1. Timothy W. Felton, Caroline Baxter, Caroline B. Moore, Stephen A.Roberts, William W. Hope,and David W. Denning Clinical Infectious Diseases 2010; 51:1383–1391 R2. 석화영 /Pf. 손준성 Efficacy and safety of posaconazole for chronic pulmonary aspergillosis

2. Introduction  Chronic pulmonary aspergillosis (CPA)  progressive respiratory infection  multiple pulmonary cavities  increased levels of antibodies to Aspergillus species  Therapeutic goals for CPA  prevention of destruction of the lungs  minimization of respiratory and constitutional symptoms

3. Introduction  Long-term therapy with triazole antifungal agents is the standard of care for CPA  Itraconazole  extensively used for this purpose  toxicity and the emergence of resistance  Voriconazole  alternative agent  adverse events, such as phototoxicity  Parenteral agents, such as polyenes and echinocandins  impractical and extremely expensive  Alternative therapeutic options are urgently required

4. Introduction  Posaconazole  broad-spectrum triazole agent  potent activity against Aspergillus species  safe and effective agent for the prevention and treatment of a range of invasive fungal infections  First series of patients with CPA who have received posaconazole, and this study represents an important advance for the treatment of this syndrome

5. Methods-study design  Retrospective study  Single centre (National Aspergillosis Centre, University Hospital of South Manchester,United Kingdom)  Posaconazole 400 mg twice per day

6. Methods-definition  All conditions were required for the diagnosis of CPA  progressive pulmonary cavitation on imaging  positive Aspergillus Ab titer or isolation or visualization of Aspergillus species in a biopsy specimen from the lung or pleura  elevated inflammatory markers  constitutional or pulmonary symptoms lasting for at least 3 months  exclusion of other causes that can mimic this syndrome (eg, M.tuberculosis infection or pulmonary malignancy)  no significant systemic immunosuppression (uncontrolled HIV infection, haematological malignancy, chronic granulomatous disease, corticosteroid treatment)

7. Methods-definition  Both clinical and radiological data were used to assess the response to therapy

8. Methods-definition  Response to posaconazole therapy  if clinical and/or radiological deterioration were absent  Overall improvement  clinical improvement in the presence of radiographic stability  radiographic improvement in the presence of clinical stability  combined clinical and radiographic improvement

9. Results

11. Aspergillus IgG titers from undetectable to 1:516 92% of patients had a detectable Ab titer Initial precipitating Aspergillus IgG titers were similar in both groups

12. Results  Response to therapy  At 6 months  response : 41 patients (61%) of 67  failed : 26 patients (39%) of 67  overall improvement: 9 patients (13%)  At 12 months  response : 19 patients (46%) of 41  failed : 22 patients (54%) of 41  overall improvement: 6 patients (15%)

15. Results  Assessment of safety  12 (15%) of 79 patients.  5 patients : nausea (most common reaction)  5 patients : cutaneous reactions  1 patient : headache, lethargy  The lack of recurrence or progression of peripheral neuropathy, rash, and hepatitis caused by other triazoles

16. median value for the random plasma posaconazole concentrations was 1.28 mg/L (range, 0.42–3.48 mg/L)

17. Discussion  Chronic pulmonary aspergillosis  insidious and progressive syndrome  current regimens are complicated by drug-associated toxicity and antifungal resistance  In this study, the response rates for patients with CPA to posaconazole after 6 and 12 months of therapy were 61% and 46%

19. Discussion  The lack of recurrence or progression of peripheral neuropathy, rash, and hepatitis caused by other triazoles is noteworthy  Long-term triazole therapy is also compounded by increasing reports of triazole resistance  In this study, a response to posaconazole therapy was seen in ∼ 50% of patients with an isolate that had an itraconazole MIC of >8 mg/L but a posaconazole MIC of ≤1 mg/L.

20. Conclusion  Posaconazole is at least as effective as other agents for CPA.  Furthermore, this compound is well tolerated and can be used for patients with adverse events to other triazoles.  A successful clinical response may be observed for some patients infected with isolates that have elevated MICs for other triazoles.  Randomized clinical trials are now required to further optimize the clinical outcome of CPA.