Abstract.: Background: The incidence of fungal infections, including those due to Aspergillosis species has continued to increase in recent years. Invasive aspergillosis remains an important cause of morbidity and mortality, despite therapeutics interventions. Patients and Methods: We reported five cases of invasive pulmonary aspergillosis treated with voriconazole failing to respond to conventional treatments. Results: The clinical and radiological resolution of pulmonary aspergillosis reported in these cases following therapy with voriconazole is remarkable, considering the infections had proved refractory to standard antifungal therapies. Long-term therapy (in two cases ≥ 1 year, in one case 6 months) was very well tolerated by patients who were unable to tolerate other antifungal agents. Conclusion: Therapy with voriconazole offers a new therapeutic option for otherwise difficult-to-treat infections and the potential to significantly improve the management of Aspergillosis infection

Garbino, J.

Kolarova, L.

Lew, D.

Ondrusova, A.

Rohner, P.

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Infection 31 · 2003 · No. 4 © URBAN & VOGEL 241Successful Treatment of Pulmonary InvasiveAspergillosis with Voriconazole in Patients whoFailed Conventional TherapyJ. Garbino, P. Rohner, L. Kolarova, A. Ondrusova, D. LewAbstractBackground: The incidence of fungal infections, includingthose due to Aspergillosis species has continued to increasein recent years. Invasive aspergillosis remains an importantcause of morbidity and mortality, despite therapeuticsinterventions.Patients and Methods: We reported five cases of invasivepulmonary aspergillosis treated with voriconazole failing torespond to conventional treatments.Results: The clinical and radiological resolution ofpulmonary aspergillosis reported in these cases followingtherapy with voriconazole is remarkable, considering theinfections had proved refractory to standard antifungaltherapies. Long-term therapy (in two cases ≥ 1 year, in onecase 6 months) was very well tolerated by patients who wereunable to tolerate other antifungal agents.Conclusion: Therapy with voriconazole offers a newtherapeutic option for otherwise difficult-to-treat infectionsand the potential to significantly improve the managementof Aspergillosis infections.Infection 2003; 31: 241–243DOI 10.1007/s15010-003-3176-4IntroductionThe incidence of fungal infections, including those due toAspergillus species, has continued to increase in recentyears. Invasive aspergillosis remains an important cause ofmorbidity and mortality, despite therapeutic interventions[1]. Survival of patients with invasive pulmonary as-pergillosis is generally very poor, at least partly due to thelack of effective treatment options for this disease [2]. As-pergillus spp. are widespread in the environment and arethe most common cause of invasive mould infections inimmunocompromised individuals [3]. Aspergillus infectionscan result in pneumonia and brain abscesses in this popu-lation, which includes patients with burns, HIV infection,cancer, organ transplant recipients and those receiving im-munosuppressive therapy [4–6]. Although the overall inci-dence of invasive aspergillosis is not high, certain patientpopulations are at particular risk. The disease typically af-fects 5% of bone marrow transplant recipients, 15% of pa-tients with hematological malignancies and 10–14% of solidorgan transplantation cases [7, 8].Early initiation of antifungal therapy is associated withimproved clinical outcomes [9]. However, as conventionaltreatments can result in severe adverse reactions and com-plications, rapid diagnosis of the infection is also vital. Theincidence of Aspergillus colonization is very high in respi-ratory samples, so early diagnosis of invasive pulmonary as-pergillosis remains difficult. By the time the infection is con-firmed, mortality may reach 50–95% in patients with dis-seminated infection [5].Voriconazole is a new broad-spectrum triazole anti-fungal agent with activity against a wide range of clinicallyimportant and emerging fungal pathogens. Studies haveshown voriconazole to result in good