Strategy of Following Voriconazole versus Amphotericin B Therapy with Other Licensed Antifungal Therapy for Primary Treatment of Invasive Aspergillosis: Impact of Other Therapies on Outcome

Patterson, Thomas F.; Boucher, Helen W.; Herbrecht, Raoul; Denning, David W.; Lortholary, Olivier; Ribaud, Patricia; Rubin, Robert H.; Wingard, John R.; DePauw, Ben; Schlamm, Haran T.; Troke, Peter F.; Bennett, John E.

doi:10.1086/497126

Cited by 99 publications

(48 citation statements)

References 12 publications

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“…[1][2][3] In these patients, invasive aspergillosis continues to be associated with a mortality rate that exceeds 50%, 3,4 and treatment with conventional antifungal agents such as amphotericin B is associated with a high level of toxicity and intolerance. 5,6 Posaconazole is a potent extended-spectrum triazole shown to have activity in vitro and in animal studies against Aspergillus spp., including amphotericin B-resistant Aspergillus terreus. [7][8][9] In a multicenter clinical study that predated the use of echinocandins, posaconazole salvage therapy for invasive aspergillosis in patients with diverse underlying diseases was found to be superior to conventional antifungal therapy (consisting mainly of an amphotericin B-based regimen, itraconazole or both) in a historical control group.…”

Section: Introductionmentioning

confidence: 99%

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

et al. 2007

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In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at X7.5 mg kg À1 per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (Pp0.001) and 11% for combination therapy (Po0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (Pp0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; Po0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (Pp0.02) and hepatotoxicity (Po0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

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Section: Introductionmentioning

confidence: 99%

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

et al. 2007

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“…Aspergillus-active triazoles are considered first-line therapy for IPA and have proven efficacy in initial and salvage therapy (13)(14)(15)(16). However, the recent emergence of A. fumigatus isolates exhibiting reduced susceptibility to triazoles is a threat to this class (17)(18)(19)(20)(21).…”

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confidence: 99%

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

Lepak

Marchillo

VanHecker

et al. 2013

Antimicrob Agents Chemother

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Previous studies examining combination therapy for invasive pulmonary aspergillosis (IPA) have revealed conflicting results, including antagonism, indifference, and enhanced effects. The most commonly employed combination for this infection includes a mold-active triazole and echinocandin. Few studies have evaluated combination therapy from a pharmacodynamic (PD) perspective, and even fewer have examined combination therapy against both wild-type and azole-resistant Cyp51 mutant isolates. The current studies aim to fill this gap in knowledge. Four Aspergillus fumigatus isolates were utilized, including a wildtype strain, an Fks1 mutant (posaconazole susceptible and caspofungin resistant), and two Cyp51 mutants (posaconazole resistant). A neutropenic murine model of IPA was used for the treatment studies. The dosing design included monotherapy with posaconazole, monotherapy with caspofungin, and combination therapy with both. Efficacy was determined using quantitative PCR, and results were normalized to known quantities of conidia (conidial equivalents [CE]). The static dose, 1-log kill dose, and associated PD target area under the curve (AUC)/MIC ratio were determined for monotherapy and combination therapy. Monotherapy experiments revealed potent activity for posaconazole, with reductions of 3 to 4 log 10 Aspergillus CE/ml with the two "low"-MIC isolates. Posaconazole alone was less effective for the two isolates with higher MICs. Caspofungin monotherapy did not produce a significant decrease in fungal burden for any strain. Combination therapy with the two antifungals did not enhance efficacy for the two posaconazole-susceptible isolates. However, the drug combination produced synergistic activity against both posaconazole-resistant isolates. Specifically, the combination resulted in a 1-to 2-log 10 decline in burden that would not have been predicted based on the monotherapy results for each drug. This corresponded to a reduction in the freedrug posaconazole AUC/MIC ratio needed for stasis of up to 17-fold. The data suggest that combination therapy using a triazole and an echinocandin may be a beneficial treatment strategy for triazole-resistant isolates.

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“…Current practice guidelines recommend amphotericin B formulations, fluconazole, and echinocandins as first-line therapy for patients with candidemia; and amphotericin B formulations or voriconazole are the drugs of choice for the primary therapy of invasive aspergillosis (32,56,59,81). For patients who fail the primary therapy or who have intolerable adverse reactions, the common practice is to switch to a different class of antifungal agents (60,73).With regard to the safety of antifungal therapies, amphotericin B desoxycholate is known for its infusion-related adverse effects and nephrotoxicity; approximately 30% of patients developed abnormal renal function during treatment, and treatment was discontinued in 5% of patients because of toxicity (4, 28). Other amphotericin B formulations, including amphotericin B colloidal dispersion, amphotericin B lipid complex, liposomal amphotericin B (Ambisome), and other, newer antifungal agents, are associated with substantially fewer infusionrelated and nephrotoxic events.…”

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confidence: 99%

mentioning

confidence: 99%

Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection

Wang

Chang

Young‐Xu³

et al. 2010

Antimicrob Agents Chemother

145

137

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To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.Invasive fungal infection is a leading cause of morbidity and mortality among immunocompromised and debilitated patients, including those with hematological malignancy, solid organ or bone marrow transplantation, and neutropenia and those receiving systemic corticosteroid therapy. Candida species and Aspergillus species are the two predominant causative fungi, with the case fatality rates being 30% and 50% among those infected with members of these two fungal genera, respectively (19,53). Over the past few decades, amphotericin B has been the mainstay treatment of candidiasis and aspergillosis, whereas fluconazole has been extensively used among patients with Candida albicans infection. After randomized controlled trials showed that extended-spectrum azoles (itraconazole, voriconazole, posaconazole) and echinocandins (anidulafungin, caspofungin, micafungin) had efficacies similar to those of amphotericin B and fluconazole, these newer antifungal agents have been used more frequently for the treatment of patients with probable or proven invasive fungal infection (18,32,56,59,81). Current practice guidelines recommend amphotericin B formulations, fluconazole, and echinocandins as first-line therapy for patients with candidemia; and amphotericin B formulations or voriconazole are the drugs of choice for the primary therapy of i...

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Strategy of Following Voriconazole versus Amphotericin B Therapy with Other Licensed Antifungal Therapy for Primary Treatment of Invasive Aspergillosis: Impact of Other Therapies on Outcome

Abstract: This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis.

Cited by 99 publications

References 12 publications

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection

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