To the Editors:
Voriconazole is a broad-spectrum antifungal agent that is effective against moulds such as Aspergillus fumigatus. It inhibits the cytochrome P450-dependent 14-α–lanosterol demethylase, preventing the conversion of lanosterol to ergosterol. This results in the accumulation of toxic methylsterols in the fungal wall and the inhibition of fungal growth [1]. Voriconazole is available as an intravenous infusion solution containing a cyclodextrin molecule (Captisol®; Ligand Pharmaceuticals Inc., La Jolla, CA, USA) to increase its solubility in water [2]. Adverse effects, such as gastrointestinal disorders, visual disturbances and elevated transaminase levels, complicate the use of voriconazole if used systemically. The therapeutic concentration range of voriconazole is from 1 to 5.5 μg·mL−1 and, although higher concentrations (>5.5 μg·mL−1) are associated with better clinical outcomes, they are also associated with more severe and less common side-effects, including encephalopathy and hallucinations [1]. Inhaled voriconazole reduces histological manifestations of invasive aspergillosis in rodents [3] and it has been proposed that a favourable lung tissue to plasma concentration ratio is obtained through this route of administration [4]. Consequently, inhaled voriconazole may provide higher concentrations at the site of infection without increasing the risk of systemic side-effects. We present three cases in which life-threatening invasive aspergillosis was treated with systemic voriconazole, but due to unacceptable adverse effects, the treatment had to be withdrawn. With no other conventional treatment options, inhaled voriconazole was administered.
In September 2009, a 66-yr-old, otherwise healthy male was admitted to our Dept of Infectious Diseases due to symptomatic pneumonia that had lasted for 4 weeks. The patient was a previous smoker (40 pack-yrs) and due to brain surgery for an incidental meningioma, he was treated with steroids. Due to complications, he was treated with methylprednisolone (100 mg) for >1 month.
Computed tomography (CT) imaging performed in October 2009 showed marked emphysema, a unilateral abscess and infiltration, but did not suggest lung cancer. Blood samples showed positive Aspergillus antigen compatible with invasive Aspergillus infection of the lung and oral voriconazole treatment was initiated.
Due to progressive aspergillosis in March 2010, the antimycotic treatment was intensified. Initially, the patient received a combination of antibiotics and antifungal therapy with oral voriconazole and i.v. anidulafungin without significant clinical effects. Inhaled amphotericin B was added to the antimycotic treatment but was not tolerated due to nausea, abdominal pain and vomiting.
In May 2010, chest radiography showed a slight lung infiltrate remission and the patient had nearly normalised C-reactive protein. By that time, the patient had developed polyneuropathy and progressive increases in liver enzyme levels. Consequently, antifungal treatment was halted, which normalised liver enzymes but was also associated with a worsened clinical condition and elevated C-reactive protein and leukocytes. Therefore, in July 2010, the patient started monotherapy with inhaled voriconazole at an initial total dose of 40 mg t.i.d. that was reduced to 40 mg b.i.d. after 2 weeks and was instructed to continue this at home on a daily basis. On inhaled voriconazole, as single therapy for 3 months, the patient recovered completely and could perform normal daily activities. Chest radiography performed in August 2010 showed remission of both the unilateral abscess and the parenchymal infiltration. The treatment was stopped after 6 months and follow-up 6 months later showed no sign of recurrence of the disease.
In September 2009, a 61-yr-old male with interstitial pulmonary fibrosis underwent bilateral lung transplantation. The post-operative period was complicated by graft dysfunction after 9 months.
In April 2010, the patient was admitted due to progressive respiratory insufficiency. Bronchoscopy with bronchoalveolar lavage showed invasive lung aspergillosis. Consequently, the patient started oral voriconazole and i.v. anidulafungin treatment but with a clinically insufficient response. Furthermore, elevation of liver enzymes was observed in relation to the treatment. The dose was therefore reduced and inhaled amphotericin B was added. Subsequently, reduced renal function and worsened dyspnoea were observed. At this point, chest radiography showed lung infiltrate progression and pleural effusion, and the patient started inhaled voriconazole with an initial total dose of 40 mg t.i.d. that was reduced to 40 mg b.i.d. after 2 weeks. A significant clinical response and chest CT remission were seen in July 2010 (fig. 1a and b). There was a slight change in the position of the lesion due to respiration. The maximum diameter of the lesion is shown in both images. 1 month later, the patient was discharged in a good condition and advised to continue with daily inhalations of voriconazole. The patient tolerated this treatment well and without any side-effects or influence on liver enzyme levels or pulmonary function tests. Due to severe graft dysfunction, the patient died 2 months later.
