Cystic Fibrosis Pharmacist Group
Aspergillus exposure — a growing problem for cystic fibrosis patients
Aspergillus is a ubiquitous fungus that is becoming a major pathogen
in patients with cystic fibrosis, Keith Brownlee, consultant paediatrician
at the Leeds regional cystic fibrosis unit, told the meeting. It produces
spores between 2µm and 5µm in diameter that, when inhaled,
can penetrate the bronchial tree. The average person inhales 200 to 300
spores daily. In patients with medical conditions affecting the lungs
this can lead to progressive lung damage.
Allergic bronchopulmonary aspergillosis (ABPA), a complex lung disease,
is often seen in these patients, with the incidence in cystic fibrosis
patients been reported as being between 0.9 and 15 per cent. Exposure
to aspergillus spores leads to an immune response within the lungs, leading
to worsening inflammation and mucus plugging, resulting in progressive
lung damage. The mainstay of treatment is with oral corticosteroids.
However, since long courses of treatment are usually required, patients
may experience adverse effects such as diabetes, osteoporosis, growth
failure and cataracts.
Some CF centres treat with oral antifungal agents in addition to the
steroids. Itraconazole at a dose of 5mg/kg per day is considered the
antifungal of choice. Itraconazole capsules are poorly absorbed in CF
patients so the liquid preparation is preferred. However its unpleasant
taste has led to adherence problems so voriconazole is now being used
more often. It is better absorbed but is expensive, costing around £1,000
to £2,000 per month. It is also associated with numerous adverse
effects, including visual disturbances and photo-sensitivity. Dr Brownlee
emphasised that pharmacists should monitor patients for adverse effects
while on treatment for ABPA. Adherence and attitude to medication
Amanda Plummer, pharmacy clinical services manager at Sheffield Adult
Cystic Fibrosis Centre, discussed a research project she had carried
out, looking at adherence and attitudes to medication in adult CF patients
at her unit. She found that many patients expressed negative childhood
memories regarding medicine-taking, with many using non-adherence as
a form of control. Most patients understood the necessity of their
medication but there was some concern regarding over-usage, especially
with antibiotics, and side effects.
The median number of medicines taken was nine (range: three to 17).
Adherence varied with treatments with once-daily tablets having the
highest adherence
and nebulisers having the lowest. Adherence was found to be low with
treatments taken during the day, in public and before food.
She recommended that education and patient involvement play a role in
improving adherence. Treatment regimens should be individualised and
medication reviews should be carried out addressing patients’ views
about their treatment. Renal issues
Christine Etherington, a senior doctor at the Leeds Adult Cystic Fibrosis
Unit, talked about the renal issues associated with CF. Nephrotoxic
drugs are the commonest cause of renal injury in patients with cystic
fibrosis. Aminoglycosides are the main class of drugs associated with
renal complications, due to their wide usage to treat pulmonary exacerbation’s
caused by Pseudomonas aeruginosa. The nephrotoxicity manifests clinically
as non-oliguric renal failure with a slow rise in serum creatinine.
Risk factors include high dose, prolonged therapy, cumulative exposure,
dehydration, concurrent nephrotoxic medication (eg, non-steroidal anti-inflammatory
drugs) and pre-existing renal disease. She said that pharmacists were
important in the therapeutic drug monitoring of aminoglycosides and
the prevention of concurrent prescribing of other nephrotoxic agents.
Routine methods are not sensitive enough to detect aminoglycoside renal
damage because toxicity is not detected until there is a large reduction
in nephron mass. Dr Etherington discussed the use of N-acetyl-b-D-glucosaminidase
(NAG), a lysosomal enzyme, as a marker of acute renal tubular injury.
In a study that she carried out (Journal of Cystic Fibrosis 2007;6:67–73),
looking at urinary NAG before, during and after treatment with intravenous
antibiotics, she found that there was a three- to five-fold increase
in median urinary NAG from day 1 to day 14 of treatment.
In patients who received treatment with tobramycin there was an eight-fold
increase in urinary NAG levels compared to that with colistin which showed
a two-fold increase. The NAG levels returned to baseline after treatment
was stopped in the tobramycin patients but stayed elevated from baseline
in the colistin group. She also found a significant correlation between
baseline NAG and previous antibiotic exposure. Atypical mycobacteria
Miles Denton, consultant microbiologist at Leeds Teaching Hospitals,
talked about the treatment options for atypical mycobacteria. There
has been an increased emergence of CF patients being colonised
with atypical
bacteria, such as Mycobacterium abscessus, M avium and M
chelonae.
The increased emergence may be due to better laboratory methods
for culturing,
growing and identifying the bacteria, an increased awareness of the
bacteria or the successful eradication of Ps aeruginosa, he said.
Atypical mycobacteria are difficult to treat because of their inherent
resistance properties. There is a lack of randomised controlled trails
with regards to treatment of these infections. Treatment is often
guided by in vitro data, anecdotal reports and expert opinion.
He emphasised
the importance of using three or four drug combinations that have
been shown to have better clinical outcomes than two-drug regimens,
and
that one cannot assume that drugs in the same therapeutic class are
equally
active.
Lung function often declines once patients are colonised with these
pathogens. The decision to treat is based on clinical symptoms and
microbiological,
radiological and immunological findings. In the future there may
be potential for serological tests to aid clinical decision making.
Susceptibility varies widely between the strains of bacteria. Dr
Denton stated that macrolides were the most active agents against
M avium.
He recommended the combination of daily oral clarithromycin or azithromycin
plus rifampicin and ethambutol for the first-line treatment of M
avium infection. Intravenous or nebulised amikacin and oral clofazimine
can
be added as second-line agents. Daily treatment can be reduced to
three times weekly once the patient is clinically stable. Treatment
must
be
continued until cultures remain negative for one year, he emphasised.
For rapid growing mycobacteria such as M abscessus and M
chelonae,
Dr Denton recommended the use of intravenous amikacin, imipenem and
oral
clarithromycin for two to four weeks, until there is a clinical response.
For maintenance treatment he suggested nebulised amikacin plus oral
clarithromycin. Currently there is no evidence or guidance on how
long to continue treatment.
Concluding his presentation, Dr Denton stressed the need to update
treatment guidelines urgently, particularly with respect to cystic
fibrosis. |
The
Pharmaceutical Journal