clinical responses in60% of patients with acute pulmonary or tracheobronchialinvasive aspergillosis [10] and to be both more effective andbetter tolerated than amphotericin B in patients with inva-sive aspergillosis [11].When used empirically in febrile neu-tropenic patients, voriconazole is a suitable alternative toliposomal amphotericin B, with fewer breakthrough infec-tions (including those due to Aspergillus spp.) occurringduring therapy with voriconazole compared with ampho-tericin B [12].PatientsCase 1A 74-year-old Caucasian male with right nephrectomy due to gen-itourinary tuberculosis and ischemic cardiopathy since 1998, suf-fered terminal renal failure due to nephroangiosclerosis. He hadreceived hemodialysis since 1996 and underwent renal transplan-tation in February 2000. Immunosuppressive therapy consisted ofInfection Brief ReportJ. Garbino (corresponding author), L. Kolarova, A. Ondrusova, D. Lew Division of Infectious Disease, Dept. of Internal Medicine, University Hos-pital Geneva, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland;Phone: (+41/22) 372-9839, Fax: -9832, e-mail: jorge.garbino@hcuge.chP. RohnerClinical Microbiology Laboratory, Dept. of Internal Medicine, UniversityHospital Geneva, SwitzerlandReceived: August 27, 2002 • Revision accepted: December 23, 2002prednisone (25 mg od), mycophenolate mofetil (1,000 mg bid) andtacrolimus (2 mg bid).Two months after transplantation, the patient was hospital-ized due to febrile agranulocytosis in the context of immunosup-pressive therapy and pulmonary aspergillosis was suspected on thebasis of chest X-rays (cavitary image). Although Aspergillus wasnot detected in tracheal secretions, the patient was treated withitraconazole (200 mg bid), due to the high risk of aspergillosis andwas discharged from the hospital.One month later, thoracic CT scans revealed a rosette-typeexcavated infiltrate on the left side and bilateral parenchymatousinfiltrates (Figure 1). Laboratory follow-ups showed an increasein neutrophil count after a further 2 weeks and the patient re-ported severe asthenia. He was rehospitalized and Aspergillus fu-migatus was cultured from bronchoalveolar lavage (BAL); renalinsufficiency was still present. Due to the severity of disease, im-munosuppressive therapy was reduced and iv voriconazole treat-ment (6 mg/kg q12h iv  2 doses on day 1, followed by 200 mg bidorally) was initiated. Treatment with amphotericin B was not in-troduced due to renal impairment. The patient was treated withvoriconazole for 1 year, resulting in a clear improvement in tho-racic CT scans (compared to the 1st month) and the pulmonarylesions were considered cured.Adverse events observed during voriconazole treatment weredizziness and ocular disturbances, which both occurred during theinitial infusion, a few minutes later the patient recovered withoutsequelae.Voriconazole treatment was well tolerated for 1 year andno liver function test abnormalities were observed.Case 2A 37-year-old Caucasian male with a past medical history ofchronic granulomatous disease since the age of 14 years, inguinaladenitis caused by Candia albicans, pulmonary anguilliasis  andtype 1 diabetes mellitus presented in January 2000 with tracheo-bronchitis and received clarithromycin therapy.One month later, the patient reported recurrence of coughwith purulent sputum, night sweating and weight loss (3–4 kg). Asubcutaneous tumefaction was noted below the left breast and A.fumigatus was cultured from the biopsy. Thoracic CT scans indi-cated a large subpectoral mass on the left side, corresponding withan area of pleural thickness. The scans also revealed osteolyticchanges to the fourth and fifth anterior left ribs, a pulmonary ab-scess in contact with pericardium, mediastinal adenopathies, infil-trates and pleuro-parenchymatous synechia in the lingula lobe(Figure 2). Bone scintigraphy showed hyperactivity in the fourthand fifth anterior left ribs.Treatment was started with conventional amphotericin B(1 mg/kg/day), but was switched to a lipid formulation 11 days later(Ambisome® 3 mg/kg/day) due to adverse events (anemia and re-nal insufficiency). This treatment regimen was