Uses
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Aspergillosis
Voriconazole is used for the treatment of invasive aspergillosis. Voriconazole has been evaluated in clinical studies for primary and salvage therapy of invasive aspergillosis, including treatment of invasive aspergillosis in patients intolerant of, or whose disease was refractory to, other antifungals. In these studies, the majority of isolates were Aspergillus fumigatus.
The Infectious Diseases Society of America (IDSA) considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative. For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole. For empiric or preemptive therapy of presumed aspergillosis, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole.
For the treatment of invasive aspergillosis in adults and adolescents with human immunodeficiency virus (HIV) infection, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend voriconazole as the drug of choice; IV amphotericin B, IV echinocandins (caspofungin, micafungin, anidulafungin), and oral posaconazole are recommended as alternatives. Voriconazole also is considered the drug of choice for treatment of invasive aspergillosis in HIV-infected children; IV amphotericin B and IV caspofungin are alternatives.
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Clinical Experience
Efficacy of voriconazole as primary or salvage therapy for invasive aspergillosis was evaluated in an open-label, noncomparative study in 116 patients 18-79 years of age with definite or probable invasive aspergillosis. A complete or partial response was achieved in 48% of patients in this study, but lower response rates observed in patients with definite disease (38%) than in those with probable disease (58%).
In a randomized, nonblinded study of voriconazole as primary therapy for invasive aspergillosis, 277 patients 12-79 years of age with definite or probable invasive aspergillosis received voriconazole (6 mg/kg IV twice daily for 2 doses and then 4 mg/kg IV twice daily for at least 7 days followed by oral voriconazole 200 mg twice daily) or amphotericin B (1-1.5 mg/kg IV once daily) for up to 12 weeks. At the end of the study, a complete or partial response was achieved in 53% of patients randomized to receive voriconazole compared with 32% of those randomized to receive amphotericin B and the survival rate at the end of the study was 71 or 58%, respectively. Pooled analysis of data from this study and an additional study in patients intolerant of, or whose disease was refractory to, other antifungals indicate a response rate of 44 or 40% in patients with invasive infections caused by A. fumigatus or other Aspergillus species, respectively,
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Candidemia and Disseminated Candida Infections
Voriconazole is used for the treatment of candidemia in nonneutropenic patients and for the treatment of disseminated Candida infections involving the skin, abdomen, kidney, bladder wall, or wounds. The drug has been effective in Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, and C. krusei infections.
For the treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis in such patients, the IDSA recommends fluconazole or an echinocandin (caspofungin, micafungin, anidulafungin) for initial therapy; amphotericin B is the preferred alternative. These experts state that voriconazole offers little advantage over fluconazole and generally has been reserved for step-down oral therapy for treatment of C. krusei candidiasis or for treatment of fluconazole-resistant, voriconazole-susceptible C. glabrata infections. Although an echinocandin is preferred for initial treatment of C. glabrata infections, if the patient initially received fluconazole or voriconazole, continuation of the azole antifungal until treatment completion is reasonable if the patient is clinically improved and follow-up culture results are negative.
For the treatment of candidemia in neutropenic patients, the IDSA recommends an echinocandin (caspofungin, micafungin, anidulafungin) or amphotericin B for initial therapy; fluconazole is a reasonable alternative in those who are less critically ill or have not recently received an azole; voriconazole can be used as an alternative when broader antifungal coverage is required. An echinocandin is preferred for C. glabrata infections; fluconazole or amphotericin B is preferred for C. parapsilosis infections; an echinocandin, amphotericin B, or voriconazole is recommended for C. krusei infections. Although an echinocandin is preferred for initial treatment of C. glabrata infections, if the patient initially received fluconazole or voriconazole, continuation of the azole antifungal until treatment completion is reasonable if the patient is clinically improved and follow-up culture results are negative. For initial empiric treatment of suspected invasive candidiasis in neutropenic patients, amphotericin B, caspofungin, or voriconazole is recommended; alternatives are fluconazole or itraconazole.
Voriconazole has been used prophylactically to reduce the incidence of candidiasis in patients at risk, including hematopoietic stem cell transplant recipients.
