Combination Therapy For Invasive Aspergillosis Research Articles

In vitro and in vivo Efficacy of a Synergistic Combination of Itraconazole and Verapamil Against Aspergillus fumigatus.

The incidence of aspergillosis continues to rise sharply, while the progress made in expanding the antifungal drug arsenal remains extremely slow, indicating an urgent need for new strategies. Previous studies have shown that the calcium signaling pathway, which is evolutionarily conserved in mammals and fungi, is involved in regulating the tolerance of azoles in fungi. In this study, we performed a preliminary screening among various combinations of different clinical calcium channel blockers and different antifungal drugs. We found that the combination of itraconazole and verapamil showed the best synergistic effect against Aspergillus fumigatus. Thereafter, using the checkboard assays we observed synergistic effects of the combination treatment against most of the A. fumigatus strains tested, including itraconazole-sensitive and itraconazole-resistant strains, with a fractional inhibitory concentration index (FICI) < 0.5. Furthermore, we showed that verapamil strongly decreased the cytosolic calcium transients following itraconazole stimulation by an aequorin-mediated method. Moreover, verapamil influenced the efflux of rhodamine 6G, an azole mimic substance. An ergosterol assay revealed that verapamil alone had no effect on ergosterol biosynthesis, but the combination of itraconazole and verapamil treatment decreased the ergosterol level. Further murine assays were performed using a luciferase-probed bioluminescence imaging method. Drug combination therapy reduced lung burden and improved survival rate. In conclusion, verapamil is a promising candidate to enhance the antifungal activity of itraconazole against A. fumigatus. In addition, our study suggests the effectiveness of an emerging approach based on bioluminescence imaging in monitoring the efficacy of drug combination therapy for invasive aspergillosis.

Combination Therapy for Invasive Aspergillosis: Controversies and Conclusions

Historically poor outcomes have generated many efforts toward improving outcomes of invasive pulmonary aspergillosis in immunosuppressed hosts, by improving prevention strategies, use of early diagnostics, and employing new antifungals, including combinations of drugs. The latter approach is supported by theoretical benefits in both the antimicrobial activity and pharmacologic properties of drugs, with in vitro and animal studies suggesting potential utility. Because drug combinations can also increase toxicities, interactions, and costs, demonstrating therapeutic effects in clinical trials is imperative. Here, clinical data evaluating combination antifungal therapy for aspergillosis are reviewed. Results to date suggest potential benefit of antifungal combinations, especially those including azoles and echinocandins, but conclusions are not definitive. This important topic warrants further study.

Antifungal combination therapy for invasive aspergillosis.

The outcome of invasive aspergillosis (IA) continues to be associated with significant attributable mortality, especially in patients with hematological malignancies and in hematopoietic stem cell transplant recipients. In this context, antifungal combined therapy (ACT) has become an emerging strategy against IA. In an attempt to evaluate the benefits of ACT, a large number of experimental studies, clinical series, and randomized trials have been performed, with varying results. In addition, several controlled trials have been registered; however, in most cases, their final results have not been made available. In summary, there is an imbalance between the lack of published evidence regarding the benefits of ACT and its extensive and increasing use in current clinical practice, despite its associated cost. Here, we present a critical analysis of the available information regarding ACT for the treatment of IA as well as the authors' opinion with respect to its use.

¿Por qué micafungina puede ser de elección en el paciente pediátrico?

