, body mass index, hospital admissions or antibiotic use over time. The mean FEV₁ decreased over time. Compared with at surgery, decline in FEV₁ in the year before surgery was −5.4% (P=0.024) and decline in the year after surgery was −1.3% (P=0.513); however, the difference in the rate of decline was not statistically significant.

CONCLUSION:

In patients with CF and localized worsening bronchiectasis and/or recurrent hemoptysis/pneumothorax, lobectomy carried a significant risk of mortality, especially in patients with FEV₁ ≤40% of predicted, and should only be considered when all other measures fail.     

Pregnancy in patients with cystic fibrosis

As more patients with cystic fibrosis reach adulthood, questions arise about the potential hazards of pregnancy. We reviewed the medical records of eight women with cystic fibrosis who had a total of 11 completed pregnancies and had been evaluated within 1 year before conception. In five women (Group 1), the overall maternal condition was little affected by the pregnancy, and in three women (Group 2), the mother's condition deteriorated during and after pregnancy and did not return to the pregravid state. With regard to pregravid status, significant differences between patients in Group 1 and Group 2 were found in Shwachman-Kulczycki clinical scores, weight for height values, Brasfield chest radiograph scores, and pulmonary function. A quantitative assessment of pregravid nutritional and pulmonary status is useful in counseling women with cystic fibrosis about the risk of pregnancy.     

Nontuberculous mycobacteria in adult patients with cystic fibrosis.

Because patients with cystic fibrosis (CF) may be predisposed to airway infections with unusual microorganisms, we screened the sputum of adult CF patients for mycobacterial organisms. Acid-fast bacilli (AFB) smears and mycobacterial culture were performed on 297 sputum specimens from 87 patients. Cultures for mycobacteria were frequently overgrown with other bacteria; 22.6 percent of cultures were contaminated. Despite this limitation of mycobacterial culture, 17 patients had at least one positive culture for a Mycobacterium other than tuberculosis (MOTT). Eleven patients were positive for Mycobacterium avium-intracellulare (MAI), two for MAI and M chelonei, three for M chelonei, and one for M fortuitum. None was positive for M tuberculosis. Patients with CF with MOTT were similar to patients with CF without MOTT; only a slightly different (older) age distribution was recognized. The clinical significance of MOTT was difficult to determine in any individual patient, but patients with positive AFB smears appeared more likely to suffer pathogenic effects. We conclude that MOTT is frequently recovered from adult CF patients in the southeastern United States. A specific risk factor for colonization and/or pathogenic infection in this patient group was not evident. The general prevalence and clinical pathogenesis in CF patients in the United States remains to be determined.     

Fertility and pregnancy in patients with cystic fibrosis.

Issues related to fertility and pregnancy, once moot, are now extremely relevant to the care of a growing number of CF patients entering adulthood. With rare exception, men are infertile, due to the almost universal presence of malformations of the reproductive tract causing obstructive azoospermia. Emphasis in the care of these patients should be directed toward confirmation of infertility and counseling to allay anxieties. In contrast, a significant albeit unknown proportion of women are fertile and a steadily increasing number of these women are conceiving. The accumulated clinical experience has demonstrated that pregnancy is well-tolerated by patients with mild disease while associated with increased maternal and fetal complications in those with severe disease. In light of current uncertainties in accurately predicting outcome in all but the most clear-cut cases, the physician must exercise clinical judgment in providing a realistic assessment of the medical risks involved and of the advisability of pregnancy. This assessment should be based on a thorough and objective evaluation of the pulmonary, cardiac, and nutritional status of the patient. Future efforts, assisted by data collected for the national CF patient registry, should be directed toward better defining the long-term impact of pregnancy on the natural history of CF and more precisely defining the pregravid parameters useful in predicting outcome for both mother and child.     