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Clinical Experience
Efficacy of voriconazole for the treatment of candidemia and other disseminated or invasive infections caused by Candida was evaluated in an open-label comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized to receive IV voriconazole (followed by oral voriconazole) or IV amphotericin B (followed by oral fluconazole); antifungal therapy was continued for a median of 15 days. In patients evaluated for efficacy, most infections were caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%). Analysis at 12 weeks after the end of therapy indicates that voriconazole is as effective as IV amphotericin B followed by oral fluconazole. A successful response (defined as resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, or infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drugs) was observed in 41% of patients in each group.
Voriconazole has resulted in a favorable response in patients with invasive fungal infections (intra-abdominal infection, kidney and bladder wall infection, deep tissue abscess or wound infection, pneumonia/pleural space infection, skin lesions, suppurative phlebitis, hepatosplenic infection) caused by Candida whose disease was refractory to, or who were intolerant of, other antifungals.
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Oropharyngeal Candidiasis
Voriconazole has been used for the treatment of oropharyngeal candidiasis refractory to other antifungals.
For the treatment of mild oropharyngeal candidiasis, the IDSA recommends topical treatment with clotrimazole lozenges or nystatin oral suspension; oral fluconazole is recommended for moderate to severe disease. For refractory oropharyngeal candidiasis, including fluconazole-refractory infections, itraconazole oral solution, oral posaconazole, or oral voriconazole is recommended. An IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B also are recommended as alternatives for refractory infections.
For the treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend oral fluconazole as the drug of choice for initial episodes; if topical therapy is used for the treatment of mild to moderate episodes, the drugs of choice are miconazole buccal tablets or clotrimazole lozenges. Alternatives for systemic treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents are itraconazole oral solution or oral posaconazole; nystatin oral suspension is an alternative if topical treatment is used. For fluconazole-refractory oropharyngeal infections in HIV-infected adults and adolescents, oral posaconazole is preferred; itraconazole oral solution is an alternative.
Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis, patients with frequent or severe recurrences (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, the potential for azole resistance should be considered.
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Esophageal Candidiasis
Voriconazole is used for the treatment of esophageal candidiasis. The drug has been effective in immunocompromised patients with esophageal candidiasis caused by C. albicans, C. glabrata, or C. krusei.
Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).
The IDSA recommends oral fluconazole as the preferred drug of choice for the treatment of esophageal candidiasis; if oral therapy is not tolerated, IV fluconazole, IV amphotericin B, or an IV echinocandin (caspofungin, micafungin, anidulafungin) is recommended. For fluconazole-refractory infections, preferred alternatives are itraconazole oral solution, oral posaconazole, or oral or IV voriconazole; other alternatives are an IV echinocandin or IV amphotericin B.
For the treatment of esophageal candidiasis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend oral or IV fluconazole as the drug of choice and itraconazole oral solution as the preferred alternative. Other alternatives include oral or IV voriconazole, oral posaconazole, IV echinocandins (caspofungin, micafungin, anidulafungin), or IV amphotericin B. For refractory esophageal candidiasis, including fluconazole-refractory infections, in HIV-infected adults and adolescents, oral posaconazole is preferred; alternatives include itraconazole oral solution, IV amphotericin B, IV echinocandins (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.
Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for esophageal candidiasis, patients with frequent or severe recurrences (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or oral posaconazole; however, the potential for azole resistance should be considered.
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Clinical Experience
Efficacy of voriconazole has been evaluated in a comparative study in immunocompromised patients with esophageal candidiasis documented by endoscopy. Patients were randomized to receive oral voriconazole (200 mg twice daily) or oral fluconazole (200 mg once daily); antifungals were given for a median of 15 days. A successful response (defined as normal endoscopy at end of treatment or at least a 1 grade improvement over baseline endoscopic score) occurred in 98% of those who received voriconazole and in 95% of those who received fluconazole. In voriconazole-treated patients, mycologic eradication was achieved in 84% of those with C. albicans infection, in 57% of those with C. glabrata infection, and in the single patient with C. krusei infection.
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Coccidioidomycosis
Voriconazole has been used for the treatment of coccidioidomycosis caused by Coccidioides immitis or C. posadasii, and is recommended as an alternative for the treatment or prevention of these infections.
Antifungal treatment may not be necessary in patients with mild, uncomplicated coccidioidal pneumonia since such infections often are self-limited and may resolve spontaneously. However, antifungal treatment is recommended for patients with more severe or rapidly progressing coccidioidal infections, those with chronic pulmonary or disseminated infections, and immunocompromised or debilitated individuals (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).
