Oral Administration Of Voriconazole Research Articles

Single oral or intravenous administration of voriconazole achieved recommended therapeutic minimum inhibitory concentrations against Aspergillus in the common raven (Corvus corax).

To determine the pharmacokinetics of voriconazole after single IV or orally administered boluses in common ravens (Corvus corax). 8 healthy common ravens. Voriconazole (5 mg/mL, 10 mg/kg IV) was administered to 8 birds, and then plasma voriconazole concentrations were measured at various time points by high-pressure liquid chromatography with mass spectrometry. Starting 6 months later in a randomized 3-treatment 3-period regimen, birds received a single oral dose of voriconazole suspension (10 mg/mL; 6, 12, and 24 mg/kg PO). The study period was May 2015 to March 2016. Voriconazole (10 mg/kg IV) achieved an initial plasma concentration of 6.31 µg/mL when measured over 21 hours. After oral administration of voriconazole at 6, 12, and 24 mg/kg, the relative bioavailability was 67.5%, 209%, and 183%, respectively. For the 6-mg/kg dose, the maximum plasma concentration was reached at 30 minutes after administration and remained in the therapeutic range of 0.5 to 1 µg/mL for approximately 15 hours. The 12- and 24-mg/kg doses resulted in concentrations in a potentially toxic range. Voriconazole was well tolerated. All 4 doses resulted in plasma concentrations of voriconazole > 0.5 µg/mL, which is the minimum inhibitory concentration recommended for pathogenic species of Aspergillus fungi known to affect birds. A single dose of voriconazole administered as 10 mg/kg IV or 6 mg/kg PO resulted in recommended target plasma concentrations. Administration of voriconazole 6 mg/kg PO 2 to 3 times daily may be adequate for treatment without exceeding the toxic range.

Utility of systemic voriconazole in equine keratomycosis based on pharmacokinetic-pharmacodynamic analysis of tear fluid following oral administration.

ObjectiveTo clarify the detailed pharmacokinetics (PK) of orally administered voriconazole in tear fluid (TF) of horses for evaluating the efficacy of voriconazole secreted into TF against equine keratomycosis.Animals studiedFive healthy Thoroughbred horses.ProceduresVoriconazole was administrated through a nasogastric tube to each horse at a single dose of 4.0 mg/kg. TF and blood samples were collected before and periodically throughout the 24 hours after administration. Voriconazole concentrations in plasma and TF samples were analyzed using liquid chromatography‐electrospray tandem‐mass spectrometry. The predicted voriconazole concentration in both samples following multiple dosing every 24 hours was simulated by the superposition principle.ResultsThe mean maximum voriconazole concentrations in plasma and TF were 3.3 μg/mL at 1.5 h and 1.9 μg/mL at 1.6 h, respectively. Mean half‐life in both samples were 16.4 and 25.2 h, respectively. The ratio of predicted AUC0–24 at steady state in TF (51.3 μg∙h/mL) to previously published minimum inhibitory concentration (MIC) of Aspergillus and Fusarium species was >100 and 25.7, respectively.ConclusionsThis study demonstrated the detailed single‐dose PK of voriconazole in TF after oral administration and simulated the predicted concentration curves in a multiple oral dosing. Based on the analyses of PK‐PD, the simulation results indicated that repeated oral administration of voriconazole at 4.0 mg/kg/d achieves the ratio of AUC to MIC associated with treatment efficacy against Aspergillus species. The detailed PK‐PD analyses against pathogenic fungi in TF can be used to provide evidence‐based medicine for equine keratomycosis.

Oral administration of voriconazole with surgical fungal plaque debridement for the treatment of sinonasal aspergillosis with cribriform plate lysis in three dogs.

3 dogs with chronic sinonasal signs (sneezing, nasal discharge, or epistaxis [or a combination of signs]) were examined. For all 3 dogs, CT revealed variable degrees of nasal turbinate destruction and frontal sinus involvement with cribriform plate lysis. Fungal plaques were detected during rhinoscopy or sinusoscopy. Results of fungal culture (2 dogs) or cytologic examination of a plaque specimen (1 dog) supported a diagnosis of sinonasal aspergillosis. All dogs underwent surgical rhinotomy or sinusotomy (or both) for fungal plaque debridement followed by oral treatment with voriconazole and periodic physical examinations, clinicopathologic analyses, and assessments of serum drug concentrations for a period ≥ 22 weeks. All dogs had considerable to complete reduction of their clinical signs and tolerated voriconazole treatment with minimal adverse effects. Adverse effects included development of reversible neurotoxicosis (associated with high serum voriconazole concentration) and mildly high serum liver enzyme activities. The dosage of voriconazole administered to achieve therapeutic serum concentrations (2.5 to 3.3 mg/kg [1.1 to 1.5 mg/lb], PO, q 12 h) was substantially lower than dosages suggested by previously published studies in dogs. The 3 dogs remained clinically normal or had mild clinical signs after voriconazole discontinuation for follow-up times of 6 to 15 months. Findings in these 3 dogs indicated that surgical fungal plaque debridement followed by oral treatment with voriconazole may be an effective treatment option for dogs with sinonasal aspergillosis and cribriform plate lysis. Further evaluation of this treatment regimen with repeated CT examinations and longer follow-up times is warranted.

