Clinical relevance of Scedosporium spp. and Exophiala dermatitidis in patients with cystic fibrosis: A nationwide study.

An increased prevalence of various filamentous fungi in sputum samples of patients with cystic fibrosis (CF) has been reported. The clinical significance, however, is mostly unclear. The aim of this study was to investigate the clinical relevance of Scedosporium spp. and Exophiala dermatitidis from sputum samples of patients with CF in the Netherlands. In this cross-sectional study, all CF patients of the Dutch national CF registry who were treated at five of the seven recognized CF centers during a 3-year period were included. We linked clinical data of the national CF registry with the national Dutch filamentous fungal database. We investigated the association between clinical characteristics and a positive sputum sample for Scedosporium spp. and E. dermatitidis, using logistic regression. Positive cultures for fungi were obtained from 3787 sputum samples from 699 of the 1312 patients with CF. Scedosporium spp. was associated with severe genotype, CF-related diabetes, several microorganisms, and inhaled antibiotics. E. dermatitidis was associated with older age, female sex, and Aspergillus spp. CF patients with and without Scedosporium spp. or E. dermatitidis seemed comparable in body mass index and lung function. This study suggests that Scedosporium spp. and E. dermatitidis are probably no major pathogens in CF patients in the Netherlands. Greater understanding of epidemiologic trends, risk factors, and pathogenicity of filamentous fungi in the respiratory tracts of patients with CF is needed.

Importance of bacteriology in upper airways of patients with Cystic Fibrosis.

BACKGROUND: Recently the influence of the upper airways (UAW) on the general health of a patient with Cystic Fibrosis (CF) has been acknowledged. Surprisingly the microbiology of the upper compartment of the airways receives barely any attention in the treatment of CF. The aim of the present study was to investigate the microbiology of the upper airways in adult patients with CF, to correlate these findings with cultures from the lower airways (LAW) and with clinical characteristics. METHODS: In this cross-sectional study bacteriological and clinical data were gathered from 104 adult patients with CF. UAW samples for culture were collected by nasal lavage and middle meatal swabs; LAW cultures were performed on expectorated sputum or cough swabs. Each patient performed the Rhinosinusitis Outcome Measure (RSOM-31). RESULTS: In 72 patients (69.2%) UAW cultures yielded microorganisms other than normal nasal flora and in 50 patients (48.1%) Pseudomonas aeruginosa grew from the UAW cultures. Similarity between UAW and LAW cultures was determined in 50.0% of these 72 patients. In 3 patients P. aeruginosa was cultured from the UAW after successful eradication of P. aeruginosa from the LAW. P. aeruginosa in the UAW did not influence symptoms of sinonasal disease compared to other microorganisms. CONCLUSIONS: Comparison of UAW and LAW cultures in adult patients with CF showed one or more concordant microorganism in 50.0% of the patients. P. aeruginosa was most frequently cultured from the UAW. P. aeruginosa can be cultured from the UAW after eradication therapy which may suggest persistence of P. aeruginosa in the UAW. We feel this is may be a motive to include the UAW in eradication therapy in Cystic Fibrosis.

Clinical impact of a highly prevalent Pseudomonas aeruginosa clone in Dutch cystic fibrosis patients.

Studies suggest that infection with highly prevalent Pseudomonas aeruginosa clones in cystic fibrosis (CF) is associated with an unfavourable clinical outcome. We studied the clinical characteristics of patients infected with a recently described, highly prevalent P. aeruginosa clone (ST406) in two CF centres in The Netherlands. Multilocus sequence typing data were available for 219 patients, of whom 40 (18.3%) were infected with ST406 and 179 with other sequence types. ST406 infection was independently associated with age, having a sibling with ST406 infection and use of inhaled antibiotics, but not with unfavourable clinical outcome, suggesting that high transmissibility is not necessarily associated with high virulence.

Transmission of Pseudomonas aeruginosa in children with cystic fibrosis attending summer camps in The Netherlands.