maintained for 6weeks, during which time renal insufficiency improved, but a bloodtransfusion was necessary to correct the persistent anemia.The pa-tient was then switched to therapy with voriconazole (6 mg/kgq12h iv  2 doses on day 1, followed by 200 mg bid orally). Onemonth later, CT scans indicated that the pectoral mass on the leftside had resolved and that the infiltrates in the superior left lobewere slightly reduced. A small parenchymatous pulmonary con-densation at the level of the lingual lobe persisted, as did theadenopathies. A follow-up CT scan 1 year later showed furtherimprovement in the pulmonary infiltrates.The patient tolerated voriconazole treatment very well. Af-ter 1 year of treatment, a cutaneous rash attributable to the drugoccurred, which improved when voriconazole was reduced from200 mg bid to 150 mg bid orally. The patient continues to receiveprophylactic treatment with voriconazole.Case 3A 65-year-old Caucasian male had a past medical history of viralpericarditis and idiopathic pulmonary fibrosis, which was treatedwith immunosuppressive drugs.In November 1998, the patient underwent bi-pulmonarytransplantation.Three days later, A. fumigatus and C. albicans werecultured from the respiratory tract. In the context of immunosup-pressive therapy and suspected pulmonary aspergillosis with acompatible chest X-ray, excavated infiltrates, itraconazole therapywas initiated (400 mg/day). Bronchoscopy 1 week later revealedsutures covered by plaques on the left side, which reached the rightsuperior bronchus and biopsy cultured A. fumigatus.AmphotericinB was stopped due to patient’s intolerance. Due to lack of responseJ. Garbino et al. Voriconazole for Treating Invasive Aspergillosis242 Infection 31 · 2003 · No. 4 © URBAN & VOGELFigure 1. Thoracic CT scan showing a pulmonary rosette-type exca-vated infiltrate on the left side, bilateral parenchymatous infiltratesand adenopathies.Figure 2. Thoracic CT scan showing a pulmonary abscess in contactwith the pericardium and chest wall, mediastinal adenopathies, infil-trates and pleuro-parenchymatous synechia in the lingual lobe.to itraconazole, voriconazole therapy was started 1 month aftertransplantation (6 mg/kg q12h iv  2 doses on day 1, followed by200 mg bid orally). Respiratory tract cultures became negative andthe infection was considered cured after 3 months of treatment.The patient died 5 months later, due to a cardiorespiratory arrest.Case 4A 56-year-old Caucasian male had a past medical history of aleukemia diagnosed in 2001 and wastreated with chemotherapy.During chemotherapy, the patient developed thrombocytopeniaand severe anemia, which necessitated blood transfusions. Neu-tropenia below 500 granulocytes/l lasted for 2 days.In September 2001, blepharoconjunctivitis occurred and thepatient was treated with cefepime and teicoplanin for 4 weeks; acy-clovir was also administered for 3 weeks, due to positive herpesserology. One month later, the patient became febrile and a fungalinfection was suspected. Amphotericin B therapy (1 mg/kg/day)was initiated, and pulmonary aspergillosis was subsequently con-firmed by thoracic CT scans (halo sign) and positive serologic test(galactomanan). Due to intolerance of the amphotericin B treat-ment (renal impairment and hypokalemia), the patient wasswitched to voriconazole (6 mg/kg q12h iv  2 doses on day 1, fol-lowed by 200 mg bid orally) for 6 months, which resulted in reso-lution of the radiological images. The patient did not present anydrug intolerance.Case 5A 77-year-old Caucasian male had a past medical history of res-piratory insufficiency due to pulmonary fibrosis and was treatedwith prednisone (20 mg/day) and azathioprine (25 mg/day).The patient was admitted to hospital with bronchopneumo-nia and respiratory insufficiency. Antimicrobial treatment(imipenem, clarithromycin) was initiated, but no clinical responsewas observed. Invasive pulmonary aspergillosis was diagnosed bylung biopsy (cultures grew A. fumigatus), and itraconazole ther-apy (400 mg/day) was started. After 1 week, no clinical improve-ment was observed and treatment was switched to amphotericinB (1 mg/kg/day). The patient