Application of different pharmacokinetic models to describe and predict pharmacokinetics of voriconazole in magellanic penguins following oral administration.

Aspergillosis is a condition causing serious morbidity and mortality in captive penguins and other bird species. It can be treated with antifungal drugs, such as voriconazole. However, the pharmacokinetics of voriconazole are variable between different animal and bird species. Therefore, the pharmacokinetics of voriconazole were investigated in this study in Magellanic penguins. Pharmacokinetic models were constructed and applied to predict the pharmacokinetics of voriconazole during long‐term treatment in Magellanic penguins, since the voriconazole treatment duration in chronic aspergillosis cases can last up to several months. Plasma voriconazole concentration–time data from adult Magellanic penguins (Spheniscus magellanicus; n = 15) following a single oral (PO) dose of either 2.5 mg/kg or 5 mg/kg in a herring in three separate study periods 7–12 months apart were collected. Mean plasma voriconazole concentrations were above the targeted MIC for Aspergillus fumigatus for 2 hr following a single 2.5 mg/kg voriconazole dose while the plasma concentrations exceeded the MIC for least 24 hr following a 5 mg/kg dose. Nonlinear mixed‐effects modeling was used to fit two pharmacokinetic models, one with first‐order and another with saturable elimination, to the single‐dose data. Fits were good for both, as long as dose was included as a covariate for the first‐order model so that clearance was lower and the half‐life longer for animals receiving the 5 mg/kg dose. Although the single‐dose data suggested saturated elimination at higher concentrations, the model with saturable elimination did not predict plasma voriconazole concentrations well for a clinical aspergillosis case receiving long‐term treatment, possibly because of induction of metabolizing enzymes with chronic exposure. Pharmacokinetic models should accurately predict plasma drug concentrations for different dosage regimens in order to be applicable in the field. Future studies should focus on determining clearance at steady‐state to be able to refine the pharmacokinetic models presented here and improve model performance for long‐term oral voriconazole administration in Magellanic penguins.

Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.

The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and voriconazole trough levels were quantified by a validated high-performance liquid chromatography method. Cytochrome P450 genotypes for CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable, and possible invasive fungal infections were reported for 8/104 (7.7%), 42/104 (40.4%), and 54/104 (51.9%) patients, respectively. Receiver operating characteristic (ROC) curve analysis indicated that trough concentrations of ≥1.3 μg/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 μg/ml) (P < 0.001) and that those of <5.3 μg/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 μg/ml) (P < 0.001). Voriconazole trough levels were significantly higher for heterozygous extensive metabolizers, poor metabolizers, and individuals receiving coadministration with proton pump inhibitors. For ultrarapid metabolizers, oral administration of voriconazole, and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patient age, weight, or gender or coadministration of tacrolimus and cyclosporine with the voriconazole trough level. In conclusion, the results of our analysis indicate large inter- and intraindividual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations of ≥1.3 μg/ml and <5.3 μg/ml are optimal for treatment and for minimization of adverse events. Optimization of drug efficacy and safety requires the use of rational doses for voriconazole therapy.

Evaluation of the Interaction of Intravenous and Oral Voriconazole with Oral Cyclosporine in Iranian HSCT Patients.

