Transcript Aspergillosis in Cystic Fibrosis

Neurological toxicity of
Tri-azole Antifungals
DR CAROLINE BAXTER
Clinical Research Fellow
www.aspergillus.org.uk
Tri-azole Antifungals
Voriconazole
Posaconazole
Itraconazole
Type 1 and 3
hypersensitivity
ABPA
‘ASPERGILLUS BRONCHITIS’
SAFS
ASPERGILLOMA
CPA
Tri-azole side effects
50
45
Total patients
• 40216 patients taking itraconazole
35
• 3046% experienced adverse side effect
• 25Neurological: 21% sleep disturbance/poor memory and
20concentration, 11% peripheral neuropathy, 4% tremor.
15
• 10Seizures described but rare.
5
P
er
G
ip
Iu
he
ps
ra
l O et
P
S
ar
le
ed
ep
ae
em
st
d
is
he
a
tu
si
rb
a/
an
pe
R
ce
rip
as
*
he
h/
pr
ra
ur
ls
itu
B
e
re
ns
s
at
or
hl
y
es
lo
ss
sn
H
ea
es
da
s/
P
ch
N
e/
D
di
zz
in
es
s
Tr
em
or
B
ru
is
H
in
yp
g
er
t
A
en
bn
si
or
on
m
al
LF
Ts
M
H
ya
yp
lg
er
ia
gl
Ta
yc
st
ae
e
M
m
di
en
ia
st
st
ur
ru
ba
al
nc
A
di
e
dr
st
en
ur
ba
al
nc
su
e
pp
re
ss
io
n
0
Features
Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30
Toxicity and drug levels
Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30
Therapeutic Drug Level Monitoring
Vor ic onazole Concent r at ion ( mg/ L)
12
10
8
6
4
2
0
0
70
140
210
Tim e ( hour s)
280
350
Tremor
• 216 patients on itraconazole
• 5 cases reported – confirmed by
accelerometry
• Onset 3wk-12 months
• 3 of 5 cases itraconazole
level>15mg/l
• Dose reduction did not alter
symptoms
• 1 case resolved off treatment and
recurred with recommencement
of the drug
• Also described with voriconazole
and posaconazole.
• Unlikely class effect
Lestner et al, J Neurol Neurosurg Psychiatry. 2010 Mar;81(3):327-9
Peripheral Neuropathy
• Retrospective study
• Patients with aspergillosis commenced on tri-azoles between
2007-2010.
• 222 patients were commenced on tri-azole antifungals: 107
itraconazole, 75 voriconazole and 40 posaconazole.
• 24 patients described symptoms of PN, 1 excluded as
diagnosed median nerve palsy.
• 3 patients described symptoms with both itraconazole and
voriconazole.
• Total of 26 ‘clinical episodes’ of PN.
Baxter et al. J Antimicrob Chemother. 2011 Sep;66(9):2136-9
Peripheral Neuropathy
• 22 presented as a sensory disturbance of the
hands and/or feet developing over a median
of 3 months.
• 4 presented with acute predominant lower
limb weakness and difficulty walking over 1 to
4 weeks.
• 12 male, 11 female. Mean age 59.
• 26 episodes: 18 itraconazole, 7 voriconazole, 1
posaconazole
Drug Levels
• 11 of the 26 had persistently elevated drug
levels (despite dose reductions) in the 3
months prior to onset of symptoms.
• 10 of the 11 were high itraconazole levels and
1 elevated posaconazole level. All 7 patients
experiencing symtoms with voriconazole had
therapeutic drug levels.
NCS
• 15 of the 26 episodes had formal nerve conduction
studies performed.
• 12 of the 15 had confirmed PN:
- 6 sensory predominant axonal neuropathy
- 2 small fibre sensory neuropathy
- 3 motor predominant axonal neuropathy
- 1 mixed axonal/demyelinating neuropathy
• Of the 3 negative studies – no baseline, no small
fibre studies, all spent >1 month off therapy prior to
NCS
Outcome
• 2 patients had persistent symptoms despite
cessation of medication.