BACKGROUND: Cross-infection of Pseudomonas aeruginosa has been reported to occur at holiday camps for children with Cystic Fibrosis (CF) with varying frequency. The study aimed to establish the degree of transmission resulting in subsequent infection of P. aeruginosa among CF children (n=80) attending holiday camps in The Netherlands. METHODS: The study was performed in the summer of 2001 in four camps organised simultaneously at different locations. Sputum was collected on day 1 of the holiday, and three and six months later. Different morphotypes of P. aeruginosa from sputum were genotyped by AFLP analysis. Criteria were defined for the degree of evidence of transmission. RESULTS: There were 18 cases possible, 2 cases of probable transmission and 1 case of highly probable transmission. Two predominant types of P. aeruginosa were found (types 18 and 23). Type 18 was already prevalent on day 1 mostly in younger children and was involved in eleven cases of transmission; type 23 was involved in six cases of transmission among older children. CONCLUSIONS: There was a considerable risk of transmission of P. aeruginosa during holiday camps for CF children in The Netherlands. Two genotypes of P. aeruginosa appeared to be easily transmissible, one of which seemed common in the Dutch CF population.

Dry powder inhalation of antibiotics in cystic fibrosis therapy: part 2. Inhalation of a novel colistin dry powder formulation: a feasibility study in healthy volunteers and patients.

The aim of the present study was to perform a proof of principle study with a new colistin dry powder inhalation system in six healthy volunteers and five patients with cystic fibrosis. All subjects were asked to inhale 25 mg colistin sulfate dry powder. The patients were also asked to nebulize 160 mg colistin sulfomethate as a solution. Colistin serum concentrations were determined as an indirect parameter to compare both forms of administration. Pulmonary function tests were performed. Peak serum colistin concentrations ranged from 14 to 59 microg/l in volunteers after inhalation of 25 mg as dry powder. In patients, peak concentrations ranged from 18 to 64 microg/l after nebulization of 160 mg colistin sulfomethate solution and from 77 to 159 microg/l after inhalation of 25 mg colistin sulfate dry powder. Pulmonary function tests were not significantly different after inhalation of the dry powder by the volunteers nor after nebulization of the solution by the patients. In some patients a decrease in pulmonary function and moderate to severe cough was observed after inhalation of the dry powder. The new colistin inhaler provides an attractive alternative for nebulized colistin and was highly appreciated by the patients. The decrease in pulmonary function and cough in patients is a drawback, which may be overcome by dose reduction and a further improvement of the new dosage form.

Can tobramycin inhalation be improved with a jet nebulizer?

Data on the pharmacokinetics of antibiotics after inhalation are limited. The aim of this pilot study was to assess the pharmacokinetics of tobramycin under optimalized and standardized aerosol circumstances and, furthermore, to be able to consider possible treatment of exacerbations with inhalation therapy. Six patients were studied after inhalation of 600 mg tobramycin. A jet nebulizer loaded with a 10% solution of tobramycin in water was used. The percentage of the dose that was systemically absorbed ranged from 1.0% to 16.6%. The maximum serum levels of tobramycin ranged from 0.77 mg/L to 3.63 mg/L (mean 1.70 +/- 1.01). The pharmacokinetic data were best described by a two-compartment model. Compared to intravenous administration, the long terminal half-life (mean 9.47 h +/- 3.28 h) could be explained by the slow absorption of tobramycin from the site of administration (flip-flop model). Despite standardized aerosol conditions, considerable interpatient variability was observed. However, the relatively low serum levels allow a further increase of the dose.

Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics.

Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime by continuous infusion in 17 adult patients with cystic fibrosis at home. Ceftazidime was delivered via an infusion pump and the effects of this 3 week home intravenous antibiotic treatment (HIVAT) were prospectively studied over a 2 year period. Patients with cystic fibrosis (eight male and nine female patients; mean age 26.9 +/- 7.6 years, range 15-52 years), received a total of 33 courses of continuous ceftazidime (100 mg/kg/24 h). Clinical data were collected at the start, the end and 4-6 weeks after the end of treatment in 12 patients. Ceftazidime pharmacokinetic data during continuous infusion were obtained from ten patients. The treatment was supervised by the clinician without home visits. All 25 clinically evaluable courses in 12 patients proved efficacious. The mean duration of the courses was 21 days. The entire antibiotic course was administered at home in 88% of the courses. The other 12% was started for 2-3 days as an inpatient. Objective clinical parameters significantly improved. Clinical improvement was noted in 91% of the patients, and lasted at least until 4-6 weeks after the end of the treatment in 70%. The number of cultures positive for P. aeruginosa decreased significantly during antibiotic treatment. Bacterial count returned to pretreatment values 4-6 weeks after treatment. Multiple courses of ceftazidime monotherapy did not result in a lasting increase of ceftazidime-resistant pseudomonas strains. Total body clearance was 9.1 +/- 1.3 L/h. The steady-state ceftazidime serum concentration during continuous infusion was 28.4 +/- 5.0 mg/L. Sputum concentrations were in the range of 0.5-13 mg/L (3.9 +/- 4.0 mg/L). In conclusion, HIVAT with ceftazidime administered by continuous infusion proved clinically effective and did not result in an increase in lasting resistance.

Salmonella enteritidis in an endometriotic ovarian cyst.

Isolated Salmonella infections are rare. In view of the rarity, we present a case of a 16-year-old patient with an endometriotic ovarian cyst where Salmonella enteritidis was isolated from aspirated material from the cyst. We include a review of the world literature on ovarian Salmonella infection from 1966 to June 1996.

Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis.

This study was performed to determine the clinical pharmacokinetics of tobramycin in six patients with cystic fibrosis (CF) after inhalation of 600 mg. Tobramycin was administered with an ultrasonic nebulizer (WISTO SENIOR). Blood and urine were sampled until 24 h after inhalation. Maximum tobramycin levels in serum varied from 0.19 to 2.57 mg/liter (mean 1.27 mg/liter; standard deviation, 1.07 mg/liter). Systemic availability (calculated from urinary output) ranged from 6.0 to 27.4% (mean, 17.5%; standard deviation, 8.8%). The results illustrate that, provided that the systemic availability of tobramycin is a reflection of pulmonary deposition, inhalation studies with CF patients should have a concentration-controlled design. Furthermore, reliance on dose recommendations from the literature for a new patient starting on this treatment is not justified, but it is mandatory that deposition kinetics be studied for each patient and for each nebulizer. It may well be that, with higher levels of deposition, dosages lower than those recommended in the literature will suffice to obtain the desired clinical effect. In addition, the reverse may also be the case.

Systemic Fusarium nygamai infection in a patient with lymphoblastic non-Hodgkin's lymphoma.

We report the case history of a 35-year-old male patient with lymphoblastic non-Hodgkin's lymphoma who acquired a systemic infection with Fusarium nygamai during the granulocytopenic phase of cytostatic treatment. The patient survived this infection after haematological recovery and treatment with intravenous amphotericin B (total dose 543 mg). Subsequent chemotherapy courses were not complicated by fungal infections. A recent trip to Egypt and severe chemotherapy-induced mucositis were probably the major causes of this severe infection.

Inhalation of antibiotics in cystic fibrosis.

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.

Diagnostic problems with imported cases of mycetoma in The Netherlands.

Eight cases of imported mycetomata in The Netherlands are reviewed. Seven of these were cultured; only one isolate, Actinomadura madurae, belonged to a species commonly known as an agent of mycetoma. The remaining strains either belonged to very rare species, such as Phialophora cyanescens, or could not be identified at all. The list of possible agents of mycetoma apparently needs to be expanded. In addition, the concept of endemic occurrence of aetiological agents of eumycetoma needs revision. Divergent saprophytes may be involved which are able to survive in human tissue.