The IDSA and others state that an oral azole (fluconazole or itraconazole) usually is recommended for initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis. However, IV amphotericin B is recommended as an alternative and is preferred for initial treatment of severely ill patients who have hypoxia or rapidly progressing disease, for immunocompromised individuals, or when azole antifungals have been ineffective or cannot be used (e.g., pregnant women).
For the treatment of clinically mild coccidioidomycosis (e.g., focal pneumonia) in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend initial therapy with oral fluconazole or oral itraconazole. These experts state that, although clinical data are limited, oral voriconazole or oral posaconazole may be used as an alternative for the treatment of clinically mild coccidioidomycosis that has not responded to fluconazole or itraconazole.
HIV-infected individuals who have been adequately treated for coccidioidomycosis should receive long-term (usually life-long) secondary prophylaxis to prevent recurrence or relapse. Although oral fluconazole or oral itraconazole are the drugs of choice recommended by the CDC, NIH, and IDSA for secondary prophylaxis to prevent recurrence or relapse of coccidioidomycosis in HIV-infected adults and adolescents, these experts state that oral voriconazole or oral posaconazole can be used as an alternative for secondary prophylaxis of coccidioidomycosis if the patient did not initially respond to fluconazole or itraconazole.
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Exserohilum Infections
Amphotericin B has been used for the treatment of infections known or suspected to be caused by Exserohilum rostratum.
Exserohilum is a common mold found in soil and on plants, especially grasses, and thrives in warm and humid climates.E. rostratum is considered an opportunistic human pathogen and rarely has been involved in human infections, including cutaneous and subcutaneous infections or keratitis, typically as the result of skin or eye trauma. More invasive infections (e.g., infections involving the sinuses, heart, lungs, or bones) and life-threatening infections also have been reported rarely, usually in immunocompromised individuals. In addition, E. rostratum was identified as the predominant pathogen in the 2012-2013 multistate outbreak of fungal meningitis and other fungal infections that occurred in the US in patients who received contaminated preservative-free methylprednisolone acetate injections prepared by a compounding pharmacy.Exserohilum infections cannot be transmitted person-to-person.
Although data are limited and the clinical relevance of in vitro testing remains uncertain, in vitro studies indicate that Exserohilum is inhibited by some triazole antifungals (e.g., voriconazole, itraconazole, posaconazole) and amphotericin B. Echinocandins (e.g., caspofungin, micafungin) have variable in vitro activity and fluconazole has poor in vitro activity against the fungus.
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Exserohilum Infections Related to Contaminated Injections
In September 2012, the CDC and US Food and Drug Administration (FDA) initiated investigations in response to fungal CNS infections (including some fatalities) reported in patients who received epidural injections of contaminated extemporaneously prepared methylprednisolone acetate injections from the New England Compounding Center (NECC). Subsequently, there were reports of joint infections and osteomyelitis in some patients who received intra-articular injections of methylprednisolone acetate from NECC, as well as infections possibly related to other NECC products.
Out of an abundance of caution at that time, the FDA recommended that health-care professionals and consumers not use any product that was produced by NECC, and the company recalled all products that were compounded at and distributed from its facility in Framingham, Massachusetts. Recall information is available at http://www.neccrx.com.
The predominant pathogen identified in samples taken from patients who received contaminated products from NECC has been E. rostratum;Aspergillus also was identified in an index patient and Cladosporium cladosporioides was recovered from several other patients. The presence of E. rostratum was confirmed in recalled lots of the contaminated products. Other organisms identified in unopened vials from these recalled lots were C. cladosporioides, Bacillus subtilis, B. pumilus, Paecilomyces formosus, Rhodotorula laryngis, and Rhizopus stolonifer;Rhodotorula and Rhizopus are not known to cause human disease and do not grow at human body temperature.
