Background:The TOPIC study (a randomised clinical trial investigating efficacy and toxicity of OD versus TD tobramycin in children and adults with CF) has demonstrated that OD 10 mg/kg tobramycin is at least equally effective and probably less nephrotoxic than TD 3.3 mg/kg.However, tobramycin PK have not been compared previously in a large series children and adults with CF receiving OD or TD tobramycin.Methods: therapeutic drug monitoring data in children and adults who participated in the TOPIC study were analysed retrospectively.Population PK models stratified to treatment schedule were created and individual PK parameters were calculated.Results: In paediatric patients, tobramycin volume of distribution per kg body weight (V1) was greater with OD treatment compared to TD (0.401±0.092 versus 0.354±0.041L/kg, p = 0.003).V1 decreased with increasing age (r2 = 0.3, p < 0.001).Tobramycin elimination rate (Kel) was reduced in all patients receiving OD compared to TD (children: 0.00197±0.00027versus 0.00291±0.00041h-1, p < 0.001, adults: 0.00252±0.00008versus 0.00322±0.00050h-1, p < 0.001).The OD group received tobramycin in the afternoon or early evening.Conclusions: The higher V1 in children implies that a relative higher tobramycin dose in these patients is needed for the same target peak serum concentration.The reduced Kel in OD treatment may either be caused by circadian pharmacokinetic behaviour of tobramycin or indicate early renal damage from the high tobramycin doses not detected by biochemical measurements.However, results of the TOPIC study suggest that OD administration of tobramycin may be less nephrotoxic. Pharmacokinetics of Azithromycin during once weekly dosing in cystic fibrosis patients

Increasing numbers of cystic fibrosis (CF) patients are surviving into adulthood. An understanding of the psychiatric and psychosocial aspects of CF in adults and adolescents is therefore more important than ever. There is a large body of evidence indicating that the psychological and psychosocial functioning of people with CF is similar to that of well people, until the disease becomes severe. However, there is also evidence that patients do suffer an increased likelihood of psychiatric problems, such as depression, and of scoring poorly on physical functioning measures of quality of life. Studies have found conflicting evidence as to any association between degree of respiratory impairment and psychological functioning. Coping styles seem to have a large effect upon the quality of life of CF patients. People with cystic fibrosis can have problems with sexuality, platonic relationships and independence. Families of patients also suffer problems, which can affect the patients themselves. Non-compliance is a complicated problem with many patients. New treatments for people with CF are emerging, such as lobe transplants from live donors and gene therapy, with possible new psychosocial problems resulting. Furthermore, older studies are becoming increasingly inapplicable as treatment and prognosis changes. Therefore, more research is needed in this field.

BACKGROUND:Malnutrition is a common management problem in patients with cystic fibrosis (CF). Various approaches to supplemental nutrition by both parenteral and enteral routes have been used.AIM:To analyse the efficacy and acceptability of supplemental overnight feeding using a percutaneous endoscopic gastrostomy (PEG) in patients with CF.PATIENTS:53 patients with CF (43 adults; age >17 years) with severe pulmonary disease.METHODS:The technical success and complications of PEG insertion were documented together with changes in nutritional and pulmonary status of the cohort.RESULTS:PEG tubes were successfully inserted in all patients, with immediate complications (respiratory depression) in two (4%) and late complications in 13 (25%). Feeding was well tolerated by 50/51 (98%) of the cohort during a mean (SEM) follow up of 14.5 (2.1) months. The adult cohort had a significant increase in weight and body mass index at six months which was maintained at 12 months. Serum albumin concentration remained stable at six months but had fallen by 12 months, although the differences were not statistically significant. These results were reflected in the paediatric cohort. Pulmonary function in those followed up for one year had apparently stabilised, but the number of admissions to hospital over the year before and the year after PEG did not change. Half of the cohort were accepted for heart-lung/lung transplantation, the improvement in nutritional status being a prerequisite for this.CONCLUSION:Supplemental PEG tube feeding is well tolerated and results in a significant improvement in nutritional status and an apparent stabilisation of pulmonary function in severely malnourished CF patients with advanced pulmonary disease

