Neurological toxicity ofTri-azole Antifungals

DR CAROLINE BAXTERClinical Research Fellow

www.aspergillus.org.uk

Tri-azole AntifungalsVoriconazole Posaconazole

Itraconazole

‘ASPERGILLUS BRONCHITIS’

SAFS

ABPA

Type 1 and 3 hypersensitivity

ASPERGILLOMA CPA

Tri-azole side effects

Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30

• 216 patients taking itraconazole• 46% experienced adverse side effect• Neurological: 21% sleep disturbance/poor memory and

concentration, 11% peripheral neuropathy, 4% tremor.• Seizures described but rare.

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Toxicity and drug levels

Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30

Therapeutic Drug Level Monitoring

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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 Random 0.5mg/L• 03.02.03 Random <0.4 no drug detected• 25.03.03 Post-dose 2.1• 03.07.03 Random 1.8• 27.08.03 Post-dose 1.6• 17.11.03 Post-dose 2.9• 16.01.04 Random 2.3• 14.06.04 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 09Admit

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 1.3 1.6 1.3

FVC 2.15 2.0 1.8 2.3 2.1

Rx Abx Pred 40 Pred 30 Pred 20

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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?

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