Micafungin is an echinocandin approved by the European Medicines Evaluation Agency for the treatment of invasive candidiasis in children, including premature infants born before 29 weeks of pregnancy, and as prophylaxis in children undergoing hematopoietic stem-cell transplantation or patients at risk of prolonged neutropenia. This drug has good activity in several Candida spp., including those resistant to fluconazole. Although micafungin is active against Aspergillus spp., it has been used mainly in combination therapy for invasive aspergillosis. There is ample information on the use of micafungin in children, including neonates, and this drug is the only echinocandin approved for use in infants aged less than 3 months. The efficacy, pharmacokinetics and safety of micafungin have been evaluated in phase II and III clinical trials in children, in which its efficacy and safety were demonstrated in comparison with liposomal amphotericin B and fluconazole. The pharmacokinetic profile of micafungin in children allows once daily intravenous administration, with greater clearance than in adults, and consequently pediatric doses are relatively higher. The most appropriate dose in children weighing less than 40 kg is 2 mg/kg/day in the treatment of invasive candidiasis and 1 mg/kg/day as prophylaxis in children undergoing hematopoietic stem-cell transplantation. Doses in neonates should be higher. In premature infants, the most appropriate doses to achieve levels in the brain parenchyma are 7 mg/kg/day and 10 mg/kg/day in those weighing more and less than 1,000 g, respectively. Micafungin has few drug-drug interactions and an acceptable safety profile. Withdrawal of this drug due to adverse effects is rare, although transaminase monitoring is recommended during treatment, as well as evaluation of the risk-benefit balance in patients with liver disease or concomitant administration of hepatotoxic drugs.

Antifungal Agents in Hematopoietic Stem Cell Transplantation

Invasive fungal infections are major complications of stem cell transplantation associated with significant morbidity and mortality. Allogeneic stem cell transplant recipients are at a significantly greater risk for fungal infection than recipients of autologous transplantation. Although with the wide use of fluconazole prophylaxis the incidence and associated mortality of invasive candidiasis has been minimized, mold diseases remain a significant complication during periods of prolonged immunosuppression for graft versus host disease. Posaconazole prophylaxis during periods of high risk was recently demonstrated to be effective in preventing fungal infections and associated mortality. Preemptive strategy employing laboratory markers and serial CT scans to identify mold infection at an early stage is promising. However its efficacy has to be validated in clinical trials. Several new antifungal agents have been introduced lately, characterized by improved safety profile and broader antifungal spectrum. Voriconazole has become the standard of care for the treatment of invasive aspergillosis. Finally there has been increasing interest on combination therapy for invasive aspergillosis due to the high rate of failure of the currently available antifungals, especially in the profoundly immunocompromised host.

The Echinocandins

The changing pattern in fungal infections has driven the need to expand the targets of antifungal activity. The echinocandins are the newest addition to the arsenal against fungal infections. Three echinocandins have been approved by the United States Food and Drug Administration: caspofungin, micafungin, and anidulafungin. These agents have a broad spectrum of activity and are similar to each other with respect to in vitro activity against Candida sp, with micafungin and anidulafungin having similar minimum inhibitory concentrations (MICs) that are generally lower than the MIC of capsofungin. The MICs of the echinocandins are highest against Candida parapsilosis; however, whether this will affect clinical outcomes is unknown. Several case reports have identified clinical failure due to elevated MICs with caspofungin or micafungin against Candida albicans, Candida krusei, and C. parapsilosis. Resistance to the echinocandin class was present in some but not all of the isolates. Empiric therapy with one of the echinocandins for candidemia or invasive candidiasis in patients with neutropenia and those without neutropenia appears to be appropriate when one factors in mortality rate, the increasing frequency of non-albicans Candida infections, and the broad spectrum, safety, and fungicidal effect of the echinocandins. After speciation of the organism, continued therapy with an echinocandin can and should be reevaluated. The echinocandins demonstrate similar in vitro and in vivo activity against Aspergillus sp, but only caspofungin is approved for treatment in patients who are intolerant of or refractory to other therapies. Voriconazole and amphotericin B have demonstrated synergy with the echinocandins. The clinical response to combination therapy has been variable; however, the mortality rate appears to be lower with combination therapy than monotherapy. Large controlled trials are needed to determine the role of combination therapy for invasive aspergillosis. Micafungin and anidulafungin generally have a lower frequency of adverse reactions compared with caspofungin. Phlebitis (3.5-25% of patients) and elevated liver enzyme levels (1-15%) occur more often with caspofungin compared with micafungin and anidulafungin (< 8%). Overall, the three echinocandins are relatively safe and effective agents for the treatment of Candida infections.