Objective:Voriconazole as a triazole antifungal agent is widely used for prophylaxis or treatment of fungal infections in allogeneic hematopoietic stem cell transplantation (HSCT). It can increase blood concentrations of other medications including cyclosporine A (CsA) which are substrates for cytochrome P450 3A4. The aim of this study was to evaluate comparatively the interaction between oral/intravenous (IV) voriconazole and oral CsA.Methods:Twenty-nine recipients of allogeneic HSCT who had been already on a steady dose of CsA and were started on oral or IV voriconazole were evaluated in a prospective cohort study. Blood concentration of CsA was determined before and 5–8 days after voriconazole initiation. Plasma concentration of voriconazole was measured in steady state. The changes in blood concentration of CsA after administration of voriconazole were evaluated.Findings:The concentration/dose (C/D) ratio of CsA increased significantly (P < 0.001) after voriconazole initiation in both routes of administration (8.40%–174.10% increase in C/D ratio). The C/D ratio alteration of CsA did not differ significantly between oral and IV voriconazole group (P = 0.405). There was a significant correlation in all patients between plasma concentration of voriconazole and percentage of CsA C/D ratio increment (P = 0.046).Conclusion:There was a significant intrapatient variability in the magnitude of CsA blood concentration increment after voriconazole initiation. We also demonstrated that magnitude of drug interaction did not differ in IV and oral voriconazole administration. Furthermore, we found that the magnitude of drug interaction was correlated with plasma concentration of voriconazole.

Oral administration and younger age decrease plasma concentrations of voriconazole in pediatric patients.

Voriconazole is used for treating or preventing invasive aspergillosis and other invasive fungal infections. To minimize adverse reactions and to maximize treatment effects, therapeutic drug monitoring should be performed. However, it is challenging to optimize daily voriconazole dosing because limited data have been published so far on pediatric patients. We retrospectively analyzed voriconazole concentrations in patients aged 0-18 years. In addition, a literature review was conducted. In our study cohort, younger age and oral administration were significantly associated with lower plasma voriconazole concentrations (P < 0.01). An unfavorable outcome was associated with low concentrations of voriconazole (P = 0.01). Reports of voriconazole administration in pediatric patients show that higher doses are required in younger children and in patients receiving oral administration. Hence, the current data suggest that we should escalate both initial and maintenance doses of voriconazole in pediatric patients, particularly in patients of younger age receiving an oral administration of voriconazole.

Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy.

Voriconazole plasma concentrations have been correlated with oral dosing in healthy subjects, but have been poorly characterized in ill patients with hematological malignancies receiving intensive chemotherapy. The relationship between orally administered voriconazole, plasma concentrations and liver toxicity was examined in a cohort of 69 primarily acute leukemia patients undergoing intensive chemotherapy. Oral administration of voriconazole was associated with significant interpatient variability, with voriconazole steady-state concentrations ranging from 0 μg/mL to 16.6 μg/mL. Approximately 20% of patients achieved steady-state concentrations <1 μg/mL. When adjusted for weight, patients receiving higher voriconazole doses tended toward higher plasma concentrations; however, there was no significant relationship between the plasma concentration and genotype, age, sex or use of concomitant proton pump inhibitors. Voriconazole concentrations were correlated with higher serum alkaline phosphatase levels at day 6 to 8, and with higher bilirubin and aspartate aminotransferase levels at day 14 to 16, but not with other liver enzyme levels. In ill patients with acute leukemia and related disorders undergoing treatment with oral voriconazole, there is a poor correlation between the voriconazole dose and plasma concentrations, and many patients achieve levels that are considered to be subtherapeutic. The findings support the routine use of therapeutic drug monitoring in these patients.

SUCCESSFUL TREATMENT OF A SEVERE CASE OF FUSARIOMYCOSIS IN A BELUGA WHALE (DELPHINAPTERUS LEUCAS LEUCAS)

An adult male beluga whale (Delphinapterus leucas leucas) was presented with a 4-cm-diameter, raised, firm nodule on the medial aspect of the left pectoral fin. A fissure developed within the center of the nodule, which formed an ulcerated cyst-like lesion. The lesion rapidly progressed in size, and, with peeling of material present within the cyst, the lesion flattened to a 36 x 25-cm cutaneous ulcer that extended into the axilla. Histopathologic features were consistent with lymphocytic and suppurative dermatitis with intralesional fungi. Fusarium solani was diagnosed by polymerase chain reaction (PCR). Fungal susceptibility testing was performed and revealed drug resistance to multiple antifungal medications tested individually and in combination therapies. Treatments used included serial surgical debridement of affected and surrounding tissue, topical application and regional infusion of various azole, and allylamine antifungals combined with either dimethyl sulfoxide or Tricide for absorption potentiation, and oral voriconazole administration. Although susceptibility testing revealed resistance to voriconazole, visible improvement of the lesion was noted after 6 weeks of oral voriconazole therapy. The voriconazole dosage was tapered based on serum levels and was administered over a 12-mo period. No local recurrence or new lesions were visible by 14 mo from first presentation.