BACKGROUND:The treatment for endstage cystic fibrosis is, where appropriate, double-lung, heart-lung or, occasionally, heart-lung-liver transplantation. Optimising the timing of transplantation depends upon an accurate prediction of survival, but while current criteria give some guidance to this, they are not based upon statistically derived prognostic models.METHODS:Data collected prospectively on 403 patients with cystic fibrosis, recruited between 1969 and 1987 (cohort A), were analysed by log rank and univariate Cox regression analysis to determine variables that accurately predict survival. The significant variables were then subject to time dependent multivariate Cox regression analysis to generate a prognostic model. The model was validated, within the study population, using split sample testing, and was subsequently validated in a further cohort of patients recruited since October 1988 (cohort B).RESULTS:One hundred and eighty eight (50.4%) of the study cohort died within the study period. Percentage predicted forced expiratory volume in one second (FEV1), percentage predicted forced vital capacity (FVC), short stature, high white cell count (WBC), and chronic liver disease (as evidenced by the presence of hepatomegaly) were negatively correlated with survival. These variables, when combined into a prognostic index, accurately predicted one year survival in the study population and in the cohort recruited since 1988.CONCLUSION:This prognostic index may prove valuable in predicting prognosis in other cohorts with cystic fibrosis and thereby improve the timing of transplantation.

Cystic fibrosis (CF), a genetic disorder, is characterized by chronic pulmonary infection/inflammation which leads to respiratory failure. The presence of anti-neutrophil cytoplasmic autoantibodies (ANCA) has previously been observed in the sera of patients with CF. In view of the known relationship of ANCA with primary vasculitis and of their putative pathogenetic role in these disorders, we studied the presence, specificity and isotype of ANCA and their clinical associations in 66 adult CF patients. None of the 66 CF samples had autoantibodies to the major ANCA antigens, proteinase 3 or myeloperoxidase. However, 60/66 (91%) CF samples contained IgG, and 55/66 (83%) IgA, autoantibodies to bactericidal/permeability-increasing protein (BPI), a recently-characterized ANCA specificity. All the IgA anti-BPI-positive samples were also IgG anti-BPI-positive. The autoantibody specificity was confirmed by inhibition assay and immunoblotting of CF sera against a neutrophil granule preparation. Furthermore, in this cross-sectional study, anti-BPI levels were inversely correlated with the observed reductions in FEV1 and FVC (IgA anti-BPI & FEV1: r = -0.508, p < 0.0001), and both IgG and IgA anti-BPI levels were higher in CF patients with secondary vasculitis (n = 6) than in those without (p < 0.05). ANCA with specificity for BPI were present in the majority of CF sera in this study and autoimmune processes may be associated with the development of pulmonary injury in CF.

Aerosol administration of antipseudomonal antibiotics is commonly used in cystic fibrosis. However, its contribution to the improvement of lung function, infection and quality of life is not well-established. All articles published from 1965 until the present time concerning the inhalation of antibiotics in cystic fibrosis were collected by computerized literature search and analysed. Effective aerosol delivery is compromised by nebulizers with limited capacity to produce particles in the respirable range. Twelve studies concerning maintenance treatment were published. Four uncontrolled studies evaluating antibiotic aerosol maintenance treatment in stable patients indicated a beneficial effect in terms of reducing the number of hospital admissions. Eight placebo-controlled studies were found; six of these showed a significant improvement of lung function in the treatment group. Four studies showed a reduction of the number of hospital admissions. In some studies, there was a considerable negative effect of the nebulized placebo solution on the outcome, probably due to the improper choice of its osmolarity. Studies with antibiotic aerosols as adjunct to intravenous therapy in cystic fibrosis patients with an acute exacerbation showed no enhancement of the clinical effects of the intravenous antibiotic by the aerosol; sputum colony counts, however, were lower. Toxicity studies carried out so far have shown no renal or ototoxicity; however, long-term toxicity studies still have to be performed using higher dosages. Introduction or selection of resistant bacteria is relatively rare, but remains a matter of concern. Aerosol maintenance treatment with an appropriate antibiotic in high enough dosage can be recommended for patients with cystic fibrosis chronically infected with P. aeruginosa, and may improve lung function and reduce the number of hospital admissions due to an acute exacerbation.