High-resolution computed tomography images a) before and b) after 5 weeks of treatment with inhaled voriconazole. Between the two images, there was a slight change in the position of the lesion due to respiration. The maximum diameter of the lesion is shown in both images. c) Particle size of the aerosolised voriconazole.
In September 1997, a 37-yr-old female with Eisenmenger’s syndrome underwent heart and bilateral lung transplantation. There were no operative or immediate post-operative complications. 1 yr after the operation, the patient’s forced expiratory volume in 1 s (FEV1) was 2.7 L and her forced vital capacity was 3.4 L. The patient’s lung function decreased to an FEV1 of 2.0 L in 2002 and further to 1.3 L in 2005. Azithromycin treatment was introduced in 2008 for bronchiolitis obliterans syndrome. In 2010, the patient’s FEV1 was 1.1 L and in 2011, three sputum samples showed A. fumigatus. Thus, treatment with oral voriconazole (200 mg b.i.d.) was initiated. After a few weeks, blurred vision and vomiting started. The dose was reduced but the symptoms continued. The medication was changed to posaconazole but after 2 weeks, the treatment was stopped due to adverse reactions, including tiredness, constipation, mental depression and elevated liver enzymes. After 1 week, side-effects had disappeared and inhalation of voriconazole (40 mg·day−1) was started. After 2 months, the patient’s FEV1 had increased to 1.4 L, galactomannan antigen in blood had decreased from 4.4 to <0.5 and two sputum cultures showed no evidence of Aspergillus.
In all cases, aerosolised voriconazole was prepared as follows. The dry powder formulation of voriconazole (200 mg) for i.v. use was diluted in 20 mL of water and 4 mL, equivalent to 40 mg, was nebulised using a well-known and validated jet nebuliser (Sidestream®; Philips Respironics, Pittsburgh, PA, USA). The nebuliser was driven by a compressor (Portaneb; Medic-Aid, Pagham, UK) at a flow rate of 8 L·min−1. Nebulisation lasted 15 min with the patient breathing quietly with their spontaneous breathing pattern. No breath holding was used and no specific precautions such as fume hoods were taken in order to reduce exhausted voriconazole aerosol.
The aerosol particle size was characterised using a seven-stage Anderson cascade impactor (Copley Scientific, Nottingham, UK), showing a mass median aerodynamic diameter of 2.4 μm (geometric standard deviation 1.5 μm) (fig. 1c). Finally, 93% of the particles were in the fine-particle fraction (<5 μm) and were thus considered in the respirable range.
To our knowledge, this is the first report on the successful administration of inhaled voriconazole for life-threatening invasive aspergillosis after the failure or withdrawal of conventional treatment regimes due to adverse effects.
After i.v. administration, voriconazole distributes well into tissues, including the lungs [5, 6], liver and brain [6]. Studies in rats have shown higher concentrations of voriconazole in wet lung tissue than in plasma after inhalation [4, 7], but it is unknown how voriconazole is distributed to other tissues after inhalation. The daily dose used (40 mg t.i.d./40 mg q.d.) in our cases was lower than the usual dose for oral administration. Analysis of the aerosol showed very favourable characteristics with >90% of the particles in the respirable range, favouring peripheral lung deposition [8]. Therefore, we hypothesise that delivery directly to the lungs resulted in high local concentrations and effective inhibition of fungal growth, while systemic concentrations and side-effects were reduced.
Elevated liver enzymes returned to normal levels during inhalation therapy. Also, there were no local side-effects attributed to the inhalational route of administration. Thus, inhaled voriconazole seems to be safe and well tolerated.
Nebulisation was performed with the hospital’s standard nebuliser without attempts to control the respiratory pattern of the patients. Use of a breath-actuated nebuliser, as opposed to continuous nebulisation, might have reduced waste of the medication and, thus, might reduce the cost of this expensive treatment. Lung deposition was not determined but is expected to be high due to a favourable fine particle fraction of 93%. Targeting the respiratory pattern would probably increase the pulmonary deposition since high tidal volumes and low inspiratory flow rates increase lung deposition [9]. Use of other more efficient nebulisers, such as mesh nebulisers, would also be expected to increase lung deposition and reduce nebulisation time, and should be pursued in future trials.
Together with the animal experiments reporting on both the effectiveness [3] and tolerability [7] of inhaled voriconazole, our three cases suggest that the safety and therapeutic potential of inhaled voriconazole therapy are promising and should be investigated in future controlled trials.
Footnotes
Statement of Interest
None declared.
- ©ERS 2012