Long-term Risk of Atypical Fungal Infection After Near-Drowning Episodes: In Reply

We thank Drs Garzoni and Garbino for their letter regarding our article.1 We appreciate their comments and believe that the observations they have made in 2 adult tsunami survivors on the long-term risk of severe infections with Scedosporium apiospermum (the asexual form of Pseudallescheria boydii) after submersion are very relevant for the management of the infectious complications in patients after submersion.2 It is important to share this information, because most data on invasive fungal infections are based on studies in neutropenic patients. Victims of submersion are supposed to be healthy and immunocompetent, leading to a particular course of their infections, which mandates a specific and especially aggressive diagnostic and therapeutic approach. This is demonstrated nicely by both a Garzoni et al article2 and our article.1Nevertheless, 2 comments can be made. First, although similar very late and silently progressive complications after submersion can be expected for Aspergillus species as well, they have not been described, thus far, to the same extent. In the 3 published cases of central nervous system (CNS) aspergillosis after near-drowning, the time interval between the submersion incident and first radiologic signs of nonpulmonary invasive aspergillosis was 13, 14, and 15 days, respectively.1,3,4Second, we do not agree with the antifungal treatment (voriconazole + amphotericin B) proposed by Garzoni and Garbino as the empirical treatment of choice in suspected fungal infections after submersion. Although the optimal therapy for invasive aspergillosis is actually not yet known, we believe that there are 2 reasons why amphotericin B has no place in the empirical treatment of suspected invasive fungal infections after submersion. In the first place, the vast majority of published cases were correlated with P boydii, which responds poorly to amphotericin B. Moreover, the histologic and microbiologic resemblance of this fungus to Aspergillus may interfere with a correct diagnosis, which may give rise to an Aspergillus-directed but incorrect antifungal treatment.5 In the second place, amphotericin B penetrates poorly into the cerebral tissue, which makes it useless in case of CNS invasion irrespective of the antifungal spectrum of the involved fungus.Although systematically designed prospective research is currently lacking, we believe, on the basis of the available evidence, that voriconazole should be considered as the treatment of choice for a suspected pulmonary or invasive fungal infection after submersion. Voriconazole is effective against Aspergillus species and P boydii and is the only antifungal drug that penetrates sufficiently into the CNS tissue.Currently, no data are available to support the combination of antifungal drugs for the treatment of P boydii. Recently published research suggests the potential superiority of combination therapy for invasive aspergillosis. On the basis of theoretical considerations and 1 retrospective evaluation, the combination of voriconazole and caspofungin may be superior compared with voriconazole alone.6,7 Caspofungin exerts in vitro activity against both Aspergillus species and P boydii. If combination therapy is considered for a patient after submersion for the treatment of a suspected invasive fungal infection, the combination of voriconazole and caspofungin is currently the most reasonable one.

Invasive aspergillosis in organ transplant recipients: new issues in epidemiologic characteristics, diagnosis, and management

Changing transplantation practices, novel immunosuppressive protocols, and evolving recipient characteristics have led to notable changes in the epidemiology of invasive aspergillosis in transplant recipients. The frequency of disseminated infection and of central nervous system involvement has declined significantly in organ transplant recipients in the recent years. Amongst variables that may have contributed to these trends is an overall lesser severity of illness of transplant recipients in the current era. Calcineurin-inhibitor immunosuppressive agents may also have had a role in altering the disease course and the risk of dissemination. A new paradigm in the management of post-transplant immunosuppression is the use of calcineurin-inhibitor and corticosteroid sparing regimens by pretreatment of the recipient with T-cell depleting agents (Campath 1-H or thymoglobulin) and utilization of minimal post-transplant immunosuppression. The impact of these potent lymphoablative regimens on opportunistic mycoses in organ transplant recipients remains to be fully discerned. Although still unacceptably high, the mortality rate in organ transplant recipients with invasive aspergillosis in the current era appears to have declined. A focus of a great interest and controversy is the use of combination therapy for invasive aspergillosis in transplant recipients.