BACKGROUND--Provision of medical care for adult patients with cystic fibrosis is an increasing problem as the number of patients surviving into adulthood increases. Recent reports have suggested that care is best provided in specialist centres because of longer survival. Recent changes in the National Health Service funding and delivery of service may adversely affect the provision of such a specialist service. The aim of this study was to assess the current pattern of medical service received by adults with cystic fibrosis and to compare the type of care between special cystic fibrosis and general clinics. METHODS--Confidential postal questionnaires were sent to all 1052 members of the Association of Cystic Fibrosis Adults (ACFA) comprising 59% of the UK population of cystic fibrosis patients over 15 years and 80% over 25 years of age. The response rate was 82%. RESULTS--Two thirds of patients were attending special cystic fibrosis clinics for either adults or adults and children. There were significant differences in the proportion of patients using special cystic fibrosis clinics between regions but not between social class groups. Significant differences between cystic fibrosis and general clinics were noted. Patients attending cystic fibrosis clinics were more likely to have had simple clinical investigations (blood tests, sputum culture, oxygen saturation, chest radiography, weight and lung function measurement) in the previous year. They were also more likely to have received intravenous antibiotics at home, and to have access to paramedical personnel. Patients attending cystic fibrosis clinics were taking higher doses of pancreatic enzyme supplements with respect to quantity and potency of preparation. Such patients also had less severe symptoms irrespective of social class, and were more likely to be satisfied with professional aspects of their care. Regardless of type of clinic, potential deficiencies were identified in overall medical care with omission of clinical investigations in severely affected patients and evidence of undertreated respiratory and digestive symptoms in patients with moderate and severe disease. CONCLUSIONS--This survey provides evidence that adults with cystic fibrosis attending special cystic fibrosis clinics receive more intensive care, have better symptom control, and are more satisfied with the service provided than those attending general clinics.

Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied. Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg.kg-1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg.kg-1). The mean maximum blood concentration of CsA for the oral dose was 776 ng.ml-1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng.ml-1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%). The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.

OBJECTIVE:To obtain information about social and demographic characteristics and lifestyle of adult patients with cystic fibrosis, including those who do not attend major specialist clinics.DESIGN:Confidential self completion postal questionnaire to adult patients with cystic fibrosis, asking about social and demographic characteristics, social class and occupation, employment, education, insurance and social security benefits, symptom severity, and medical care.SETTING:National association for adults with cystic fibrosis.SUBJECTS:1052 adult members of the Association of Cystic Fibrosis Adults UK, accounting for 68% of those with cystic fibrosis in the United Kingdom population over 16 years of age and over 80% of those over 25 in June 1990.RESULTS:The response rate was 82% (397 women, 423 men). Most adults with cystic fibrosis were found to be living fulfilling lives into adulthood. Significantly fewer men were married or cohabiting than women (110 (26%) men, 175 (44%) women). 420 (55%) responders were working, and of these 235 (56%) had less than two weeks' sick leave a year. Half of those not employed gave ill health as the reason. Revealing that they had cystic fibrosis at job interviews reduced likelihood of being employed for those with mild to moderate disease. People with cystic fibrosis had been less successful than the general population in achieving O level or equivalent qualifications, but more successful in achieving A level or higher qualifications. Achievement of any qualifications enhanced employment prospects irrespective of disease severity.CONCLUSION:Contrary to an image of chronic ill health and disability, a high proportion of adults with cystic fibrosis are living full and productive lives.

In 31 adult patients with cystic fibrosis (CF) who were chronically infected with Pseudomonas aeruginosa we examined the effect of giving regular three monthly oral ciprofloxacin. Patients received ciprofloxacin or placebo for 10 days every 3 months for 1 yr in a randomized, double-blind, placebo-controlled study. During each course of treatment patients receiving ciprofloxacin reported an improvement in cough, sputum production and peak expiratory flow (PEF) P = < 0.005. During the year of study patients receiving ciprofloxacin showed an improvement in PEF when compared with those receiving placebo (P = < 0.05) but the changes in FEV1 and FVC were not statistically different in either group. Regular oral ciprofloxacin was well tolerated but did not prevent hospital admissions or reduce the number of courses of intravenous antibiotics throughout the year. The median MIC to ciprofloxacin in the active treatment group rose from 0.5 mg l-1 to 0.75 mg l-1 during treatment. We conclude that CF patients are likely to benefit from oral ciprofloxacin for exacerbations of respiratory symptoms. However, regular treatment with ciprofloxacin over 1 yr improves PEF but does not reduce the rate of hospital admissions with acute exacerbations of respiratory symptoms.