• 2 resolved with dose reduction
• All others resolved with stopping medication
• 3 patients had symptoms with both
itraconazole and voriconazole
• 3 patients successfully changed to an
alternative triazole
Discussion
• Remarkably high rate of PN: itra 17%, vori 9%.
• No direct relationship to drug levels but some on itraconazole
with high levels do respond to a reduction in dose.
• First ever described case of posaconazole PN.
• Most sensory predominant axonal neuropathy but must note
4 cases of rapid debilitating motor axonal neuropathy.
• Must screen for other causes of PN.
• Pathogenesis unknown – metronidazole (imidazole),
mitochondrial disorders, accumulation in phospholipids in
neurons.
Discussion
•
•
•
•
Risk, although low, of non recovery
Early detection vital
Neuropathy scales (chemotherapy, diabetes)
Baseline NCS and small nerve studies
Clinical Case
•
•
•
•
•
HR
Female
20 years old
Cystic fibrosis ∆F508/∆F508
Transferred to adult services (MACFU) in
March 2007
Clinical Case
CF past history:
• Hearing loss due to iv aminoglycosides.
• Chronic transmissible strain Pseudomonas
auerginosa. Intermittent Staphylococcus
aureus.
• 1998 RLL lobectomy - aspergilloma (histology).
Post surgery treatment with itraconazole
200mg bd.
Clinical Case
• Clinically stable since surgery.
Itraconazole 200mg bd continued.
DRUG LEVEL MONITORING
•
•
•
•
•
•
•
•
01.11.02
03.02.03
25.03.03
03.07.03
27.08.03
17.11.03
16.01.04
14.06.04
Random 0.5mg/L
Random <0.4 no drug detected
Post-dose 2.1
Random 1.8
Post-dose 1.6
Post-dose 2.9
Random 2.3
Random 2.8
Clinical Case
•
•
•
•
•
Compliance
Brand
Time taken/food
Other medication
CF – GI absorption
Clinical Case
• 2004 - Developed bilateral hand weakness and
parasthesia.
• Seen by neurologist – peripheral neuropathy
secondary to itraconazole. Itraconazole
stopped. No recovery but no progression.
• Poor fine motor skills.
Clinical Case
• After transfer to MACFU, HR remained well
with no complications
• Annual november 2008 – FEV1 1.8, FVC 2.15
(approx 65% predicted)
• Total IgE 880 KIU/l
• Specific IgE Aspergillus 15.2 KUa/l
• Eosinophils 0.13
Clinical Case
•
•
•
•
•
•
January 2009
Attended clinic feeling unwell
Increasing shortness of breath and cough
FEV1 1.7, FVC 2.0
CXR – no acute changes
Last sputum culture – Pseudomonas aeruginosa and Candida
glabrata.
• Given 2 weeks oral ciprofloxacin and increased dose of
azithromycin.
• Deterioration despite antibiotics (FEV1 1.0, CRP<5, culture
negative)
• Admitted to hospital
Clinical Case
• Improved in hospital with oral steroids and
physiotherapy
• Rapid decline on discharge as steroids weaned
Nov 08
Jan 09
Feb 09
Admit
Feb 09 D/C
March 09
IgE
880
3000
4800
IgE Asp
15.2
67
60.3
Eosinophils
0.13
0.6
0.5
FEV1
1.8
1.7
FVC
2.15
2.0
Rx
Abx
?
1.3
1.6
1.3
1.8
2.3
2.1
Pred 40
Pred 30
Pred 20
Altered mental function
• Wide description of different symptoms
associated with all tri-azoles.
• Common – 20% patients
• Sleep disturbance and nightmares
• Poor concentration
• Impaired memory - STM
• Depression
Conclusions
• Side effects with tri-azoles are common and often
limit their use.
• The three most common neurological side effects of
tri-azoles are poor sleep/altered mental function,
tremor and peripheral neuropathy.
• Drug level monitoring is important.
• First ensure drug levels are in therapeutic range. If
symptoms not severe can first trial a dose reduction
but maintain therapeutic levels.
• Risk balance of side effects and treatment benefit.
Questions?
www.aspergillus.org.uk