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis

BackgroundA high incidence of adverse skin reactions following long-term oral administration of voriconazole in children with cystic fibrosis and allergic bronchopulmonary aspergillosis (ABPA). The aim was to study the pharmacokinetics of voriconazole in these patients and to determine a possible association between drug levels and adverse effects. MethodsMultiple venous blood samples were collected for HPLC determination of voriconazole concentrations and routine blood tests. Adverse events were recorded. ResultsNo significant correlation was found between incidence of photosensitivity and voriconazole serum levels in 6 of 8 children with ABPA. 80% of patients had trough voriconazole concentrations<1000ng/mL and were highly variable. ConclusionsLong-term voriconazole therapy and greater sun exposure in Greece appear to play a major role in the occurrence of photosensitivity. Steady-state plasma drug concentrations were found to be highly variable and below the recommended therapeutic range in most patients, without any apparent negative influence on outcome.

Two Cases of Fungal Rhinosinusitis Infiltrating the Adjacent Structures Successfully Treated by Endoscopic Surgery and Antifugal Agents

We present herein on two cases of fungal rhinosinusitis infiltrating the adjacent structures. The first case was zygomycosis in the sphenoid sinus infiltrating the superior orbital fissure and clivus, developed in an old but immunocompetent female. Endoscopic sinus surgery followed by systemic administration of liposomal amphotericin B (L-AMB) rapidly relieved the symptoms of severe headache and high fever. The accompanying abducens palsy also recovered 3 months after the treatment. The second case was aspergillosis extending into the orbit and cavernous sinus in a 66 years old male with diabetes mellitus. While L-AMB treatment showed limited effect, alteration to voriconazole and micafungin administration dramatically improved the signs and symptoms. Oral administration of voriconazole was continued for 4 months until negative serum βD glucan confirmed. These two cases were successfully treated with endoscopic surgery and antifungal agents, but invasive fungal rhinosinusitis remians a challenging clinical state for otolaryngologists. Treatment plans should be based on the histological identification of the causal fungus.

Intravenous Voriconazole after Toxic Oral Administration

In a male patient with rhinocerebral invasive aspergillosis, prolonged high-dosage oral administration of voriconazole led to hepatotoxicity combined with a severe cutaneous reaction while intravenous administration in the same patient did not. High concentrations in the portal blood precipitate liver enzyme abnormalities, and therefore, oral administration of voriconazole may have a hepatotoxicity profile different from that of intravenous (i.v.) administration. Intravenously administered voriconazole might still be an option after oral-voriconazole-induced toxicity has resolved.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis)

To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). 15 clinically normal adult Hispaniolan Amazon parrots. Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial. Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (C(max)) and area under the curve (AUC). In the multiple-dose trial, C(max), AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident. In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.

Case Report of Acremonium Intraocular Infection after Cataract Extraction

A 64-year-old woman was referred to our clinic for the treatment of chronic uveitis in her left eye, which had started two weeks after an uncomplicated cataract extraction. She was treated with topical steroids with an initially good response, yet she subsequently developed severe inflammation and plaque-like material around the intraocular lens, despite continuous steroid therapy. She underwent pars plana vitrectomy, smear and culture of the aqueous and vitreous fluids, and intravitreal antibiotic injection under the impression of Propionibacterium acne (P. acne) endophthalmitis. As a result of the smear and culture of the vitreous fluid identified as an Acremonium species, she was treated with intravenous amphotericin B injections for five days, followed by oral voriconazole administration. During the post-operative 18-month follow-up, she was stable without significant relapse of uveitis. In this case, the best correction of visual acuity was an improvement from 20/40 to 20/20.

A multi‐centre comparison of nursing staff time required for the preparation and administration of liposomal amphotericin B and amphotericin B deoxycholate vs. voriconazole

To compare the nursing time and cost required for preparation and administration of liposomal amphotericin B, amphotericin B deoxycholate and voriconazole. Cost comparison study. Nurse activities associated with the preparation and administration of the three study drugs were divided into 11 tasks and timed by observers at five hospitals. Target tasks were defined as those likely to be affected by the differences between drugs and excluded those tasks likely to differ owing to site-specific factors. Mean times for administration of a single day of therapy for each study drug were compared. Costs of preparation and administration of a 14-day regimen were estimated. Sixty-nine patients were observed receiving a total of 256 doses of study medications. Labour times were 20, 16, 14 and 3 minutes per day for liposomal amphotericin B, amphotericin B deoxycholate, intravenous voriconazole and oral voriconazole, respectively. Administration time was significantly lower for intravenous voriconazole compared with liposomal amphotericin B (p < 0.05), and for oral voriconazole compared with all intravenous regimens (p < 0.05). Preparation of medications took the longest time for intravenous formulations and was longer for liposomal amphotericin B than for the other drugs by 3-5 minutes. Average non-drug costs associated with preparation and administration of a 14-day regimen were greatest in the amphotericin B deoxycholate arm at US$ 335, followed by liposomal amphotericin B (US$ 310) and voriconazole (US$ 180). Intravenous voriconazole required less time to prepare and administer on a daily basis than liposomal amphotericin B, and was similar to amphotericin B deoxycholate. Measurements of intravenous vs. oral voriconazole administration suggest the opportunity to save 10-17 minutes per day with the oral formulation. Oral voriconazole may provide significant savings in terms of nursing time compared with intravenous antifungal drugs.