CDC data indicate that, as of September 6, 2013, there were a total of 750 cases of fungal infections (including 64 deaths) reported in 20 states that have been linked to 3 specific lots of contaminated methylprednisolone acetate injections. Although the majority of initial cases involved fungal meningitis (some with stroke), subsequent reports involved localized spinal or paraspinal infections (e.g., epidural abscess). More than 6 months after the outbreak related to contaminated products was first identified, the CDC continued to receive reports of patients presenting with localized spinal and paraspinal infections (e.g., epidural abscess, phlegmon, discitis, vertebral osteomyelitis, arachnoiditis, or other complications at or near the site of injection). These localized infections have occurred in patients with or without a diagnosis of fungal meningitis. In some patients being treated for fungal meningitis who had no previous evidence of localized infections, such infections were found at the site of injection using magnetic resonance imaging (MRI) studies. Some cases have occurred in patients without any previous evidence of infection or in those with persistent, worsening, or new symptoms.
Patients with meningitis generally presented 1-4 weeks or longer after receiving contaminated methylprednisolone acetate injections; the greatest risk for development of fungal meningitis appeared to be during the first 6 weeks after an epidural or paraspinal injection. Data from one group of patients indicate that the median time from the last injection with contaminated product to the date of the first MRI finding indicative of infection was 50 days (range 12-121 days) for all patients with a spinal or paraspinal infection, and the median time from the first positive lumbar puncture finding to the first positive MRI finding was 21 days for those with meningitis and spinal or paraspinal infections.
Clinicians treating fungal infections in patients who received contaminated methylprednisolone acetate injections from NECC should consult an infectious disease expert to assist with diagnosis, management, and follow-up, which may be complex and prolonged. A clinical consultant network for clinicians can be reached by calling CDC at 800-232-4636. Because of evidence of latent disease, the CDC cautions clinicians to maintain a high index of suspicion and remain vigilant for fungal infections in patients who received the contaminated methylprednisolone acetate injections, especially in those who have mild or baseline symptoms, and to consider MRI evaluation if clinically warranted.
In October 2012, the CDC released interim treatment guidance documents containing recommendations for empiric antifungal treatment of CNS and parameningeal infections and osteoarticular infections associated with the contaminated methylprednisolone acetate products. As additional information became available, these treatment guidance documents were updated and revised several times. Although the following information regarding the CDC recommendations for treatment of these fungal infections was current at the time the voriconazole monograph was finalized for publication, these recommendations may change and the most recent CDC guidance documents at http://www.cdc.gov/hai/outbreaks/meningitis.html should be consulted for the most current recommendations for selection of antifungal agents and the appropriate dosages and duration of treatment.
For the treatment of CNS infections (including meningitis, stroke, and arachnoiditis) and/or parameningeal infections (epidural or paraspinal abscess, discitis or osteomyelitis, and sacroiliac infection) in adults who received the contaminated methylprednisolone acetate injections, the CDC recommends voriconazole. In most patients with these CNS or parameningeal infections, voriconazole should be given IV initially and a transition to oral voriconazole considered only after the patient is clinically stable or improving. Initial treatment with oral voriconazole should be considered only in patients with mild disease who can be monitored closely. Use of IV amphotericin B liposomal in addition to IV voriconazole should be strongly considered in patients who present with severe disease and in patients who do not improve or experience clinical deterioration or manifest new sites of disease activity while receiving voriconazole monotherapy. IV amphotericin B liposomal also is an alternative in patients who are unable to tolerate voriconazole. IV amphotericin B liposomal is preferred over other lipid formulations of amphotericin B because of better CNS penetration. Because of limited data and associated toxicities, routine use of intrathecal amphotericin B is not recommended. Although posaconazole or itraconazole has been used in some patients who could not tolerate voriconazole or amphotericin B, efficacy of these drugs for the treatment of infections associated with the contaminated methylprednisolone acetate injections has not been established. Expert consultation is advised when making decisions regarding alternative regimens.
For the treatment of osteoarticular infections (discitis, vertebral osteomyelitis, and epidural abscess or osteoarticular infections not involving the spine) in adults who received intra-articular injections of contaminated methylprednisolone acetate, the CDC recommends voriconazole. Voriconazole should be given IV initially in those with more severe osteoarticular infections, clinical instability, discitis, vertebral osteomyelitis, or epidural abscess; a transition to oral voriconazole should be considered only after the patient is clinically stable or improving. Initial treatment with oral voriconazole should be considered only in patients with mild osteoarticular infections not involving the spine who can be monitored closely. Use of a lipid formulation of IV amphotericin B in addition to IV voriconazole should be considered in patients with severe osteoarticular infection and/or clinical instability. A lipid formulation of IV amphotericin B, posaconazole, or itraconazole are alternatives in patients who cannot tolerate voriconazole. Expert consultation is advised when making decisions regarding alternative regimens.
