1. Neurological toxicity of Tri-azole Antifungals DR CAROLINE BAXTER Clinical Research Fellow www.aspergillus.org.uk

2. Tri-azole Antifungals VoriconazolePosaconazole Itraconazole

3. ASPERGILLUS BRONCHITIS SAFS ABPA Type 1 and 3 hypersensitivity ASPERGILLOMACPA

4. 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.

5. Toxicity and drug levels Lestner et al, Clin Infect Dis, 2009 Sep 15;49(6):928-30

6. Therapeutic Drug Level Monitoring

7. 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

8. 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

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

10. 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.

11. 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

12. 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

13. 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.

14. Discussion Risk, although low, of non recovery Early detection vital Neuropathy scales (chemotherapy, diabetes) Baseline NCS and small nerve studies

15. Clinical Case HR Female 20 years old Cystic fibrosis F508/F508 Transferred to adult services (MACFU) in March 2007

16. 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.

17. 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

18. Clinical Case Compliance Brand Time taken/food Other medication CF – GI absorption

19. 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.

20. Clinical Case After transfer to MACFU, HR remained well with no complications Annual november 2008 – FEV 1 1.8, FVC 2.15 (approx 65% predicted) Total IgE 880 KIU/l Specific IgE Aspergillus 15.2 KUa/l Eosinophils 0.13

21. Clinical Case January 2009 Attended clinic feeling unwell Increasing shortness of breath and cough FEV 1 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

22. Clinical Case Improved in hospital with oral steroids and physiotherapy Rapid decline on discharge as steroids weaned Nov 08Jan 09Feb 09 Admit Feb 09 D/CMarch 09 IgE88030004800 IgE Asp15.26760.3 Eosinophils0.130.60.5 FEV 1 1.81.71.31.61.3 FVC2.152.01.82.32.1 RxAbxPred 40Pred 30Pred 20 ?

23. 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

24. 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.

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