developed renal failure and wasswitched to voriconazole (6 mg/kg q12h iv  2 doses on day 1, fol-lowed by 200 mg bid orally).The patient’s clinical condition wors-ened, he developed septic shock and was transferred to the inten-sive care unit. He required mechanical ventilation and vasopres-sors (ephedrine and dobutamine), but died 3 days later; death wasnot attributable to fungal infection.DiscussionThe clinical and radiological resolution of pulmonary as-pergillosis reported in these cases following therapy withvoriconazole is remarkable, considering the infections hadproved refractory to standard antifungal therapies. Long-term therapy (in two cases ≥ 1 year, in one case 6 months)was very well tolerated by patients who were unable to tol-erate other antifungal agents, including those with under-lying conditions such as renal insufficiency, which can re-strict the selection of conventional antifungal agents.Voriconazole appears to offer a new therapeutic option forotherwise difficult-to-treat infections, such as those in pa-tients with chronic granulomatous disease. Echinocandinscould be another treatment alternative. Therapy withvoriconazole also offers the potential to significantly im-prove the management of Aspergillus infections. In thecases reported here, aspergillosis was considerably im-proved or resolved and the clinical conditions of these in-dividuals were stabilized. Using voriconazole to stabilizepatients with previously difficult-to-treat infections may ul-timately allow long-term therapeutic interventions, such asbone marrow transplantation, to be undertaken.AcknowledgmentVoriconazole was provided by Pfizer Inc. in the context of com-passionate use treatment.References1. Kontoyiannis DP, Bodey GP: Invasive aspergillosis in 2002: an up-date. Eur J Clin Microbiol Infect Dis 2002; 21: 161–172.2. Oren I, Goldstein N: Invasive pulmonary aspergillosis. Curr OpinPulm Med 2002; 8: 195–200.3. Warnock DW, Hajjeh RA, Lasker BA: Epidemiology and preven-tion of invasive aspergillosis. Curr Infect Dis Rep 2001; 3:507–516.4. McKinsey DS, Wheat LJ, Cloud GA, et al.: Itraconazole prophy-laxis for fungal infections in patients with advanced human im-munodeficiency virus infection: randomized, placebo-con-trolled, double-blind study. National Institute of Allergy and In-fectious Diseases Mycoses Study Group. Clin Infect Dis 1999; 28:1049–1056.5. Paterson DL, Singh N: Invasive aspergillosis in transplant recipi-ents. Medicine (Baltimore) 1999; 78: 123–138.6. Vogeser M, Wanders A, Haas A, Ruckdeschel G: A four-year re-view of fatal aspergillosis. Eur J Clin Microbiol Infect Dis 1999;18: 42–45.7. Denning DW, Evans EG, Kibbler CC, et al.: Guidelines for the in-vestigation of invasive fungal infections in haematological ma-lignancy and solid organ transplantation. British Society forMedical Mycology. Eur J Clin Microbiol Infect Dis 1997; 16:424–436.8. Morrison VA, Haake RJ, Weisdorf DJ: The spectrum of non-Can-dida fungal infections following bone marrow transplantation.Medicine (Baltimore) 1993; 72: 78–89.9. Ellis M: Invasive fungal infections: evolving challenges for diag-nosis and therapeutics. Mol Immunol 2002; 38: 947–957.10. Denning DW, Ribaud P, Milpied N, et al.: Efficacy and safety ofvoriconazole in the treatment of acute invasive aspergillosis.Clin Infect Dis 2002; 34: 563–571.11. Herbrecht R, Denning D, Patterson T, et al.: Voriconazole versusamphotericin B for primary therapy of invasive aspergillosis. NEngl J Med 2002; 347: 408–415.12. Walsh TJ, Pappas P, Winston DJ, et al.: Voriconazole comparedwith liposomal amphotericin B for empirical antifungal therapyin patients with neutropenia and persistent fever. N Engl J Med2002; 346: 225–234.J. Garbino et al. Voriconazole for Treating Invasive AspergillosisInfection 31 · 2003 · No. 4 © URBAN & VOGEL 243

Successful Treatment of PulmonaryInvasive Aspergillosis with Voriconazole in Patients who FailedConventional Therapy

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Successful Treatment of PulmonaryInvasive Aspergillosis with Voriconazole in Patients who FailedConventional Therapy

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