Changes in spirometry during consecutive admissions for treatment of pulmonary infective exacerbations were studied in 45 patients (24 males, 21 females) with cystic fibrosis (CF) who had required five or more such admissions. Over the overall study period there was a mean (SD) decline in FEV1 of -112.1 (188.0) ml yr-1 (P less than 0.001) and in FVC of -47.9 (82.4) ml yr-1 (P less than 0.001). FEV1 and FVC increased during each admission with treatment; however, the magnitude of this change became less over consecutive admissions by a mean value of -33.3 ml (45.0) (P less than 0.001) for FEV1, and -26.0 (72.2) ml (P less than 0.05) for FVC. In the majority of patients that died or underwent transplantation, FEV1 at the time of the last admission did not rise above 800 ml despite full treatment.

Vasculitis Vasculitis is a disorder involving venules, capillaries, arterioles and larger vessels. It can affect the skin alone or any other organ. The cellular reaction may be neutrophils, lymphocytes or granulomatous in nature. It is an unusual complication of cystic fibrosis (CF). The term vasculitis has been used to describe many clinically differing disorders, namely urticaria, allergic vasculitis, anaphylactoid purpura, drug eruptions, infection, erythema multiforme, erythema nodosa, polyarteritis nodosa, focal granulomatous lesions and systemic lupus erythematosis. It is thought to be due to inappropriate activity ofthe immune response causing liberation of inflammatory mediators, deposition of immune complexes and infiltration with cells. Some cases we have seen in recent years in patients with CF and reported by Finnegan et aL1 are described below. The results of investigations are given in Table 1.

Background Pseudomonas aeruginosa infection is seldom eradicated in patients with cystic fibrosis despite intensive antipseudomonal treatment. Upper airway sites of infection may contribute to perpetuation of lower airways infection. This study was designed to find out which extrapulmonary sites are infected and whether the strains at these sites are identical to those in the lungs.Methods Sputum and upper airway samples from 42 patients were cultured for P aeruginosa and stool samples from 20 patients were also tested. Nineteen isolates from sputum and extra-pulmonary sites from four patients were genotyped with the pCM tox probe.Results P aeruginosa was isolated from the sputum of 36 patients, 34 of whom had infection in the upper airways. Six of the 20 patients tested were positive for P aeruginosa in the stool. The nasopharynx was colonised in 30 patients, the oropharynx in 29, the middle meatus in 13, the external nares in six, and the inferior turbinate in four. Three of four patients tested had the same strain of P aeruginosa (a different one in each individual) in the sputum and the upper airways, and in two of the three the stool isolate was a different strain.Conclusion Most adults with cystic fibrosis and P aeruginosa pulmonary infection have upper airway reservoirs of the organism and strains from these sites are identical to those in the lungs.

Seventy-four of 403 (18.4%) sputum isolates of Pseudomonas aeruginosa from 49 of 136 (36.0%) adults with cystic fibrosis (CF) were auxotrophic mutants. Two of 11 (18.2%) isolates of P. aeruginosa taken from patients with non-CF bronchiectasis were also auxotrophic. All 99 strains taken from non-bronchiectatic sources were prototrophic. Forty-six of 55 (83.6%) CF auxotrophs required one or more of 36 growth factors tested; the requirements for the remaining 9 isolates were not identified. Methionine was the sole factor required by 17 of 22 (77.3%) isolated which depended on a single factor. We conclude that auxotrophy is a feature of P. aeruginosa infection in cystic fibrosis.

Ribotyping of 25 isolates of Pseudomonas cepacia taken from the sputum of 21 adults with cystic fibrosis (CF) who were registered at the Royal Brompton Hospital between 1987 and 1991, revealed that seven patients (33·3%) shared strains of a similar ribotype pattern with others, while 14 patients (63·7%) harboured strains unique to each individual. Constancy of sputum strain carriage was seen in two of three patients sampled twice over a 3-month period. Although no evidence for patient-to-patient transmission of P. cepacia within this group of patients was found, the fact that one third of CF patients shared strains of the same ribotype with others, suggests that nosocomial acquisition of this organism may have occurred.