Adequate duration of antifungal treatment for Exserohilum infections associated with contaminated methylprednisolone acetate injections is unknown, but prolonged therapy is required.
(See Exserohilum Infections under Dosage and Administration: Dosage.) In addition, close follow-up monitoring after completion of treatment is essential in all patients to detect potential relapse.The CDC website at http://www.cdc.gov/hai/outbreaks/meningitis.html and FDA website at http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm should be consulted for the most recent information regarding the contaminated NECC products and associated infections. The CDC website includes specific information regarding case definitions and diagnostic testing as well as management and treatment of these infections.
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Fusarium and Scedosporium Infections
Voriconazole is used for the treatment of serious fungal infections caused by Fusarium (including F. solani) or Scedosporium apiospermum (asexual form of Pseudallescheria boydii) in patients intolerant of, or whose disease is refractory to, other antifungals.
For the treatment of fusariosis, the most appropriate antifungal should be selected based on in vitro susceptibility testing. Amphotericin B may be preferred for infections caused by F. solani or F. verticillioides; either voriconazole or amphotericin B are recommended for infections caused by other Fusarium.
For the treatment of scedosporiosis, some clinicians consider voriconazole the drug of choice and posaconazole the preferred alternative.
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Histoplasmosis
Voriconazole has been used for the treatment of histoplasmosis caused by Histoplasma capsulatum.
The drugs of choice for the treatment of histoplasmosis are IV amphotericin B or oral itraconazole. IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection. Oral itraconazole generally is used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up therapy in the treatment of severe infections after a response has been obtained with IV amphotericin B. Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) are considered second-line alternatives to oral itraconazole.
For the treatment of less severe disseminated histoplasmosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend initial treatment with oral itraconazole. These experts state that, although clinical data are limited, oral voriconazole or oral posaconazole may be used as an alternative for the treatment of less severe disseminated histoplasmosis in patients intolerant of itraconazole who are only moderately ill.
HIV-infected individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent recurrence or relapse. Oral itraconazole is the drug of choice for secondary prophylaxis of histoplasmosis in HIV-infected adults and adolescents. The role of voriconazole for secondary prophylaxis of histoplasmosis in HIV-infected patients has not been evaluated to date.
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Penicilliosis
Voriconazole is used for treatment of penicilliosis caused by Penicillium marneffei.
For the treatment of severe acute penicilliosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend an initial regimen of IV amphotericin B liposomal followed by oral itraconazole. These experts state that a voriconazole regimen (IV initially, then oral) can be used as an alternative in patients with severe penicilliosis, including those who fail to respond to a regimen of amphotericin B followed by itraconazole.
For the treatment of mild penicilliosis in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend oral itraconazole as the drug of choice and oral voriconazole as an alternative.
HIV-infected patients who have been treated for penicilliosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse. An optimal voriconazole regimen for secondary prophylaxis of penicilliosis has not been identified to date.
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Empiric Therapy in Febrile Neutropenic Patients
Voriconazole also has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients.
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Clinical Experience
Efficacy of voriconazole for empiric therapy in febrile neutropenic patients has been evaluated in an open-label, randomized, multicenter study in patients 12-82 years of age who were neutropenic following chemotherapy or stem cell transplantation. In this study, patients received voriconazole or amphotericin B liposomal for up to 3 days following neutrophil recovery, or for a maximum of 12 weeks. A response (based on a composite assessment including no breakthrough infections within 7 days of the completion of therapy, survival for 7 days following completion of therapy, discontinuance of the drug because of toxicity or lack of efficacy prior to recovery from neutropenia, resolution of fever during neutropenia, and complete or partial response in patients with baseline fungal infections by the completion of therapy) was obtained in 26 or 31% of patients receiving voriconazole or amphotericin B liposomal, respectively. The composite results failed to meet protocol-defined statistical criteria for concluding that voriconazole was not inferior to amphotericin B liposomal. Exploratory analyses of the individual elements of the composite measure suggested that breakthrough infections occurred in a smaller proportion of patients receiving voriconazole (1.9%) compared with amphotericin B liposomal (5%); exploratory analyses of the other individual elements of the composite measure failed to identify other substantial differences between the 2 regimens.
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