Appearance of Anaphylactic Shock after Long-Term Intravenous Itraconazole Treatment

To report a rare but severe adverse effect of intravenous itraconazole, anaphylactic shock with hypotension and hypoxemia, in a female patient with acute lymphoblastic leukemia (ALL). A 36-year-old woman with ALL received antifungal therapy for pulmonary fungal infections. On day 17 of itraconazole treatment, she developed hypotension and hypoxemia shock after intravenous administration of itraconazole 200 mg, which was eventually reversed by steroid treatment. On days 18 and 19, the patient developed the same type of shock 2 more times in the course of itraconazole administration. These 2 episodes of shock occurred more quickly after intravenous itraconazole administration (100 mg on day 18, 40 mg on day 19), and were reversed by stopping itraconazole and applying steroid treatment. In the modified antifungal therapy, intravenous administration of itraconazole was replaced by oral administration of voriconazole 200 mg twice daily. Shock did not recur after discontinuation of itraconazole treatment. The Naranjo probability scale showed a probable relationship between itraconazole treatment and shock occurrence. Itraconazole is a widely used antifungal drugs and is well tolerated. However, long-term itraconazole treatment might lead to serious and even life-threatening adverse effects such as anaphylactic shock, as seen in our patient. T cell reduction caused by immunosuppression and itraconazole accumulation in patients with ALL are considered to be important causal factors for this delayed-type hypersensitivity reaction. Anaphylactic shock represents a previously undocumented severe adverse effect associated with long-term itraconazole treatment; patients receiving this therapy and should be monitored closely.

Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life

Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine. A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.

Emergence of Mucormycosis in Onco-Hematology after Prolonged Use of Voriconazole: Attention Required.

Voriconazole is a broad spectrum antifungal agent however ineffective against Mucor sp. It has proven to have a higher efficacy in the control of invasive aspergillosis when compared to amphotericin B. However, the prophylactic use of voriconazole has not yet been defined. Nevertheless, it has become an attractive option because of the broad spectrum, limited toxicity and possible oral administration of voriconazole. We report here four cases of mucormycosis (3 in 2003, 1 in 2004) that occured after prolonged use of voriconazole in hematologic patients. Patients 1 and 2 (23 and 34 years old, respectively) had relapsed acute myeloid leukemia, patient 3 (3 years old) had chronic myelomonocytic leukemia, and patient 4 (52 years old) had high-grade B cell lymphoma. All patients were severely immunosuppressed. Patient 1 had received a T cell depleted, haploidentical stem cell transplantation (SCT). Patients 2 and 3 had each received a matched unrelated allogeneic SCT complicated by subsequent acute and chronic graft versus host diseases. Patient 4 had been treated for 5 years with mycophenolate mofetil and steroids after a renal transplantation. All four patients received continuous treatment with the oral form of voriconazole for 7 to 30 weeks prior to the diagnosis of mucormycosis: three as primary prophylaxis and one for a bronchial aspergillosis. Mucormycosis was diagnosed 9 weeks after the lymphoma or between 27 and 33 weeks after SCT for the transplanted patients. Patients were subsequently treated with liposomal amphotericin B. Fever was the most common symptom, indicating an invasive infection in the 3 patients who died rapidly at 12, 13 and 45 days after the diagnosis. The surviving patient, an allogeneic SCT recipient, had a localized bronchial mucormycosis. No evidence of mucormycosis had been observed prior to the introduction of treatment with voriconazole beginning in October 2002. In addition, to date, mucormycosis has only been observed in patients that have had pre-exposure to voriconazole. Physicians should be mindful of the potential risk of invasive mucormycosis after prolonged use of voriconazole in immunocompromised hematologic patients. Moreover, the question of prophylactic use of voriconazole needs to be adressed further in randomized trials.