Undiagnosed patients with cystic fibrosis

The missing cystics, the undiagnosed patients who have inherited cystic fibrosis (CF), have been the subject of many a question. That they exist is not to be doubted, for patients diagnosed in their 30s have been missing for 30 or more years, and even a patient diagnosed at age 1 has been missing a year. The important questions about the missing cystics are of two kinds: demographic—how many?, age distributions?, death rate?, survival rate?, proportion of all CF patients?; and clinical—does treatment alter the course of CF?, does early diagnosis make any difference?, can the diagnosis be made before the clinical syndrome is obvious?, can CF be diagnosed by screening?In this paper we will use the age at diagnosis of all new patients reported to the United States CF Patient Registry for 11 consecutive years to answer the demographic questions. Since treatment does alter the course of cystic fibrosis [1, 2], since early diagnosis improves prognosis [3], since CF can be diagnosed before the full clinical picture develops [4] and since a high risk of CF can be determined by screening tests [5], we will use our analysis to suggest a strategy for changing the answers to both the clinical and the demographic questions.     

The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis

Decreased survival in patients with cystic fibrosis has been related to FEV1, BMI, and infection with Burkholderia cepacia complex (BCC). We have assessed the relationship of blood, sputum, and urine inflammatory markers to lung function, BMI, colonization with B cenocepacia (Bc), and patient survival. Thirty-nine stable cystic fibrosis (CF) patients (10 with Bc) were enrolled in a study to determine the effect of alpha-1-antitrypsin on airways inflammation. Pre-treatment measurements were used in this study. Demographics, sputum microbiology, heart rate, oxygen saturation, lung function were recorded. Blood samples were obtained for white blood count (WBC), C-Reactive Protein (CRP), and plasma neutrophil elastase/AAT complexes (pNEC). Neutrophil elastase (NE), neutrophil elastase/AAT complexes (sNEC), interleukin-8 (IL-8), TNF-receptor 1 (sTNFr), and myeloperoxidase (MPO) were measured in sputum and urinary desmosine concentration determined. Patients with Bc had significantly higher levels of pNEC, 332 +/- 91.4 ng/ml (mean +/- SEM) versus 106 +/- 18.2 ng/ml (P = 0.0005) and sNEC, 369 +/- 76.6 ng/ml versus 197 +/- 36.0 ng/ml compared to those who were not. Five deaths were reported at the end of 1 year, (four with Bc) (P = 0.011). Patients who subsequently died had significantly lower lung function FEV1, 1.2 +/- 0.2 L versus 2.0 +/- 0.1 L (P = 0.03) and FVC, 2 +/- 0.3 L versus 3.1 +/- 0.2 L (P = 0.01), compared to those that survived. There was significantly higher NE activity, 3.6 +/- 1.6 U/ml versus 1.5 +/- 0.6 U/ml (P = 0.03), pNEC, 274 +/- 99 ng/ml versus 142 +/- 30 ng/ml (P = 0.05), MPO, 163 +/- 62 mcg/ml versus 54 +/- 6.9 mcg/ml (P = 0.03), and urinary desmosines 108 +/- 19.9 pM/mg creatinine versus 51.1 +/- 3.3 pM/mg creatinine (P = 0.001), in those patients who subsequently died compared to those that survived. These data suggest there is increased neutrophil degranulation in patients infected with Bc and these patients have a poor outcome.     

Airway microbiota in patients with paediatric cystic fibrosis: Relationship with clinical status

Introduction

New massive sequencing techniques make it possible to determine the composition of airway microbiota in patients with cystic fibrosis (CF). However, the relationship between the composition of lung microbiome and the clinical status of paediatric patients is still not fully understood.

The cystic fibrosis gene and relationships to clinical status.

Cystic fibrosis (CF) is a disease characterized by significant variability in both presentation and clinical course. The genetic and environmental factors responsible for the phenotypic expression of CF are most likely legion, and their relationship to the disease complex. Therefore, it was not until the isolation and characterization of the CF gene and the ability to genotype individual patients that further elucidation of the genotype-phenotype relationship in CF was possible. Currently, the pancreatic status of CF patients appears to be primarily determined by genetic factors and patients homozygous for the most common mutation, delta F508 are, as a rule, pancreatic insufficient. Other specific alleles that confer pancreatic sufficiency have been identified. Patients having these alternative alleles remain pancreatic sufficient, are diagnosed later, have lower sweat chloride values, milder respiratory disease, and a better prognosis than patients with alleles associated with pancreatic insufficiency. Other clinical manifestations, including meconium ileus and the presence of liver disease, appear to be associated with pancreatic insufficiency. The variability in the pulmonary course for homozygous delta F508 patients suggests that genetic heterogeneity at other loci or environmental factors are important. Therefore, the CF genotype does not precisely predict pulmonary status.